EA040023B1 - SOMATOSTATIN MODULATORS AND THEIR USES - Google Patents

Description

The present application claims priority under US Provisional Application No. 62/362,493, filed July 14, 2016; and U.S. Provisional Application No. 62/411,338, filed October 21, 2016; each of which is incorporated herein by reference in its entirety.

Regulations regarding research financed from the state budget

This study was supported by the Government of the United States of America under SBIR grant no. 1R44NSO92231-01 by the National Institutes of Health.

The field of technology to which the present invention relates

This document describes compounds that are modulators of somatostatin, methods for preparing such compounds, pharmaceutical compositions and medicaments containing such compounds, as well as methods for using such compounds in the treatment of conditions, diseases or disorders for which modulation of somatostatin activity would be effective.

Background of the Invention

Somatostatin is a peptide hormone that regulates the endocrine system and influences neurotransmission and cell proliferation by interacting with G-protein coupled somatostatin receptors and inhibiting the release of numerous secondary hormones. Six types of somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular somatostatin receptor subtype, or a combination thereof, holds promise for the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

The essence of the invention

The compounds described herein are somatostatin modulator compounds. In some embodiments, the compounds described herein modulate one or more of the somatostatin receptor protein subtypes. In some embodiments, the compounds described herein modulate two or more subtypes of somatostatin receptor proteins. Peptide analogs of somatostatin such as octreotide and pasireotide, developed as depot injections, are widely used to normalize hormone levels for the treatment of GH-secreting adenomas, pancreatic neuroendocrine tumors, and carcinoid tumors. Unfortunately, these analogs are only effective in about half of acromegaly patients with adenomas resulting from GH, and patients with carcinoid tumors often become resistant to therapy as a result of internalization and desensitization of the SST2A receptor. In addition, these peptide drugs are extremely expensive and require frequent doctor visits due to painful injections that can lead to injection site reactions. The compounds described herein are molecules that are structurally different from the peptide analogs. The compounds described herein are somatostatin modulators that are effective inhibitors of hormone secretion.

In one aspect, the present invention provides a compound of formula (A2), or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof.

Ri .R ² N

where each R ^a independently represents hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3, -OCF3, -CH2OH or -CH2CH2OH;

each R ^b is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3 or -OCF3;

m is 1 or 2;

n is 0, 1 or 2;

R.B. is

- 1 040023

each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CO2H, -CO2CH3 , -CO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHOCH3, -C(=O)N(CH ₃ )2, -SO2N(CH3)2, -C(=NOCH3)H, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, - N(CH3)2, -NHCO ₂ CH ₃ , -NHSO ₂ CH ₃ , -CH2NH2, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , CH(CF ₃ )NH ₂ , azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH (CH3) (CH2CH3), -C (CH ₃ ) ₃ , -CH2OH, -CH2CN, -CH2F, -CHF2, -CF ₃ , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCF3, -OCH2OCH3, -OCH2OCH2CH3, -OCH2CH2OH, -C(=O)NHOCH3, -C(=NOH)H, -C(=NOCH3)H, -CH2C(=O) NH2, -NH2, NHCO2CH3, NHSO2CH3, NH(C=O)NHCH3, NH(C=O)NHOCH3 or CH(CF3)NH2;

or if one R ^c and one R ^d are on adjacent atoms of ring B, then the adjacent R ^c and R ^d groups are taken together with the intermediate atoms to which they are attached to form a 5- or 6-membered monocyclic heterocycle containing at least 1 atom N, O or S and a total of 1-2 N atoms, 0-2 O atoms and 0-1 S atoms in the heterocycle;

p is 1 or 2;

q is 0, 1 or 2;

X is CR ^f or N;

Y is CR ^f or N;

Z is CR ^f or N;

R ^e is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, _-CF3 , -CN, -OH, -OCH3, -OCH2CH3 or -OCF3;

each R ^f is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCH2CH3 or -OCF3;

R ¹ is hydrogen;

R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl or tert- butyl or oxetanyl;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH ₃ )2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH ₂ F, - CHF2 or -CF ₃ , -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2;

or R ² and R ⁵ are taken together with the intermediates to which they are attached to form azetinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or azepanyl.

In one embodiment, each R ^a is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCF3, -CH2OH, or -CH2CH2OH;

each R ^b is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; every

R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -NH2, -C(=O) NH2, -C(=NOCH ₃ )H, -SO ₂ N(CH ₃ ) ₂ , azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, - C(=O)NHOCH3, NH2, NHCO2CH3, NH(C=O)NHOCH3 or CH2(C=O)NH2; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form a 5-membered monocyclic heterocycle.

In one embodiment, a compound has the following structure, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof:

- 2 040023

In one embodiment, each R ^a is independently hydrogen, F, Cl, Br,

-CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -CH2OH or -CH2CH2OH;

each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3 or -OCF3; each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -NH2, -C(=O) NH ₂ , -C(=NOCH ₃ )H, -SO2N(CH ₃ )2, azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, - C(=O)NHOCH3, -NH2, -NHCO2CH3, -NH(C=O)NHOCH ₃ or -CH ₂ (C=O)NH ₂ ;

R ^e is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; each R ^f is hydrogen; R ¹ is hydrogen;

R ² is hydrogen;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, - CF3, -CN, -C(=O)OCH3, -C(=O)NH ₂ , -C(=O)NHCH or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl.

In one embodiment, each R ^a is independently hydrogen, F, Cl, —CH ₃ , —CF3, —CN, —OH, —OCH3, —OCF3, —CH2OH, or —CH2CH2OH;

each R ^b is independently hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -OCH3 or -OCF3; each R ^c is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ , -NH2, -C(=O)NH ₂ or -C(=NOCH ₃ )H ;

each R ^d is independently hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -OCH3, -OCF3, or -NH2;

X is CR ^f ;

Y is CR ^f and

Z is CR ^f or X is N;

Y is CR ^f and Z is CR ^f ; or X is CR ^f ; Y is N and Z is CR ^f ; or X is CR ^f ; Y is CR ^f ; and Z is N; R ^e represents hydrogen, F or Cl; each R ^f is hydrogen; R ¹ is hydrogen; R ² is hydrogen; R ⁵ is hydrogen; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form morpholinyl.

In one embodiment, a compound is characterized by the following structure of formula (AVb), or a pharmaceutically acceptable salt, diastereomeric mixture, or individual ^r1 \/ ^r2 enantiomers thereof

Formula (AVb) where

^RB represents

^Rc

Rc ^/ ;

R ¹ is hydrogen;

R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, tert- butyl or oxetanyl;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, - CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or azepanil.

In one embodiment, R ^a is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -CH2OH, or -CH2CH2OH; R ^b is hydrogen, F, Cl, Br, -CH3,

- 3 040023

-CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ;

each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH,

-OCH ₃ , -OCF ₃ , -NH2, -C(=O)NH2, -C(=NOCH ₃ )H, -SO2N(CH ₃ )2, azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, - C(=O)NHOCH3, -NH2, -NHCO2CH3, -NH(C=O)NHOCH3 or -CH2(C=O)NH2;

R ^e is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ;

R ¹ is hydrogen;

R ² is hydrogen;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ )2, -OCH2CH3, -OCF ₃ , -CH3, -CH2CH3, -CH2F , -CHF2, -CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl.

In one embodiment, R ^a is hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -CH2OH, -CH2CH2OH, -OCH3, or -OCF3;

R ^b is hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ , or -OCF ₃ ; each R ^c is independently hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -NH2, -OCH3, -OCF3, -CONH2, or -C(=NOCH3)H;

each R ^d is independently hydrogen, F, Cl, —CH ₃ , —CF ₃ , —CN, —OH, —NH2, —OCH ₃ , or —OCF3;

R ^e is hydrogen;

R ¹ is hydrogen;

R ² is hydrogen; R ⁵ is hydrogen, or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form morpholinyl.

In one aspect of the invention, the compound is

1-1: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-5-fluorobenzamide;

1-2: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-4: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-5-fluorobenzamide;

1-5: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-6: 3-{4-[cis-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-7: 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-2-hydroxybenzonitrile;

1-8: 5-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-2,3-dihydro-1 Η-1, 3-benzode iazol-2-one;

1-9: 4-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-2,3-dihydro-1 Η-1, 3-benzode iazol-2-one;

1-10: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-11: 3-[4-(4-aminopiperide in-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-12: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6yl]-5-fluoro-2-hydroxybenzonitrile;

- 4 040023

1-13: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide;

1-14: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-5-fluorobenzamide;

1-15: 3-[4-(4-Aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)cinnolin-3-yl]-5-fluorobenzamide;

1-16: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro-1 Η-1,3-benzodiazol -2-he;

1-17: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile;

1-18: 3-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-19: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-fluorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-20: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile;

1-21: 3-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ichlorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-22: 3-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

1-23: 6-[4-(4-Aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-4-fluoro-2,3-dihydro-1 Η -1,3-benzode iazol-2-one;

1-24: 4-[4-(4-Aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6fluoro-2,3-dihydro-1 Η-1 ,3-benzode iazol-2-one;

1-25: 3 - [7-chloro-3 - (3-fluoro-5-methylphenyl) -4- { 4- [(2-fluoroethyl) amino] piperidin-1 yl } cinnolin-6-yl] -5 -fluorobenzamide;

1-26: 3-{4-[trans-4-amino-3-hydroxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-27: 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

1-28: 6-[4-(4-Aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-4-fluoro

2,3-dihydro-1 Η-1,3-benzode iazol-2-one;

1-29: 2-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6fluorophenol;

1-30: 3 - [4-(4-aminopiperide in-1 -yl)-3 - (3,5-d ichlorophenyl) cinnolin-6-yl] -5

- 5 040023 fluorobenzamide;

1-31: 3-[3-(3,5-d-ichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1yl}cinnolin-6-yl]-5-fluorobenzamide;

1-32: 3-[3-(3,5-dichlorophenyl)-4-{4-[(3,3,3-trifluoropropyl)amino]piperidin-1 yl}cinnolin-6-yl]-5-fluorobenzamide ;

1-33: 3-[3-(3,5-dichlorophenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin6-yl]-5-fluorobenzamide;

2-1: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2hydroxybenzonitrile;

2-2: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2hydroxybenzonitrile;

2-3: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-hydroxybenzonitrile;

2-4: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}benzonitrile;

2-5:3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile;

2-6: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]phenol;

2-7: 6-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]pyridine-2-carboxamide;

2-8: 4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1 Η-1,3-benzodiazol -2-he;

2-9: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1 Η-1,3-benzodiazol -2-he;

2-10: 3-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

2-16: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

2-19: 3 - {4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile ;

2-20: 3 - {4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3 -(3-fluoro-5methylphenyl)quinolin-6-yl} -2-hydroxybenzonitrile ;

2-56: 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenoxy}acetic acid;

2-57: 4-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenoxy}butanoic acid;

- 6 040023

2-58: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-(methoxymethoxy)benzonitrile;

2-59: 3-{4-[(3K,4K)-4-amino-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-hydroxybenzonitrile;

2-60: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-hydroxybenzonitrile;

2-61: 3-{4-[(3S,4R)-4-aMHHO-3-methoxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-62: 3-{4-[(3R,4 8)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitr silt;

2-63: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin 6-yl}-5-fluoro-2-hydroxybenzonitrile;

2-65: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2hydroxyethoxy)benzonitrile;

2-66: 3-{4-[(3R,4S)-4-amino-3-methoκcipipiperidin-l-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-67: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(1,3 dihydroxypropan-2-yl)oxy ]benzamide;

2-68: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]quinolin 6-yl]-2-hydroxybenzonitrile;

2-69: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2-hydroxybenzonitrile;

2-70: 3 - [4-(4-aminopiperidin-1 -yl)-3 - { 3 -fluoro-5 - [(1E) (methoxyimino)methyl]phenyl}quinolin-6-yl]-2-hydroxybenzonitrile ;

2-72: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2methoxyethoxy)benzonitrile;

2-73: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(oxetan 3-yloxy)benzonitrile;

2-74: 1 - [3 - (3,5 -d iftorophenyl) -6- [5 -fluoro-4- (oxetan-3 -yloxy) pyridin-3 yl] quinolin-4-yl] piperidin-4- amine;

2-75: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6 (azetidin-1-yl)pyridine-3-carbonitrile ;

2-76: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6 (azetidin-1-yl)pyridine-3-carboxamide ;

2-77: 2-amino-3 - [4-(4-aminopiperidin-1 -yl)-3 - (3,5-d iftorophenyl) quinoline-6

- 7 040023 yl] benzonitrile;

2-7 8: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2·(methoxymethoxy)benzonitrile;

2-7 9: 3-[4-(4-aminopiperidin-1-yl)-3-{3-[(ethoxyimino)methyl]-5 fluorophenyl}quinolin-6-yl]-2-hydroxybenzonitrile;

2-80: 6-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-fluoro -2,3-dihydro-1 Η-1,3-benzode andazol-2-one;

2-81: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-[(methoxyimino)methyl]phenol;

2-83: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]4,6-difluorophenyl}carbamate;

2-84: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitrile;

2-85: 6-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} pyride in-2 -carboxamide;

2-86: N-{2-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4,6difluorophenyl}methanesulfonamide;

2-87: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-2-[(2methoxyethoxy)methoxy]benzonitrile;

2-88: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6(azetidine-1-carbonyl)phenol;

2-92: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline 4-yl]piperidine-3-carbonitrile;

2-94: cis-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-diφτopφenyl)quinolin-4yl]piperidine-3-carbonitrile;

2-99: 3-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4.5-difluoro-2-hydroxybenzonitrile;

2-100: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5d ifluorophenyl)quinolin-6-yl} -4, 5-d iftoro-2-hydroxybenzonitrile;

2-115: 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6[(methoxyimino)methyl]phenol;

2-116: 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4fluoro-6-[(methoxyimino)methyl]phenol;

2-123: methyl-M-{2-[4-(4-aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 3,4,6-trifluorophenyl}carbamate ;

- 8 040023

2-125: methyl-N-{3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 5-cyanopyridin-4-yl} carbamate ;

2-126: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2[(hydroxyimino)methyl]phenyl}quinolin-4-yl]piperidin-4-amine;

2-129: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(methoxyimino)methyl]phenyl}quinolin 4-yl]piperidine-4-amine;

2-132: 1-{6-[3-(1-Amino-2,2,2-trifluoroethyl)phenyl]-3-(3,5-difluorophenyl)quinolin-4 yl}piperidine-4-amine;

2-134: 2-[4-(4-aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chloro

3,4-difluorophenol;

2-139: 1-{2-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4,6difluorophenyl}-3-methoxyurea;

2-141: 6-[4-(4-Aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-chloro

2,3-dihydro-1 Η-1,3-benzode iazol-2-one;

2-142: 5-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d ifluorophenyl)quinolin-6-yl]-2,3 dihydro-1,3-benzoxazol-2- He;

2-143: methyltrans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate;

2-144: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-6-fluorophenol ;

2-145: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylic acid;

2-146: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxamide;

2-147: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro-4-fluoro-2-hydroxybenzonitrile;

2-148: methyl^{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 6-cyanophenyl} carbamate;

2-149: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-M-methylpiperidine-3-carboxamide;

2-150: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6 trifluorophenol;

2-151: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-HM-dimethylpiperide in-3-carboxamide;

2-152: 1-[3-(3,5-difluorophenyl)-6-{5-fluoro-4-[(hydroxyimino)methyl]pyridine-3

- 9 040023 yl }quinolin-4-yl] piper id in-4-amine;

2-161: 1-[3-(3-fluoro-5-methoxyphenyl)-6-(2,3,5-trifluoro-6-hydroxyphenyl)quinolin4-yl]piperidin-4-ol;

2-164: G{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]4,6-difluorophenyl}-3-methoxyurea;

2-165: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin6-yl]-4,6-difluorophenyl} carbamate;

2-166: 1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methoxyphenyl)quinolin-4-yl)piperidine-4-amine;

2-167: methyl-N-{2-[4-(4-aminopiperide in-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-cyanophenyl (carbamate;

2-168: 1 - (6- { 5 -fluoro-4- [(hydroxyimino) methyl] pyridin-3 -yl } -3 - (3 - fluoro-5 methylphenyl) quinolin-4-yl) piperidin-4-amine ;

2-169: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-amine;

2-170: methyl-(trans)-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate;

2-171: methyl N-f 3 -[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-5-fluoropyridin-4-yl} carbamate;

2-172: G{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-yl}-3-methoxyurea ;

2-173: methyl-N-{2-[4-(4-aminopiperide in-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-fluorophenyl}carbamate;

2-174: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]6-fluorophenyl}-3-methoxyurea;

2-175: Ν-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]6-fluorophenyl}azetidine-1-carboxamide;

2-176: 1 - (6- { 5 -fluoro-4- [(hydroxyimino)methyl] pyridin-3 -yl } -3 - [3 -fluoro-5 (trifluoromethyl) phenyl] quinolin-4-yl) piperidin- 4-amine;

2-177: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6 yl]pyridine-3-carbonitrile;

2-178: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2-amine;

2-179: 2-amino-3-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]4,5-difluorobenzonitrile;

- 10 040023

2-180: methyl-N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-6-cyano-3,4-d-ifluorophenyl} carbamate ;

2-181: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4-amine;

2-182: methyl N-f 3 -[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-5-fluoropyridin-2-yl} carbamate;

2-183: 1 - { 3 - [4-(4-aminopiperidin-1 -yl)-3 - (3 -fluoro-5-methylphenyl) quinolin-6-yl] -5 fluoropyridin-2-yl} -3 - methoxyurea;

2-184: methyl-N-f 3 -[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-5-chloropyride in-4-yl } carbamate;

2-185: methyl-N-f 2-[4-(4-aminopiper idin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-4-cyanophenyl} carbamate;

2-186: 1 - { 3 - [4-(4-aminopiperidin-1 -yl)-3 - (3 -fluoro-5-methylphenyl) quinolin-6-yl] -5 chloropyridin-4-yl } -3 - methoxyurea;

2-187: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]pyridine-3-carbonitrile;

2-189: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4cyanophenyl}-3-methoxyurea;

2-190: 3-f4-[(4αS,8αS)-oκtahydro-lH-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2 -hydroxybenzonitrile;

2-191: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyano-3,4-difluorophenyl} -3-methoxy -3-methylurea;

2-192: 1-(6-{5-chloro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-(3,5 difluorophenyl)quinolin-4-yl)piperidin-4-amine;

2-193: 3 - f 4-[(4aR, 8aK)-octahydro-1 H-pyride o [3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl} -2-hydroxybenzonitrile;

2-194: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2(methoxymethoxy)benzonitrile;

2-195: 1-[3-(3,5-d-ifluorophenyl)-6-{3-[(hydroxyimino)methyl]pyridin-2yl}quinolin-4-yl]piperide in-4-amine;

2-196: 1-[3-(3,5-d-yfluorophenyl)-6-f2-[(hydroxyimino)methyl]pyridin-3yl}quinolin-4-yl]piperide in-4-amine;

2-197: methyl N-{2-[4-(4-aminopiperide in-1-yl)-3-(3-fluoro-5-methylphenyl)x inolin6-yl]-4,6-difluorophenyl} carbamate;

2-198: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

- 11 040023

4,6-difluorophenyl } -3-methoxy-3-methylurea;

2-199: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl} -3,3-dimethylurea;

2-200: 1-[3-(3,5-d-ifluorophenyl)-6-{6-[(hydroxyimino)methyl]pyridin-2yl}quinolin-4-yl]piperide in-4-amine;

2-201: 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenylmethyl carbonate;

2-202: 1-[3-(3,5-d iflorphenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]-6methylphenyl}quinolin-4-yl]piperidin-4-amine;

2-203: 1-[3-(3,5-d-ifluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-4yl}quinolin-4-yl]piperide in-4-amine;

2-204: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluoro-2-(2-methoxyethoxy)benzonitrile;

2-205: methyl X-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-6-cyano-3,4-d iflorphenyl} carbamate;

2-206: 1 - {2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6cyano-3,4-difluorophenyl} -3 -methoxy-3-methylurea;

2-207: 1-(2-{4-[cis-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-4,6-difluorophenyl )-3-methoxyurea;

2-209: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-6-fluorophenyl} carbamate;

2-210: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6fluorophenyl}-3-methoxy-3-methylurea ;

2-213: 4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2[(methoxyimino)methyl]phenol;

2-215: 1 - {3 - [4-(4-aminopiperidin-1 -yl)-3 -(3-fluoro-5-methylphenyl)quinolin-6-yl] -4methylpyridine in-2-yl} -3 - methoxyurea;

2-216: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl } -3 - (propan-2-yloxy) urea;

2-217: trans-1 - (6- { 3 -fluoro-2- [(hydroxyimino)methyl] phenyl } -3 - (3 -fluoro-5 methylphenyl) quinolin-4-yl) -3-methoxypiperidin-4- amine;

2-218: methyl-M-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-6-cyanophenyl ) carbamate;

2-219: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2-hydroxybenzonitrile;

- 12 040023

2-220: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-5-fluoro-2-(2- methoxyethoxy)benzonitrile;

2-221: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-6-[ (methoxyimino)methyl]phenol;

2-222: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4cyanophenyl}-3-methoxyurea;

2-223: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluorophenyl}-3-methoxyurea;

2-224: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-2-(2-methoxyethoxy)benzonitrile ;

2-225: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(2-methoxyethoxy)benzonitrile;

2-226: 1 - { 3 - [4- (4-aminopiperidin-1 -yl) -3 - (3 -fluoro-5 -methylphenyl) quinolin-6 yl] pyride in-2-yl } -3 -methoxyurea ;

2-227: cis-4-amino-1 -(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5methylphenyl)quinolin-4-yl)piperidine- 3-ol;

2-228: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methyl-phenyl)-quinolin-6-yl]

4,6-difluorophenyl } -3-ethoxyurea;

2-230: ^{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]4,6-difluorophenyl}-2-methoxyacetamide;

2-231: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2(cyanomethoxy)benzonitrile;

2-232: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-5-fluoro-2-(2-methoxyethoxy) benzonitrile;

2-233: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methyl-phenyl)-quinolin-6-yl]

4,6-difluorophenyl }-3-(2,2,2-trifluoroethoxy)urea;

2-234: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluoro-M-(2-methoxyethyl)pyridine-2 -amine;

2-235: methyl-M-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-4,6- difluorophenyl) carbamate;

2-236: 1-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-4,6-d iflorphenyl)-3-methoxyurea;

2-237: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4cyano-6-fluorophenyl}-3-methoxyurea ;

2-238: 1 - { 2- [4- (4-aminopiperidin-1 -yl) -3 - (3,5-difluorophenyl) quinolin-6-yl] -4- 13 040023 cyanophenyl) -3- (2, 2,2-trifluoroethoxy)urea;

2-239: 1 - { 3 - [4- (4-aminopiperidin-1 -yl) -3 - (3 -fluoro-5-methylphenyl) quinolin-6-yl] -6 methylpyridine in-2-yl } -3 - methoxyurea;

2-240: 1-{4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]phenyl}-3-methoxyurea;

2-241: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-6-bromo3,4-difluorophenol;

2-242: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-[(2methoxyethyl)amino]pyridine-3-carbonitrile ;

2-243: 2- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5d ifluorophenyl) quinolin-6-yl } -6- [(1 E)-(methoxyimino)methyl]phenol;

2-244: 5-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-aminopyridine -3-carbonitrile;

2-246: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl)pyridin-2- amine;

2-247: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-methylpyridine -3-amine;

2-248: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}pyridin-2- ol;

2-250: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-methylpyride in-3-amine;

2-251: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-3-hydroxypyridine -4-carbonitrile;

2-252: 5-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-[ (2-methoxyethyl)amino]pyridine-3-carbonitrile;

2-254: 5-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-hydroxypyridine -3-carbonitrile;

2-256: 3 - {4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}-5-fluoropyridine -4-ol;

2-258: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-methylpyridine -3-ol;

2-259: 3 - {4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}-5-fluoropyridine -2-ol;

2-261: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-3-fluoropyridine -4-carbonitrile;

- 14 040023

2-262: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-3-aminopyr idine-4-carbonitrile;

2-263: 2- { 4- [trans-octahydro-1 H-pyride o [3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyridin-3 - ol;

2-264: M-[(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl} pyride in-2-yl)methylidene]hydroxylamine;

2-265: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-5-fluoropyr idine-3-amine;

2-266: 3 - { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -5 - [ (methoxyimino)methyl]pyridine-4-amine;

2-267: 3 - {4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}-5-cyclopropylpyridine -4-amine;

2-269: 2-{4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-[ (methoxyimino)methyl]pyridine-3-amine;

2-272: 3 - { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -5 - ( prop-1-yn-1-yl)pyridine-4-amine;

2-273: 1 - (3 - { 4- [trans-octahydro-1 H-pyride o [3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyride in-2-yl)-3-methoxyurea;

2-274: 3 - {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -5-ethynylpyridine -4-amine;

2-275: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-chloropyr idine-3-amine;

2-283: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5difluorophenyl) quinolin-6-yl } pyridin-3 - amine;

2-284: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-methoxypyr idine-3-amine;

3-1: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluorobenzamide;

3-2: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2-hydroxybenzonitrile;

3-3: 4-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2 yl]-6-fluoro-2,3- dihydro-1 Η-1,3-benzode iazol-2-one;

3-4: 5 - [8-(4-aminopiperidin-1 -yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2 yl] -2,3-dihydro-1 Η -1,3-benzode iazol-2-one;

3-5: 6-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridine-2

- 15 040023 yl] -4-fluoro-2,3-dihydro-1 Η-1,3-benzode andazol-2-one;

3-9: 6-[8-(4-Aminopiperidin-1-yl)-7-(3,5-difluorophenyl)-1,5-naphthyridin-2-yl]-4fluoro-2,3-dihydro-1H- 1,3-benzodiazol-2-one;

3-10: 6-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5difluorophenyl)-1,5-naphthyridin-2-yl} - 4-fluoro-2,3-dihydro-1 Η-1,3-benzodiazol-2-one;

4-1: 3-[5-(4-Aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2hydroxybenzonitrile;

4-2: 3-[5-(4-Aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3yl]-2-hydroxybenzonitrile;

4-3: 3-[5-(4-Aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3yl]-5-fluoro-2-hydroxybenzonitrile;

4-4:3 - [5-(4-aminopiperid in-1-yl)-6-(3-chloro-5-methylphenyl)-1,8-naphthyridin-3-yl] 2-hydroxybenzonitrile;

or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof. In one aspect of the invention, a compound of the following structure is provided:

or a pharmaceutically acceptable salt thereof.

In one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof, and at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is formulated for administration to a mammal via intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In one embodiment, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

In one aspect of the invention, there is provided the use of a compound of the present invention, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof, for the treatment of a disease or condition in a mammal for which modulation of somatostatin receptor subtype 2 (SSTR2) activity is effective, wherein the disease or condition is acromegaly. , neuroendocrine tumor, ocular disease or condition, neuropathy, nephropathy, respiratory system disease or condition, cancer, pain, neurodegenerative disease or condition, inflammatory disease or condition, psychiatric disease or condition, or combinations thereof.

In one aspect of the invention, the use of a compound of the present invention, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof, is provided for the treatment of acromegaly, a neuroendocrine tumor, or combinations thereof.

In one aspect of the invention, the use of a compound of the present invention, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof, is provided for modulating somatostatin receptor subtype 2 (SSTR2) activity in a mammal with acromegaly or a neuroendocrine tumor.

In one aspect of the invention, the use of a compound of the present invention, or a pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers thereof, is provided for agonizing somatostatin 2 receptor subtype (SSTR2) activity in a mammal with acromegaly or a neuroendocrine tumor.

Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be appreciated, however, that the detailed description and specific examples, while describing specific embodiments, are for illustrative purposes only, as various changes and modifications to the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

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Detailed disclosure of the present invention

Somatostatin (SST), also known as somatotropin release inhibitory factor (SRIF), was originally isolated as a 14 amino acid peptide from the sheep hypothalamus (Brazeau et al., Science 179, 77-79, 1973). Subsequently, a 28 amino acid N-terminally extended peptide with biological activity similar to 14 amino acid somatostatin was isolated (Pradayrol et al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci USA, 77, 6827-6831, 1980). SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth hormones. SST acts through both endocrine and paracrine pathways with effects on its target cells. Many of these effects are associated with inhibition of the secretion of other hormones, predominantly growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and intestines and have numerous functions, including modulating the secretion of growth hormone (GH), insulin, glucagon, and many other hormones that are antiproliferative.

These pleiotropic actions of somatostatins are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All receptors are members of the class A subgroup GPCR superfamily. The SST2A receptor is the most widely expressed subtype in human tumors and is the dominant receptor by which GH secretion is suppressed. Unless otherwise indicated, the term SSTR2 means SSTR2a.

It is possible to selectively regulate any of the somatostatin receptor subtypes or a combination thereof. In accordance with some embodiments, selective modulation of any of the somatostatin receptor subtypes with respect to other somatostatin receptor subtypes, or a combination thereof, is useful in a number of clinical applications. In accordance with some embodiments, selective modulation of any of the somatostatin receptor subtypes relative to other somatostatin receptor subtypes reduces unwanted side effects in a number of clinical applications.

For example, modulation of SSTR2 activity mediates inhibition of growth hormone (GH) release from the anterior pituitary and glucagon release from the pancreas. SSTR2 is also involved in many other biological functions such as, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis. In some embodiments, the SSTR2 selective modulator is used in the treatment of acromegaly, neuroendocrine tumors of the intestine, pain, neuropathies, nephropathies and inflammation, and retinopathy resulting from abnormal growth of blood vessels. In accordance with other embodiments, the SSTR2 selective modulator is used in the treatment of arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, Cushing's disease, acute lung injury, acute respiratory distress syndrome, and eye disorders such as age-related macular degeneration. (AMD), diabetic retinopathy, diabetic macular edema, and Graves' ophthalmopathy, among others.

In some embodiments, SSTR4 agonists have anti-inflammatory and antinociceptive effects.

In some embodiments, SSTR3 agonists inhibit insulin secretion.

In some embodiments, SSTR5 agonists inhibit insulin secretion. In addition, SSTR5 was also involved in the modulation of growth hormone release.

The peptide somatostatin and its receptor subtypes are also widely expressed in the brain, and disruption or reduction of its activity is potentially associated with several psychiatric and neurodegenerative diseases. For example, somatostatin concentrations in the cerebral cortex and hippocampus are reduced in schizophrenics, and one of the most consistent neuropathological findings in this group of patients is a deficiency of somatostatin-expressing cortical inhibitory interneurons. Somatostatin is also highly expressed in areas of the brain associated with seizures and plays an important role in epilepsy. Somatostatin levels are reduced in the hippocampus of Alzheimer's and Parkinson's patients, suggesting restoration of somatostatin signaling as a potential drug target in neurodegeneration.

In one aspect, the compounds described herein are SSTR2 modulators. In some embodiments, the compounds described herein selectively modulate the activity of SSTR2 with respect to other somatostatin receptors.

In some embodiments, the compounds described herein are for oral administration to a mammal in need of somatostatin modulator treatment.

- 17 040023

In accordance with some embodiments, the somatostatin receptor modulators described herein are useful in a wide range of therapeutic applications. In some embodiments, somatostatin receptor modulators are used in the treatment of a number of diseases or conditions, such as, but not limited to, acromegaly, neuroendocrine tumors, retinopathy and other ocular disorders, neuropathy, nephropathy, respiratory diseases, cancers, pain, neurodegenerative diseases, inflammatory diseases. and psychiatric and neurodegenerative disorders. In accordance with some embodiments, the somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal. In some embodiments, the somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals. In some embodiments, the compounds are used to suppress certain endocrine secretions such as, but not limited to, GH, insulin, glucagon, and prolactin. Suppression of certain endocrine secretions is useful in the treatment of disorders such as acromegaly; endocrine tumors and carcinoids, VIPomas, insulinomas and glucagonomas; or diabetes mellitus and diabetes-related pathologies, including retinopathy, neuropathy and nephropathy. In accordance with some embodiments, the somatostatin receptor modulators described herein are used to suppress secretions in the pancreas, stomach, and intestines in the treatment of disorders such as pancreatitis, fistulas, bleeding ulcers, and diarrhea associated with diseases such as AIDS or cholera. Disorders involving autocrine or paracrine secretions of trophic factors such as IGF-1 (as well as certain endocrine factors) that can be treated by administering the compounds described herein include breast, prostate, and lung cancers (both small cell and and non-small cell epidermoids), as well as hepatomas, neuroblastomas, adenocarcinomas of the colon and pancreas (ductal type), chondrosarcomas and melanomas, retinopathy and atherosclerosis associated with vascular implants and restenosis after angioplasty.

In accordance with some embodiments, the somatostatin receptor modulators described herein are used to suppress neurogenic inflammatory mediators (eg, substance P or tachykinins) and may be used in the treatment of rheumatoid arthritis; psoriasis; local inflammation, for example, associated with sunburn, eczema or other sources of itching; inflammatory bowel disease; irritable bowel syndrome; allergies, including asthma and other respiratory diseases. In accordance with other embodiments, the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system and are useful in the treatment of Alzheimer's disease and other forms of dementia, pain and headaches. In some embodiments, the somatostatin receptor modulators described herein provide cytoprotection for disorders involving visceral blood flow, including cirrhosis and esophageal varices.

In one aspect, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a diastereomeric mixture, an enantiomer, or a prodrug thereof.

Formula (A) where

R ^a is hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ - heteroalkyl, or an unsubstituted or substituted ring A, which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring A is substituted then ring A is substituted by m R ^a and n R ^b ;

each R ^a and R ^b independently represents hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C 1 -C ₆ -fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ - 18 040023 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ ,

-CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF ₃ )N(R ¹⁵ )2, -NR ¹⁵ C(=O) R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ ,

-S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

R ^B is unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl or unsubstituted or a substituted ring B which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted then ring B is substituted with p R ^c and q R ^d ;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(= O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C (=O)NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

-C(=NOR ¹⁵ )R ¹⁵ , N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2,

-NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2, C(=O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2 or

-C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each Rf is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O) N(R ¹⁵ ) ₂ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2 ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl and unsubstituted or substituted € ₁ - € 6fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C1- _C2 alkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR10R ¹¹ - or absent;

- 19 040023

L ³ is -(CR ¹² R ¹³ ) _t - or absent;

t is 1 or 2;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ - heterocycloalkyl, unsubstituted or substituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O) R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6- membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

In one aspect, a compound of formula (A) is characterized by the structure of formula (I), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a diastereomeric mixture, an enantiomer, or a prodrug thereof

where Ring A is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted CrC6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN , -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(= O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted

- 20 040023

5- or 6-membered monocyclic heterocycle;

ring B is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C^C^ fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, - OR ¹⁴ , -C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N( R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O) NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C (=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

-C(=NOR ¹⁵ )R ¹⁵ , N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2,

-NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2, C(=O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ ) ₂ or

C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ ) ₂ ;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each Rf is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O) N(R ¹⁵ ) ₂ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ b;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C2-C6 heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -heteroalkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ .C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR ¹⁰ R ¹¹ - or absent;

L ³ is -(CR ¹² R ¹³ ) _t - or absent;

t is 1 or 2;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl and unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

- 21 040023 each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ -heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ ) ₂ ;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

Also described herein is a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable adjuvant. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

This document also describes a method of treating a disease or condition in a mammal that would benefit from modulation of somatostatin receptor activity, comprising administering a low molecular weight non-peptidyl compound, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof. In accordance with some embodiments, the low molecular weight non-peptidyl compound is administered orally. In accordance with some embodiments, the low molecular weight non-peptidyl compound is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the small molecular weight non-peptidyl compound is the SSTR2 modulator described herein, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the disease or condition is an acromegaly, a neuroendocrine tumor, an ocular disease or condition, a neuropathy, a nephropathy, a respiratory disease or condition, a cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or their combinations.

According to any of the above aspects, further embodiments are provided wherein an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt (a) thereof is administered systemically to a mammal; and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered to the mammal by injection; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to a mammal; and/or (j) administered to the mammal non-systemically or locally.

In any of the above aspects, further embodiments are provided that provide for single administrations of an effective amount of the compound, including further embodiments wherein the compound is administered to the mammal once a day, or the compound is administered to the mammal several times over the course of one day. In some embodiments, the compound is administered in a continuous dosing regimen. In some embodiments, the compound is administered on a continuous daily dosing schedule.

According to any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, the compounds provided herein are administered orally to a human.

Articles are presented that include a packaging material, a compound of formula (I) or a pharmaceutically acceptable salt thereof in a packaging material and a label indicating that the compound or composition or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically the active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof is used to modulate one or more somatostatin receptor protein subtypes, or to treat, prevent, or alleviate one or more symptoms of a disease or condition for which modulation of one or more protein subtypes would be effective somatostatin receptors.

Connections

Compounds of formula (A), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are somatostatin receptor modulators. In some embodiments, compounds of formula (A), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are SSTR2 receptor modulators. In some embodiments, somatostatin receptor modulators are somatostatin receptor agonists.

In one aspect, the present invention provides a compound of formula (A), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a diastereomeric mixture, an enantiomer, or a prodrug thereof.

Formula (A) where

R ^a is hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₂ -C ₆ -alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ - a heteroalkyl or unsubstituted or substituted ring A which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring A is substituted then ring A is substituted with m R ^a and nR ^b ;

each R ^a and R ^b independently represents hydrogen, halogen, unsubstituted or substituted C1-C6-αalkyl, unsubstituted or substituted C1-C6-fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) 2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S (=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

R ^B is unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C 2 -C 6 alkenyl, unsubstituted or substituted C 2 -C 6 alkynyl, unsubstituted or substituted C 1 C 6 heteroalkyl, or unsubstituted or substituted ring B which is unsubstituted or a substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted then ring B is substituted with p R ^c and q R ^d ;

each R ^c and R ^d independently represents hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl, unsubstituted or substituted mono- 23 040023 cyclic carbocycle, unsubstituted or substituted monocyclic heterocycle , -CN, -OH, -OR ¹⁴ ,

-C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N(R ¹⁵ ) 2, -NR ¹⁵ C(=O)N(R ¹⁵ )2,

-NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O)NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N (R ¹⁵ )2, -CH2N(R ¹⁵ )2,

-CH(CF ₃ )N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

-C(=NOR ¹⁵ )R ¹⁵ , N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2,

-NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2, C(=O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ ) ₂ or

-C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ ) ₂ ;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each Rf is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O) N(R ¹⁵ ) ₂ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2 ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted € ₁ -€6 alkyl, unsubstituted or substituted C ₁ -C ₆ -heteroalkyl and unsubstituted or substituted € ₁ - € 6fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR10R ¹¹ - or absent;

L ³ is -(CR ¹² R ¹³ )t- or absent;

t is 1 or 2;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl and unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ -heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, ^-C^ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

According to some embodiments of a compound of formula (A)

R ^a is hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ - a heteroalkyl or unsubstituted or substituted ring A which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring A is substituted then ring A is substituted with m R ^a and nR ^b ;

each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted Ο1-Ο6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) 2, -CHN(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or - SO2N(R ¹⁵ )2;

m is 1 or 2; n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

R ^B is unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₂ -C ₆ alkenyl, unsubstituted or substituted C ₂ -C ₆ alkynyl, unsubstituted or substituted C1C ₆ heteroalkyl, or unsubstituted or substituted ring B , which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted then ring B is substituted with p R ^c and q R ^d ;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, - CH2N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

p is 1 or 2; q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each Rf is independently hydrogen, halogen, unsubstituted or substituted Ο ₁ -Ο ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O) N(R ¹⁵ ) ₂ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2 ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, or

- 25 040023 substituted or unsubstituted C ₂ -Ci-heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ ) ₂ , -CN, unsubstituted or substituted C ₁ -C ₆ alkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C 6 alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR ¹⁰ R ¹¹ - or absent;

L ³ is -(CR ¹² R ¹³ ) _t - or absent;

t is 1 or 2;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl and unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, substituted heterocycloalkyl, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN , -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O )R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

In one aspect, a compound of formula (A) is characterized by the structure of formula (AI), or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a diastereomeric mixture, an enantiomer, or a prodrug thereof

- 26 040023

Formula (AI) where

R ^B is an unsubstituted or substituted ring B which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted then ring B is substituted by p R ^c and q R ^d ;

p is 1 or 2;

q is 0, 1 or 2.

In one aspect, a compound of formula (A) or formula (AI) is characterized by the structure of formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, enantiomer or prodrug thereof /hk R ¹ L ¹

Formula (I) wherein Ring A is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH ₂ C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH ₂ N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH ₂ NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

ring B is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(= O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C (=O)NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

- C(=NOR ¹⁵ )R ¹⁵ , -N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2,

-NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2, C(=O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ ) ₂ or

- C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

- 27 040023

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) ₂ , -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each R ^f is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ )2, unsubstituted or substituted € ₁ - € ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ -heteroalkyl and unsubstituted or substituted € ₁ - € ₆ fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl or unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR ¹⁰ R ¹¹ - or absent;

L ³ is -(CR ¹² R ¹³ )t- or absent;

t is 1 or 2;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl and unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ ) ₂ , -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C1- _C6 alkyl, C1- _C6 heteroalkyl, _C3 - _C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

In some embodiments of a compound of formula (I), ring A is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted Ci-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ ) 2, -CH2N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or - SO2N(R ¹⁵ )2;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

ring B is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C1-C ₆ alkyl, unsubstituted or substituted C1-C ₆ fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH , -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N( R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ ) 2;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, unsubstituted or substituted C1-C ₆ alkyl, unsubstituted or substituted C1-C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N( R ¹⁵ )2, -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

each Rf is independently hydrogen, halogen, unsubstituted or substituted C1- _C6 alkyl, unsubstituted or substituted C1- _C6 fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -C(=O)N( R ¹⁵ ) ₂ , -N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ h;

R ¹ and R ² independently represent hydrogen, unsubstituted or substituted C1-C ₆ alkyl, unsubstituted or substituted C1-C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, or substituted or unsubstituted C ₂ -C ₆ - heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, unsubstituted or substituted C1- _C6 alkyl and unsubstituted or substituted C1- _C6 fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C1- _C2 alkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-C ₆ alkyl, and unsubstituted or substituted C1-C ₆ fluoroalkyl;

R ⁷ is hydrogen, unsubstituted or substituted C1-C ₆ alkyl, or unsubstituted or substituted C1-C ₆ fluoroalkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CR8R ⁹ -;

L ² is -CR ^1o R ¹¹ - or absent;

L ³ is -(CR ¹² R ¹³ )t- or absent;

t is 1 or 2;

- 29 040023 each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen, unsubstituted or substituted C ₁ -C ₆ -alkyl and unsubstituted or substituted C ₁ -C ₆ - fluoroalkyl;

or R ⁵ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or an unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁵ and R ¹³ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

or R ⁷ and R ⁸ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted monocyclic carbocyclic or unsubstituted or substituted monocyclic heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C 6 heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ ) ₂ ;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

For any and all embodiments, the substituents are selected from a subset of the alternatives set forth. For example, in some embodiments, m is 1 or 2. In other embodiments, m is 1. In some other embodiments, m is 2.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is is 1. In some embodiments, n is 2.

In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is is 1. In some embodiments, q is 2.

In some embodiments, R ⁴ and R ⁶ are each independently selected from the group consisting of hydrogen and -CH3; R ⁷ is hydrogen, -CH3 or -CH ₂ CH ₃ ; or R ² and R ⁷ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted N-containing C2-C8 heterocycloalkyl; each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ is independently selected from the group consisting of hydrogen and —CH3.

In some embodiments, L ¹ is absent or is -CH ₂ -, -CHCH3- or -CH(CH2CH3)-; L ² is -CH2- or absent; L ³ is -CH2-, -CH2CH2- or absent. In some embodiments, L ¹ is absent or is -CH2-; L ² is -CH2- or absent; L ³ is -CH2-, -CH2CH2 or absent.

In some embodiments, X is CRf; Y is CRf; and Z is CRf.

In some embodiments, X is N; Y is CR ^f ;

- 30 040023 and Z is CR ^f .

In some embodiments, X is CR ^f ; Y is N and Z is CR ^f

In some embodiments, X is CR ^f ; Y represents

CR ^f and Z is N.

In some embodiments, X is N; Y is N and Z is CR ^f

In some embodiments, X is CR ^f ; Y is N; and Z is N.

In some embodiments, X is N; Y is N and Z is N.

In some embodiments, a compound of formula (I) has the structure of formula (Ia), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

^Rf

Formula (1a).

In some embodiments, a compound of formula (I) is characterized by the structure of formula (Ib), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof:

^Rf

Formula (Ib).

In some embodiments, a compound of formula (I) has the structure of formula (Ic), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

^Rf

Formula (1s).

In some embodiments, a compound of formula (I) is characterized by the structure of formula (Id), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

- 31 040023

Formula (Id).

In some embodiments, a compound of formula (I) has the structure of formula (Ie), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, a compound of formula (I) has the structure of formula (If), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, R ^e is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, or -OR ¹⁴ and each R ^f is independently hydrogen, halogen, C1-C4 alkyl, C1- C ₄ -fluoroalkyl, -CN, -OH or -OR ¹⁴ .

In some embodiments, R ^e is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3, -OCH2CH3 or -OCF3; each R ^f is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), - C(CH3)3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3 or -OCF3.

In some embodiments, Ring A is a monocyclic carbocycle or a monocyclic heterocycle.

In some embodiments, Ring A is a monocyclic carbocycle that is phenyl, C ₃ -C 6 cycloalkyl, or C ₅ -C ₆ cycloalkenyl.

In some embodiments, ring A is phenyl.

In some embodiments, R ^A is

In some embodiments, R ^A is

According to some embodiments

- 32 040023

represents

In some embodiments, is

In some embodiments, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

According to some embodiments

n is 0, 1 or 2.

In some embodiments, Ring A is a bicyclic carbocycle, which is naphthyl, indanyl, indenyl, or tetrahydronaphthyl.

In some embodiments, ring A is a monocyclic heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or a monocyclic heterocycle containing 0-4 N atoms and 1 O or S atom.

In some embodiments, Ring A is a monocyclic heterocycle that is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

In some embodiments, Ring A is a monocyclic heterocycle that is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

According to some embodiments

n is 0, 1 or 2.

According to some embodiments

- 33 040023 is is is is

n is 0, 1 or 2.

In some embodiments, n is 0, 1, or 2.

In some embodiments, is

- 34 040023

n is 0, 1 or 2.

In some embodiments, ring A is a bicyclic heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or a bicyclic heterocycle containing 04 N atoms and 1 O or S atom.

In some embodiments, Ring A is a bicyclic heterocycle which is quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, indolinyl, isoindolinyl, indolinonyl, isoindolinonyl or quinolinonyl.

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH ₂ C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH ₂ N( R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ ) 2; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₄ alkyl, unsubstituted or substituted C 1 -C ₄ fluoroalkyl, unsubstituted or substituted C 1 -C ₄ heteroalkyl, -CN, -OH, -O -(unsubstituted or substituted C1- _C4 alkyl) or -O-(unsubstituted or substituted C1- _C4 fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2 , -NR ¹⁵ C(=O)R ¹⁴ or -CH2NR ¹⁵ C(=O)R ¹⁴ ; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1- _C4 heteroalkyl, -CN, -OH, -O-(unsubstituted or substituted C1- _C4 alkyl) or -O-(unsubstituted or substituted C1-C4fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH ₂ C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH ₂ N( R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C ₁ -C ₄ fluoroalkyl, unsubstituted or substituted C ₁ -C ₄ heteroalkyl, -CN, -OH, -O (unsubstituted or substituted C 1 -C ₄ alkyl) or -O- (unsubstituted or substituted C ₁ -C ₄ fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2 , -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ or -CH2NR ¹⁵ C(=O)R ¹⁴ ; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C1- _C4 alkyl, unsubstituted or substituted C1- _C4 fluoroalkyl, unsubstituted or substituted C1- _C4 heteroalkyl, -CN, -OH, -O- (unsubstituted or substituted C1- _C4 alkyl) or -O(unsubstituted or substituted C1-C4 fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -ODSCCHCH3b, -CH(CH3)(CH2CH3), - C (CH3) 3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2OH, -CH2CH2OH, -CO ₂ H, -CO2CH3, -CO2CH2CH3, -CH2CO2H, -CH ₂ CO ₂ CH ₃ , -CH2CO2CH2CH3, -C(=O)NH ₂ , -C(=O)NHCH3, -C(=O)N(CH ₃ )2, -CH2C( =O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2 ; each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), - C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3 or -OCF3.

In some embodiments, each R ^a is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -CH2CH2OH; each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3.

- 35 040023

In some embodiments, Ring B is a monocyclic carbocycle or a monocyclic heterocycle.

In some embodiments, Ring B is a monocyclic carbocycle that is phenyl, C ₃ -C 6 cycloalkyl, or C ₅ -C ₆ cycloalkenyl.

In some embodiments, ring B is phenyl.

In some embodiments, is

In some embodiments, is

According to some embodiments

represents

In some embodiments, is

In some embodiments, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

According to some embodiments

represents

- 36 040023

q is 0, 1 or 2.

In some embodiments, ring B is a bicyclic carbocycle, which is naphthyl, indanyl, indenyl, or tetrahydronaphthyl.

In some embodiments, ring B is a monocyclic 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atom, or a monocyclic heterocycle containing 0-4 N atoms and 1 O or S atom.

In some embodiments, Ring B is a monocyclic 5 or 6 membered heterocycle that is furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

In some embodiments, Ring B is a monocyclic 6-membered heterocycle that is pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

In some embodiments, is is is is is is

q is 0, 1 or 2.

In some embodiments, or q is 0, 1, or 2.

In some embodiments, q is 0, 1, or 2.

According to some embodiments

- 37 040023 is

q is 0, 1 or 2.

In some embodiments, ring B is a bicyclic heteroq is 0, 1, or 2.

In some embodiments, is q is 0, 1, or 2.

In some embodiments, R ^B is

- 38 040023 Rocycle containing 1-4 N atoms and 0 or 1 O or S atom, or bicyclic heterocycle containing 04 N atoms and 1 O or S atom.

In some embodiments, Ring B is a bicyclic heterocycle that is quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnolinyl, phthalazinyl, pteridinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, indolinyl, isoindolinyl, indolinonyl, isoindolinonyl or quinolinonyl.

In some embodiments, each R ^c is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2 , -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2; and each R ^d is independently hydrogen, halogen, unsubstituted or substituted C1- _C4 alkyl, unsubstituted or substituted C1- _C4 fluoroalkyl, unsubstituted or substituted _C1 - _C4 heteroalkyl, -CN, -OH, -O -(unsubstituted or substituted C1- _C4 alkyl) or -O-(unsubstituted or substituted C1- _C4 fluoroalkyl); or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O)NR ¹⁵ OR ¹⁵ ,-CH2C(= O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 , -C=N(R ¹⁴ )OR ¹⁵ or N(R ¹⁵ ) SO2R ¹⁴ ; and R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₄ alkyl, unsubstituted or substituted C 1 -C ₄ fluoroalkyl, unsubstituted or substituted monocyclic 4-7 membered heterocycle, -CN, -OH, -O -(unsubstituted or substituted C ₁ -C ₄ -alkyl), -O- (unsubstituted or substituted C ₁ -C ₄ -heteroalkyl), -O- (unsubstituted or substituted C 1 -C 4 -fluoroalkyl), -C (=O) R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C (=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O)NR ¹⁵ OR ¹⁵ , -CH2C(= O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CHN(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SO2N(R ¹⁵ )2, -C(=NOR ¹⁵ )R ¹⁵ , -N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ or -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , -C(=NR ¹⁵ )N(R ¹⁵ )2; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5 or 6 membered monocyclic carbocycle, or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)( CH ₂ CH3), -C (CH3) 3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3 , -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -CH2C(=O)NH2, -CH2C(= O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3, -CH ₂ N(CH ₃ ) ₂ , azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), - C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3 or -OCF3; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)( CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3, - CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHOCH3, -C(=O)N(CH3)2, -SO2N(CH3)2 , -C(=NOCH3)H, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCO2CH3, -NHSO2CH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, CH(CF3)NH2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -OCH2OCH3, -OCH2OCH2CH3, -OCH2CH2OH, -C(=O)NHOCH3, -C(=NOCH3)H, -CH2C(=O)NH2, -NH2, NHCO2CH3, NHSO2CH3, NH(C=O)NHCH3, NH(C=O )NHOCH3, CH(CF3)NH2; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

- 39 040023

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, CONH2, azetidinyl, or pyrrolidinyl ; each R ^d is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, -C(=O )NH2, -CH(=NOCH3), -SO2N(CH3)2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2OCH3, -OCF3, -CH2OH-C(=O)NH2 , -CH2C(=O)NH2, -NH2, -NHC(=O)OCH ₃ , -NHSO ₂ CH ₃ ; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH3, - OCF3, -NH2, -C(=O)NH2, -C(=NOCH3)H, -SO2CH3, -SO2N(CH3)2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH3, -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH ₃ , -OCF3, -OCH2OCH3, -CH2OH, - OCH2CH2OH, -C(=O)NH2, -C(=O)NHOCH3, NH2,

NHCO ₂ CH ₃ ,NH(C=O)NHOCH ₃ , CH ₂ (C=O)NH ₂ ; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle.

In some embodiments, a compound of formula (AI) has the structure of formula (AII), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

Where

RB is an unsubstituted or substituted ring B which is an unsubstituted or substituted monocyclic phenyl or an unsubstituted or substituted pyridinyl, where if ring B is substituted then ring B is substituted with p R ^c and q R ^d ;

p is 1 or 2;

q is 0, 1 or 2.

In some embodiments, a compound of formula (AII) or formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

where each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle , -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , - S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

- 40 040023 m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, - OR ¹⁴ , -C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N( R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O) NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C (=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

-C(=NOR ¹⁵ )R ¹⁵ , N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2, C(= O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ ) ₂ or

-C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ ) ₂ ;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, -CN, -OH or -OR ¹⁴ ;

each Rf is independently hydrogen, halogen, C1-C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, -CN, -OH or -OR ¹⁴ ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C2-C6 heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁷ is hydrogen or unsubstituted or substituted C ₁ -C ₄ alkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CHR ⁸ -;

L ² is -CH2- or absent;

L ³ is -CH2-, -CH2CH2- or absent;

R ⁷ is hydrogen or C ₁ -C ₄ alkyl;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O) R ¹⁷ , -SO2R ¹⁷

- 41 040023 or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl,

C ₂ -C ₆ -heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

According to some embodiments of a compound of formula (II), each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C ₆ alkyl, unsubstituted or substituted C1-C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CHN(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

m is 1 or 2; n is 0, 1 or 2;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , - CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CHN(R ¹⁵ )2, -NR ¹⁵ C( =O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ or -SO2N(R ¹⁵ )2;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, -CN, -OH or -OR ¹⁴ ;

each Rf is independently hydrogen, halogen, C1-C ₄ -alkyl, C ₁ -C ₄ -fluoroalkyl, -CN, -OH or -OR ¹⁴ ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, or substituted or unsubstituted C 2 -C 6 - heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ³ and R ⁵ are each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, unsubstituted or substituted C ₁ -C ₆ alkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl;

or R ³ and R ⁵ are taken together to form a bond or C ₁ -C ₂ -αkylene;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁷ is hydrogen or unsubstituted or substituted C ₁ -C ₄ alkyl;

or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

L ¹ is absent or is -CHR ⁸ -;

L ² is -CH2- or absent;

L ³ is -CH2-, -CH2CH2- or absent;

R ⁸ represents hydrogen or C ₁ -C ₄ -alkyl;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C ₁ -C ₆ alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O) R ¹⁷ , -SO2R ¹⁷

- 42 040023 or -SO2N(R ¹⁶ )2;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl,

C ₂ -C ₆ -heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C1- _C6 alkyl, C1- _C6 heteroalkyl, _C3 - _C6 cycloalkyl, _C2 - _C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

In some embodiments, L ² is -CH2-; L ³ is -CH2-.

In some embodiments, L ² is absent; L ³ is -CH2CH2-.

In some embodiments, L ² is absent; L ³ is missing.

In some embodiments, L ² is or is not; L ³ is -CH2-.

In some embodiments, R ¹ is hydrogen; R ² is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or substituted or unsubstituted C2C6 heterocycloalkyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a ring C which is an unsubstituted or substituted N-containing C2-C8 heterocycloalkyl; R ³ is hydrogen; R ⁵ is each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2 , -CN, C1-C6-alkyl and €1-€6fluoroalkyl; or R ³ and R ⁵ are taken together to form a bond or -CH2- or -CH2CH2-; or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring; R ⁷ is hydrogen or C1-C4 alkyl; or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered N-containing C2- _C8 heterocycloalkyl.

In some embodiments, R ¹ is hydrogen; R ² is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or substituted or unsubstituted C2C6 heterocycloalkyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a ring C which is an unsubstituted or substituted N-containing C2- _C6 heterocycloalkyl; R ³ is hydrogen; R ⁵ is each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ alkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl; or

R ³ and R ⁵ are taken together to form a bond of either -CH2- or -CH2CH2-; or

R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

R ⁷ is hydrogen or C1-C4 alkyl; or R ² and R ⁷ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered N-containing C2- _C8 heterocycloalkyl.

In some embodiments, R ¹ is hydrogen; R ² is hydrogen, -CH3, -CH2CH3, -CH2CH2OCH3, CH2CH2F, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CH2CH2F, CH2CH2CH2OCH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; or

R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form ring C which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl;

R ³ is hydrogen;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH ₃ , -NH2, -NHCH ₃ , -N(CH ₃ )2, -OCH ₂ CH ₃ , -OCF ₃ , -CH3, -CH2CH3, -CH2F, -CHF2 or -CF3; or

R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl; R ⁷ is hydrogen, -CH3 or -CH2CH3; or R ² and R ⁷ are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted

- 43 040023 or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

In some embodiments, R ¹ is hydrogen;

R ² is hydrogen, -CH3, -CH2CH3, -CH2CH2OCH3, CH2CH2F, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CH2CH2F, CH2CH2CH2OCH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form ring C which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl; R ³ is hydrogen; R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH ₂ , -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2 or -CF ₃ , -CN, -C(=O)OCH ₃ , -C(=O)NH2, -C(=O)NHCH ₃ , -C(=O)N(CH ₃ )2; or

R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 4 to 7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl; R ⁷ is hydrogen, -CH ₃ or -CH2CH3; or R ² and R ⁷ are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted pyrrolidinonyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

In some embodiments, L ¹ is absent or is -CH2-, -CHCH3- or -CH(CH2CH3)-.

In some embodiments, L ¹ is absent.

In some embodiments, L ¹ is -CH2-, -CHCH3- or -CH(CH2CH3)-. In some embodiments, L ¹ is -CH2-.

According to some embodiments

represents

In some embodiments, is

- 44 040023 or

In some embodiments, is

In some embodiments, is

In some embodiments, is

- 45 040023

represents

According to some embodiments

In some embodiments, is

In some embodiments, is

- 46 040023

In some embodiments, is

In some embodiments, is

In some embodiments, is

- 47 040023

In some embodiments, is wherein ring C is unsubstituted or substituted N-containing C2-C6 heterocycloalkyl.

In some embodiments, represents

In some embodiments, is

- 48 040023

represents

According to some embodiments

According to some embodiments

In some embodiments, is is is is

- 49 040023

In some embodiments, is

In some embodiments, is

In some embodiments, a compound of formula (AII) has the structure of formula (A2), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

where each R ^a and R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle , -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , - S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2 or -C(=NOR ¹⁵ )R ¹⁵ ;

m is 1 or 2;

n is 0, 1 or 2;

or if one R ^a and one R ^b are on adjacent atoms of ring A, then the adjacent R ^a and R ^b groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted

- 50 040023

5- or 6-membered monocyclic heterocycle;

R ^B is an unsubstituted or substituted ring B which is an unsubstituted or substituted phenyl or an unsubstituted or substituted pyridinyl, wherein if the ring

B is substituted, then ring B is substituted with p R ^c and q R ^d ;

each R ^c and R ^d is independently hydrogen, halogen, unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, -CN, -OH, - OR ¹⁴ , -C(=O)R ¹⁵ , -OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N( R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O) NR ¹⁵ OR ¹⁵ , -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C (=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2,

- C(=NOR ¹⁵ )R ¹⁵ , -N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , C(=NR ¹⁵ )N(R ¹⁵ )2,

-NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ )2, -NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ )2,C(=O)NR ¹⁵ C(=NR ¹⁵ )N(R ¹⁵ ) ₂ or

- C(=O)NR ¹⁵ C(=CR ¹⁴ R ¹⁵ )N(R ¹⁵ ) ₂ ;

p is 1 or 2;

q is 0, 1 or 2;

or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or a substituted 5- or 6-membered monocyclic heterocycle;

X is CRf or N;

Y is CRf or N;

Z is CRf or N;

R ^e is hydrogen, halogen, C1- _C4 alkyl, C1- _C4 fluoroalkyl, -CN, OH or -OR ¹⁴ ;

each Rf is independently hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, -CN, -OH, or -OR ¹⁴ ;

R ¹ and R ² are independently hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₃ -C ₆ -cycloalkyl or substituted or unsubstituted C2-C6 heterocycloalkyl;

or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a C ring which is an unsubstituted or substituted N-containing C ₂ -C ₈ heterocycloalkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, - CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ -alkyl, unsubstituted or substituted C ₁ -C ₆ -heteroalkyl and unsubstituted or substituted C ₁ -C ₆ -fluoroalkyl;

or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring;

each R ¹⁴ is independently selected from unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

each R ¹⁵ is independently selected from hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₂ -C ₁₀ - heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or two R ¹⁵ on the same N atom are taken together with the N atom to which they are attached to form an unsubstituted or substituted N-containing heterocycle;

wherein each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more R ^s groups independently selected from the group consisting of halo, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR ¹⁶ , -CO2R ¹⁶ , -C(=O)N(R ¹⁶ )2, -N(R ¹⁶ )2, -NR ¹⁶ C(=O)R ¹⁷ , -SR ¹⁶ , -S(=O)R ¹⁷ , -SO2R ¹⁷ or -SO2N(R ¹⁶ ) ₂ ;

each R ¹⁶ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6 -membered heteroaryl; or two R ¹⁶ groups are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁷ is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl .

In some embodiments, a compound of formula (AII) or formula (A2) is characterized by the structure of formula (AIIa), formula (AIIb), formula (AIIc), formula (AIId), formula (AIIe), formula (AIIf), or its pharmaceutically acceptable salt, solvate, diastereomeric mixture, individual enantiomers or prodrug:

- 51 040023

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (AIIa), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof.

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (AIIb), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof.

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (AIIc), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof.

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (AIId), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, individual enantiomers, or prodrug thereof.

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (IIe), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof.

In some embodiments, a compound of formula (AII) or formula (A2) has the structure of formula (AIIf), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof.

In some embodiments, ^Re is hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, or -OCF3; each R ^f is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2F _{, -CHF2} , _-CF3 , -CN, -OH, -OCH3, -OCH2CH3 or -OCF3.

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , - CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH2C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, - CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ ,-SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ ) ₂ or -C=N(R ¹⁴ )OR ¹⁵ ; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C1-52 040023

C ₄ -alkyl, unsubstituted or substituted C1-C ₄ -fluoroalkyl, unsubstituted or substituted C1-C ₄ heteroalkyl, -CN, -OH, -O- (unsubstituted or substituted C1-C ₄ -alkyl) or -O- (unsubstituted or substituted C ₁ -C ₄ -fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroαalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -CH ₂ C(=O)N(R ¹⁵ )2, -N(R ¹⁵ )2 or -CH ₂ N( R ¹⁵ )2; and each R ^b is independently hydrogen, halogen, unsubstituted or substituted C1- _C4 alkyl, unsubstituted or substituted C1- _C4 heteroalkyl, -CN, -O-(unsubstituted or substituted C1- _C4 alkyl), or -O -(unsubstituted or substituted C ₁ -C ₄ -fluoroalkyl).

In some embodiments, each R ^a is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3) ₂ , -CH2CH2CH2CH3, -CH ₂ CH(CH ₃ ) ₂ , -CH( CH ₃ )(CH ₂ CH ₃ ),

-С(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CH2OH, -CH2CH2OH, -CO2H, -CO2CH3, - CO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -CH2C(=O)NH2, -CH2C( =O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2;

each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), - C(CH3)3, -CH2OH, -CH2CN, -CH2F,

-CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3.

In some embodiments, each R ^a is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, or -CH2CH2OH; each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OCH3, -OCF3. In some embodiments, R ^B is

In some embodiments, RB is

In some embodiments, RB is

In some embodiments, RB is

In some embodiments, each R ^c is independently hydrogen, halogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C1-C4 fluoroalkyl, unsubstituted or substituted C1-C4 heteroalkyl, -CN, -OH, -OR ¹⁴ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O)NR ¹⁵ OR ¹⁵ ,-CH ₂ C (=O)N(R ¹⁵ )2, -N(R ¹⁵ )2, -CH ₂ N(R ¹⁵ ) ₂ , -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(=O)R ¹⁴ , -SR ¹⁴ , -S(=O)R ¹⁴ , -SO2R ¹⁴ , -SO2N(R ¹⁵ )2, -C=N(R ¹⁵ )OR ¹⁵ or N (R ¹⁵ )SO ₂ R ¹⁴ ; And

R ^d is independently hydrogen, halogen, unsubstituted or substituted C ₁ -C ₄ -alkyl, unsubstituted or substituted C 1 -C ₄ -fluoroalkyl, unsubstituted or substituted monocyclic 47-membered heterocycle, -CN, -OH, -O- (unsubstituted or substituted C1- _C4 alkyl), -O-(unsubstituted or substituted C1- _C4 heteroalkyl), -O-(unsubstituted or substituted C1- _C4 fluoroalkyl), -C(=O)R ¹⁵ , - OC(=O)R ¹⁵ , -CO2R ¹⁵ , -CH2CO2R ¹⁵ , -C(=O)N(R ¹⁵ )2, -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O) N(R ¹⁵ )2, -NR ¹⁵ C(=O)OR ¹⁴ , -NR ¹⁵ C(=O)NR ¹⁵ OR ¹⁴ , -C(=O)NR ¹⁵ OR ¹⁵ , -CH2C(=O)N( R ¹⁵ )2, -N(R ¹⁵ )2, -CH2N(R ¹⁵ )2, -CH(CF3)N(R ¹⁵ )2, -NR ¹⁵ C(=O)R ¹⁴ , -CH2NR ¹⁵ C(= O)R ¹⁴ , -SO2N(R ¹⁵ )2, -C(=NOR ¹⁵ )R ¹⁵ , -N(R ¹⁵ )SO2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ or -S (=O)2NR ¹⁵ C(=O)R ¹⁴ , -C(=NR ¹⁵ )N(R ¹⁵ )2; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted

- 53 040023

5- or 6-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, —CH ₃ , —CH2CH3, —CH ₂ CH ₂ CH ₃ , —CH(CH ₃ ) ₂ , —CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) (CH ₂ CH ₃ ), -C (CH3) 3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, - OH, -OCH3, -OCH2CH3, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH ₂ CO ₂ CH ₂ CH ₃ , -C(=O)NH ₂ , -C(=O )NHCH ₃ , -C(=O)NHOCH ₃ , -C(=O)N(CH3)2, -SO2N(CH3)2, -C(=NOH)H, -C(=NOCH3)H, -CH2C (=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -NH ₂ , -NHCH3, -N(CH3)2, -NHCO2CH3, -NHSO2CH3, -CH2NH2, - CH2NHCH3, -CH ₂ N(CH ₃ ) ₂ , CH(CF ₃ )NH ₂ , azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2CH3, -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) (CH ₂ CH ₃ ), -C (CH ₃ ) ₃ , -CH2OH, -CH2CN, -CH2F, -CHF2, -CF ₃ , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH ₃ , -OCH2CH3, -OCF3, -OCH2OCH3, -OCH2OCH2CH3, OCH2CH2OH, -C(=O)NHOCH3, -C(=NOH)H, -C(=NOCH3) H, -CH ₂ C(=O)NH ₂ , -NH ₂ , NHCO2CH3, NHSO2CH3, NH(C=O)NHCH ₃ , NH(C=O)NHOCH ₃ , CH(CF ₃ )NH ₂ ; or ^c T> ^d T) ^c n ^d if one R ^c and one R ^d are on adjacent atoms of ring B, then the adjacent R ^c and R ^d groups are taken together with the intermediate atoms to which they are attached to form an unsubstituted or substituted 5 - or a 6-membered monocyclic heterocycle.

In some embodiments, each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH,

-OCH3, -OCF3, -NH2, -C(=O)NH ₂ , -CONHCH3, -C(=NOH)H, -C(=NOCH3)H, -SO2CH3, -SO2N(CH3)2, azetidinyl or pyrrolidinyl ; each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, -C (=O)NH ₂ , -C(=O)NHOCH3,

NH2, NHCO2CH3,NH(C=O)NHOCH3, CH2(C=O)NH2; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle.

In some embodiments, a compound of formula (AI), formula (AII), or formula (A2) has the structure of formula (AIII), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

Formula (ASH)

In some embodiments, a compound of formula (I) or formula (II) is characterized by the structure of formula (III), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof:

Formula (III).

In some embodiments, R ⁷ is hydrogen or methyl.

In some embodiments, a compound of formula (AIII) is characterized by the structure of formula (AIIIa), formula (AIIIb), formula (AIIIc), formula (AIIId), formula (AIIIe), formula (AIIIf), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture thereof , single enantiomers or prodrug

- 54 040023 is is is is

According to some embodiments

Formula (ASHe)

According to some embodiments

According to other embodiments

- 55 040023 is

In other embodiments, is

In some embodiments, is

In other embodiments, is

According to some embodiments

represents

- 56 040023

In some embodiments, R ¹ is hydrogen;

R ² is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or substituted or unsubstituted C2-C6 heterocycloalkyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form a ring C which is an unsubstituted or substituted N-containing C2- _C6 heterocycloalkyl;

R ⁵ is each independently selected from the group consisting of hydrogen, halogen, -OH, -OR ¹⁴ , -S(=O)2R ¹⁴ , -N(R ¹⁵ )2, -CN, -C(=O)OR ¹⁵ , -C(=O)N(R ¹⁵ ) ₂ , unsubstituted or substituted C ₁ -C ₆ alkyl and unsubstituted or substituted C ₁ -C ₆ fluoroalkyl; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted 4-7 membered saturated N-containing heterocyclic ring.

In some embodiments, R ¹ is hydrogen;

R ² is hydrogen, -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2OCH3, CH2CH2F, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, -CH2CH2CH2F, CH2CH2CH2OH, CH2CH2CH2OCH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form ring C which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl or unsubstituted or substituted azepanil;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH, -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2 or - CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

In some embodiments, a compound of formula (III) has the structure of formula (IIIa), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, a compound of formula (AIII) has the following structures, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

- 57 040023

In some embodiments, a compound of formula (III) is characterized by the structure of formula (IIIb), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture thereof, separately

In some embodiments, a compound of formula (AIII) has the following structures, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

- 58 040023

In some embodiments, R ¹ is hydrogen; and R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl or oxetanyl. In some embodiments, R ² is hydrogen; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form ring C which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl.

In some embodiments, R ¹ is hydrogen and

R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl or oxetanyl. In some embodiments, R ² is hydrogen.

In some embodiments, a compound of formula (I) or formula (II) has the structure of formula (IV), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

- 59 040023

Formula (IV).

In some embodiments, a compound of formula (I) or formula (II) has the structure of formula (V), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, R ⁷ is hydrogen or methyl.

In some embodiments, R ⁸ is hydrogen or methyl or ethyl.

In some embodiments, a compound of formula (AI), formula (AII), or formula (A2) has the structure of formula (AV), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, a compound of formula (AV) is characterized by the following structure of formula (AVa), formula (AVb), formula (AVc), formula (AVd), formula (AVe), formula (AVf), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers or prodrug

- 60 040023

In some embodiments, a compound of formula (AV) has the following structures, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

- 61 040023

In some embodiments, a compound of formula (AV) has the following structures, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, single enantiomers, or prodrug thereof

In some embodiments, R ^B is

^Rc

R ¹ is hydrogen;

R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, or tert-butyl or oxetanyl;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₂ CH _{3 , -OCF 3 ,} -CH3, -CH2CH3 , -CH2F, -CHF2 or -CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3h; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

In some embodiments, R ^B is

- 62 040023

R ¹ is hydrogen;

R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, or tert-butyl or oxetanyl;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH ₃ , -NH ₂ , -NHCH3, -N(CH ₃ ) ₂ , -OCH ₂ CH ₃ , -OCF3, -CH3, -CH2CH3, - CH2F, -CHF2 or -CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 4-7 membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

In some embodiments, R ^a is hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -CH2OH, or -CH2CH2OH;

R ^b is hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ;

each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH ₃ , -OCF ₃ , -NH ₂ , -C(=O)NH ₂ , -C(=NOH)H, -C(=NOCH ₃ )H, -SO ₂ CH ₃ , -SO ₂ N(CH ₃ ) ₂ , azetidinyl or pyrrolidinyl;

each R ^d is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, -C( =O)NH2, -C(=O)NHOCH3, -NH2, -NHCO2CH3, -NH(C=O)NHOCH3, -CH2(C=O)NH2; R ^e is hydrogen, F, Cl, Br, -CH3, -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3 or -OCF3;

R ¹ is hydrogen;

R ² is hydrogen;

R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, - CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted monocyclic 6-membered heterocyclic ring selected from unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl .

In some embodiments, R ^a is hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -CH2OH, -CH2CH2OH, -OCH3 or -OCF3; R ^b is hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -OCH3 or -OCF3;

each R ^c is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -NH ₂ , -OCH ₃ , -OCF3, -CONH2, -C(C=NOH)H, - C(C=NOCH3)H;

each R ^d is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -NH ₂ , -OCH ₃ , -OCF3;

R ¹ is hydrogen;

R ² is hydrogen; R ⁵ is hydrogen or

R ² and R ⁵ are taken together with the intermediates to which they are attached to form an unsubstituted or substituted morpholinyl.

In some embodiments, R ¹ is hydrogen and R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2methylaminoethyl, 2-dimethylaminoethyl, 2-carboxyethyl, n-propyl, isopropyl, cyclopropyl, 3fluoropropyl, 3-methoxypropyl, 3-carboxypropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, cyclobutyl or oxetanyl. In some other embodiments, R ¹ is hydrogen and R ² is methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl or tert-butyl or oxetanyl; or R ¹ and R ² are taken together with the nitrogen atom to which they are attached to form ring C which is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl.

In some embodiments, R ¹ is hydrogen and R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2methylaminoethyl, 2-dimethylaminoethyl, 2-carboxyethyl, n-propyl, isopropyl, cyclopropyl, 3fluoropropyl, 3-methoxypropyl, 3-carboxypropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, cyclobutyl or oxetanyl. According to some other embodiments, R ¹ is a

- 63 040023 road; And

R ² is methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl or tert-butyl or oxetanyl.

According to some embodiments

Represents And, as described in table. 1, 2, 3 or 4.

In some embodiments, R ³ is hydrogen.

In some embodiments, R ⁵ is hydrogen, -F, -Cl, -Br, -OH, -OCH3, -OCH2CH3, -SH, -SCH3, -SCH2CH3, -SCH(CH3)2, -SCH2CH2CH3, -S( =O)CH3, -S(=O)CH2CH3, -S(=O)CH(CH3)2, -S(=O)CH2CH2CH3, -S(=O)2CH3, -S(=O)2CH2CH3, - S(=O)2CH(CH3)2, -S(=O)2CH2CH2CH3, -NH2, -NH(CH ₃ ), -NH(CH2CH ₃ ), -N(CH ₃ ) ₂ , -N(CH2CH ₃ ) 2, -CN, methyl, ethyl, fluoroethyl, n-propyl, fluoropropyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or cyclobutyl. In some embodiments, R ⁵ is hydrogen, fluoro, or methoxy.

According to some embodiments of R ^A

represents

According to some embodiments of R ^A

is as described in Table. 1, 2, 3, or 4. In some embodiments, is

as described in table. 1, 2, 3 or 4.

In some embodiments, R ^B is (R' (R

According to some variants of implementation of R ^B is described in table. 1, 2, 3, or 4. In some embodiments,

represents R ^B as described in table. 1, 2, 3 or 4.

According to some variants of implementation of R ^e described in table. 1.

According to some embodiments

represents And, as described in table. 1, 2, 3 or 4.

In some embodiments, the compounds described herein are rasterized with the following structure, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

^Ra

^Rb

Where R ^a , R ^b , A and R ^B are described in table. 1, 2, 3 or 4;

R ^e are described in table. 1.

According to some variants of implementation of R ^a , R ^b , A, R ^B and R ^e are described in table. 1.

In some embodiments, the compounds described herein have the following structure, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

Where

R ^a , R ^b , A and R ^B are described in table. 1, 2, 3 or 4.

According to some variants of implementation of R ^a , R ^b , A and R ^B are described in table. 2.

In some embodiments, the compounds described herein have the following structure, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

Where

R ^a , R ^b , A and R ^B are described in table. 1, 2, 3 or 4.

According to some variants of implementation of R ^a , R ^b , A and R ^B are described in table. 3.

In some embodiments, the compounds described herein are characterized by the following structure, or a dimensional mixture or individual enantiomers:

its pharmaceutically acceptable salt, solvate, diastereo-

Where

R ^a , R ^b , A and R ^B are described in table. 1, 2, 3 or 4.

According to some variants of implementation of R ^a , R ^b , A and R ^B are described in table. 4.

Any combination of the groups described above for various variables is contemplated herein. Throughout the description, the groups and their substituents are selected by those skilled in the art to ensure stable moieties and compounds.

Exemplary compounds of formula (I) include those described in the following tables:

- 65 040023

Table 1

^Ra

conn. no. R ^{B Re} A ^{Ra Rb} 1-1 O^NH ₂ Ha Cl nh ₂ ό 3-CHz 5-SNz 1-2 CN X Cl hh ₂ 3-CHz 5- _CH3 1-3 Cl Cl hh ₂ 3-CHz 5-SNz 1-4 ΊΊoxz Cl hh ₂ 3-F 5-SNz 1-5 τι 2=\p W X D? Cl nh ₂ σ 1 (racemic) 3-F 5-SNz 1-6 T X st LL Cl nh ₂ (racemic) 3-F 5-SNz

- 66 040023

1-7 CN _/ X / ^OH ex Cl nh ₂ ό JVV\P 3-F 5-SNz 1-8 O Y--NH HN XX Cl nh ₂ ό ΛΛΛΡ 3-F 5-SNz 1-9 o HN-y Xa z ^nh Ον Cl nh ₂ f 3-F 5-SNz 1-10 O<^/NH ₂ Xx Cl D ^{2 1} Y 1 (racemic) 3-F 5-SNz 1-11 CN /v/ ^OH QT Cl nh ₂ f 3-C1 5-C1 1-12 CN /f/OH i T Cl nh ₂ ό 1 owv* 3-C1 5-SNz 1-13 CX.NH _2XX H nh ₂ φ 3-F 5-SNz 1-14 CX.NH ₂ Xx p/\U\/ H nh ₂ ό uvvv 3-F 5-F

- 67 040023

1-15 ιΑ H nh ₂ F 3-F 5-CONH2 1-16 U-NH HN, to u H nh ₂ ¢) 3-F 5-SNz 1-17 CN L.ON cc H nh ₂ ό 3-F 5- _CH3 1-18 CN cX H nh ₂ ό 3-C1 5-SNz 1-19 CN X/ ^OH cc H nh ₂ ύ 3-C1 5-F 1-20 CN CL H nh ₂ ό 3-F 5-F 1-21 CN 4¾. .OH cc H hh ₂ 3-C1 5-C1 1-22 CN ./X / ^OH XX H nh ₂ ό 3-C1 5-SNz 1-23 I HN _F XX H nh ₂ Q 3-C1 5-SNz

- 68 040023

1-24 “Π nl H NH ₂ ό 3-C1 5-SNz 1-25 And LL Cl c 3-F 5-SNz 1-26 ΟLL Cl nh ₂ (racemic) 3-F 5-SNz 1-27 x. O \ § LL H NH ₂ ό LLLG 3-C1 5-C1 1-28 at" Χλ H nh ₂ ό 3-C1 5-C1 1-29 F CL H nh ₂ Φ 3-C1 5-SNz 1-30 and LL H nh ₂ ύ 3-C1 5-C1 1-31 Οχ,ΝΗ, zOy H °v Z\ ό 3-C1 5-Cl

- 69 040023

1-32 Ο \=\ LL H ³ NH 3-Cl 5-C1 1-33 O LL H T 3-C1 5-C1 1-34 O LL H ^/NH ₂ n 3-Cl 5-C1 1-35 YY^ O ^=/ LL Cl Ti 3-Cl 5-SNz 1-36 CN ίY Cl T 3-Cl 5- _CH3 1-37 Y^T ο \=/ LL Cl ^F 3 ^C \ CT \ ό 3-Cl 5-SNz 1-38 "P /=\P w\ i/ r? Cl O; 2\ \Z NH F 3-Cl 5-SNz 1-39 CN .xL .on i Y Cl o; 3-Cl 5-SNz

- 70 040023

1-40 LL H 3-C1 5-SNz 1-41 νΧ O \=\ LL Cl nh ₂ (racemic) 3-C1 5- _CH3 1-42 I L Cl nh ₂ ό JVVU> 3-C1 5-SNz 1-43 ο^νη ₂ Cl Cl nh ₂ ό 3-C1 5-SNz 1-44 (X N Cl nh ₂ ό ΛΛΛΛ 3-C1 5-SNz 1-45 o V H nh ₂ Φ 3-C1 5-SNz 1-46 yy^ LL H cr 1 3-C1 5-SNz 1-47 T uul LL H 3-C1 5-SNz

- 71 040023

1-48 Ο ^Ζ LL H (racemic) 3-C1 5-CH ₃ 1-49 “Π Q4 H (racemic) 3-C1 5-CH ₃ 1-50 L > AO LL H With 3-C1 5-SNz 1-51 CN OQ H ST 1 (racemic) 3-C1 5-C1 1-52 CN A/ ^He Cl H HN' ^/ ^ ^X | ST 1 (racemic) 3-C1 5-SNz 1-53 r . O % H ΗΝ'^^^ι (racemic) 3-F 5-SNz 1-54 CN .xL >en cc H (racemic) 3-F 5-F

- 72 040023

1-55 CN nV ² H 0' JL (racemic) 3-F 5-F 1-56 CN t H (U JL (racemic) 3-F 5-SNz 1-57 CN% H ΗΝ' ^/Χχ | sU JL (racemic) 3-F 5-F 1-58 CN A H ΗΝ' ^/Χχ | sU JL (racemic) 3-F 5-SNz

Connections in the table. 1 are called

1-1: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-5-fluorobenzamide;

1-2: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-d-imethylphenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-3: 1-[6,7-dichloro-3-(3,5-dimethylphenyl)cinnolin-4-yl]piperidine-4-amine;

1-4: 3-[4-(4-aminopiperidin-1-yl)-7-chl op-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-5-fluorobenzamide;

1-5: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-6: 3-{4-[cis-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-7: 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-2-hydroxybenzonitrile;

- 73 040023

1-8: 5 - [4- (4-aminopiperidin-1 -yl) -7-chloro-3 - (3 -fluoro-5 - methylphenyl) cinnolin-6 yl] -2,3 -dihydro-1 Η- 1,3-benzode iazol-2-one;

1-9: 4-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6 yl]-2,3-dihydro-1 Η- 1,3-benzode iazol-2-one;

1-10: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-11: 3-[4-(4-aminopiperide in-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-12: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

1-13: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide;

1-14: 3-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)cinnolin-6-yl]-5 fluorobenzamide;

1-15: 3-[4-(4-aminopiperide in-1-yl)-6-(3-fluoro-5-methylphenyl)cinnolin-3-yl]-5 fluorobenzamide;

1-16: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro-1 Η-1,3-benzodiazol -2-he;

1-17: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile;

1-18: 3-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-19: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-fluorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-20: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile;

1-21: 3-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ichlorophenyl)cinnolin-6-yl]-2hydroxybenzonitrile;

1-22: 3-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

1-23: 6-[4-(4-Aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-4fluoro-2,3-dihydro-1 Η-1 ,3-benzode iazol-2-one;

1-24: 4-[4-(4-Aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6 fluoro-2,3-dihydro-1 Η -1,3-benzode iazol-2-one;

1-25: 3 - [7-chloro-3 - (3-fluoro-5-methylphenyl) -4- { 4- [(2-fluoroethyl) amino] piperidine-1

- 74 040023 yl } cinnolin-6-yl]-5-fluorobenzamide;

1-26: 3-{4-[trans-4-amino-3-hydroxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-27: 3-[4-(4-aminopiperide in-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

1-28: 6-[4-(4-Aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-4-fluoro2,3-dihydro-1 Η-1,3- benzode iazol-2-one;

1-29: 2-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6fluorophenol;

1-30: 3-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ichlorophenyl)cinnolin-6-yl]-5 fluorobenzamide;

1-31: 3-[3-(3,5-d-ichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1yl}cinnolin-6-yl]-5-fluorobenzamide;

1-32: 3-[3-(3,5-dichlorophenyl)-4-{4-[(3,3,3-trifluoropropyl)amino]piperidin-1yl}cinnolin-6-yl]-5-fluorobenzamide ;

1-33: 3-[3-(3,5-dichlorophenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin6-yl]-5-fluorobenzamide;

1-34: 3 - { 4 - [ 3 - (aminomethyl) azetide in-1 -yl] -3 - (3,5-dichlorophenyl) cinnolin-6-yl } -5 fluorobenzamide

1-35: 3 -[7-chloro-3 -(3-chloro-5-methylphenyl)-4- { 4- [(2-fluoroethyl)amino] piperidin-1 yl} cinnolin-6-yl] -5 - fluorobenzamide;

1-36: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1yl}cinnolin-6-yl]-5- fluoro-2-hydroxybenzonitrile;

1-37: 3-[7-chloro-3-(3-chloro-5-methylphenyl)-4-{4-[(3,3,3trifluoropropyl)amino]piperidin-1-yl}cinnolin-6-yl] -5-fluorobenzamide;

1-38: 3 - [7-chloro-3 - (3-chloro-5-methylphenyl) -4- {4- [(oxetan-3 -yl) amino] piperidin-1 yl} cinnolin-6-yl] - 5-fluorobenzamide;

1-39: 3 - [7-chloro-3 - (3-chloro-5-methylphenyl) -4- { 4- [(oxetan-3 -yl) amino] piperidin-1 yl } cinnolin-6-yl] - 5-fluoro-2-hydroxybenzonitrile;

1-40: 3 - [3 - (3 -chloro-5 -methylphenyl) -4- { 4- [(oxetan-3 -yl) amino] piperidin-1 yl } cinnolin-6-yl] -5 -fluoro- 2-hydroxybenzonitrile;

1-41: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-chloro-5methylphenyl)cinnolin-6-yl}-5-fluorobenzamide;

1-42: 6-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]pyridine-2-carboxamide;

- 75 040023

1-43: 6-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6yl]-5-chloropyridine-2-carboxamide;

1-44: 2-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6yl]pyridine-4-carboxamide;

1-45: 2-[4-(4-aminopiperide in-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6fluoro-3-methylphenol;

1-46: 3-{4-[(3S)-3-aminopiperidin-1-yl]-3-(3-chloro-5-methylphenyl)cinnolin-6-yl}5-fluorobenzamide;

1-47: 3-{4-[(3R)-3-aminopiperidin-1-yl]-3-(3-chloro-5-methylphenyl)cinnolin-6-yl}5-fluorobenzamide;

1-48: 3-{4-[cis-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5methylphenyl)cinnolin-6-yl}-5-fluorobenzamide ;

1-49: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5methylphenyl)cinnolin-6-yl}-5-fluorobenzamide ;

1-50: 3-[3-(3-chloro-5-methylphenyl)-4-{1,7-diazaspiro[3.5]nonan-7-yl}cinnolin-6yl]-5-fluoro-benzamide;

1-51: 3 - { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5d ichlorophenyl) cinnolin-6-yl } -2- hydroxybenzonitrile;

1-52: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-chloro-5methylphenyl)cinnolin-6-yl}-2-hydroxybenzonitrile ;

1-53: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methylphenyl)cinnolin-6-yl}-2-hydroxybenzonitrile ;

1-54: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)cinnolin-6-yl}-2-hydroxybenzonitrile;

1-55: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)cinnolin-6-yl}-4-aminopyridin-3 -carbonitrile;

1-56: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methylphenyl)cinnolin-6-yl}-4-aminopyr idine-3-carbonitrile;

1-57: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)cinnolin-6-yl}-3-aminopyridin-4 -carbonitrile;

1-58: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methylphenyl)cinnolin-6-yl}-3-aminopyridine -4-carbonitrile. In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound as described in Table 1. 1.

- 76 040023

table 2

^Ra

conn. no. R ^B A ^{Ra Rb} 2-1 nh ₂ F 3-F 5-SNz 2-2 CN Ly / ^OH CL nh ₂ F 3-F 5-F 2-3 CN J.OH Oy G i L (racemic) 3-F 5-F 2-4 CNL D ¹ U JL (racemic) 3-F 5-F 2-5 CNL nh ₂ f 3-F 5-F 2-6 Cl νη ₂ f 3-F 5-F 2-7 I nh ₂ f 3-F 5-SNz

- 77 040023

2-8 O HN-V nh ₂ ό llg 3-F 5-SNz 2-9 o _v U-NH HN XX nh ₂ ό ll/\g 3-F 5-SNz 2-10 CN nh ₂ φ 3-F 5-F 2-11 H nh ₂ φ 3-C1 5-C1 2-12 CN ^^ ² 3-F 5-SNz 2-13 CN ^^nh ₂ jZ 3-C1 5-SNz 2-14 O^/ ^NH 2 --NH2 3-F 5-SNz 2-15 CN /L /OH XX (G — ^NH2 N X 3-C1 5-SNz 2-16 CN nh ₂ φ 3-F 5-SNz

- 78 040023

- 79 040023

- 80 040023

- 81 040023

2-38 GL h, o I Η g 3-F 5-SNz 2-39 CN XX + 4+ y l 1 3-F 5-SNz 2-40 X LL ⁿ / /.Ν Ας < — he Λ 3-F 5-SNz 2-41 LL l 3-F 5-SNz 2-42 CN ss / ΝιλΙλΤ 3-F 5-SNz 2-43 CN XX £l 3-F 5-SNz 2-44 χLL Λ 3-F 5-SNz 2-45 CN XX Λ 3-F 5-SNz

- 82 040023

- 83 040023

2-53 1.0CN < XL Η X JiL ^he 3-F 5-SNz 2-54 LL Η X Ν OH "LAAR 3-F 5-SNz 2-55 HN to A Η with 3-F 5-SNz 2-56 Oh CN CL νη ₂ φ 3-F 3-F 2-57 (X o νη ₂ φ 3-F 3-F 2-58 1 .о CN < ώφ νη ₂ racemic 3-F 3-F 2-59 CN CL νη ₂ φ 3-F 3-F 2-60 T . ° X νη ₂ X 1 racemic 3-F 3-F

- 84 040023

- 85 040023

- 86 040023

2-77 CN 0 _x nh ₂ nh ₂ ό 3-F 3-F 2-78 CN [^0 z° hh ₂ 3-F 3-F I JWV' 2-79 CN _XOH nh ₂ ό I 3-F 5: Ah ΝΛΛ(^ LLG 2-80 y" ^hn 1 X' HN^^y A Novl/v* 3-F 5-F racemic O' §-N hh ₂ 2-81 _XOH 0 3-F 5-F 2-82 CN .OH Г T 3-F 5-SNz F hh ₂ 2-83 ^x4 ,NH ύ llg 3-F 5-F NH ₂ I 1 2-84 CN 1^,0 z° F N I 3-F 5-F YY ⁴ racemic

- 87 040023

2-85 °γ ^ΝΗ ; And ΗΝ'^χ cY 1 racemic 3-F 5-F 2-86 V LL νη ₂ Y 3-F 5-F 2-87 Wow O---1 --O νη ₂ ό 3-F 5-F 2-88 /=\ p l o /__/ I νη ₂ Y 3-F 5-SNz 2-89 CN oh ΗΝ^ Ο\Ζ° ϊ <llll racemic 3-F 5-F 2-90 CN .ON Ον ΗΝ^ ύ' ϊ i/WW racemic 3-F 5-SNz 2-91 CN ABOUT ΗΝ ^Ζ ^ /η**' ⁰ ϊ 4LLLR racemic 3-F 5-OSNz

- 88 040023

2-92 CN .-L .OH cc nh ₂ I l/w racemic 3-F 5-F 2-93 IN NH ₂ O I I i/VW racemic 3-F 5-F 2-94 T. O \ nh ₂ X σνύν racemic 3-F 5-F 2-95 T. O \ he g g ¹ & Ϊ *llg racemic 3-F 5-F 2-96 T. O \ d racemic 3-F 5-F 2-97 T. O \ NH ₂ ό'' I • LALG racemic 3-F 5-F 2-98 CN cc NH ₂ cY ¹ I ./VW* 3-F 5-F

- 89 040023

racemic 2-99 ^5λ LL nh ₂ ό 3-F 5-F 2-100 ^5λ LL HN' ^X ^^| 0 1 racemic 3-F 5-F 2-101 ^5λ LL HN \ /Lx ⁰ Ϊ l/w racemic 3-F 5-F 2-102 ^5λ LL D ² 1 b” 1 racemic 3-F 5-F 2-103 ^5λ LL nh ₂ ό 3-F 5-SNz 2-104 ^5λ LL ό'' JL racemic 3-F 5-SNz 2-105 “Π yyL ^§ X 8 ΗΝ^ su •llll racemic 3-F 5-SNz

- 90 040023

2-106 Π X ο I Γ ¹ 1 racemic 3-F 5-SNz 2-107 δ% υ_ νη ₂ % racemic 3-F 5-OSNz 2-108 Π %ο I νη ₂ φ 3-F 5-F 2-109 Τ . Ο LL 1 racemic 3-F 5-F 2-110 Π X" ο I ΗΝ^ X racemic 3-F 5-F 2-111 Τ . ΟX LL Γ ^{2 1} JL racemic 3-F 5-F 2-112 Π %ο I Γ ^{2 1} φ racemic 3-F 5-SNz

- 91 040023

2-113 F Π νη ₂ Γ racemic 3-F 5-OSNz 2-114 § ctL /OH γ Y νη ₂ 3-F 5-F 2-115 cX § r ^N .χ. .° ⁿ ss νη ₂ cj 3-F 5-SNz 2-116 § /C/ ⁰¹⁴ XX νη ₂ ί ¹ 3-F 5-SNz 2-117 .xL .on ίY (Y F νη ₂ 3-F 5-SNz 2-118 Ό § GT yy/ γγ ΗΝ' ^/ ^ς σ JL racemic 3-F 5-SNz 2-119 CN /X /OH γ Y ρ'^ηΥγΥ F νη ₂ ΑγΥ ^Ν ϊ uplg racemic 3-F 5-F

- 92 040023

- 93 040023

2-128 CN .on CQ nh ₂ 3-F 5-F 2-129 07 nh ₂ 3-F 5-F 2-130 Cl nh ₂ y 3-F 5-F 2-131 CN nh ₂ 3-F 5-F 2-132 u_ nh ₂ y 3-F 5-F 2-133 F NH ₂ nh ₂ y 3-F 5-F 2-134 Cl XX F nh ₂ y 3-F 5-F 2-135 Π /C/s ΗΝ'^χ su JL racemic 3-F 5-F

- 94 040023

2-136 Cl .on XX nh ₂ ό 3-F 5-F 2-137 R nh ₂ ό 3-F 5-F 2-138 T. O \ HN^^^ cU 1 racemic 3-F 5-F 2-139 H about XX nh ₂ ό 3-F 5-F 2-140 “Π GXx Y ZI < HN'^^ c racemic 3-F 5-F 2-141 ο _ν y.” ΗΝ _Κ ϊ XX nh ₂ F 3-F 5-F 2-142 y'gy nh ₂ ό wvv> 3-F 5-F 2-143 CN X nh ₂ o yv I •/VW" racemic 3-F 5-F

- 95 040023

- 96 040023

2-151 CN A X Ϊ ιΛΛΛΤ racemic 3-F 5-F 2-152 ABOUT nh ₂ φ 3-F 5-F 2-153 ex % of t ^N^ racemic 3-F 5-F 2-154 J' z About t racemic 3-F 5-F 2-155 / Z% ABOUT T racemic 3-F 5-OSNz 2-156 1 l) Sf ⁿ racemic 3-F 5-OSNz 2-157 F 1 ΝΗ 1 racemic 3-F 5-OSNz

- 97 040023

- 98 040023

- 99 040023

2-174 Η CK / f ό .mi QT nh ₂ ό 3-F 5-OSNz 2-175 .ΝΗ QT νη ₂ ύ 3-F 5-OSNz 2-176 ΞΕ Ο % Η YJ νη ₂ ύ 3-F 5- _CF3 2-177 Ν II Lh ^! νη ₂ ύ 3-F 5-F 2-178 CXI » LL νη ₂ ύ 3-F 5-SNz 2-179 N II f Y F νη ₂ ύ 3-F 5-F 2-180 “P 4ζΗ ^ζ νη ₂ ύ 3-F 5-F 2-181 Cl Γ^Υ™ ² Yy νη ₂ ύ 3-F 5-SNz

- 100 040023

- 101 040023

- 102 040023

- 103 040023

- 104 040023

2-213 A hh ₂ 6 3-F 5-SNz Ju hh ₂ 2-214 1 ό <lSg 3-F 5-SNz HCK-N. / 0 nh _2A . 2-215 rv ^NH O 3-F 5-SNz F X 2-216 C\ X^X ^h _n.h.2 s 3-F 5-SNz XX -OH Ϊ ί hh ₂ 2-217 1l| OS X 3-F 5-SNz racemic N | γ\ nh ₂ A-'°^ 2-218 A Uuvlnr 3-F 5-SNz racemic N 1 _n.h.2 1.0 2-219 /OH f 1 I 3-F 5-SNz H ,1 _F ^Z \/ y racemic

- 105 040023

- 106 040023

- 107 040023

- 108 040023

2-243 4 ΗΝ'^^ su X racemic 3-F 5-F 2-244 G A A \LLLA racemic 3-F 5-F 2-245 su X racemic 3-F 5-F 2-246 I su X racemic 3-F 5-F 2-247 Chl At X racemic 3-F 5-F 2-248 .N. JUN cX su kALLT racemic 3-F 5-F 2-249 \^/ ^ΝΗ 2 ^ν Χ A X racemic 3-F 5-F

- 109 040023

2-250 (J hh ₂ NH ₂ ό 3-F 5-F N 1 2-251 .OH X racemic 3-F 5-F 2-252 N ,NH su liv- 3-F 5-F racemic 2-253 to about ,.04 J ΗΝ' ^χΧ ^| At 3-F 5-F racemic N II ΗΝ' ^Χ ^^| 2-254 c ⁴ .OH X 3-F 5-F racemic HN' ^X ^ ^X | 2-255 O hh ₂ Ilv, 3-F 5-F racemic 2-256 F II .OH 3-F 5-F racemic

- 110 040023

2-257 0 -X HN'^^dr racemic 3-F 5-F 2-258 ί t HN'^^dr X racemic 3-F 5-F 2-259 LL HM^^ dr X racemic 3-F 5-F 2-260 I O % Η A- σ X racemic 3-F 5-F 2-261 r 1f 7 \l 1 A / G dr X racemic 3-F 5-F 2-262 l f j x .NH ₂ j 7^ HN'^^i L racemic 3-F 5-F 2-263 ex N X racemic 3-F 5-F

- 111 040023

.He II ΗΝ^Ο A 2-264 at Ι| X 3-F 5-F racemic nggd . _.ΝΗ ₂ DU 2-265 At σνΙ/ν* 3-F 5-F racemic ξ ΛΑ ΗΝ^ η rV 2-266 G ,νη ₂ X 3-F 5-F racemic ΗΝ'^χ D^° 2-267 ^νη ₂ X 3-F 5-F racemic p^ ΗΝ' ^Χ ^^| D^ 2-268 At νη ₂ X 3-F 5-F racemic 0 ngg D 1 DU 2-269 G /ΝΗ ₂ X 3-F 5-F racemic 2-270 at _χ ΟΗ N X 3-F 5 Me

- 112 040023

racemic 2-271 N HN^^J N X racemic 3-F 5-F OS 2-272 g ^N \ ΗΝ' ^Χ ^^| A racemic 3-F 5-F 2-273 X s n X ΗΝ'^^ι σ' racemic 3-F 5-F 2-274 at ^N \ _NH2 A Ν σνΙ/ν* racemic 3-F 5-F 2-275 With X ΗΝ' ^Χ ^^| /g Ιϊν- racemic 3-F 5-F 2-276 4^ ^NH2 ΗΝ' ^χΧ ^| A CL racemic 3-F 5-F

- 113 040023

- 114 040023

racemic 2-284 A 1 racemic 3-F 5-F 2-285 vA Y ---/ ΖσνχΟ o \ ⁴ I ΗΝ^^| ST 1 Simple enantiomer 3-F 5-F 2-286 SAL V ---/ ΖσνχΟ o \ ⁴ I Simple enantiomer 3-F 5-F 2-287 ^z GH\ Y--if Z^O ζ \ r? & JL Simple enantiomer 3-F 5-F 2-288 ^z CXa Y--Z^O ζ \ r? Simple enantiomer 3-F 5-F 2-289 O— ² Then z? 1 Simple 3-F 5-F

- 115 040023

- 116 040023

Simple enantiomer 2-296 Simple enantiomer 3-F 5-F 2-297 ear I ΗΝ^^ 0' 1 Simple enantiomer 3-F 5-F 2-298 T ° X Simple enantiomer 3-F 5-F 2-299 CN 4¾. .HE XX ΗΝ'^^ X Simple enantiomer 3-F 5-F 2-300 CN .OH χΎ Simple enantiomer 3-F 5-F

Connections in the table. 2 are called:

2-1: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2

- 117 040023 hydroxybenzonitrile;

2-2: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2hydroxybenzonitrile;

2-3: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-hydroxybenzonitrile;

2-4: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}benzonitrile;

2-5:3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile;

2-6: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]phenol;

2-7: 6-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]pyridine-2-carboxamide;

2-8: 4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3d ihydro-1 Η-1,3-benzodiazol -2-he;

2-9: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1 Η-1,3-benzodiazol -2-he;

2-10: 3-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

2-11: 1-[3-(3,5-d-ichlorophenyl)quinolin-4-yl]piperidin-4-amine;

2-12: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}2-hydroxybenzonitrile;

2-13: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}2-hydroxybenzonitrile;

2-14: 3-{4-[3-(aminomethyl)-3-methylazetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5-fluorobenzamide;

2-15: 3-{4-[3-(aminomethyl)-3-methylazetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2-hydroxybenzonitrile;

2-16: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile;

2-17: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}5-fluoro-2-hydroxybenzonitrile;

2-18: 3-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin6-yl)-5-fluoro-2-hydroxybenzonitrile.

2-19: 3 - {4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile ;

2-20: 3 - { 4- [trans-octahydro-1 H-pyrido[3,4-b] morpholin-6-yl]-3 - (3-fluoro-5 - 118 040023 methylphenyl) quinolin-6-yl }-2-hydroxybenzonitrile;

2-21: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-fluorophenyl)quinolin-6-yl}-5fluoro-2-hydroxybenzonitrile;

2-22: 3 - { 4-[3 - (aminomethyl) azetidin-1 -yl] -3 - (3 - chloro-5 - methylphenyl) quinolin-6-yl }

-fluoro-2-hydroxybenzonitrile;

2-23: 3-{4-[3-(aminomethyl)azetide in-1-yl]-3-(3,5-d-ifluorophenyl)quinolin-6-yl}-5fluoro-2-hydroxybenzonitrile;

2-24: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(2 fluoroethyl) amino] methyl } azetidin-1 -yl) quinolin-6-yl ]-2-hydroxybenzonitrile;

2-25: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(propan-2 yl)amino]methyl }azetidin-1-yl)quinoline-6 -yl]-2-hydroxybenzonitrile;

2-26: 3-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin 6-yl)-5-fluorobenzamide;

2-27: 3 - [3 - (3 -fluoro-5 - methylphenyl) -4- (3 - {[(2-methoxyethyl) amino] methyl } azetidin-1 yl) quinolin-6-yl] -5 - fluoro -2-hydroxybenzonitrile;

2-28: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(3 fluoropropyl) amino] methyl } azetidin-1 -yl) quinolin-6-yl] -2-hydroxybenzonitrile;

2-29: 3 - (4- { 3 - [(cyclopropylamino) methyl] azetidin-1 -yl } -3 - (3 -fluoro-5 methylphenyl) quinolin-6-yl) -5-fluoro-2-hydroxybenzonitrile ;

2-30: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(pyrrolidin-1-ylmethyl)azetidin-1yl]quinolin-6-yl]-2-hydroxybenzonitrile ;

2-31: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1 yl}quinolin-6-yl]-2-hydroxybenzonitrile;

2-32: 3-{4-[3-(aminomethyl)azetidin-1-yl]-3-(3-chloro-5-methylphenyl)quinolin-6-yl}5-fluoro-2-hydroxybenzonitrile;

2-33: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(oxetan-3 yl)amino]methyl } azetidin-1 -yl)quinoline-6 -yl]-2-hydroxybenzonitrile;

2-34: 3 - (4- { 3 - [(cyclopentylamino) methyl] azetidin-1 -yl } -3 - (3 -fluoro-5 methylphenyl) quinolin-6-yl) -5-fluoro-2-hydroxybenzonitrile ;

2-35: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-4-ylmethyl)azetide in-1 yl]quinolin-6-yl]-2- hydroxybenzonitrile;

2-36: 3-[3-(3-fluoro-5-methylphenyl)-4-[3-(piperazin-1-ylmethyl)azetide in-1 yl]quinolin-6-yl]-5-fluoro-2- hydroxybenzonitrile;

2-37: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(oxan-4 yl)amino]methyl } azetidin-1 -yl)quinoline-6 -yl]-2-hydroxybenzonitrile;

- 119 040023

2-38: 2-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinoline

6-yl)-6-fluoro-3-methylphenol;

2-39: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(1-methoxy-2-methylpropan-2 yl)amino]methyl}azetidine-1 -yl)quinolin-6-yl]-2-hydroxybenzonitrile;

2-40: 5-fluoro-3 -[3-(3-fluoro-5-methylphenyl)-4-(3-{[(2-hydroxy-2 methylpropyl)amino]methyl }azetidin-1-yl)quinoline -6-yl]-2-hydroxybenzonitrile;

2-41: 5-fluoro-3 - [3 - (3 -fluoro-5 - methylphenyl) -4- (3 - {[(1 -hydroxybutan-2 yl) amino] methyl } azetidin-1 -yl) quinoline -6-yl]-2-hydroxybenzonitrile;

2-42: 3-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1 yl}quinolin-6-yl]-2-hydroxybenzonitrile;

2-43: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(2 hydroxyethyl) amino] methyl } azetidin-1 -yl) quinolin-6-yl ]-2-hydroxybenzonitrile;

2-44: 3 - [4-(3 - {[ethyl (2-hydroxyethyl) amino] methyl } azetidin-1 -yl) -3 - (3 -fluoro-5 methylphenyl) quinolin-6-yl] -5- fluoro-2-hydroxybenzonitrile;

2-45: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(oxolan-3 yl)amino] methyl } azetidin-1 -yl) quinolin-6- yl]-2-hydroxybenzonitrile;

2-46: 3,6-difluoro-2-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidine 1-yl}quinolin-6-yl]phenol;

2-47: 3 - (4- { 3 - [(3,3 -d iftorpyrrolide in-1 -yl) methyl] azetidin-1 -yl } -3 - (3 -fluoro-5 methylphenyl) quinolin-6-yl )-5-fluoro-2-hydroxybenzonitrile;

2-48: 5 -fluoro-3 - [3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(3R) -3 -fluoropyrrolidin-1 yl] methyl } azetidin-1 -yl) quinoline -6-yl]-2-hydroxybenzonitrile;

2-49: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(3 S) -3 -fluoropyrrolidin-1 yl] methyl } azetidin-1 -yl) quinolin-6-yl]-2-hydroxybenzonitrile;

2-50: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-[3-(piperidin-1-ylmethyl)azetidin-1 yl]quinolin-6-yl]-2-hydroxybenzonitrile ;

2-51: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(2 hydroxypropyl) amino] methyl } azetidin-1 -yl) quinolin-6-yl ]-2-hydroxybenzonitrile;

2-52: 2,6-difluoro-4-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidine 1-yl}quinolin-6-yl]phenol;

2-53: 5 -fluoro-3 -[3 - (3 -fluoro-5 -methylphenyl) -4- (3 - {[(3 hydroxypropyl) amino] methyl } azetidin-1 -yl) quinolin-6-yl] -2(methoxymethoxy)benzonitrile;

2-54: 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-{[(3-hydroxypropyl)amino]methyl}azetidin-1-yl)quinolin-6-yl] -2-hydroxybenzonitrile;

- 120 040023

2-55: 4-φτορ-6-[3-(3-fluoro-5-methylphenyl)-4-{3-[(propylamino)methyl]azetidin-1 yl}quinolin-6-yl]-2,3- dihydro-1H-1,3-benzodiazol-2-one;

2-56: 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenoxy}acetic acid;

2-57: 4-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenoxy}butanoic acid;

2-58: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin 6-yl}-2-(methoxymethoxy)benzonitrile;

2-59: 3-{4-[(3R, 4R)-4-aMHHO-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin 6-yl}-2-hydroxybenzonitrile;

2-60: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin 6-yl}-2-hydroxybenzonitrile;

2-61: 3-{4-[(3S,4R)-4-aMHHO-3-methoxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-62: 3-{4-[(3R,4 8)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitr silt;

2-63: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin 6-yl}-5-fluoro-2-hydroxybenzonitrile;

2-64: 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6 cyanophenoxy}ethyl acetate;

2-65: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2hydroxyethoxy)benzonitrile;

2-66: 3-{4-[(3R,4S)-4-amino-3-methoκcipipiperidin-l-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-67: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(1,3 dihydroxypropan-2-yl)oxy ]benzamide;

2-68: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]quinolin 6-yl]-2-hydroxybenzonitrile;

2-69: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2-hydroxybenzonitrile;

2-70: 3 - [4-(4-aminopiperidin-1 -yl)-3 - { 3 -fluoro-5 - [(1E) (methoxyimino)methyl]phenyl}quinolin-6-yl]-2-hydroxybenzonitrile ;

2-71: 3 - [4- (4-aminopiperide in-1 -yl) -3 - { 3 - [(3,3 - difluoroazetidin-1 -yl) methyl] -5 fluorophenyl} quinolin-6-yl] - 2-hydroxybenzonitrile;

2-72: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2-121 040023 methoxyethoxy)benzonitrile;

2-73: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(oxetane )

3-yloxy)benzonitrile;

2-7 4: 1 - [3 - (3,5 -d iftorophenyl) -6- [5 -fluoro-4- (oxetan-3 -yloxy) pyridin-3 yl] quinolin-4-yl] piperidin-4 -amine;

2-7 5: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6 (azetidin-1-yl)pyridine-3- carbonitrile;

2-7 6: 5 - [4- (4-aminopiperidin-1 -yl) -3 - (3,5 -difluorophenyl) quinolin-6-yl] -6 (azetidin-1 -yl) pyridin-3 - carboxamide;

2-7 7: 2-amino-3-[4-(4-aminopiperidin-1-yl)-3-(3,5-d iφτopφenyl)quinolin-6 yl]benzonitrile;

2-7 8: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2(methoxymethoxy)benzonitrile;

2-7 9: 3-[4-(4-aminopiperidin-1-yl)-3-{3-[(ethoxyimino)methyl]-5 fluorophenyl}quinolin-6-yl]-2-hydroxybenzonitrile;

2-80: 6-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-fluoro -2,3-dihydro-1 Η-1,3-benzode andazol-2-one;

2-81: 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-[(methoxyimino)methyl]phenol;

2-82: 3-(4-{3-[(lS)-l-aminopropyl]azetidin-1-yl} -3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5-fluoro-2 -hydroxybenzonitrile;

2-83: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 4,6-difluorophenyl} carbamate;

2-84: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitrile;

2-85: 6-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}pyridin-2- carboxamide;

2-86: N-{2-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}methanesulfonamide;

2-87: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-d iffluorophenyl)quinolin-6-yl]-2-[(2-methoxyethoxy)methoxy]benzonitrile;

2-88: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6(azetidine-1-carbonyl)phenol;

2-89: 3 - {4-[trans-decahydropyrido[3,4-b] [1,4]oxazepin-7-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile ;

- 122 040023

2-90: 3 - {4-[trans-decahydropyrido[3,4-b] [1,4] oxazepin-7-yl]-3 -(3 -φτορ-5 methylphenyl) quinolin-6-yl}- 2-hydroxybenzonitrile;

2-91: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3-fluoro-5 methoxyphenyl)quinolin-6-yl}- 2-hydroxybenzonitrile;

2-92: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline 4-yl]piperidine-3-carbonitrile;

2-93: propan-2-yl-trans-4-amino-1 - [3 - (3,5 - difluorophenyl) -6- (3 - ethynyl-2 hydroxyphenyl) quinolin-4-yl] piperidin-3 - carboxylate;

2-94: cis-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4 yl]piperidine-3-carbonitrile;

2-95: 3-{4-[trans-4-amino-3-(2-hydroxyethoxy)-piperidin-1-yl]-3-(3.5d iffluorophenyl)-quinolin-6-yl}-2-hydroxybenzonitrile;

2-96: 3-{4-[cis-4-amino-3-(2-hydroxyethoxy)piperidin-1-yl]-3-(3.5d iffluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-97: 3 - {4-[trans-4-amino-3 -(2-methoxyethox i)piperid in-1-yl] -3 -(3.5d ifluorophenyl)quinolin-6-yl} -2 -hydroxybenzonitrile;

2-98: 3-{4-[cis-4-amino-3-(2-methoxyethoxy)piperidin-1-yl]-3-(3.5d iffluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile;

2-99: 3-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4.5-difluoro-2-hydroxybenzonitrile;

2-100: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5d ifluorophenyl) quinolin-6-yl} -4, 5-d iftoro-2-hydroxybenzonitrile;

2-101: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3,5 d ifluorophenyl)quinolin-6-yl} -4 ,5-d iftoro-2-hydroxybenzonitrile;

2-102: 3 - { 4-[trans-4-amino-3-methoxypiperidin-1 -yl] -3 - (3.5d ifluorophenyl) quinolin-6-yl } -4,5 -d ifluoro-2-hydroxybenzonitrile ;

2-103: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4.5-difluoro-2-hydroxybenzonitrile;

2-104: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl} -4.5 -d iftor-2-hydroxybenzonitrile;

2-105: 3-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3-fluoro-5 methylphenyl)quinolin-6-yl} - 4,5-d iftoro-2-hydroxybenzonitrile;

2-106: 3 - { 4-[trans-4-amino-3-methoxypiperidin-1 -yl] -3 - (3 -fluoro-5 methylphenyl) quinolin-6-yl } -4,5 -d iftoro-2 -hydroxybenzonitrile;

2-107: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5

- 123 040023 methoxyphenyl) quinolin-6-yl} -4,5-d iftor-2-hydroxybenzonitrile;

2-108: 2-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4,6-difluoro-3-methylphenol;

2-109: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl} -4.6 -d iftor-3-methylphenol;

2-110: 2-{4-[trans-decahydropyrido[3,4-b][1,4]oxazepin-7-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-4, 6-d iftoro-3-methylphenol;

2-111: 2- {4-[trans-4-amino-3-methoxypiperidin-1 -yl] -3 -(3.5 difluorophenyl)quinolin-6-yl} -4,6-d iftoro-3 - methylphenol;

2-112: 2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-4,6-d iftor-3 -methylphenol;

2-113: cis-4-amino-1-[6-(3,5-difluoro-2-hydroxy-6-methylphenyl)-3-(3-fluoro-5 methoxyphenyl)quinolin-4-yl]piperidin- 3-ol;

2-114: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-fluoro-6[(methoxyimino)methyl]phenol;

2-115: 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6[(methoxyimino)methyl]phenol;

2-116: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4 fluoro-6-[(methoxyimino)methyl]phenol ;

2-117: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-3,4difluoro-6-[(methoxyimino)methyl]phenol ;

2-118: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5 methylphenyl)quinolin-6-yl}-4 -fluoro-6-[(1E)-(methoxyimino)methyl]phenol;

2-119: trans-4-amino-1 -[6-(3-cyano-5,6-d ifluoro-2-hydroxyphenyl)-3 -(3,5 difluorophenyl)quinolin-4-yl]piperidin-3 -carbonitrile;

2-120: cis-4-amino-1 -[6-(3-cyano-5,6-d ifluoro-2-hydroxyphenyl)-3 -(3,5 difluorophenyl)quinolin-4-yl]piperidin-3 -carbonitrile;

2-121: trans-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5 methylphenyl)quinolin-4-yl]piperidin- 3-carbonitrile;

2-122: cis-4-amino-1-[6-(3-cyano-5,6-difluoro-2-hydroxyphenyl)-3-(3-fluoro-5 methylphenyl)quinolin-4-yl]piperidine- 3-carbonitrile;

2-123: methyl-M-{2-[4-(4-aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 3,4,6-trifluorophenyl}carbamate ;

2-124: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl] 5-fluoropyridin-4-yl} carbamate;

- 124 040023

2-125: methyl N-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]5-cyanopyridin-4-yl} carbamate;

2-126: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2[(hydroxyimino)methyl]phenyl]quinolin-4-yl]piperidin-4-amine;

2-127: 1-(6-{3-chloro-2-[(hydroxyimino)methyl]phenyl)-3-(3,5difluorophenyl)quinolin-4-yl)piperidine-4-amine;

2-128: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2[(hydroxyimino)methyl]benzonitrile;

2-129: 1-[3-(3,5-d-ifluorophenyl)-6-{3-fluoro-2-[(methoxyimino)methyl]phenyl(quinolin 4-yl]piperidine-4-amine;

2-130: 1-(6-{3-chloro-2-[(methoxyimino)methyl]phenyl (-3-(3,5-difluorophenyl (quinolin 4-yl)piperidin-4-amine;

2-131: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-2-[(1E)(methoxyimino)methyl]benzonitrile;

2-132: 1-{6-[3-(1-Amino-2,2,2-trifluoroethyl)phenyl]-3-(3,5-difluorophenyl)quinolin-4 yl (piperidine-4-amine;

2-133: 1 - {6-[2-(1-amino-2,2,2-trifluoroethyl)-3-fluorophenyl]-3-(3,5difluorophenyl)quinolin-4-yl(piperidin-4-amine;

2-134: 2-[4-(4-aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chloro

3,4-difluorophenol;

2-135: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl(-6-chloro -3,4-difluorophenol;

2-136: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-6-chloro-4-fluorophenol;

2-137: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6 chlorophenol;

2-138: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl(-6-chlorophenol ;

2-139: 1 - { 2-[4-(4-aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-4,6-difluorophenyl (-3-methoxyurea;

2-140: 1 - (2- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl (- 4,6-difluorophenyl)-3-methoxyurea;

2-141: 6-[4-(4-Aminopiperide in-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-chloro

2,3-dihydro-1 Η-1,3-benzode iazol-2-one;

2-142: 5-[4-(4-Aminopiperide in-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-2.3

- 125 040023 dihydro-1,3-benzoxazol-2-one;

2-143: methyl trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate;

2-144: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-6-fluorophenol ;

2-145: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidine-3-carboxylic acid;

2-146: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidine-3-carboxamide;

2-147: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro-4fluoro-2-hydroxybenzonitrile;

2-148: methyl-N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6 yl]-6-cyanophenyl} carbamate;

2-149: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]-M-methylpiperidine-3-carboxamide;

2-150: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6trifluorophenol;

2-151: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]-X,X-dimethylpiperide in-3-carboxamide ;

2-152: 1 - [3 -(3,5-d ifluorophenyl)-6- { 5-fluoro-4- [(hydroxyimino)methyl] pyridin-3 yl} quinolin-4-yl] piper id in-4- amine;

2-153: N-[(2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -6-fluorophenyl)methylidene]hydroxylamine;

2-154: H-[(2-{4-[(trans)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4,6-difluorophenyl)methylidene]hydroxylamine;

2-155: X-[(2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methoxyphenyl)quinolin-6-yl} -6-fluorophenyl)methylidene]hydroxylamine;

2-156: 4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-[3-fluoro-2-(1nimidazol-2-yl)phenyl]-3-( 3-fluoro-5-methoxyphenyl)quinoline;

2-157: 4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-[3-fluoro-2-(1nimidazol-5-yl)phenyl]-3-( 3-fluoro-5-methoxyphenyl)quinoline;

2-158: 3 - { 4-[trans-octahydro-1 H-pyrido[3,4-b] morpholin-6-yl]-3 - (3-fluoro-5 methoxyphenyl) quinolin-6-yl } -4 ,5-d iftoro-2-hydroxybenzonitrile;

2-159: 3 - { 4-[trans-octahydro-1 H-pyrido[3,4-b] morpholin-6-yl]-3 - (3-fluoro-5 methoxyphenyl) quinolin-6-yl } -4 ,5-d iftoro-2-hydroxybenzonitrile;

- 126 040023

2-160: 2-(4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5methoxyphenyl)quinolin-6-yl (-3.4 ,6-trifluorophenol;

2-161: 1-[3-(3-fluoro-5-methoxyphenyl)-6-(2,3,5-trifluoro-6-hydroxyphenyl(quinolin4-yl]piperidin-4-ol;

2-162: 1 - { 3 - [4-(4-aminopiperidin-1 -yl)-3 - (3,5-difluorophenyl) quinolin-6-yl] -5 hydroxypyridin-4-yl (-3-methoxyurea ;

2-163: G{ 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]6-chlorophenyl (-3-methoxyurea;

2-164: D{ 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]4,6-difluorophenyl (-3-methoxyurea;

2-165: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-4,6-difluorophenyl (carbamate;

2-166: 1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl (-3-(3-fluoro-5-methoxyphenyl)quinolin-4-yl)piperidine-4-amine;

2-167: methyl-N-[2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-cyanophenyl (carbamate;

2-168: 1 - (6- { 5 -fluoro-4- [(hydroxyimino) methyl] pyridin-3 -yl (-3- (3 - fluoro-5 methylphenyl) quinolin-4-yl) piperidin-4-amine ;

2-169: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-amine;

2-170: methyl-(trans)-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate;

2-171: methyl-N-f 3 -[4-(4-aminopiperidin-1 -yl)-3 -(3-fluoro-5-methylphenyl)quinolin 6-yl]-5-fluoropyridin-4-yl (carbamate;

2-172: G{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-yl (-3-methoxyurea ;

2-173: methyl-N-f2-[4-(4-aminopiperidin-l-yl)-3-(3-φtor-5-methoxyphenyl)quinolin-6-yl]-6-fluorophenyl (carbamate;

2-174: G{ 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]6-fluorophenyl (-3-methoxyurea;

2-175: N-(2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]6-fluorophenyl(azetidine-1-carboxamide;

2-176: 1-(6-(5 -fluoro-4- [(hydroxyimino)methyl] pyridin-3 -yl (-3 - [3 -fluoro-5 (trifluoromethyl)phenyl]quinolin-4-yl)piperidin- 4-amine;

2-177: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinoline-6

- 127 040023 yl] pyridine-3-carbonitrile;

2-178: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2-amine;

2-179: 2-amino-3 - [4-(4-aminopiperide in-1 -yl)-3 - (3,5-d ifluorophenyl) quinolin-6-yl]

4,5-difluorobenzonitrile;

2-180: methyl-N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-6-cyano-3,4-d-ifluorophenyl} carbamate ;

2-181: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4-amine;

2-182: methyl N-f 3 -[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-5-fluoropyridin-2-yl} carbamate;

2-183: 1 - { 3 - [4-(4-aminopiperidin-1 -yl)-3 - (3 -fluoro-5-methylphenyl) quinolin-6-yl] -5 fluoropyridin-2-yl } -3 - methoxyurea;

2-184: methyl-N-f 3 -[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-5-chloropyride in-4-yl } carbamate;

2-185: methyl-N-f 2-[4-(4-aminopiper idin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-4-cyanophenyl} carbamate;

2-186: 1-{3 - [4-(4-aminopiperidin-1 -yl)-3 -(3-fluoro-5-methylphenyl)quinolin-6-yl] -5 chloropyridin-4-yl} -3 - methoxyurea;

2-187: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]pyridine-3-carbonitrile;

2-188: 1 - [3 - (3,5 -difluorophenyl) -6- { 5 - [(hydroxyimino)methyl] -1 -methyl-1 H-pyrazol4-yl} quinolin-4-yl] piper idine-4 -amine;

2-189: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4cyanophenyl}-3-methoxyurea;

2-190: 3-f4-[(4αS,8αS)-oκtahydro-lH-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl}-2 -hydroxybenzonitrile;

2-191: G { 2- [4- (4-aminopiperidin-1 -yl) -3 - (3,5 - difluorophenyl) quinolin-6-yl] -6 cyano-3,4-difluorophenyl } -3 - methoxy-3-methylurea;

2-192: 1-(6-{5-chloro-4-[(hydroxyimino)methyl]pyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl)piperidin-4-amine;

2-193: 3 - {4-[(4aR, 8αR)-oκτahydro-1 H-pyride o [3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl) -2-hydroxybenzonitrile;

2-194: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2(methoxymethoxy)benzonitrile;

- 128 040023

2-195: 1-[3-(3,5-d-ifluorophenyl)-6-{3-[(hydroxyimino)methyl]pyridin-2yl}quinolin-4-yl]piperide in-4-amine;

2-196: 1-[3-(3,5-d-yfluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-3yl}quinolin-4-yl]piperide in-4-amine;

2-197: methyl A-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-4,6-difluorophenyl} carbamate;

2-198: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl } -3-methoxy-3-methylurea;

2-199: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl} -3,3-dimethylurea;

2-200: 1-[3-(3,5-d-ifluorophenyl)-6-{6-[(hydroxyimino)methyl]pyridin-2-yl}quinolin-4-yl]piperide in-4-amine;

2-201: 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenylmethyl carbonate;

2-202: 1-[3-(3,5-d iflorphenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]-6methylphenyl}quinolin-4-yl]piperidin-4-amine;

2-203: 1-[3-(3,5-d-ifluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-4yl}quinolin-4-yl]piperide in-4-amine;

2-204: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluoro-2-(2-methoxyethoxy)benzonitrile;

2-205: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-6-cyano-3,4-d iforophenyl } carbamate;

2-206: 1 - {2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6cyano-3,4-difluorophenyl} -3 -methoxy-3-methylurea;

2-207: 1-(2-{4-[cis-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-4,6-difluorophenyl) -3-methoxyurea;

2-208: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6cyano-3,4-difluorophenyl} -3 -methylurea;

2-209: methyl-M-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-6-fluorophenyl} carbamate;

2-210: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6fluorophenyl}-3-methoxy-3-methylurea ;

2-211: 1 - [6-(3-amino-1-methyl-1 H-pyrazol-4-yl)-3 -(3-fluoro-5-methylphenyl)quinolin 4-yl] piper idin-4- amine;

2-212: 1 - {4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-1

- 129 040023 methyl-1 H-pyrazol-3 -yl } -3-methoxyurea;

2-213: 4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2[(methoxyimino)methyl]phenol;

2-214: methyl-M-{4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin6-yl]-1-methyl-1H-pyrazole-3 -yl } carbamate;

2-215: 1 - {3 - [4-(4-aminopiperidin-1 -yl)-3 -(3-fluoro-5-methylphenyl)quinolin-6-yl] -4methylpyridine in-2-yl} -3 - methoxyurea;

2-216: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl } -3 - (propan-2-yloxy) urea;

2-217: trans-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5methylphenyl)quinolin-4-yl)-3-methoxypiperidin-4- amine;

2-218: methyl-M-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-6-cyanophenyl ) carbamate;

2-219: cis-3-{4-[4-Amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2-hydroxybenzonitr silt;

2-220: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5-fluoro-2-( 2-methoxyethoxy)benzonitrile;

2-221: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}- 6-[(methoxyimino)methyl]phenol;

2-222: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4cyanophenyl}-3-methoxyurea;

2-223: 1-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluorophenyl}-3-methoxyurea;

2-224: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-2-(2-methoxyethoxy)benzonitrile;

2-225: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(2-methoxyethoxy)benzonitrile;

2-226: 1-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]pyride in-2-yl}-3-methoxyurea;

2-227: cis-4-amino-1 -(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5methylphenyl)quinolin-4-yl)piperidine- 3-ol;

2-228: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl } -3-ethoxyurea;

2-229: 1 - [3 - (3 -fluoro-5 - methylphenyl) -6- { 3 - [(2-methoxyethyl) amino] -1 - methyl-1H- pyrazol-4-yl} quinolin-4-yl ]piperidine-4-amine;

- 130 040023

2-230: N-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]4,6-difluorophenyl}-2-methoxyacetamide;

2-231: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2(cyanomethoxy)benzonitrile;

2-232: cis-3-{4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-5-fluoro-2-(2-methoxyethoxy) benzonitrile;

2-233: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]

4,6-difluorophenyl }-3-(2,2,2-trifluoroethoxy)urea;

2-234: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluoro-M-(2-methoxyethyl)pyridine-2 -amine;

2-235: methyl-M-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-4,6 -difluorophenyl)carbamate;

2-236: 1-(2-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-4,6-difluorophenyl) -3-methoxyurea;

2-237: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4cyano-6-fluorophenyl}-3-methoxyurea ;

2-238: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4cyanophenyl}-3-(2,2,2- trifluoroethoxy)urea;

2-239: 1 - { 3 - [4-(4-aminopiperidin-1 -yl)-3 - (3 -fluoro-5-methylphenyl) quinolin-6-yl] -6methylpyridine in-2-yl } -3 - methoxyurea;

2-240: 1-{4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6yl]phenyl}-3-methoxyurea;

2-241: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-d-ifluorophenyl)quinolin-6-yl]-6-bromo3,4-difluorophenol;

2-242: 5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-[(2methoxyethyl)amino]pyridine-3-carbonitrile ;

2-243: 2- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5d ifluorophenyl) quinolin-6-yl } -6- [(1 E)-(methoxyimino)methyl]phenol;

2-244: 5-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-aminopyridine -3-carbonitrile;

2-245: 4-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-1-methyl-1H -pyrazole-3-amine;

2-246: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl}pyridin-2- amine;

2-247: 2- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5- 131 040023 difluorophenyl) quinolin-6-yl } -4-methylpyridine-3-amine;

2-248: 3 - {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyride in -2-ol;

2-249: 4- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -1 -methyl-1H-pyrazole-5-amine;

2-250: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4methylpyridin-3-amine;

2-251: 2- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -3 -hydroxypyridine-4-carbonitryl;

2-252: 5-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-4 -[(2-methoxyethyl)amino]pyridine-3-carbonitrile;

2-253: N- [(4- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6- yl } -1-methyl-1 H-pyrazol-5 -yl)methylidene] hydroxylamine;

2-254: 5- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -4 -hydroxypyridine-3-carbonitrile;

2-255: 4- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyrimidin- 5-amine;

2-256: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl} -5-fluoropyridine -4-ol;

2-257: 4- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl} -1 -methyl-1H-pyrazole-3-carboxamide;

2-258: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -4 -methylpyridin-3 -ol;

2-259: 3 - {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -5 -fluoropyridin-2-ol;

2-260: N- [(4- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6- yl } -1-methyl-1 H-pyrazol-3 -yl)methylide ee] hydroxylamine;

2-261: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -3 -fluoropyridine-4-carbonitrile;

2-262: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -3 -aminopyridine-4-carbonitrile;

2-263: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyridin- 3 -ol;

2-264: H-[(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5 difluorophenyl)quinolin-6-yl} pyride in-2-yl)methylidene]hydroxylamine;

- 132 040023

2-265: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-5-fluoropyr idine-3-amine;

2-266: 3 - { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -5 - [ (methoxyimino)methyl]pyridine-4-amine;

2-267: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5difluorophenyl)quinolin-6-yl} -5-cyclopropylpyridine -4-amine;

2-268: 4- { 4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -1 - ( oxetan-3-yl)-1 H-pyrazol-5-amine;

2-269: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-[ (methoxyimino)methyl]pyridine-3-amine;

2-270: 3-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6 yl]-2-hydroxybenzonitrile;

2-271: 3-[3-(3,5-difluorophenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6-yl] 2-hydroxybenzonitrile;

2-272: 3 - {4-[trans-octahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -3 -(3,5 difluorophenyl)quinolin-6-yl}-5 -(prop-1-yn-1-yl)pyridine-4-amine;

2-273: 1 - (3 - {4- [trans-octahydro-1 H-pyride o [3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } pyride in-2-yl)-3-methoxyurea;

2-274: 3 - {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl} -5 -ethynylpyridine-4-amine;

2-275: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -4 -chloropyridine-3-amine;

2-276: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -4 -cyclopropylpyridine-3-amine;

2-277: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -4 -ethynylpyr idine-3-amine;

2-278: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -6 -(oxetan-3-yl)phenol;

2-279: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl } -6 -(oxetan-2-yl)phenol;

2-280: 2- {4- [trans-octahydro-1 H-pyride o[3,4-b] morpholin-6-yl] -3 - (3,5 difluorophenyl) quinolin-6-yl} -4 -(oxetan-3-yl)pyr idine-3-amine;

2-281: 2-{4-[trans-octahydro-1H-pyride o[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-4 -(oxetan-2-yl)pyr idine-3-amine;

2-282: 3-amino-2-[3 -(3-fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidine-1

- 133 040023 yl]quinolin-6-yl]pyridine-4-carbonitrile;

2-283: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}pyridin-3-amine;

2-284: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-methoxypyridine- 3-amine;

2-285: 2-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -6 - [(methoxyimino)methyl]phenol;

2-286: 2-{4-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -6 - [(methoxyimino)methyl]phenol;

2-287: 2-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 - [(methoxyimino)methyl]pyridine-3-amine;

2-288: 2-{4-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 - [(methoxyimino)methyl]pyridine-3-amine;

2-289: 2-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -3 -aminopyridine-4-carbonitrile;

2-290: 2-{4-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -3 -aminopyridine-4-carbonitrile;

2-291: (5-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} - 4-aminopyridine-3-carbonitrile;

2-292: (5-{4-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} - 4-aminopyridine-3-carbonitrile;

2-293: 3-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} pyride in -2-amine;

2-294: 3-{4-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} pyride in -2-amine;

2-295: 2-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 -methylpyridine-3-amine;

2-296: 2-{4-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 -methylpyridine-3-amine;

2-297: 2-{4-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 -methylpyridin-3 -ol;

2-298: 2-{4-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -4 -methylpyridin-3 -ol;

2-299: 3-{4-[(4oK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} -5 -fluoro-2-hydroxybenzonitrile;

2-300: 3-{4-[(4oc8,8oc8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-5 -fluoro-2-hydroxybenzonitrile.

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound as described in Table 1. 2.

- 134 040023

Table 3

conn. no. R ^B A ^{Ra Rb} 3-1 pX o LL νη ₂ ό 3-F 5-SNz 3-2 CN i _he νη ₂ 0 t/VW* 3-F 5-SNz 3-3 About HN--ξ Xx / ^ΝΗ XX νη ₂ with "Λ/νν^ 3-F 5-SNz 3-4 ^x^> ^O X νη ₂ 7 3-F 5-SNz 3-5 ο ₄ Y-NH ym χ. νη ₂ ό 3-F 5-SNz

- 135 040023

3-6 CN uS / ^0N XX nh ₂ f 3-C1 5-SNz 3-7 CN OU νη ₂ σννν* 3-F 5-SNz 3-8 F / F / ^he Ou νη ₂ ιΛΛΛΡ 3-F 5-SNz 3-9 O, Xn HN Ha νη ₂ φ 3-F 5-F 3-10 O, )-NH HN Ha ΗΝ^^ι χ ϊ racemic 3-F 5-F 3-11 nA ° uX A ⁿ Ha χ N racemic 3-F 5-SNz 3-12 .0 X X racemic 3-F 5-F

Connections in the table. 3 are called:

3-1: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-5-fluorobenzamide;

- 136 040023

3-2: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-5-fluoro-2-hydroxybenzonitrile;

3-3: 4-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-6-fluoro-2,3-dihydro- 1H-1,3-benzodiazol-2-one;

3-4: 5 - [8-(4-aminopiperidin-1 -yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-2,3-dihydro-1H-1, 3-benzodiazol-2-one;

3-5: 6-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-4-fluoro-2,3-dihydro- 1 Η-1,3-benzode iazol-2-one;

3-6: 3-[8-(4-aminopiperidin-1-yl)-7-(3-chloro-5-methylphenyl)-1,5-naphthyridin-2-yl]5-fluoro-2-hydroxybenzonitrile;

3-7: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-2-hydroxybenzonitrile;

3-8: 2-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-6-fluorophenol.

3-9: 6-[8-(4-aminopiperide in-1-yl)-7-(3,5-difluorophenyl)-1,5-naphthyr idin-2-yl]-4fluoro-2,3-dihydro- 1 Η-1,3-benzode iazol-2-one;

3-10: 6-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5d ifluorophenyl)-1,5-naphthyr idin-2-yl } -4-fluoro-2,3-dihydro-1 Η-1,3-benzodiazol-2-one;

3-11: 4-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3-fluoro-5methylphenyl)-1,5-naphthyride in-2- yl } -6-fluoro-2,3-dihydro-1 Η-1,3-benzodiazol-2-one;

3-12: 4-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5d ifluorophenyl)-1,5-naphthyr idin-2-yl } -1 H,2H, 3H-imidazo[4,5-c]pyridin-2-one.

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound as described in Table 1. 3.

- 137 040023

Table 4

^Ra

conn. no. R ^B Α ^{Ra Rb} 4-1 1 ί si νη ₂ ό 3-F 5-F 4-2 1 ί X νη ₂ ύ 3-F 5-SNz 4-3 about ⁴ τ νη ₂ ό 3-F 5-SNz 4-4 1 if (1 νη ₂ ό 3-C1 5-SNz 4-5 1 x 1 .011 HN^^j ό N Simple enantiomer 3-F 5-SNz 4-6 If HE ΗΝ'^'^ X Simple enantiomer 3-F 5-SNz 4-7 Y Ον ΗΝ'^*^ ό'° X Simple 3-F 5-SNz

- 138 040023

enantiomer 4-8 N /Αχ^° ^Ι\Γ lll Simple enantiomer 3-F 5-SNz XX 4-9 N 1 Αγη i T ΗΝ'^^χ Ut N σννν- Simple enantiomer 3-F 5-F 4-10 h X X-OH /Ax ⁴ Ν ^Ζ σννν- Simple enantiomer 3-F 5-F 4-11 1 f T _1X.NH2 ΗΝ' ^Χ ^^| ST Ν ULLAG Simple enantiomer 3-F 5-F 4-12 1 G T 1x, _NH2 /A\^° llllg simple enantiomer 3-F 5-F

- 139 040023

4-13 N & N Simple enantiomer 3-F 5-F ² 4-14 G GK 4 '^/NH ^{2 X} N ^Z Simple enantiomer 3-F 5-F 4-15 l G T _NH2 br N Simple enantiomer 3-F 5-SNz 4-16 l G b . TJH ₂ /Ν^^ο ^zL- Simple enantiomer 3-F 5-SNz 4-17 l T j. _.NH2 N Simple enantiomer 3-F 5-C1

- 140 040023

4-18 1 G T 1 4 /NH ₂ UUU ΗΝ'^'χ uhh Simple enantiomer 3-F 5-C1 4-19 1 f t 1V/ ^NH2 ΗΝ' ^Χ ^^ Xx Simple enantiomer 3-C1 5-SNz 4-20 1 f T 1 V / ^NH2 <Χ Chlg Simple enantiomer 3-C1 5-SNz 4-21 § /X/NHJ i T ΗΝ' ^χΧΧχ | Xx Simple enantiomer 3-F 5-F 4-22 o /C / ^nh 2 i T Simple enantiomer 3-F 5-F

- 141 040023

4-23 § A ⁿ /X/ ^nh 2 ex N at Simple enantiomer 3-C1 5-CH ₃ 4-24 § yAy ^NH2 ex N y AA Simple enantiomer 3-C1 5-SNz 4-25 N X at Simple enantiomer 3-F 5-F 4-26 ΞΕ Fg Simple enantiomer 3-F 5-F 4-27 (e ^z ΞΕ ΗΝ' ^/ ~Χ| X σνίηρ Simple enantiomer 3-F 5-C1

- 142 040023

4-28 Ν lie Simple enantiomer 3-F 5-C1 4-29 τ 6' AC Simple enantiomer 3-F 5-OSNz 4-30 N σνίνSimple enantiomer 3-F 5-OSNz 4-31 τ G σνν\τ Simple enantiomer 3-C1 5-SNz 4-32 (Х τ σνίπτ Simple enantiomer 3-C1 5-SNz

- 143 040023

4-33 N su Simple enantiomer 3-C1 5-C1 4-34 N OS Simple enantiomer 3-C1 5-C1 4-35 I f' Simple enantiomer 3-F 5-F 4-36 I Simple enantiomer 3-F 5-F 4-37 cm & Ag Simple enantiomer 3-F 5-SNz

- 144 040023

4-38 cm /Αχχ° Simple enantiomer 3-F 5-SNz 4-39 ^Ν _χ ,ΝΗ ₂ ss & ts Simple enantiomer 3-F 5-OSNz 4-40 CM /Αχχ° Simple enantiomer 3-F 5-OSNz 4-41 I ό Simple enantiomer 3-F 5-C1 4-42 CM /Α\χ° JjX Simple enantiomer 3-F 5-C1

- 145 040023

4-43 I & UT Simple enantiomer 3-C1 5-CH ₃ 4-44 I 3-C1 5-SNz Simple enantiomer 4-45 I ΗΝ ^/ ς & 3-C1 5-C1 Simple enantiomer 4-46 I 3-C1 5-C1 Simple enantiomer

Connections in the table. 4 are called:

4-1: 3-[5-(4-Aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2hydroxybenzonitrile;

4-2: 3-[5-(4-aminopiper idin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyr idin-3yl]-2-hydroxybenzonitrile;

4-3: 3-[5-(4-Aminopiper idin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyr idin-3yl]-5-fluoro-2-hydroxybenzonitrile ;

4-4: 3-[5-(4-Aminopiperidin-1-yl)-6-(3-chloro-5-methylphenyl)-1,8-naphthyridin-3-yl]2-hydroxybenzonitrile;

4-5: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5-146 040023 methylphenyl)-1 , 8-naphthyr idin-3 -yl } -2-hydroxybenzonitrile;

4-6: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5 methylphenyl)-1,8 -naphthyr idin-3 -yl } -2-hydroxybenzonitrile;

4-7: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5 methylphenyl)-1,8 -naphthyr idin-3 -yl } -5-fluoro-2-hydroxybenzonitrile;

4-8: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5 methylphenyl)-1,8 -naphthyr idin-3 -yl } -5-fluoro-2-hydroxybenzonitrile;

4-9: 3 - { 5 -[(4aR, 8αR)-oκτahydro-1 H-pyride o[3,4-b]morpholin-6-yl] -6-(3,5 difluorophenyl)-1,8- naphthyr idin-3-yl}-5-fluoro-2-hydroxybenzonitrile;

4-10: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8-naphthyr idin-3-yl}-5-fluoro-2-hydroxybenzonitrile;

4-11: 2-{5-[(4ocR,8ocR)-octahydro-lH-pyrido[3,4-b]morpholin-6-yl]-6-(3-φtor-5 methylphenyl)-1,8- naphthyre idin-3-yl} -3-aminopyr idine-4-carbonitryl;

4-12: 2-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3-fluoro-5 methylphenyl)-1,8 -naphthyr idin-3 -yl } -3 -aminopyr idine-4-carbonitryl;

4-13: 5-{5-[(4otR,8otR)-octahydro-lH-pyrido[3,4-b]morpholin-6-yl]-6-(3,5 difluorophenyl)-1,8-naphthyridine -3 -yl} -4-aminopyridine-3-carbonitrile;

4-14: 5-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-6-(3,5-difluorophenyl)-1,8-naphthyr idin-3-yl } -4-aminopyr idin-3-carbonitrile;

4-15: 2-{5-[(4αR,8ocR)-octahydro-lH-pyrido[3,4-b][l,4]ocazin-6-yl]-6-(3-φtorop-5 methylphenyl) -1,8-naphthyr idin-3 -yl} -3-aminopyr idine-4-carbonitryl;

4-16: 2-{5-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5 methylphenyl )-1,8-naphthyride in-3 -yl } -3-amino pyride in-4-carbonitryl;

4-17: 2-{5-[(4otR,8otR)-octahydro-lH-pyrido[3,4-b][l,4]ocazin-6-yl]-6-(3-chloro-5 fluorophenyl) -1,8-naphthyr idin-3 -yl} -3-aminopyridine-4-carbonitrile;

4-18: 2-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5 fluorophenyl) -1,8-naphthyr idin-3 -yl} -3-aminopyridine-4-carbonitrile;

4-19: 2-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl) -1,8-naphthyride in-3 -yl } -3-amino pyride in-4-carbonitryl;

4-20: 2-{5-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5-methylphenyl) -1,8-naphthyride in-3 -yl } -3-amino pyride in-4-carbonitryl;

4-21: 2-{5-[(4otR,8αR)-oκtaahydro-lH-pyrido[3,4-b][l,4]ocazin-6-yl]-6-(3,5 difluorophenyl)-1 ,8-naphthyr idin-3-yl}-4-[(methoxyimino)methyl]pyridine-3-amine;

4-22: 2-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3.5

- 147 040023 difluorophenyl)-1,8-naphthyridin-3 -yl } -4-[(methoxyimino)methyl] pyridin-3-amine;

4-23: 2-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl}-4-[(methoxyimino)methyl]pyridine-3-amine;

4-24: 2-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl}-4-[(methoxyimino)methyl]pyridine-3-amine;

4-25: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5difluorophenyl)-1, 8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-26: 3-{5-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5difluorophenyl)-1, 8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-27: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5fluorophenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-28: 3-{5-[(4oc8,8oc8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5fluorophenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-29: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5methoxyphenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-30: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5methoxyphenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-31: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-32: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl}-2-hydroxybenzonitrile;

4-33: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5d ichlorophenyl)-1 ,8-naphthyr idin-3-yl }-2-hydroxybenzonitrile;

4-34: 3-{5-[(4a8.8oc8)-octahydro-1H-pyrido[3.4-b][1.4]oxazin-6-yl]-6-(3.5d ichlorophenyl)-1 ,8-naphthyr idin-3-yl }-2-hydroxybenzonitrile;

4-35: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5d ifluorophenyl)-1 ,8-naphthyr idin-3-yl } pyride in-2-amine;

4-36: 3-{5-[(4a8,8oc8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5d ifluorophenyl)-1 ,8-naphthyr idin-3-yl } pyride in-2-amine;

4-37: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5methylphenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-38: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5methylphenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-39: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5-148 040023 methoxyphenyl)-1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-40: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-fluoro-5methoxyphenyl)- 1,8-naphthyr idin-3-yl}pyridine-2-amine;

4-41: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5fluorophenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-42: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5fluorophenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-43: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-44: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3-chloro-5methylphenyl)- 1,8-naphthyr idin-3-yl } pyridine-2-amine;

4-45: 3-{5-[(4aK,8aK)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5dichlorophenyl)-1, 8-naphthyr idin-3-yl } pyride in-2-amine;

4-46: 3-{5-[(4a8,8a8)-octahydro-1H-pyrido[3,4-b][1,4]oxazin-6-yl]-6-(3,5dichlorophenyl)-1, 8-naphthyridin-3-yl}pyridine-2-amine.

In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound as described in Table 1. 4.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, active metabolites of such compounds that exhibit the same type of activity are included within the scope of this disclosure. In addition, the compounds described in the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided in the present invention are also considered as disclosed in the present invention.

As used herein, pharmaceutically acceptable refers to a substance, such as a carrier or diluent, that does not take away the biological activity or properties of a compound and is relatively non-toxic, i.e., the substance was administered to a subject without causing undesirable biological effects or without interacting in an inappropriate manner with any of the components of the composition in which it is contained.

The term pharmaceutically acceptable salt refers to the form of the therapeutically effective agent that consists of the cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts are typically more soluble and more rapidly soluble in the stomach and gastric juice than non-ionic species. , and thus are usable as solid dosage forms. Moreover, since their solubility is often a function of pH, selective dissolution in one or the other part of the gastrointestinal tract is possible and this ability can be controlled as one aspect of extended and sustained release regimens. Also, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (ie the free base form) is basic and reacts with an organic acid or inorganic acid. Inorganic acids include, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, without limitation, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactic acid; gentisin acid 149 040023 slot; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; butyric acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (para) and undecenoic acid.

In some embodiments, the compound of formula (I) is obtained as the chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of formula (I) with a base. In some embodiments, the compound of formula (I) is acidic and reacts with a base. In such cases, the acidic proton of the compound of formula (I) is replaced by a metal ion, for example a lithium, sodium, potassium, magnesium, calcium or aluminum ion. In some cases, the compounds described in the present invention interact with an organic base, such as, without limitation, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other instances, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Suitable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds are provided as the sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt, or ammonium salt.

It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition products. In some embodiments, the solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and they are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol. Solvates of the compounds described in the present invention for the sake of convenience were obtained or formed during the methods described in the present invention. In addition, the compounds of the present invention optionally exist in unsolvated as well as solvated forms.

The methods and compositions described in the present invention include the use of N-oxides (if necessary) or pharmaceutically acceptable salts of compounds characterized by the structure of formula (I), as well as active metabolites of such compounds with one type of activity.

In some embodiments, sites on organic radicals (eg, alkyl groups, aromatic rings) of compounds of formula (I) are susceptible to various metabolic reactions. Inclusion of appropriate substituents on organic radicals will shorten, minimize or eliminate such a metabolic pathway. In particular embodiments, an appropriate substituent for reducing or desensitizing an aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, alkyl group, haloalkyl group, or deuteroalkyl group.

In another embodiment, the compounds described herein are labeled isotopically (eg, with a radioisotope) or by other means, including, without limitation, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein include isotopically labeled compounds which are identical to the compounds set forth in the various formulas and structures provided herein, but with one or more atoms replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, such as, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ³² P, and ³³ P. In one aspect, the isotopically labeled compounds described herein, for example compounds incorporating radioactive isotopes such as ³ H and ¹⁴ C are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic benefits resulting from greater resistance to metabolic inactivation, such as, for example, increased in vivo half-life or altered metabolic pathways to reduce unwanted metabolites, or reduced dosage.

In some embodiments, compounds of formula (I) have one or more stereocenters, and each stereocenter exists independently in any of the R or S configurations. For example, in some embodiments, a compound of formula (I) exists in the R configuration if one stereocenter is present. In other embodiments, the compound of formula (I) exists in the S configuration if one stereocenter is present. In some embodiments, a compound of formula (I) exists in the RR configuration if two stereocenters are present. In some embodiments, a compound of formula (I) exists in the RS configuration if two stereocenters are present. In some embodiments, a compound of formula (I) exists in the SS configuration if two stereocenters are present. In some embodiments, a compound of formula (I) exists in the SR configuration if two stereocenters are present.

The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric and epimeric forms, as well as their respective mixtures. The compounds and methods provided herein include all cis, trans, syn, anti, opposite (E), and one side (Z) isomers, as well as their respective mixtures.

Individual stereoisomers are obtained, if necessary, by methods such as stereoselective synthesis and/or separation of stereoisomers using chiral chromatographic columns or separation of diastereomers using either non-chiral or chiral chromatographic columns or crystallization and recrystallization in an appropriate solvent or mixture of solvents. In certain embodiments, the compounds of formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound/salt pair, separating the diastereomers and reducing the optically pure individual enantiomers. In some embodiments, cleavage of the individual enantiomers of the compounds of formula (I) is carried out using covalent diastereomeric derivatives of the compounds described herein. According to another embodiment, the diastereomers of the compounds of formula (I) are separated by separation/cleavage methods based on differences in solubility. In other embodiments, separation of stereoisomers of compounds of formula (I) was performed by chromatography or by formation of diastereomeric salts and separation by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are prepared by stereoselective synthesis.

Separation of individual enantiomers from a racemic mixture is possible using chiral supercritical liquid chromatography (SFC) or chiral high performance liquid chromatography (HPLC). In some embodiments, the enantiomers described herein are separated from each other using chiral SFC or chiral HPLC. In some embodiments, compounds of formula (I) that include one or more chiral centers (e.g., compounds of formula (I) that include a trans-octahydro-1H-pyrido[3,4-b]morpholine-6 moiety -yl), separated into individual enantiomers using chiral SFC or chiral HPLC. A wide range of conditions and suitable columns are available.

Daicel's polysaccharide chiral stationary phases (CSPs) are present among the columns used for chiral SFC separations. According to some Daicel embodiments, CHIRALPAK and CHIRALCEL HPLC analytical fixed and coated columns can be used for SFC analysis.

In some embodiments, SFC column suitability screening was performed on four main stationary phases (CHIRALPAK IA, IB, IC and ID) and four main coated columns (CHIRALPAK AD and AS and CHIRALCEL OD and OJ) with varying concentrations of organic modifier. A range of column phases are available, including but not limited to OD and OJ, OX and OZ chlorinated phases, and a range of additional CHIRALCEL cellulose based phases including OA, OB, OC, OF, OG and OK.

Non-limiting examples of chiral selectors for use in resolution of enantiomers include tris(3,5-dimethylphenylcarbamate) amylose, tris(3,5-dimethylphenylcarbamate) cellulose, tris(3,5-dichlorophenylcarbamate) cellulose, tris(3-chlorophenylcarbamate) amylose, tris(3-chlorophenylcarbamate) amylose, tris(3,5-dichlorophenylcarbamate), amylose tris(3-chloro,4-methylphenylcarbamate), amylose tris((S)-alpha-methylbenzylcarbamate), amylose tris(5-chloro-2-methylphenylcarbamate), cellulose tris(4- methyl benzoate), tris(4-chloro-3-methylphenylcarbamate) cellulose, and tris(3chloro-4-methylphenylcarbamate) cellulose.

Non-limiting examples of chiral columns contemplated for use in separating enantiomers include CHIRALPAK IA SFC, CHIRALPAK AD-H SFC, CHIRALPAK IB

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SFC CHIRALPAK IC SFC CHIRALPAK ID SFC CHIRALPAK IE SFC CHIRALPAK IF SFC CHIRALPAK AZ-H SFC CHIRALPAK AS-H SFC CHIRALPAK AY-H SFC CHIRALCEL OJ-H SFC CHIRALCEL OX -H SFC and CHIRALCEL OZ-H SFC.

In some embodiments, the compounds described herein are obtained as prodrugs. The term prodrug refers to an agent that is converted to the parent drug in vivo. Prodrugs are often used because they are easier to administer than the parent drug in some situations. They are, for example, bioavailable by oral administration, while the parent drugs are not. Alternatively or alternatively, the prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design enhances effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester (prodrug) but is then metabolically hydrolyzed to provide an active entity. Another example of a prodrug is a short peptide (polyamino acid) linked to an acidic group, the peptide being metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized in one or more steps or one or more processes to the biologically, pharmaceutically or therapeutically active form of the compound.

Prodrugs of the compounds described herein include, without limitation, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, tertiary amine quaternary derivatives, N-Mannich base, Schiff base, amino acid conjugates, phosphoric acid esters and sulfuric acid esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. Design and Application of Prodrugs in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, ether and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (ie, a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are obtained as alkyl ester prodrugs.

Prodrugs of the compounds described herein, wherein the prodrug is metabolized in vivo to provide a compound of formula (I) as set forth herein, are included within the scope of the claims. In some cases, some of the compounds described herein are a prodrug for another derivative or active compound.

In some embodiments, any of the hydroxyl group(s), amino group(s), and/or carboxylic acid group(s) is functionalized(s) in a suitable manner to form a prodrug moiety. In some embodiments, the prodrug moiety is described above.

In accordance with some embodiments, the similarity and position of the substituents in the compounds described herein help to minimize undesirable activity. For example, in accordance with some embodiments, the unwanted activity includes unwanted hERG inhibition. In some embodiments, the presence of a hydroxyl group and an adjacent cyano group on the aromatic ring significantly attenuates undesired inhibition of hERG compared to the absence of both groups, the presence of a hydroxyl group without an adjacent cyano group, or the presence of a cyano group without an adjacent hydroxyl group. For example, in some embodiments, a significant reduction in unwanted hERG inhibition is observed when RB is substituted or unsubstituted 2-hydroxy-3-cyanophenyl.

According to subsidiary or additional embodiments, the compounds described herein are metabolized upon administration to the body in need of production of a metabolite, which is then used to obtain the desired effect, including the desired therapeutic effect.

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The term metabolite of a compound disclosed herein means a derivative of the compound that is formed during the metabolism of the compound. The term active metabolite refers to a biologically active derivative of a compound that is formed during the metabolism of the compound. As used herein, the term metabolizable refers to the sum of processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) in which a particular substance is altered by the body. Thus, enzymes can provide certain structural changes to the compound. For example, cytochrome P450 catalyses a range of oxidative and reductive reactions, while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administering the compounds to the recipient and analyzing tissue samples from the recipient, or by incubating the compounds with liver cells in vitro and analyzing the resulting compounds.

Synthesis of compounds

The compounds of formula (I) described herein were synthesized using standard synthetic procedures or using methods known in the art in combination with the methods described herein.

Unless otherwise noted, traditional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology were used.

Compounds were prepared using standard organic chemistry techniques such as those described, for example, in March's Advanced Organic Chemistry, ^6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for synthesis transformations described herein can be used, such as solvent variations, reaction temperature, reaction time, as well as various chemicals and other reaction conditions.

In some embodiments, the compounds described herein are prepared as described in Scheme A.

Scheme A.

Compound I was obtained by Friedel-Crafts acylation of aniline with arylacetonitrile in the presence of BCl ₃ and AlCl ₃ . led to the formation of compound II. Nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et ₃ N or DIEA resulted in compound III. RB is introduced by an organometallic coupling reaction, such as the Suzuki-Miyaura reaction, with RBB(OH)2 or its boronic acid ester, and then all protecting groups are removed using appropriate deprotection methods, e.g., acid, to give compound IV.

In some other embodiments, the compounds described herein were prepared as described in Scheme B.

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Scheme B.

Commercially available 1-(2-amino-5-bromophenyl)ethanone was treated with NaNO2 in the presence of a strong acid such as HCl to form cinnolin-4-ol, followed by bromination to give compound V. Compound V was converted to compound VI under conditions heating under reflux in the presence of POCl ₃ /PCl ₅ . Nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et ₃ N or DIEA resulted in compound VII. Two sequential but selective Suzuki-Miyaura reactions with R ^B B (OH) ₂ or its boronic acid ester and RA (OH) 2 or its boronic acid ester, and subsequent removal of all protecting groups using appropriate deprotection methods, for example, with the help of an acid, leads to the formation of compound IV. Alkyls, substituted alkyl or oxetanyl for the R ² of compound IV were also introduced via an SN2 reaction or reductive amination if R ² is hydrogen, after deprotection or before deprotection. Alternatively, RA was introduced by a Negishi coupling reaction with an appropriate zinc reagent, or a Buchwald-Hartwig amination, or nucleophilic aromatic substitution with an appropriate cyclic saturated amine in the presence of Et3N.

In some other embodiments, intermediate VIII was synthesized as outlined in Scheme C.

Scheme C.

Compound VII was reacted with bis(pinacolato)diborone in the presence of a palladium catalyst such as Pd ₂ dba ₃ and a ligand such as X-Phos to form the boronic acid ester VIIa followed by selective Suzuki-Miyaura reactions with R ^B X (X = Cl, Br, OTf or I) led to the formation of compound VIII. Scheme B from compound VIII to compound IV gave the final desired compounds.

In some embodiments, the compounds described herein were prepared as described in Scheme D.

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Diagram D.

Xa XI a: cyclic amine, EtsN. b: R ^B B(OH)2, Pd. c: R ^A B(OH)2, Pd. d: deprotection.

e: bis(pinacolato)diborone, Pd, X-Phos, KOAc. f: R ^B X, Pd

Compound IX was converted to compound X by nucleophilic substitution with the appropriate chlorine cyclic amine in the presence of Et ₃ N or DIEA. Using selective Suzuki-Miyaura reactions with R ^b B(OH) ₂ or its boronic acid ester, compound XI was obtained, which was also obtained by a two-sadium sequence by formation of a boronic acid ester (Xa) and selective Suzuki-Miyaura reactions with R ^B X ( X = Cl, Br or I). Suzuki-Miyaura reactions with R ^a (OH) ₂ or its boronic acid ester and deprotection of all protective groups using appropriate deprotection methods, eg acid, gave compound XII.

In some embodiments, the compounds described herein were prepared as described in Scheme E using Compound V as the starting material.

Scheme E.

^{| X} XIII XIV a: cyclic amine, ΕΐβΝ. b: R ^b B(OH)2, Pd. c: R ^A B(OH)2, Pd. d: deprotection

Compound IX was converted to compound XIII by nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et ₃ N or DIEA. Two consecutive but selective Suzuki-Miyaura reactions with R ^B B(OH)2 and R ^a B(OH)2, and subsequent deprotection of all the protecting groups using appropriate deprotection methods, e.g. acid, resulted in the formation of the compound XIV. If necessary, R ² substitution can be introduced into the compound XIII, where R ² represents hydrogen, the compound XIII can react with R 2 X (X=Br, I, OMs, OTf) with a strong base such as NaH. If necessary, R ² substitution can also be introduced into the compound XIV, where R ² represents hydrogen. Reductive amination with an aldehyde or ketone can be carried out with a reducing agent such as NaBH(OAc) ₃ or NaBH 4 to give the R ² substituted compound XIV.

In some embodiments, the compounds described herein were prepared as described in Scheme F.

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Scheme F.

Compound XVI was prepared in a two step sequence by demethylation of compound XV under reflux conditions in 6 N H O and triflate formation with trifluoromethanesulfonic anhydride in the presence of a base. Compound XVI was subjected to a selective Suzuki-Miyaura reaction with R ^B B (OH) 2 or its boronic acid ester to give compound XVII. Compound XVII was converted to compound XVIII by nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et3N. Suzuki-Miyaura reactions with R ^A (OH) 2 or its boronic acid ester and deprotection of all protective groups using appropriate deprotection methods, eg acid, resulted in compound XIX.

In some embodiments, Compound XIX described herein is prepared as described in Scheme G.

Scheme G.

protective groups

Compound XV was converted to compound XX by selective nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et ₃ N and a Suzuki-Miyaura reaction with R ^A (OH) 2 or its boronic acid ester. Compound XXI was prepared in a two-step sequence by demethylation of compound XX under reflux conditions in 6N HCl and triflate formation with trifluoromethanesulfonic anhydride in the presence of a base. Suzuki-Miyaura reactions with R ^B B (OH) 2 and deprotection of all protective groups using appropriate deprotection methods, eg acid, resulted in the formation of compound XIX.

In some embodiments, Compound XIV described herein is prepared as described in Scheme H

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Scheme N.

^{| L} XXII XIV a: cyclic amine, Et ₃ N. b: R ^b B (OH) 2, Pd. c: R ^A B(OH)2, Pd. d: CBr ₄ .PPh ₃ e: R ² R ¹ NH

Compound IX was converted to compound XXII by selective nucleophilic aromatic substitution with the appropriate cyclic amine in the presence of Et ₃ N and two successive but selective Suzuki-Miyaura reactions were performed with ^RB (OH)2 or its boronic acid ester followed by R ^a (OH ) ₂ or its boronic acid ester, and then converting the free alcohol group to bromide or mesylate by well-known methods, then replacing such a group with R2R1NH to obtain compound XIV (if necessary, deprotection at R ^B , R ² or R ¹ can be carried out) .

In some embodiments, the compounds obtained by the above methods were obtained as racemic or diastereomeric mixtures. In some other embodiments, racemic mixtures of compounds have been resolved to obtain optically pure (or optically enriched) isomers using conventional chiral separation techniques such as chiral HPLC, chiral supercritical fluid chromatography (SFC), pseudo-moving bed chromatography (SMB), etc. P.

In some other embodiments, diastereomeric mixtures of compounds have been separated to obtain optically pure (or optically enriched) isomers using crystallization techniques or conventional non-chiral chromatographic techniques such as silica gel chromatography or chiral chromatographic techniques such as chiral HPLC, chiral supercritical liquid chromatography. system (SFC), pseudo-moving bed chromatography (SMB), and the like.

In some embodiments, the compounds described herein were synthesized as described in the examples.

Certain terminology

Unless otherwise noted, the following terms used in this application are characterized by the definitions below. The use of the term including, as well as other forms such as include, includes, and included, is not limited. The section headings used herein are for organizational purposes only and are not intended to limit the subject matter discussed.

As used herein, C1-C _x includes C ₁ -C ₂ , C ₁ -C ₃ . . . C1-C _x . By way of example only, a group denoted as C1-C6 means that there are from one to six carbon atoms in the fragment, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, C1- _C4 alkyl means that the alkyl group contains from one to four carbon atoms, i.e. the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An alkyl group refers to an aliphatic hydrocarbon group. The alkyl group is a branched or straight chain. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms, i.e., C1- _C10 alkyl. In all cases where it occurs, a range of numeric values, such as 1-10, refers to each integer in the represented range; for example, 1-10 carbons means that an alkyl group is composed of 1 carbon, 2 carbons, 3 carbons, and the like, up to and including 10 carbons, although the present definition also covers the occurrence of the term alkyl where not the range of numerical values is indicated. In some embodiments, alkyl is C1C ₆ alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An alkylene group refers to a divalent alkyl radical. Any of the aforementioned monovalent alkyl groups can be alkylene by removing a second hydrogen atom from the alkyl. In some embodiments, the alkylene is C1-C6 alkylene. In other embodiments, the alkylene is C1- _C4 alkylene. Exemplary alkylene groups include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-,

-CH2CH2CH2CH2- and the like. In some embodiments, the alkylene is

-CH2-.

An alkoxy group refers to an (alkyl)O- group, where alkyl is defined herein.

The term alkylamine refers to a -N(alkyl) _x H _y group where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

Hydroxyalkyl refers to alkyl in which one hydrogen atom is replaced by hydroxyl. In some embodiments, the hydroxyalkyl is C1- _C4 hydroxyalkyl. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

Aminoalkyl refers to alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is C1- _C4 aminoalkyl. Exemplary aminoalkyl groups include, but are not limited to -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ and the like.

The term alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group is characterized by the formula -C(R)=CR ₂ where R refers to the remaining moieties of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of the alkenyl group include -CH=CH ₂ , -C (CH ₃ )=CH ₂ , -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ and -CH2CH=CH2.

The term alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkynyl group is characterized by the formula -C=CR, where R refers to the remaining moieties of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, _the alkynyl is selected from ethynyl, propynyl, butynyl, _pentynyl , _hexynyl , and the like. .

The term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from atoms other than carbon atoms, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. Heteroalkyl is attached to the remainder of the molecule at the carbon atom of the heteroalkyl.In one aspect, heteroalkyl is C1- _C6 heteroalkyl.In some embodiments, heteroalkyl is C1-C6-heteroalkyl which includes 1-2 heteroatoms selected from O, N (e.g. , -NH- or -N(C ₁ -C ₄ alkyl)-) and S. In some embodiments, the heteroalkyl is C1-C6-heteroalkyl which includes 1-2 O atoms. In some embodiments, the heteroalkyl is _exemplary heteroalkyls include _, but _are not limited _{to , -CH2OH} , _-CH2OCH3 , _{-CH2OCH2CH3 , -CH2CH2OCH3 , -CH2OCH2CH2} DOS ₃ ,

-CH2CH2OSH2CH2OSH3, -CH2SH, -CT2SCT3, -CH2SCH2CH3, -CH2CH2SCH3, -CH2SCH2CH2SCH3, CH ₂ CH ₂ SCH ₂ CH ₂ SCH ₃ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ -CH ₂ N(CH ₂ CH ₃ ) ₂ and the like. In some embodiments, heteroalkyl is -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₂ OCH ₃ or CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ .

The term aromatic refers to a planar ring with a delocalized π electron system containing 4n+2 π electrons, where n is an integer. The term aromatic includes both carbocyclic aryl (aryl, eg phenyl) and heterocyclic aryl (or heteroaryl or heteroaromatic) groups (eg pyridine). The term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.

The term carbocyclic or carbocycle refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings or heterocycles in which the ring backbone contains at least one atom that is different from the carbon atom. In some embodiments, the carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, the carbocycle is a monocyclic carbocycle. Carbocycles are non-aromatic or aromatic. Non-aromatic carbocycles are saturated or partially unsaturated. In some embodiments, the carbocycle is a bicyclic carbocycle. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

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As used herein, the term aryl refers to an aromatic ring, where each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C ₆ -C ₁₀ aryl. Depending on the structure, the aryl group is monoradical or diradical (ie, an arylene group).

The term cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, where each of the ring-forming atoms (ie, backbone atoms) is a carbon atom. In some embodiments, the cycloalkyls are spirocyclic or bridged compounds. In some embodiments, the cycloalkyls are optionally fused to an aromatic ring and the point of attachment is at a carbon atom that is not an aromatic ring carbon atom. Cycloalkyl groups include groups containing 3 to 10 ring atoms. In some embodiments, the cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, cycloalkyl is C ₃ -C ₆ cycloalkyl.

The term halo or alternatively halogen or halide means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

The term fluoroalkyl refers to alkyl in which one or more hydrogen atoms have been replaced by a fluorine atom. In one aspect, the fluoroalkyl is C ₁ -C ₆ fluoroalkyl.

The term heterocycle or heterocyclic refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, with each heterocyclic group containing from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings containing from 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings containing 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Примерами неароматических гетероциклических групп являются пирролидинил, тетрагидрофуранил, дигидрофуранил, тетрагидротиенил, оксазолидинонил, тетрагидропиранил, дигидропиранил, тетрагидротиопиранил, пиперидинил, морфолинил, тиоморфолинил, тиоксанил, пиперазинил, азиридинил, азетидинил, оксетанил, тиетанил, гомопиперидинил, оксепанил, тиепанил, оксазепинил, диазепинил, тиазепинил , 1,2,3,6tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl , pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3 ,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinoline-2(III)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[ d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolisinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, phthalazinyl , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The above groups are either C-linked (or C-linked) or N-linked where possible. For example, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C attached ). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The terms heteroaryl or alternatively heteroaromatic refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Mo

- 159 040023 nocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8naphthyridine and pteridine. In some embodiments, the heteroaryl contains 0-4 ring N atoms. In some embodiments, the heteroaryl contains 1-4 ring N atoms. In some embodiments, heteroaryl contains 0-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl is C ₁ C ₉ heteroaryl. In some embodiments, the monocyclic heteroaryl is C ₁ -C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C ₆ -C ₉ heteroaryl.

A heterocycloalkyl group refers to a cycloalkyl group in which one or more cycloalkyl backbone atoms are selected from an atom other than carbon, eg oxygen, nitrogen (eg, -NH-, -N(alkyl)-), sulfur, or combinations thereof. In some embodiments, heterocycloalkyl is fused to aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxiranyl, aziridinyl, oxetanyl, oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2,5-dithionyl, pyrrolidin-2 ,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl or thiazolidin-2-onyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, without limitation, monosaccharides, disaccharides, and oligosaccharides. In one aspect, heterocycloalkyl is C ₂ -C ₁₀ heterocycloalkyl. In another aspect, heterocycloalkyl is C4- _C10 heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 02 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

The term bond or simple bond refers to a chemical bond between two atoms or two fragments if the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, if the group described herein is a bond, there is no control group, thus allowing bond formation between the remaining established groups.

The term fragment refers to a particular segment or functional group of a molecule. Chemical moieties are often shown as chemical entities embedded in or attached to a molecule.

The term optionally substituted or substituted means that the control group is optionally substituted with one or more additional group(s) separately and independently selected from halo, -CN, -NH2, -NH(alkyl), -H(alkyl) ₂ . -OH, -CO ₂ H, -CO ₂ alkyl, -C(=O)NH ₂ , -C(=O)NH(alkyl), -C(=O)N(alkyl) ₂ , -S(=O ) ₂ NH ₂ , -S(=O) ₂ NH(alkyl), -S(=O) ₂ N(alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C1-C ₄ - alkyl), -C (= O) NH2, - C (= O) NH (C ₁ -C ₄ alkyl), -C (= O) N (C ₁ -C ₄ -alkyl) ₂ , -S (= O ) ₂ NH ₂ , -S (=O) ₂ NH (C ₁ -C ₄ -alkyl), -S (=O) ₂ N (C ₁ -C ₄ -alkyl) ₂ , C1-C4 alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -fluoroalkyl, C1 -C ₄ -heteroalkyl, C1 -C ₄ -alkoxy, C1 -C ₄ -fluoroalkoxy, -SC ₁ -C ₄ -alkyl, -S (= O) C ₁ -C ₄ -alkyl and -S(=O) ₂ C ₁ -C ₄ -alkyl. In some embodiments, the optional substituents are independently selected from halo, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ . In some embodiments, substituted groups are substituted with one or two preceding groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

Used in the present invention, the term acceptable in relation to the composition, composition or ingredient means not having a permanent adverse effect on the general health of the subject who was treated.

As used herein, the term modulate means interacting with a target either directly or indirectly to change the activity of the target, including, by way of example only, increasing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

As used herein, the term modulator refers to a molecule that interacts with a target, either directly or indirectly. Interactions include, without limitation, agonist, partial agonist, inverse agonist, antagonist, destructor, or combinations thereof. In some embodiments, the modulator is an agonist.

As used herein, the terms administer, administer process, administer, and the like. refer to methods that can be used to effect the delivery of compounds or

- 160 040023 compositions to the desired site of biological action. Such methods include, without limitation, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are aware of administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the terms co-administration or the like encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different route of administration, or at the same or different times.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of the agent or compound to be administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and/or amelioration of the signs, symptoms, or causes of a disease, or some other desired change in the biological system. For example, an effective amount for therapeutic applications is the amount of a composition containing a compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. The appropriate effective amount in any particular case is optionally determined using techniques such as a dose escalation study.

As used herein, the terms enhance or amplify means to increase or prolong either the efficacy or the duration of the desired effect. Thus, in relation to the enhancing effect of therapeutic agents, the term enhancement refers to the ability to increase or prolong either the efficacy or the duration of the effect of other therapeutic agents in the system. As used herein, the term enhancing effective amount refers to an amount suitable to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term pharmaceutical combination means a product that is the result of mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, for example both a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to the patient simultaneously in the form of a single substance or dosage. The term non-fixed combination means that the active ingredients, for example, both a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a joint agent, are administered to the patient as separate substances, either simultaneously, in parallel, or sequentially without any specific time intervals, at This introduction provides an effective content of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

The terms product and kit are used interchangeably.

The term subject or patient includes mammals. Examples of mammals include, without limitation, any member of the class Mammals: humans, non-human primates such as chimpanzees and other narrow-nosed monkeys, and other types of monkeys; farm animals such as cattle, horses, sheep, goats, pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice, guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, the terms treat, process of treatment, or treatment include reducing, alleviating, or alleviating at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as delaying the development of a disease or condition, ameliorating a disease or condition, providing regression of the disease or condition, amelioration of the condition caused by the disease or condition, or suspension of the symptoms of the disease or condition, either prophylactically and/or therapeutically.

Pharmaceutical compositions

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are conventionally formulated using one or more pharmaceutically acceptable inactive ingredients which facilitate the processing of the active compounds into pharmaceutically useful formulations. The appropriate composition depends on the chosen route of administration. Brief descriptions of the pharmaceutical compositions described herein are, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and

- 161 040023

Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical

Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), incorporated herein by reference for such disclosure.

In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, adjuvants, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein may be by any method that delivers the compounds to the site of action. These methods include, without limitation, delivery by enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including cutaneous, skin, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and impairment of the recipient. By way of example only, the compounds described herein may be administered locally to the site in need of treatment, such as by local infusion during surgery, topical application, such as creams or ointments, injection, catheter, or implant. The introduction can also be carried out by direct injection at the site of the diseased tissue or organ.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous medium. or a non-aqueous medium, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

Pharmaceutical compositions that can be used orally include tablets, hard capsules made from gelatin, and soft, stoppered capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be obtained by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in free flowing form such as powder or granules, optionally mixed with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be prepared by shaping in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient from them. All formulations for oral administration should be in dosages suitable for such administration. Hard capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fixed oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings to identify or characterize different dose combinations of the active compound.

In some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, eg, bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type previously described.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain anti-oxidants, buffers, bacteriostatics, and dissolved components that render the formulation isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or carrier vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to ensure that highly concentrated solutions are obtained.

Pharmaceutical compositions may also be formulated as a depot formulation. Such long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds can be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in a suitable oil), or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, lozenges, or gels formulated by conventional means. Such compositions may contain the active ingredient in a flavor base such as sucrose and gum arabic or gum tragacanth.

Pharmaceutical compositions can be administered topically, ie by non-systemic administration. This includes applying a compound of the present invention topically to the epidermis or buccal cavity and instilling such compound into the ear, eye and nose such that the compound does not enter the bloodstream to a significant extent. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or patches and drops suitable for administration to the eye, ear or nose. . For topical administration, the active ingredient may comprise from 0.001 to 10% w/w, for example 1 to 2% by weight of the composition.

Pharmaceutical compositions for administration by inhalation are conveniently delivered by insufflator, pressurized aerosol cans, or other suitable aerosol spray delivery means. The pressurized cylinders may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may take the form of a dry powder composition, for example a powder mixture of a compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder may be administered using an inhaler or insufflator.

It should be appreciated that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art relevant to the type of formulation in question, for example, agents suitable for oral administration, may include flavoring agents.

Dosing routes and treatment regimens

In one embodiment, the compounds of formula (I), or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal for which modulation of somatostatin activity would be effective. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprise administering to said mammal pharmaceutical compositions that include at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, an active metabolite, prodrug or pharmaceutically acceptable solvate, in therapeutically effective amounts.

In certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially relieve at least one of the symptoms of the disease or condition. Amounts effective for such use will depend upon the severity and course of the disease or condition, prior therapy, the health of the patient, weight and response to drugs, and the judgment of the attending physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and/or varying clinical trials.

- 163 040023 dose reduction.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for a particular disease, disorder or condition. Such an amount is defined as a prophylactically effective amount or dose. In this application, the exact amounts also depend on the patient's health, weight, and the like. When used in patients, effective amounts for such use will depend upon the severity and course of the disease or condition, prior therapy, the health of the patient, weight and response to drugs, and the judgment of the attending physician. In one aspect, prophylactic therapies comprise administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, to prevent relapse. symptoms of a disease or condition.

In certain embodiments, if the patient's condition does not improve, then at the physician's discretion, the administration of the compounds is chronic, that is, for an extended period of time, including throughout the life of the patient, to alleviate or otherwise control or limit the symptoms of the disease or condition of the patient. .

After the patient's condition improves, if necessary, a maintenance dose is administered. Then, in specific embodiments, the dosage or frequency of administration, or both, is reduced as a function of symptoms to a level at which improvement in the disease, disorder, or condition is maintained. In certain embodiments, however, intermittent treatment is required on a long-term basis for any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount varies depending on factors such as the particular compound, the disease state and severity, the characteristics (e.g., weight, sex) of the subject or recipient in need of treatment, but is nevertheless determined in accordance with specific circumstances associated with the case, including, for example, the specific agent to be administered, the route of administration, the condition to be treated, and the subject or recipient to be treated.

However, in general, doses used to treat an adult typically range from 0.01 to 2000 mg per day. In one embodiment, the desired dose is conventionally presented as a single dose or divided doses administered simultaneously or at appropriate intervals, eg two, three, four or more sub-doses per day.

In one embodiment, suitable daily dosages for a compound of formula (I), or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg body weight. In some embodiments, daily dosages or amounts of the active ingredient in dosage form are below or above the ranges set forth herein, depending on a number of variables in an individual treatment regimen. In various embodiments, daily and unit dosages will vary depending on a number of variables, including, without limitation, the activity of the compound used, the disease or condition being treated, the route of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

The toxicity and therapeutic efficacy of such therapeutic regimens is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, without limitation, determination of LD ₅₀ and ED ₅₀ . The ratio of dose to toxic and therapeutic effects is the therapeutic index and is expressed as the ratio of LD ₅₀ to ED ₅₀ . In certain embodiments, data obtained from cell culture assays and animal studies is used in formulating a range of therapeutically effective daily dosages and/or a therapeutically effective number of unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is in a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or the number of unit dosages varies within this range depending on the dosage form used and the route of administration used.

According to any of the above aspects, further embodiments are provided wherein an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt (a) thereof is administered systemically to a mammal; and/or (b) administered orally to the mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered to the mammal by injection; and/or (e) administered topically to the mammal; and/or (f) administered to the mammal non-systemically or locally.

According to any of the above aspects, additional embodiments are provided, providing for single administrations of an effective amount of the compound, including additional embodiments, in which (i) the compound is administered once a day; or (ii) with

- 164 040023 unity is administered to a mammal several times within one day.

According to any of the above aspects, further embodiments are provided that provide for multiple administrations of an effective amount of a compound, including further embodiments wherein (i) the compound is administered continuously or intermittently as a single dose; (ii) time intervals between multiple injections are 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday in which administration of the compound is temporarily suspended or the dose of the compound to be administered is temporarily reduced; at the end of drug holidays, dosing of the compound is resumed. According to one embodiment, the length of the drug holiday varies from 2 days to 1 year.

Complex treatment

In some instances, it is expedient to administer at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an excipient (i.e., the excipient alone has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by the patient is enhanced by administering one of the compounds described herein with another agent (which also provides for a therapeutic regimen) that also has a therapeutic benefit.

In one specific embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate various aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administering either therapeutic agent alone.

In any case, with respect to the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the sum of the two therapeutic agents, or the patient experiences a synergistic effect.

For the combination therapeutics described herein, the dosages of the co-administered compounds will vary depending on the type of drug being co-administered, the particular drug being used, the disease or condition being treated, and the like. In additional embodiments, when administered in conjunction with one or more other therapeutic agents, a compound provided herein is administered either simultaneously with one or more other therapeutic agents or sequentially.

In the case of combination therapeutics, multiple therapeutics (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If the administration is simultaneous, then several therapeutic agents, by way of example only, are provided in a single unitary form or in several forms (for example, as a single pill or as two separate pills).

Compounds of formula (I), or a pharmaceutically acceptable salt thereof, as well as combination therapeutic agents, are administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used prophylactically and administered chronically to subjects prone to developing conditions or diseases to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In specific embodiments, a compound described herein is administered as soon as possible after the onset of a disease or condition, identified or suspected, and for the length of time necessary to treat the disease. In some embodiments, the length of time required for treatment varies and the duration of treatment is set to meet the specific needs of each subject.

Examples

Abbreviations:

BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl);

DCE: 1,2-dichloroethane;

DCM: dichloromethane;

DIEA or DIPEA: diisopropylethylamine;

EtOAc: ethyl acetate;

HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

- 165 040023

IPA: isopropyl alcohol;

NBS: N-bromosuccinimide;

NCS: N-chlorosuccinimide;

PTS: para-toluenesulfonic acid;

Pd (amphos)Cl ₂ : bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);

Pd ₂ dba ₃ : tris(dibenzylideneacetone)dipalladium (0);

(pinB) ₂ : bis(pinacolato)diborone;

k.t. or RT: room temperature;

Rt: retention time;

SFC: supercritical liquid chromatography;

SST: somatostatin;

SSTR: somatostatin receptor;

TEA: trimethylamine;

TFA: trifluoroacetic acid;

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

clock: clock;

h or hour: hour.

The following examples are presented for illustrative purposes only and do not limit the scope of the claims presented herein.

Synthesis of compounds

Example 1 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5fluorobenzamide (Compound No. 1-4)

Step 1-1, preparation of 1-(2-amino-5-bromo-4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)-ethanone: To a solution of 1 M BCl ₃ (17.2 ml, 18 mmol , in DCM) in DCE (30 ml) was added 4-bromo-3-chlorophenylamine (3.5 g, 16.9 mmol) under ice-cooling. After stirring for 30 minutes, the mixture was treated successively with (3-fluoro-5-methylphenyl)acetonitrile (5.0 g, 42 mmol) and AlCl ₃ (2.5 g, 18 mmol). The reaction mixture was heated at reflux for 2 days and cooled to room temperature. The reaction was quenched with 2N HCl (16 ml) and stirred for 1 h at 80°C. The reaction was extracted with DCM (2x) and the combined organic layers were dried with anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give the title compound (1.8 g, 30%). MS(M+H)+= 356.1.

Stage 1-2, obtaining 6-bromo-7-chloro-3- (3-fluoro-5-methylphenyl) cinnolin-4-ol:

To a suspension of 1-(2-amino-5-bromo-4-chlorophenyl)-2-(3-fluoro-5-methylphenyl)ethanone (1.7 g, 4.8 mmol) in 5 N HCl (20 mL) at ice-cooling, NaNO ₂ (510 mg, 7.3 mmol) in H 2 O (3 ml) was added slowly. The reaction mixture was stirred for 1.5 h at 85°C and cooled to room temperature. The solids were filtered and the filtered solid was triturated in MeOH to give a fine powder. The solid was filtered again, washed with MeOH and dried to give the title compound (1.1 g, 64%). MS (M+H) += 367.0.

Stage 1-3, obtaining 6-bromo-4,7-dichloro-3-(3-fluoro-5-methylphenyl)-cinnoline:

A mixture of 6-bromo-7-chloro-3-(3-fluoro-5-methylphenyl)-cinnolin-4-ol (1.1 g, 3 mmol) and POCl ₃ (10 ml) was stirred for 2.5 h at 100°C. During the course of the reaction, the heterogeneous solution became a clear solution. The reaction mixture was cooled to room temperature and slowly poured into ice (~40 g) under ice-cooling. The solids were collected, washed with H2O, triturated with MeOH, filtered again and dried to give the title compound (1.1 g, 96%). MS(M+H)+= 385.3.

Step 1-4, Preparation of (1-[6-bromo-7-chloro-3-(3-fluoro-5methylphenyl)cinnolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

6-Bromo-4,7-dichloro-3-(3-fluoro-5-methylphenyl)-cinnoline (0.38 g, 0.98 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (320 mg, 1.6 mmol), triethylamine (0.66 ml, 4.9 mmol) and IPA (6 ml) were filled into a tightly closed tube and the mixture was stirred for 20 h at 130°C. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with 1 N HCl (2x), dried and concentrated. The residue was purified by column chromatography to give the title compound (0.21 g, 39%). MS(M+H)+=549.6.

Step 1-5, Preparation of {1-[6-(3-carbamoyl-5-fluorophenyl)-7-chloro-3(3-fluoro-5-methylphenyl)cinnolin-4-yl]piperidin-4 tert-butyl ester -yl|-carbamic acid:

{1-[6-Bromo-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-4yl]piperidin-4-yl}carbamic acid tert-butyl ester mixture (50 mg, 0.09 mmol) , 3-carbamoyl-5-fluorobenzeneboronic

- 166 040023 acids (25 mg, 0.14 mmol), PdCl ₂ (t-Bu ₂ PPhNMe ₂ ) ₂ (6.5 mg, 0.009 mmol) and K2CO3 (25 mg, 0.18 mmol) in dioxane/H ₂ O (10/1 = 2 ml/0.2 ml) was degassed with N2 for 5 min and then plugged. The reaction mixture was stirred for 1 h at 80°C and cooled to room temperature. The reaction mixture was filtered through a pad of celite and the volatile solvent was removed in vacuo. The residue was immediately purified by column chromatography to give the title compound (30 mg, 54%). MS(M+H)+=608.3.

Step 1-6, Preparation of 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl]-5-fluorobenzamide:

{1-[6-(3-Carbamoyl-5-fluorophenyl)-7-chloro-3-(3-fluoro-5methylphenyl)cinnolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester solution ( 30 mg, 0.049 mmol) and TFA (0.3 ml) in DCM (1.5 ml) were stirred for 1 h at room temperature. After removal of the volatile solvent, the residue was immediately purified using a reverse phase C18 column to give the title compound (15.5 mg, 62%). MS (M+H) += 508.4.

Step 1-7, Preparation of the HCl Salt: The product described in Steps 1-6 was dissolved in dioxane or DCM. The resulting solution was treated with 4 N HCl in dioxane (~2 equiv.) and stirred for 10 min at room temperature. The solution was concentrated under high vacuum to give the final product as the HCl salt.

The following compounds were prepared in a manner similar to that described in Example 1, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 1-1 504.3 1-2 484.4 1-5 526.3 1-6 526.4 1-7 488.4 1-8 503.3 1-9 503.3 1-10 538.5 1-27 508.3 1-28 523.5 1-30 510.5 1-34 496.5

Example 2 3-[4-(4-Aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile (Compound No. 1-18)

Stage 2-1, obtaining 6-bromo-cinnolin-4-ol:

Sodium nitrite solution (1.933 g, 28 .01 mmol) in H2O (5 ml). After stirring at 0° C. for 15 minutes, the reaction solution was heated at 85° C. for 1 hour. The mixture was cooled to rt. and the solid was collected by vacuum filtration and washed with water to give the title compound (3.947 g, 75.1% yield) as a brown solid. MS(M+H)+= 225.2.

Step 2-2, preparation of 3,6-dibromocinnolin-4-ol: To a suspension of 6-bromocinnolin-4-ol (3.947 g, 17.54 mmol) and sodium acetate (2.589 g, 31.57 mmol) in AcOH (25 ml) at 100°C was added a solution of bromine (1.4 ml, 27.16 mmol) in AcOH (18 ml). The mixture was heated at 100° C. for 1 hour. The mixture was cooled to rt. and diluted with water (150 ml). The solids were collected by vacuum filtration and washed with water to give the title compound (5.141 g, 96.5% yield) as a brown solid. MS(M+H)+= 304.9.

Stage 2-3, obtaining 6-bromo-3,4-dichlorocinnoline:

To 3,6-dibromocinnolin-4-ol (3.611 g, 11.88 mmol) were added POCl ₃ (15 ml, 160.5 mmol) and PCl ₅ (2.527 g, 12.14 mmol). The mixture was heated at 120° C. for 2 hours. The mixture was cooled to rt. and poured into ice. The slurry was stirred for about 30 minutes until the solid was crushed.

- 167 040023

The solid was collected by vacuum filtration and washed with water to give the title compound (3.119 g, 94.5% yield) as a brown solid. MS(M+H)+= 279.0.

Step 2-4, Preparation of [1-(6-bromo-3-chlorocinnolin-4-yl)piperidin-4-yl]carbamic acid tert-butyl ester:

Suspension of 6-bromo-3,4-dichlorocinnoline (2.000 g, 7.197 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (2.162 g, 10.79 mmol) and diisopropylethylamine (5.0 ml, 28. 72 mmol) in IPA (20 ml) in a stoppered tube was heated at 120° C. overnight. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (2.117 g, 66.6% yield) as a yellow solid. MS(M+H)+=443.4.

Step 2-5, Preparation of (1-[3-chloro-6-(3-cyano-2methoxymethoxyphenyl)cinnolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

To a mixture of [1-(6-bromo-3-chlorocinnolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.400 g, 0.905 mmol), 2-methoxymethoxy-3-(4.4 ,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile (0.314 g, 1.086 mmol), tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate mixture (molar ratio: 1/1.2) (58.9 mg, 0.0452 mmol) and K ₃ PΟ ₄ Η ₂ Ο (0.834 g, 3.620 mmol) were added THF (6 ml) and water (0.6 ml). The mixture was sparged with N2 for 10 min and then stirred at RT. within 1 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (1x). The combined organics were concentrated to dryness and the residue was purified by silica gel chromatography to give the title compound (0.396 g, 83.6% yield) as a yellow solid. MS (M+H) += 524.3.

Step 2-6, Preparation of (1-[3-(3-chloro-5-methylphenyl)-6-(3-cyano-2methoxymethoxyphenyl)cinnolin-4-yl]piperidin-4-yl-carbamic acid tert-butyl ester :

To {1-[3-Chloro-6-(3-cyano-2-methoxymethoxyphenyl)cinnolin-4-yl]piperidin-4-yl}-carbamic acid tert-butyl ester mixture (50.0 mg, 0.0954 mmol), 3-chloro-5methylphenylboronic acid (19.5 mg, 0.114 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H4)] ₂ Cl ₂ ) (8.1 mg, 10 mol.% ) and K2CO3 (39.6 mg, 0.286 mmol) dioxane (3 ml) and water (0.3 ml) were added in a stoppered tube. The reaction mixture was sparged with N2 (gas) for 10 minutes and then heated at 100°C for 30 minutes. More 3-chloro-5-methylphenylboronic acid (13.0 mg, 0.0763 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H4)] ₂ Cl ₂ ) ( 8.1 mg) and K ₂ coO ₃ (39.6 mg). After sparging N2 (gas) for 5 minutes, the reaction mixture was continued to be heated at 95° C. for another 30 minutes. The mixture was concentrated and purified by silica gel column chromatography and reverse phase C ₁₈ column chromatography ( ^2nd purification). Pure fractions were combined, basified with saturated NaHCO ₃ (aq.) and concentrated to remove MeCN. The aqueous residue was extracted with DCM (2x) and the combined organics were dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give the title compound (34.8 mg, 59.4% yield) as a brown solid. MS(M+H)+=614.3.

Step 2-7, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)-cinnolin-6-yl]-2hydroxybenzonitrile:

To a solution of {1-[3-(3-chloro-5-methylphenyl)-6-(3-cyano-2methoxymethoxyphenyl)cinnolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester (34.8 mg, 0.0567 mmol) in dioxane (0.5 ml) was added 4 N HCl in dioxane (1.0 ml). The mixture was stirred at rt. for 1 h. The solid was collected by vacuum filtration and washed with dioxane and hexane to give the title compound as the 2 HCl salt (25.7 mg, 84.4% yield) as an orange solid. MS(M+H)+=470.5.

The following compounds were prepared in a manner similar to that described in Example 2, substituting with appropriate reagents and substrates as required:

- 168 040023

connection no. MS (M+H) ⁺ 1-11 524.3 1-12 522.4 1-13 474.2 1-14 478.2 1-15 474.2 1-16 469.5 1-17 454.4 1-19 474.3 1-20 458.4 1-21 490.4 1-22 488.4 1-23 503.3 1-24 503.4 1-29 463.2

Example 3 3-[7-Chloro-3-(3-fluoro-5-methylphenyl)-4-{4-(2-fluoroethyl)amino]piperidin-1-yl}cinnoline

6-yl]-5-fluorobenzamide (compound no. 1-25)

Step 3-1, Preparation of 3-[7-chloro-3-(3-fluoro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1yl}cinnolin-6-yl]-5 -fluorobenzamide:

Mixture of 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide (10 mg, 0.019 mmol), 1 -fluoro-2-iodoethane (35 mg, 1.9 mmol) and Et ₃ N (12 ml, 0.08 mmol) in IPA (1.5 ml) were filled into a tightly closed tube, and then stirred overnight at 125°C . After removal of the volatile solvent, the residue was purified by reverse phase C18 column chromatography to give the title compound, which was converted to the HCl salt (3.0 mg, 25%) in a manner similar to that described in Steps 1-7, Example 1. MS (M +H)+= 554.4.

The following compounds were prepared in a manner similar to that described in Example 3, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 1-32 606.3 1-33 556.2

Example 4 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (Compound No. 2-2)

Step 4-1, Preparation of [1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-yl]-carbamic acid tert-butyl ester:

To an anhydrous solution of DMSO (40 ml) of 6-bromo-3,4-dichloroquinoline (14.0 mmol, 3.9 g) was added N,N-diisopropylethylamine (10 ml) and piperidin-4-yl- carbamic acid (2.0 eq., 28 mmol, 5.6 g). N ₂ was bubbled through the reaction solution for 5 minutes and the resulting solution was heated at 140° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 4.0 g of the desired product as a white solid. MS

- 169 040023 (M+H) += 442.6.

Step 4-2A (Method A), Preparation of 1-{3-chloro-6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]quinolin-4-yl}piperidin-4-yl)carbamic acid tert-butyl ester :

To THF (5.0 ml) solution of [1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-yl]carbamic acid tert-butyl ester (1.0 mmol, 440 mg) and 2- (2-Methoxyethoxymethoxy)-3-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (1.4 eq., 1.4 mmol, 460 mg) was added PdCl ₂ dppf (0.1 eq, 0.1 mmol, 75 mg) and KOAc (3.0 eq, 3.0 mmol, 300 mg). N2 was bubbled through the reaction solution for 5 min and 0.5 ml was added. The resulting mixture was heated at 80° C. for 1 hour. By LCMS analysis, conversion of approximately 50% of the starting material to the desired product was observed. Additional 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.4 eq, 1.4 mmol, 460 mg), PdCl ₂ dppf (0.1 equiv., 0.1 mmol, 75 mg) and KOAc (3.0 equiv., 3.0 mmol, 300 mg) and the resulting solution was heated at 80°C for another 2 h The reaction solution was combined with silica gel and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 0.512 g of the desired product as a white solid. MS(M+H)+=567.6.

Step 4-2B (Method B), Preparation of 1-{3-chloro-6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]quinolin-4-yl}piperidin-4-yl)carbamic acid tert-butyl ester :

1) Step 4-2B-1, obtaining tert-butyl ester {1-[3-chloro-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)quinolin- 4-yl]piperidin-4-yl}carbamic acid: Pd ₂ (dba) ₃ (0.05 eq., 0.35 mmol, 323 mg) and Xphos (0.10 eq., 0.70 mmol, 335 mg ) was added to anhydrous dioxane (25 ml). N2 was bubbled through the reaction solution for 5 minutes. [1-(6-Bromo-3chloroquinolin-4-yl)piperidin-4-yl]carbamic acid tert-butyl ester (3.1 g, 7.07 mmol), bis(pinacolato)diborane (1.5 eq. , 10.6 mmol, 2.70 g) and KOAc (3.0 eq., 21.2 mmol, 2.1 g) were added under N2 atmosphere. The reaction solution was heated at 100° C. for 4 hours. Ethyl acetate (50 ml) was added to the reaction mixture and the resulting suspension was filtered. The resulting filtrate was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-40%) to give 2.26 g of tert-butyl ester {1-[3-chloro-6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)quinolin-4yl]piperidin-4-yl}carbamic acid. MS(M+H)+=488.5.

2) Step 4-2B-2, preparation of 1-{3-chloro-6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]quinolin-4-yl}piperidin-4-yl)carbamic acid tert-butyl ester :

To a solution in dioxane (15 ml) of tert-butyl ester {1-[3-chloro-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)quinolin-4- yl]piperidin-4-yl}carbamic acid (2.12 g, 4.34 mmol) and 3-bromo-2-(2-methoxyethoxymethoxy)benzonitrile (1.3 eq., 5.6 mmol, 1.61 g ) PdCl ₂ dppf (0.1 eq, 0.43 mmol, 320 mg) and KOAc (3.0 eq, 13.02 mmol, 1.28 g) were added. N2 was bubbled through the reaction solution for 5 minutes and 1.0 ml of water was added. The reaction solution was heated at 100° C. for 1.5 hours, and it was observed by LCMS analysis that the starting material was completely consumed. The reaction solution was treated with water and brine, dried with Na ₂ SO ₄ , concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 1.34 g of the desired product. MS(M+H)+=567.5

Step 4-3, Preparation of tert-butyl ester (1-[6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl }carbamic acid:

To a solution in dioxane (5 ml) of (1-{3-chloro-6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]quinolin-4-yl}piperidin-4-yl)carbamic acid tert-butyl ester ( 0.5 mmol, 283 mg) was added Pd(amphos)Cl ₂ (0.1 eq., 0.05 mmol, 37 mg), 3,5-difluorophenylboronic acid (3.0 eq., 1.5 mmol, 250 mg) and K2CO3 (4.0 eq., 2.0 mmol, 276 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.5 ml of water was added. The resulting mixture was heated at 95° C. for 0.5 h and complete consumption of starting material was observed by LCMS analysis. The reaction solution was concentrated with silica gel and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 0.170 g of the desired product as a white solid. MS(M+H)+=645.6.

Step 4-4, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2hydroxybenzonitrile:

To a solution in dichloromethane (5.0 ml) of {1-[6-[3-cyano-2-(2methoxyethoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine tert-butyl ester -4-yl}-carbamic acid (170 mg) was added trifluoroacetic acid (2.0 ml) and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction solution was concentrated and purified by C18 reverse phase chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ , extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in ether (2.0 M) to give the final compound as the HCl salt. MS(M+H)+=457.5.

The following compounds were prepared in a manner similar to that described in Example 4, substituting the appropriate reagents and substrates as required.

connection no. Way MS (M+H) ⁺ 2-1 A 453.4 2-3 A 487.5 2-4 A 471.3 2-5 A 441.5 2-6 A 432.4 2-7 IN 456.4 2-8 A 468.2 2-9 A 468.5 2-10 A 475.4 2-12 A 439.4 2-13 A 455.4 2-14 A 473.3 2-15 A 487.3 2-16 A 471.3 2-17 A 457.4 2-19 A 499.4 2-20 A 495.5 2-21 A 477.3 2-22 A 473.2 2-23 A 461.0 2-80 A 532.1

Example 5 3-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2hydroxybenzonitrile (compound no. 3 -2)

Step 5-1, Preparation of [1-(3-chloro-6-methoxy-[1,5]naphthyridin-4yl)piperidin-4-yl]carbamic acid tert-butyl ester:

A suspension of 7,8-dichloro-2-methoxy-[1,5]naphthyridine (1.000 g, 4.364 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (1.311 g, 6.545 mmol) and DIEA (2. 30 ml, 13.2 mmol) in IPA (20 ml) in a stoppered tube was heated at 120°C for 9 hours. Due to unreacted starting material, the reaction was continued for another 9 hours after more piperidine tert-butyl ester was added -4-yl-carbamic acid (1.311 g, 6.545 mmol) and DIEA (2.30 ml, 13.2 mmol) (repeated twice). The reaction was not completed (74% conversion), but stopped. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (1.0 g, 58.0% yield) as a light yellow solid. MS(M+H)+ = 393.2.

Step 5-2, Preparation of tert-butyl ester {1-[3-(3-fluoro-5-methylphenyl)-6-methoxy[1,5]naphthyridin-4-yl]-1-piperidin-4-yl} carbamic acid:

To a mixture of [1-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)piperidin-4yl]carbamic acid tert-butyl ester (1.0 g, 2.53 mmol), 3- fluoro-5-methylphenylboronic acid (0.78 g, 5.06 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ )] ₂ Cl ₂ ) (0.21 g, 0.25 mmol ) and K ₂ CO ₃ (1.05 g, 7.59 mmol) dioxane (20 ml) and water (2 ml) were added in a stoppered tube. The reaction mixture was sparged with N ₂ for 10 min and then heated at 100°C for 1 h. acids (0.78 g, 5.06 mmol), Pd[t-Bu2P(4-NMe2C6H4)]2Cl2) (0.211 g, 0.253 mmol) and K ₂ CO ₃ (1.049 g, 7.590 mmol). The mixture was concentrated and purified by column chromatography on

- 171 040023 silica gel, and then by reverse phase C ₁₈ column chromatography. Pure fractions were combined, basified with saturated NaHCO ₃ (aq.) and concentrated to remove MeCN. The solid from the aqueous residue was collected by vacuum filtration and washed with water to give the title compound (0.8 g, 68.0% yield) as a light yellow solid. MS(M+H)+ =

467.2.

Step 5-3, Preparation of {1-[3-(3-fluoro-5-methylphenyl)-6-hydroxy[1,5]naphthyridin-4-yl]-piperidin-4-yl}-carbamic tert-butyl ester acids:

To {1-[3-(3-fluoro-5-methylphenyl)-6-methoxy-[1,5]naphthyridin-4yl]piperidin-4-yl}carbamic acid tert-butyl ester (0.74 g, 1 .58 mmol) was added 6 N HCl (aq.) (20 ml) and the mixture was heated under reflux for 7 hours, the Mixture was cooled to 0°C and neutralized with solid NaOH. The solid was collected by vacuum filtration to give the de-Boc product (0.47 g) as an off-white solid. MS(M+H)+ = 353.4. To a suspension of the de-Boc product in THF (10 ml) was added TEA (0.19 ml, 1.4 mmol) and Boc ₂ O (0.32 ml, 1.4 mmol). The mixture was stirred at rt. all night long. The mixture was quenched with water and the organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was triturated with MTBE and the solid was collected by vacuum filtration to give the title compound (0.40 g, 58.5% yield) as a white solid. MS(M+H)+ = 453.3.

Step 5-4, preparation of 8-(4-tert-butoxycarbonylaminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)[1,5]naphthyridin-2-yl ester of trifluoromethanesulfonic acid:

To a solution of {1-[3-(3-fluoro-5-methylphenyl)-6-hydroxy[1,5]naphthyridin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (287, 4 mg, 0.64 mmol) in DCM (7 ml) at 0°C was added TEA (0.35 ml, 2.5 mmol) and then slowly added Tf ₂ O (0.21 ml, 1.2 mmol) . The mixture was stirred at 0° C. for 10 minutes. The mixture was quenched with water and the organic layer was separated. The organic layer was concentrated and purified by silica gel column chromatography to give the title compound (151.1 mg, 40.7% yield) as a brown solid. MS(M+H)+ = 585.3.

Step 5-5, Preparation of tert-butyl ester {1-[6-(3-cyano-5-fluoro-2methoxymethoxyphenyl)-3-(3-fluoro-5-methylphenyl)-[1,5]naphthyridine-4- yl]piperidin-4-yl}carbamic acid:

To a mixture of trifluoromethanesulfonic acid 8-(4-tert-butoxycarbonylaminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-[1,5]naphthyridin-2-yl ester (57.8 mg, 0. 0989 mmol), 5-fluoro-2-methoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (60.7 mg, 0.198 mmol), tris( dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (6.4 mg, 0.0049 mmol) and THF was added to ₃ PO ₄ -H ₂ O (91.1 mg, 0.396 mmol) (4 ml) and water (0.4 ml). The mixture was sparged with N2 (gas) for 10 min and then stirred at rt. within 2 h. The organic layer was separated and the aqueous layer was extracted with EtOAc (1x). The combined organics were concentrated to dryness and the residue was purified by silica gel chromatography to give the title compound (82.9 mg, 55.3% yield) as a yellow solid. MS(M+H)+ = 616.6.

Step 5-6, Preparation of 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2yl]-5-fluoro-2-hydroxybenzonitrile:

To the tert-butyl ester 4-yl}-carbamic acid (82.9 mg, 0.134 mmol) was added 4 N HCl in dioxane (2.0 ml). The mixture was stirred at rt. for 1 h. The mixture was concentrated to dryness and the residue triturated with DCM. The solid was collected by vacuum filtration and washed with DCM and hexane to give the title compound as the 2 HCl salt (68.3 mg, 93.7% yield) as a yellow solid. MS(M+H)+ = 472.3.

The following compounds were prepared in a manner similar to that described in Example 5, substituting with appropriate reagents and substrates as required:

Example 6 3-[3-(3,5-Dichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6-yl]-5fluorobenzamide (Compound No. 1- 31)

- 172 040023

Stage 6-1, receiving

3-[3-(3,5-dichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-

yl}cinnolin-6-yl]-5-fluorobenzamide:

A stoppered tube was filled with 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6yl]-5-fluorobenzamide (40 mg, 0.078 mmol), 3-oxetanone (45 mg, 0.62 mmol), NaOAc (7 mg, 0.078 mmol), sodium triacetoxyborohydride (66 mg, 0.31 mmol) and DCM (3 ml). The mixture was stirred overnight at 60°C. The reaction mixture was cooled to rt. and extinguished us. NaHCO ₃ (-1 ml). The reaction mixture was diluted with DCM, washed with H ₂ O, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by reverse phase C18 column chromatography to give the title compound (9 mg, 20%). MS(M+H)+=566.5.

Example 7 3-(4-{3-[(Ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5fluoro-2-hydroxybenzonitrile (Compound No. 2-18)

Step 7-1, Preparation of [1-(6-bromo-3-chloroquinolin-4-yl)-azetidine3-ylmethyl]-carbamic acid tert-butyl ester:

To an anhydrous solution of MeCN (10 ml) of 6-bromo-3,4-dichloroquinoline (2.0 mmol, 0.554 g) was added N,N-diisopropylethylamine (2 ml) and HCl salt of 3-(boc-aminomethyl)azetidine (1, 5 equiv., 3.0 mmol, 0.666 g). The reaction solution was heated at 90° C. for 2 hours. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with water (30 ml) and brine (10 ml). The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 0.6 g of the desired product as an off-white solid. MS(M+H)+=426.0, 428.2.

Step 7-2, Preparation of (1-[3-chloro-6-(3-cyano-5-fluoro-2methoxymethoxyphenyl)quinolin-4-yl]azetidin-3-ylmethyl}carbamic acid tert-butyl ester:

To THF (5.0 mL) a solution of [1-(6-bromo-3-chloroquinolin-4-yl)azetidin3-ylmethyl]carbamic acid tert-butyl ester (1.0 mmol, 427 mg) and 5-fluoro- 2-(2-Methoxyethoxymethoxy)-3-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.3 eq., 1.3 mmol, 412 mg) was added a complex mixture of tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.05 eq., 0.05 mmol, 65 mg) and K ₃ PO ₄ -H ₂ O (3, 0 eq., 3.0 mmol, 691 mg). N ₂ was bubbled through the reaction solution for 5 minutes and 0.5 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour. Complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with EtOAc (50 ml) and washed with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 460 mg of the desired product as an oil foam. MS (M+H) += 527.3.

Step 7-3, Preparation of tert-butyl ester 3-ylmethyl}-carbamic acid:

To a solution in dioxane (3 ml) of {1-[3-chloro-6-(3-cyano-5-fluoro-2methoxymethoxyphenyl)-quinolin-4-yl]-azetidin-3-ylmethyl}-carbamic ester acid (0.3 mmol, 160 mg) was added Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ ] ₂ Cl ₂ ) (0.2 eq., 0.06 mmol, 42 mg), 3- fluoro-5-methylphenylboronic acid (4.0 eq., 1.2 mmol, 186 mg) and K ₂ CO ₃ (5.0 eq., 1.5 mmol, 207 mg). N ₂ was bubbled through the reaction solution for 5 minutes and 0.3 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of the starting material was observed by LCMS. The reaction solution was diluted with ethyl acetate (20 ml) and washed with brine. The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 118 mg of the desired product as a yellow foam. MS(M+H)+=601.4.

Step 7-4, Preparation of tert-butyl ester {1-[6-(3-cyano-5-fluoro-2methoxymethoxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]azetidine-3- ylmethyl}ethylcarbamic

- 173 040023 acids:

To an anhydrous DMF (0.5 ml) and THF (1.0 ml) solution of tert-butyl ester {1-[6-(3cyano-5-fluoro-2-methoxymethoxyphenyl)-3-(3-fluoro-5- methylphenyl)quinolin-4-yl]azetidin-3-ylmethyl}carbamic acid (0.066 mmol, 40 mg) was added sodium hydride (60% dispersion in mineral oil) (4.0 eq., 0.254 mmol, 10.6 mg) and iodoethane (3.0 eq., 0.19 mmol, 0.0164 ml). The resulting solution was stirred at ambient temperature for 0.5 h. Approximately 60% conversion to the desired product was observed by LCMS analysis. Additional sodium hydride (60% dispersion in mineral oil) (4.0 eq., 0.254 mmol, 10.6 mg) and iodoethane (3.0 eq., 0.19 mmol, 0.0164 ml) were added and the reaction mixture stirred for another 1 h. The reaction solution was diluted with ethyl acetate (20 ml) and washed with brine (5 ml). The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-70%) to give 25 mg of the desired product. MS(M+H)+=629.6.

Step 7-5, Obtaining 3-(4-{3-[(ethylamino)methyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5-fluoro-2 -hydroxybenzonitrile:

TFA (0 2 ml). The resulting solution was stirred at ambient temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by reverse phase C18 chromatography eluting with MeCN/water (0-30%). Pure fractions were combined and concentrated to give 20 mg of the desired product as the TFA salt. MS(M+H) ⁺ =485.4.

The following compounds were prepared in a manner similar to that described in Example 6, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-24 503.0 2-25 499.3 2-26 487.5 2-27 515.5 2-28 517.1 2-31 499.1

Example 8 3-[4-(3-Cyclopropylaminomethylazetidin-1-yl)-3-(3-fluoro-5-methylphenyl)-quinolin-6yl]-5-fluoro-2-hydroxybenzonitrile (Compound No. 2-29)

Stage 8-1, obtaining azetidin-3-ylmethanol:

To an anhydrous dioxane (3 ml) solution of 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (5.34 mmol, 1.0 g) was added 4.0 M HCl in dioxane (6 ml) at ambient temperature. The reaction solution was stirred at the same temperature for 2 hours. The reaction mixture was concentrated and dried under high vacuum to give 0.66 g of the HCl salt of the desired product as a colorless oil. This material was used in the next step without further purification.

Step 8-2, Obtaining [1-(6-bromo-3-chloroquinolin-4-yl)azetidin-3-yl]methanol:

To an anhydrous DMSO (25 ml) solution of 6-bromo-3,4-dichloroquinoline (5.0 mmol, 1.38 g) was added N,N-diisopropylethylamine (4 ml) and azetidin-3-yl-methanol HCl salt (0 .9 eq., 4.45 mmol, 560 mg). N ₂ was bubbled through the reaction solution for 5 minutes and the resulting solution was heated at 140° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (0-50%) to give 818 mg of the desired product as a white solid. MS (M+H) ⁺ : 327.3, 329.2.

Step 8-3, Preparation of 3-[3-chloro-4-(3-hydroxymethylazetidin-1-yl)-quinolin-6-yl]-5-fluoro-2methoxymethoxybenzonitrile:

To THF (8.0 ml) a solution of [1-(6-bromo-3-chloroquinolin-4-yl)azetidin-3-yl]methanol (1.58 mmol, 516 mg) and 5-fluoro-2-(2 -methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (1.2 eq., 1.9 mmol, 598 mg) was added a complex mixture of tris (dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.05 eq., 0.078 mmol, 102 mg) and K ₃ PO ₄ -H ₂ O (3.0 eq., 4.73 mmol, 1.10 g). N ₂ was bubbled through the reaction solution for 5 min and

- 174 040023 0.8 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour. Complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate (50 ml) and washed with brine. The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (0~50%) to give 456 mg of the desired product as an off-white solid. MS(M+H) ⁺ =428.3.

Step 8-4, Preparation of 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-hydroxymethylazetidin-1-yl)quinolin-6-yl]-2-methoxymethoxybenzonitrile:

Pd[t- Bu ₂ P(4-NMe ₂ C ₆ H ₄ ) ₂ Cl ₂ ) (0.2 eq., 0.21 mmol, 151 mg), 3-fluoro-5-methylphenylboronic acid (3.0 eq., 3, 2 mmol, 492 mg) and K ₂ CO ₃ (5.0 eq., 5.3 mmol, 735 mg). N2 was bubbled through the reaction solution for 5 minutes and 1.0 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate (40 ml) and washed with brine. The organic layer was dried with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (0~85%) to obtain 314 mg of the desired product as a yellow foam. MS(M+H) ⁺ =502.0.

Step 8-5, Preparation of 3-[4-(3-bromomethylazetidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5fluoro-2-methoxymethoxybenzonitrile:

To a solution in dichloromethane (6 ml) of 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-hydroxymethylazetidin1-yl)-quinolin-6-yl]-2-methoxymethoxybenzonitrile (200 mg , 0.40 mmol) were added tetrabromomethane (1.55 eq., 0.62 mmol, 216 mg) and triphenylphosphine (1.45 eq., 0.58 mmol, 154 mg) at 0°C. The resulting mixture was stirred at ambient temperature for 3 hours and incomplete reaction was observed by LCMS analysis. Additional tetrabromomethane (0.5 eq, 0.21 mmol, 70 mg) and triphenylphosphine (0.48 eq, 0.19 mmol, 50 mg) were added at 0° C. and the reaction solution was stirred at ambient temperature for another 1 h. The reaction mixture was diluted with dichloromethane (40 ml), washed with us. NaHCO ₃ and brine, and dried with Na ₂ SO ₄ . The organics were concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0~40%) to give 151 mg of the desired product as a white foam. MS(M+H) ⁺ =564.4, 566.3.

Step 8-6, Preparation of 3-[4-(3-cyclopropylaminomethylazetidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-methoxymethoxybenzonitrile:

To a MeCN solution (1 ml) of 3-[4-(3-bromomethylazetidin-1-yl)-3-(3-fluoro-5-methylphenyl)-quinolin-6-yl]5-fluoro-2-methoxymethoxybenzonitrile (0. 05 mmol, 29 mg) was added NaHCO ₃ (6.0 eq., 0.3 mmol, 25 mg) and cyclopropylamine (0.1 ml). The resulting mixture was heated at 90°C for 4 h and using LCMS observed the completion of the reaction. The reaction solution was diluted with dichloromethane, washed with sat. NaHCO ₃ and brine and dried with Na ₂ SO ₄ .

The organics were concentrated and purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (0~10%) to give 18 mg of the desired product as a yellow oil. MS(M+H) ⁺ =541.5.

Step 8-7, Preparation of 3-[4-(3-cyclopropylaminomethylazetidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile:

Trifluoroacetic acid (0.2 ml). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by reverse phase C18 chromatography eluting with MeCN/water (0~30%). Pure fractions were combined and concentrated to give 13 mg of the desired product as the TFA salt. MS(M+H) ⁺ =497.5.

Example 9 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-pyrrolidin-1-ylmethylazetidin-1-yl)quinolin6-yl]-2-hydroxybenzonitrile (compound no. 2- thirty)

Step 9-1, Preparation of 1-[6-(3-cyano-5-fluoro-2-methoxymethoxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]azetidin-3-ylmethyl ester methanesulfonic acid:

To anhydrous THF (2 ml) solution of 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-hydroxymethylazetidin-1-yl)quinolin-6-yl]-2-methoxymethoxybenzonitrile (step 8-4, 0.19 mmol, 95 mg) was added

- 175 040023 triethylamine (2.2 eq., 0.42 mmol, 0.058 ml) and methanesulfonyl chloride (2.2 eq., 0.42 mmol, 0.032 ml) at ambient temperature. After 1 h, the reaction solution was diluted with ethyl acetate, washed with us. NH4Cl and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-70%) to give 79 mg of the desired product as a yellow oil. MS(M+H)+=580.2.

Step 9-2, Preparation of 5-fluoro-3-[3-(3-fluoro-5-methylphenyl)-4-(3-pyrrolidin-1-ylmethylazetidin-1yl)-quinolin-6-yl]-2-hydroxybenzonitrile:

To a DMF solution (1.5 ml) of 1-[6-(3-cyano-5-fluoro-2-methoxymethoxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]-azetidin-3- ylmethyl ester of methanesulfonic acid (39 mg, 0.069 mmol) was added pyrrolidine (20 eq., 1.4 mmol, 0.11 ml). The resulting mixture was heated at 80° C. for 1.5 h and complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate, washed with sat. NaHCO ₃ and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with methanol/dichloromethane (0-20%). Pure fractions were combined and concentrated with H0 in EtOEt (2.0 M, 1 mL) to give 12.2 mg of the desired product as a yellow solid. MS(M+H) ⁺ =511.6.

Example 10 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2-hydroxyethoxy)benzonitrile (Compound No. 2-65)

Step 10-1, Preparation of {1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

To DCM (20 ml) suspension of HCl salt of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)-quinolin-6yl]-2-hydroxybenzonitrile (2-2) (2, 0 mmol, 1.06 g) were added triethylamine (4.0 eq., 8.0 mmol, 1.14 ml) and di-tert-butyl dicarbonate (1.1 eq., 2.2 mmol, 0.51 ml) at ambient temperature. After 1 h, the reaction solution was diluted with ethyl acetate, washed with water and dried over MgSO ₄ . The organic layer was concentrated and dried under high vacuum to give 1.10 g of the desired product as a yellow powder. This material was used in the next step without further purification. MS(M+H) ⁺ =557.2.

Step 10-2, preparation of 2-{2-[4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}acetic acid ethyl ester:

To a DMF solution (2.0 ml) of tert-butyl ester {1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}- carbamic acid (112 mg, 0.20 mmol) was added K ₂ CO ₃ (2.0 eq., 0.4 mmol, 52 mg) and ethyl-2-bromoacetate (5.5 eq., 1.1 mmol, 0 .12 ml). The resulting mixture was heated at 80° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 68 mg of the desired product. MS(M+H) ⁺ =643.5.

Step 10-3, Preparation of {1-[6-[3-cyano-2-(2-hydroxyethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4 tert-butyl ester -yl}carbamic acid:

To a THF solution (1.0 ml) of 2-{2-[4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}ethyl ester acetic acid (68 mg, 0.11 mmol) was added MeOH (0.5 ml) and aqueous NaOH (4.0 M, 0.5 ml). The resulting mixture was stirred at ambient temperature for 0.5 h and complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated to give 68 mg of the desired product. This material was used in the next step without further purification. MS(M+H) ⁺ =601.6.

Step 10-4, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2hydroxyethoxy)benzonitrile:

To MeOH solution (0.2 ml) of tert-butyl ester {1-[6-[3-cyano-2-(2hydroxyethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin- 4-yl}-carbamic acid HCl in dioxane (4.0 M, 1.5 ml) was added. The resulting mixture was stirred at ambient temperature for 0.5 h and complete consumption of starting material was observed by LCMS analysis. MTBE (5 ml) was added to the oil to recover the desired product and the clear layer decanted. The resulting oil was concentrated with EtOH to give the desired product as a yellow solid. MS(M+H) ⁺ =501.3.

- 176 040023

Example 11 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}acetic acid (Compound No. 2-56)

Step 11-1, Preparation of (2-[4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy)acetic acid tert-butyl ester:

To a DMF solution (1.0 ml) of {1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamic tert-butyl ester acid (56 mg, 0.10 mmol) was added K ₂ CO ₃ (5.0 eq., 0.5 mmol, 70 mg) and tert-butyl bromoacetate (2.0 eq., 0.2 mmol, 0.04 ml ). The resulting mixture was heated at 80° C. for 0.5 h and complete consumption of starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 30 mg of the desired product. MS(M+H)+=671.6.

Step 11-2, preparation of 2-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenoxy}acetic acid:

To a dichloromethane (1.0 ml) solution of {2-[4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-3(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy} tert-butyl ester acetic acid (30 mg), trifluoroacetic acid (0.3 ml) was added and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography eluting with MeCN/water (0-40% ). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in ether (2.0 M) to give 1.6 mg of the final compound as the HCl salt. MS(M+H)+=515.4.

The following compounds were prepared in a manner similar to that described in Example 11, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-57 543.3 2-67 549.6 2-72 515.5 2-73 513.4 2-204 529.3 2-231 496.6

The compound of example 2-67 was obtained using compound 2-73 with an excess of hydrogen chloride.

Example 12 cis-3-{4-[4-Amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2hydroxybenzonitrile (Compound No. 2-60)

Step 12-1, obtaining cis-4-aminopiperidin-3-ol:

To a dioxane (1.0 ml) solution of cis-4-amino-1-boc-3-hydroxypiperidine (1.0 mmol, 216 mg) was added HCl in dioxane (4.0 M, 2.0 ml). The resulting mixture was stirred at ambient temperature for 0.5 h and complete consumption of starting material was observed by LCMS analysis. The reaction solution was concentrated to give 160 mg of the HCl salt of the desired product. This material was used in the next step without further purification. MS(M+H)+= 117.2.

Step 12-2, Preparation of cis-4-amino-1-(6-bromo-3-chloroquinolin-4-yl)-piperidin-3-ol: To anhydrous DMSO (2.0 ml) solution of 6-bromo-3, 4-dichloroquinoline (0.6 mmol, 170 mg) was added N,N-diisopropylethylamine (0.4 ml) and cis-4-aminopiperidin-3-ol HCl salt (1.16 eq., 130 mg, 0.69 mmol). N ₂ was bubbled through the reaction solution for 5 minutes and the resulting solution was heated at 135° C. for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by C18 reverse phase chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organics were concentrated and dried under high vacuum to give mg of the desired product as a white solid. MS(M+H)+= 356.1, 358.1.

Step 12-3, obtaining cis-3-[4-(4-amino-3-hydroxypiperidin-1-yl)-3-chloroquinolin-6-yl]-2methoxymethoxybenzonitrile:

2-(2- methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (1.5 eq., 0.2 mmol, 58 mg), tris(dibenzylideneacetone) mixture ) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.1 eq., 0.014 mmol, 14 mg), K ₃ PO ₄ -H ₂ O (3.0 eq., 0.42 mmol, 97 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.2 ml of water was added. The resulting mixture was stirred at ambient temperature for 0.5 h and 70% conversion to the desired product was observed by LCMS analysis. 2-(2methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.75 eq., 0.1 mmol, 29 mg) was added, a mixture of tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.05 eq., 0.007 mmol, 7 mg) and K ₃ PO ₄ -H ₂ O (1.5 eq. , 0.21 mmol, 45 mg) and the reaction mixture was stirred under N ₂ for another 0.5 h. Complete consumption of the starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated to give a crude product which was used in the next step without further purification. MS(M+H)+=439.4.

Step 12-4, obtaining cis-3-[4-(4-amino-3-hydroxypiperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]-2-methoxymethoxybenzonitrile:

To a dioxane (1.5 ml) solution of the crude material from step 12-3 was added Pd(amphos)Cl ₂ (0.02 mmol, 14 mg), 3,5-difluorophenylboronic acid (0.5 mmol, 75 mg) and K2CO3 (0.5 mmol, 70 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.15 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organics were concentrated and dried under high vacuum to give 26 mg of the desired product as a yellow solid. MS(M+H)+=517.4.

Step 12-5, Obtaining cis-3-(4-[4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile:

Cis-3-[4-(4-amino-3-hydroxy-piperidin-1-yl)-3-(3,5-difluorophenyl)-quinolin-6-yl]-2-methoxymethoxybenzonitrile (24 mg) was combined with 4 .0 M HCl in dioxane (1.0 ml) and MeOH (0.1 ml). The resulting mixture was stirred at ambient temperature for 0.5 h. MTBE (1.5 ml) was added and a solid precipitated, which was collected after filtration. The resulting solid was purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO3 and NaCl, extracted with ethyl acetate and dried over MgSO4. The organics were concentrated and dried under high vacuum to give 26 mg of the desired product as a yellow solid. MS(M+H)+=473.3.

The following compounds were prepared in a manner similar to that described in Example 12, substituting appropriate reagents and substrates as required, with or without step 12-5:

connection no. MS (M+H) ⁺ 2-58 517.4 2-61 487.5 2-62 531.3 2-63 491.3 2-66 487.5 2-219 487.5

Example 13 1-[3-(3,5-Difluorophenyl)-6-[5-fluoro-4-(oxetan-3-yloxy)pyridin-3-yl]quinolin-4yl]piperidin-4-amine (Compound No. 2-74)

- 178 040023

Step 13-1, Preparation of [1-(3-bromo-6-chloroquinolin-4-yl)piperidin-4-yl]-carbamic acid tert-butyl ester:

To an anhydrous DMSO (40 mL) solution of 3-bromo-4,6-dichloroquinoline (10.0 mmol, 2.77 g) was added N,N-diisopropylethylamine (10 mL) and piperidin-4-yl- carbamic acid (2.0 eq., 20.0 mmol, 4.0 g). N ₂ was bubbled through the reaction solution for 5 min and the resulting solution was heated at 135° C. for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 2.84 g of the desired product as a white solid. MS (M+H)+= 440.4, 442.4.

Step 13-2, Preparation of {1-[6-chloro-3-(3,5-difluorophenyl)quinolin4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

3.5- difluorophenylboronic acid (1.5 eq, 4.23 mmol, 677 mg), tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.05 eq, 0.07 mmol, 75 mg), K ₃ RO ₄ -H ₂ O (3.0 eq., 4.2 mmol, 1.95 g). N2 was bubbled through the reaction solution for 5 minutes and 1.0 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour and 75% conversion to the desired product was observed by LCMS analysis. Additional 3,5-difluorophenylboronic acid (0.75 eq., 2.11 mmol, 340 mg), tris(dibenzylideneacetone)dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) (0.025 eq. ., 0.035 mmol, 37 mg) and K ₃ PO ₄ -H ₂ O (1.5 eq., 2.1 mmol, 0.97 g) and the reaction mixture was stirred at ambient temperature for another 1 h. diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 1.12 g of the desired product as a white solid. MS(M+H) ⁺ =474.2.

Step 13-3, Preparation of tert-butyl ester {1-[3-(3,5-difluorophenyl)-6-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)quinoline -4-yl]piperidin-4-yl}carbamic acid:

To a dioxane (15 ml) solution of {1-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester (0.9 g, 1.5 ml) 9 mmol) was added Pd ₂ (dba) ₃ (0.05 eq., 0.09 mmol, 87 mg), Xphos (0.10 eq., 0.19 mmol, 91 mg), bis(pinacolato)diborane (2 .0 eq., 3.8 mmol, 965 mg) and KOAc (3.0 eq., 5.1 mmol, 560 mg). N2 was bubbled through the reaction solution for 5 minutes and the resulting mixture was heated at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 0.87 g of the desired product as a white solid. MS(M+H) ⁺ =566.5.

Step 13-4 Preparation of tert-butyl ester (1-{3-(3,5-difluorophenyl)-6-[5-fluoro-4(oxetan-3-yloxy)pyridin-3-yl]quinolin-4-yl }piperidin-4-yl)carbamic acid:

To a THF solution (1.0 ml) of tert-butyl ester {1-[3-(3,5-difluorophenyl)-6-(4,4,5,5tetramethyl-[1,3,2]dioxaborolane-2- yl)quinolin-4-yl]piperidin-4-yl}carbamic acid (0.1 mmol, 56 mg) was added 3-bromo-5-fluoro-4-(oxetan-3-yloxy)pyridine (1.2 eq. , 0.12 mmol, 30 mg), a mixture of tris (dibenzylideneacetone) dipalladium / tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1 / 1.2) (0.05 eq., 0.005 mmol, 6.5 mg), K ₃ RO ₄ -H ₂ O (3.0 eq., 0.3 mmol, 69 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.1 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NH ₄ Cl, NaHCO ₃ and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 18 mg of the desired product as a white solid. MS(M+H) ⁺ =607.2.

Step 13-5, Preparation of 1-{3-(3,5-difluorophenyl)-6-[5-fluoro-4-(oxetan-3-yloxy)pyridin-3yl]quinolin-4-yl}piperidin-4-ylamine :

To a solution in dichloromethane (0.5 ml) of tert-butyl ester (1-{3-(3,5-difluorophenyl)-6-[5fluoro-4-(oxetan-3-yloxy)pyridin-3-yl]quinoline -4-yl}piperidin-4-yl)carbamic acid (18 mg)

- 179 040023 trifluoroacetic acid (0.3 ml) was added and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 7 mg of the final compound. MS (M+H) ⁺ = 507.4.

The following compounds were prepared in a manner similar to that described in Example 13, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-75 497.5 2-76 515.5 2-77 456.6 2-132 513.3 2-181 462.2 2-241 548.2

The following compounds were prepared in a manner similar to that described in Example 13 using appropriate substrates and reagents. For example, the Suzuki coupling reaction described in Step 13-4 was carried out using Pd(amphos)Cl ₂ as a catalyst in the presence of K ₂ CO ₃ in dioxane/water with heating at 100° C. and the Boc protecting group was removed with HCl or TFA:

connection no. MS (M+H) ⁺ 2-141 506.3 2-142 473.1 2-169 446.3 2-99 493.3 2-177 457.4 2-178 446.4 2-179 492.3 2-187 453.3 2-211 431.5 2-250 446.0 2-229 489.4 2-234 504.2 2-242 511.5

Example 14 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2hydroxybenzonitrile (Compound No. 2-69 )

Step 14-1, Preparation of {1-[6-chloro-3-(3-fluoro-5hydroxyphenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

To a THF solution (10 mL) of [1-(3-bromo-6-chloroquinolin-4yl)piperidin-4-yl]carbamic acid tert-butyl ester (from step 13-1) (660 mg, 1.50 mmol) 3-fluoro-5hydroxyphenylboronic acid (1.5 eq., 2.25 mmol, 351 mg), tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate mixture (molar ratio: 1/1.2) (0.05 eq. ., 0.075 mmol, 75 mg) and K ₃ PO ₄ H ₂ O (3.0 eq., 4.5 mmol, 1.03 g). N ₂ was bubbled through the reaction solution for 5 minutes and 1.0 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour and complete conversion to the desired product was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 561 mg of the desired product as a white solid. MS (M+H) ⁺ = 472.3.

Step 14-2, Preparation of (1-[6-(3-cyano-2-methoxymethoxyphenyl)3-(3-fluoro-5-hydroxyphenyl)quinolin-4-yl]piperidin-4-yl}carbamic tert-butyl ester acids:

- 180040023

To a dioxane (4 ml) solution of {1-[6-chloro-3-(3-fluoro-5hydroxyphenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester (0.64 mmol, 300 mg) was added Pd(amphos)Cl ₂ (0.10 eq., 0.064 mmol, 45 mg), 2-methoxymethoxy-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolane-2 -yl)benzonitrile (1.5 eq., 1.0 mmol, 289 mg) and K ₂ CO ₃ (1.5 eq., 1.0 mmol, 138 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.4 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 400 mg of the desired product as a yellow solid. MS(M+H)+=599.5.

Step 14-3, Preparation of tert-butyl ester (1-{6-(3-cyano-2-methoxymethoxyphenyl)3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-4-yl} piperidin-4-yl)carbamic acid:

To a DMF solution (1.0 ml) of tert-butyl ester {1-[6-(3-cyano-2-methoxymethoxyphenyl)3-(3-fluoro-5-hydroxyphenyl)quinolin-4-yl]piperidin-4- yl}carbamic acid (0.16 mmol, 100 mg), 3-tosyloxyoxetane (10 eq., 1.6 mmol, 365 mg) and K ₂ CO ₃ (10 eq., 1.6 mmol, 220 mg) were added in portions. The resulting mixture was heated at 80° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 28 mg of the desired product as a white solid. MS(M+H) ⁺ =655.2.

Step 14-4, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2-hydroxybenzonitrile:

To a solution in dichloromethane (1 ml) of tert-butyl ester {(1-{6-(3-cyano-2methoxymethoxyphenyl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-4- yl)piperidin-4-yl}carbamic acid (28 mg) was added trifluoroacetic acid (0.2 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography, eluting MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ , extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 8 mg of the final compound.

MS(M+H) ⁺ =511.5.

The following compounds were prepared in a manner similar to that described in Example 13, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-68 497.5

Example 15 3-[4-(4-Aminopiperidin-1-yl)-3-{3-fluoro-5-[(1 E)-(methoxyimino)methyl]phenyl}quinolin-6-yl]-2-hydroxybenzonitrile (connection no. 2-70)

Step 15-1, Preparation of (1-[6-chloro-3-(3-fluoro-5-formylphenyl)quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester:

To THF solution (10 ml) of [1-(3-bromo-6-chloroquinolin-4yl)piperidin-4-yl]carbamic acid tert-butyl ester (from step 13-1) (757 mg, 1.72 mmol) 3-fluoro-5-formylphenylboronic acid (1.5 eq., 2.58 mmol, 433 mg), tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate mixture (molar ratio: 1/1.2) (0.05 eq. ., 0.086 mmol, 86 mg) and K ₃ PO ₄ -H ₂ O (3.0 eq., 5.16 mmol, 1.18 g). N2 was bubbled through the reaction solution for 5 minutes and 1.0 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour and complete conversion to the desired product was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 440 mg of the desired product as a white solid. MS(M+H) ⁺ =484.4.

Step 15-2, Preparation of (1-[6-(3-cyano-2-methoxymethoxyphenyl)3-(3-fluoro-5-formylphenyl)quinolin-4-yl]piperidin-4-yl}carbamic tert-butyl ester acids:

To a solution in dioxane (5 ml) of {1-[6-chloro-3-(3-fluoro-5formylphenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0. 50 mmol, 241 mg) was added Pd(amphos)Cl2 (0.10 eq., 0.05 mmol, 35 mg), 2-methoxymethoxy-3-(4,4,5,5-tetramethyl-

[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.5 eq., 0.75 mmol, 218 mg) and K ₂ CO ₃ (1.5 eq., 0.75 mmol, 105

- 181 040023 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.50 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 270 mg of the desired product as a yellow solid.

MS(M+H)+=611.3.

Step 15-3, Preparation of tert-butyl ester (1-{6-(3-cyano-2-methoxymethoxyphenyl)3-[3-fluoro-5-(methoxyiminomethyl)phenyl]quinolin-4-yl}piperidin-4- yl) carbamic acid:

To a solution in dichloromethane (1.0 ml) of tert-butyl ester {1-[6-(3-cyano-2methoxymethoxyphenyl)-3-(3-fluoro-5-formylphenyl)quinolin-4-yl]piperidin-4- yl}carbamic acid (0.05 mmol, 30 mg) was added HCl salt of O-methylhydroxylamine (2.0 eq., 0.10 mmol, 9 mg) and pyridine (10 eq., 0.5 mmol, 0.02 ml ). The resulting mixture was stirred at ambient temperature for 2 hours and complete consumption of starting material was observed by LCMS analysis. The crude reaction solution was used in the next step without further purification.

MS(M+H) ⁺ =640.5.

Step 15-4, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-{3-fluoro-5-[(1E)-(methoxyimino)methyl]phenyl}quinolin-6-yl]-2 -hydroxybenzonitrile:

Trifluoroacetic acid (0.4 ml) was added to the crude solution obtained in step 15-3, and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 6 mg of the final compound.

MS(M+H) ⁺ =496.5.

The following compounds were prepared in a manner similar to that described in Example 15, substituting with appropriate reagents and substrates as required:

Compound No. MS (M+H)

2-79

510.5

Example 16 3-[4-(4-Aminopiperidin-1-yl)-3-{3-[(3,3-difluoroazetidin-1-yl)methyl]-5-fluorophenyl}quinolin-6-yl]-2 -hydroxybenzonitrile (compound no. 2-71)

Step 16-1, Preparation of tert-butyl ester (1-{6-(3-cyano-2-methoxymethoxyphenyl)3-[3-(3,3-difluoroazetidin-1-ylmethyl)-5-fluorophenyl]quinoline-4 -yl}piperidin-4-yl)carbamic acid:

To a solution in dichloromethane (1.0 ml) of tert-butyl ester {1-[6-(3-cyano-2methoxymethoxyphenyl)-3-(3-fluoro-5-formylphenyl)quinolin-4-yl]piperidin-4- yl}carbamic acid (step 15-2) (0.05 mmol, 30 mg) was added HCl salt of 3,3-difluoroazetidine (6.0 eq., 0.30 mmol, 40 mg), triethylamine (6 eq., 0 .3 mmol 0.042 ml) and sodium triacetoxyborohydride (12 eq., 0.6 mmol, 130 mg). The resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with us. _NH4Cl . The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was used in the next step without further purification.

MS(M+H) ⁺ =688.4.

Step 16-2, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3-[(3,3-difluoroazetidin-1-yl)methyl]-5fluorophenyl)quinolin-6-yl]- 2-hydroxybenzonitrile:

Trifluoroacetic acid (0.2 ml) was added to a dichloromethane (1.0 ml) solution of the crude product obtained in Step 16-1, and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by chromatography with C18 reversed phase eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 7 mg of the final compound.

MS(M+H) ⁺ =544.4.

Example 17 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(methoxymethoxy)benzonitrile (Compound No. 2-78)

- 182 040023

Step 17-1, Preparation of 1-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-ylamine:

To a dichloromethane (4.0 ml) solution of {1-[6-chloro-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester (from step 13-2 ) (0.5 mmol, 233 mg) was added trifluoroacetic acid (1.0 ml) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ . The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was used in the next step without further purification.

MS (M+H) += 374.0.

Step 17-2, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2(methoxymethoxy)benzonitrile:

Pd(amphos)Cl ₂ (0.10 eq., 0.05 mmol, 34 mg), 2-methoxymethoxy-3-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (2.0 eq., 1.0 mmol, 289 mg) and K ₂ CO ₃ (2.0 eq., 1.0 mmol, 138 mg). N ₂ was bubbled through the reaction solution for 5 minutes and 0.60 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour and approximately 50% conversion to the desired product was observed by LCMS analysis. Pd(amphos)Cl ₂ (0.10 eq., 0.05 mmol, 34 mg), 2methoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) benzonitrile (2.0 eq., 1.0 mmol, 289 mg) and K ₂ CO ₃ (2.0 eq., 1.0 mmol, 138 mg) were added and the resulting mixture was heated for another 1 h. The reaction mixture was diluted with ethyl acetate and washed with saline. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO3/NaCl, extracted with ethyl acetate and dried over MgSO4. The organic solution was concentrated with HCl in ether (0.2 M, 0.7 ml) to give 55 mg of the desired product as the HCl salt.

MS(M+H)+=501.3.

The following compounds were prepared in a manner similar to that described in Example 17, substituting with appropriate reagents and substrates as required:

Compound No. MS (M+H) ⁺

2-194 519.4

Example 18 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-methoxyiminomethylphenol (Compound No. 2-81)

Step 18-1, Preparation of {1-[3-(3,5-difluorophenyl)-6-(3-formyl-2hydroxyphenyl)quinolin-4-yl]piperidin-4-yl}carbamic acid tert-butyl ester:

To a solution in dioxane (1 ml) of tert-butyl ester {1-[3-(3,5-difluorophenyl)-6-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl )quinolin-4-yl]piperidin-4-yl}carbamic acid (0.10 mmol, 57 mg) was added Pd(amphos)Cl2 (0.10 eq., 0.01 mmol, 7.8 mg), 3- bromo-2-hydroxybenzaldehyde (2.0 eq., 0.2 mmol, 40 mg) and K ₂ CO ₃ (2.0 eq., 0.2 mmol, 28 mg). N ₂ was bubbled through the reaction solution for 5 minutes and 0.1 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with EtOAc/hexane (0-40%) to give 30 mg of the desired product.

MS(M+H)+=560.23.

Step 18-2, Preparation of tert-butyl ester (1-{3-(3,5-difluorophenyl)-6-[2-hydroxy-3(methoxyiminomethyl)phenyl]quinolin-4-yl}piperidin-4-yl) carbamic acid:

To a solution in dichloromethane (1.0 ml) of tert-butyl ester {1-[3-(3,5-difluorophenyl)-6-(3formyl-2-hydroxyphenyl)quinolin-4-yl]piperidin-4-yl} carbamic acid (30 mg, 0.054 mmol) was added HCl salt of O-methylhydroxylamine (2.0 eq., 0.10 mmol, 9 mg) and pyridine (10 eq., 0.5 mmol, 0.04 ml). The resulting mixture was stirred at ambient temperature for 2 hours and complete consumption of starting material was observed by LCMS analysis. The crude reaction solution was used in the next step without further purification.

- 183 040023

MS(M+H)+=589.5.

Step 18-3, Preparation of 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6methoxyiminomethylphenol:

The crude solution obtained in step 18-2 was added with trifluoroacetic acid (0.5 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water ( 0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 6 mg of the title compound.

MS(M+H)+=489.4.

The following compounds were prepared in a manner similar to that described in Example 18, substituting with the appropriate reagents and substrates as follows:

The following compounds were prepared similarly to that of Example 18, except that the Suzuki coupling reaction was carried out using tris(dibenzylideneacetone)dipalladium/tritert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2) as a catalyst in the presence of K3PO4-H2O in THF /water at ambient temperature:

connection no. MS (M+H) ⁺ 2-126 477.3 2-129 491.3

Example 19 Methyl N-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6difluorophenyl}carbamate (Compound No. 2-83 )

Step 19-1, Preparation of (1-[6-(2-amino-3,5-difluorophenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester :

To a solution in dioxane (2 ml) of tert-butyl ester {1-[3-(3,5-difluorophenyl)-6-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl )quinolin-4-yl]piperidin-4-yl}carbamic acid (0.20 mmol, 112 mg) was added Pd(amphos)Cl ₂ (0.10 eq., 0.02 mmol, 15 mg), 2-bromo -4,6-difluorophenylamine (2.0 eq, 0.4 mmol, 84 mg) and K2CO3 (2.0 eq, 0.4 mmol, 56 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.2 ml of water was added. The resulting mixture was heated at 95° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine.

The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with EtOAc/hexane (0-40%) to give 62 mg of the desired product.

- 184 040023

MS (M+H) += 567.4.

Step 19-2, Preparation of (1-[6-(3,5-difluoro-2methoxycarbonylaminophenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl)carbamic acid tert-butyl ester :

To a solution in dichloromethane (1.0) of tert-butyl ester {1-[6-(2-amino-3,5difluorophenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl }carbamic acid (30 mg, 0.05 mmol) were added pyridine (13 eq., 0.65 mmol, 0.052 ml) and methyl chloroformate (6.0 eq., 0.30 mmol, 0.03 ml). The resulting mixture was stirred at ambient temperature for 2 hours and complete consumption of starting material was observed by LCMS analysis. The crude reaction solution was used in the next step without further purification.

MS(M+H)+=625.6.

Step 19-3, preparation of methyl N-(2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-4,6-difluorophenyl} carbamate:

Trifluoroacetic acid (0.3 ml) was added to the crude solution obtained from step 19-2, and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt to give 7 mg of the desired product as the HCl salt.

MS(M+H)+=525.3.

The following compounds were prepared in a manner similar to that described in Example 19, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-86 545.3 2-230 535.5

Example 20 3-(4-{3-[(1S)-1-Aminopropyl]azetidin-1-yl}-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5fluoro-2- hydroxybenzonitrile (compound no. 2-82)

Step 20-1: Preparation of 3-[(R)-(2-methylpropane-2sulfinylimino)methyl]azetidine-1-carboxylic acid tert-butyl ester:

To a solution of 3-formylazetidine-1-carboxylic acid tert-butyl ester (500.0 mg, 2.700 mmol) and (R)-2-methylpropane-2-sulfinic acid amide (327.2 mg, 2.700 mmol) in DCM ( 5 ml) under nitrogen atmosphere was added anhydrous copper (II) sulfate (948.0 mg, 5.940 mmol). The mixture was stirred at rt. all night long. The mixture was filtered through Celite and the filtrate was concentrated to dryness in vacuo to give the crude title compound as a colorless gum.

(M+1) ⁺ : 289.3.

Step 20-2: Preparation of 3-[(S)-1-((R)-2-methylpropane-2sulfinylamino)propyl]azetidine-1-carboxylic acid tert-butyl ester

To a solution of the above crude 3-[((R)-2methylpropane-2-sulfinylimino)methyl]azetidine-1-carboxylic acid tert-butyl ester (2.700 mmol) (from step 20-1) in DCM (20 ml) under atmosphere nitrogen at -78°C was added dropwise 0.9 M solution of ethylmagnesium bromide in THF (4.5 ml, 4.05 mmol). The mixture was stirred at -78°C for 4 hours. The mixture was quenched with saturated NH4Cl (aq) and heated to rt. The mixture was extracted with DCM (1x) and the organic layer was concentrated to dryness in vacuo. The residue was purified by silica gel column chromatography to give the title compound containing 32% (R,R)-diastereomer (738.1 mg, 2.317 mmol, 85.8% yield) as a colorless gum.

MS(M+1) ⁺ : 319.2.

Step 20-3, Preparation of 3-((S)-1-aminopropyl)-azetidine-1-carboxylic acid tert-butyl ester:

To a solution of 3-[(S)-1-((R)-2-methylpropane-2sulfinylamino)propyl]azetidine-1-carboxylic acid tert-butyl ester (300.0 mg, 0.942 mmol) (from step 20-2 ) in MeOH (5 ml) at 0°C was added a 4 N HCl solution in dioxane (0.31 ml) and the mixture was stirred at 0°C for 5 h. The mixture was quenched with saturated NaHCO ₃ (aq.) and was extracted with DCM (2x ). The combined organics were dried over anhydrous Na ₂ SO ₄ and concentrated to dryness in vacuo to give the crude title compound as an off-white gum.

- 185 040023

MS(M+1)+: 215.0.

Step 20-4, Preparation of 3-((S)-1benzyloxycarbonylaminopropyl)azetidine-1-carboxylic acid tert-butyl ester:

To a solution of the crude 3-(^)-1-aminopropyl)-azetidine-1-carboxylic acid tert-butyl ester (from step 20-3) in DCM (5 mL) was added 2,5-dioxopyrrolidin-1-yl benzyl ester carboxylic acid (330.0 mg, 1.324 mmol) and the mixture was stirred at rt. within 1 h. The mixture was quenched with water and the organic layer was separated and concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography to give the title compound (222.2 mg, 0.638 mmol, 67.7% yield) as a colorless gum.

MS(M+1) ⁺ : 349.6.

Step 20-5, Preparation of ((S)-1-azetidin-3-yl-propyl)-carbamic acid benzyl ester:

TFA (0.5 ml). The mixture was stirred at rt. within 30 min. The mixture was concentrated to dryness in vacuo and redissolved in EtOAc. The organic solution was washed with saturated NaHCO ₃ (aq), dried over anhydrous Na ₂ SO ₄ and concentrated to dryness in vacuo to give the crude title compound (158.4 mg, 100% yield) as a light yellow gum. MS(M+1) ⁺ : 249.2.

Example 21 3-{4-[(3R,4R)-4-Amino-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2hydroxybenzonitrile (compound no. 2- 59)

Step 21-1, Preparation of tert-butyl ester (1-[6-(3-cyano-2-methoxymethoxyphenyl)3-(3,5-difluorophenyl)quinolin-4-yl]-3-fluoropiperidin-4-yl} carbamic acid:

To a solution in dioxane (1.0 ml) of {1-[6-chloro-3-(3,5difluorophenyl)quinolin-4-yl]-3-fluoropiperidin-4-yl}carbamic acid tert-butyl ester (obtained similarly described in step 13-2) (0.08 mmol, 40 mg) was added Pd(amphos)Cl ₂ (0.25 eq., 0.02 mmol, 15 mg), 2-methoxymethoxy-3-(4,4,5, 5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (2.0 eq., 0.16 mmol, 47 mg) and K ₂ CO ₃ (2.3 eq., 0.18 mmol, 25 mg). N ₂ was bubbled through the reaction solution for 5 minutes and 0.10 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 25 mg of the desired product as a yellow solid.

MS(M+H) ⁺ =619.6.

Step 21-2, Preparation of 3-{4-[(3R,4R)-4-amino-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile :

To a solution in dichloromethane (1.5 ml) of {1-[6-(3-cyano-2methoxymethoxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-3-fluoropiperidin-4 tert-butyl ester -yl}-carbamic acid was added trifluoroacetic acid (0.5 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%) . Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated to give 8 mg of the final compound. MS(M+H) ⁺ =475.3.

Compound 2-92 was prepared similarly to compound 2-59, except that the Suzuki coupling reaction was carried out using a Pd(amphos)Cl ₂ catalyst in the presence of K ₂ CO ₃ in dioxane/water with heating at 100°C.

(M + H) ⁺ = 481.5.

Example 22 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(2-methoxyethoxy)methoxy]benzonitrile (Compound No. 2- 87)

Step 22-1, Preparation of tert-butyl-N-[1-(6-{3-cyano-2-[(2-methoxyethoxy)methoxy]phenyl}-3-(3,5-186 040023 difluorophenyl)quinoline-4 -yl)piperidin-4-yl]carbamate:

To a solution in dichloromethane (5.0 ml) of tert-butyl ester {1-[6-(3-cyano-2hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl} carbamic acid (300 mg, 0.54 mmol) was added N,N-diisopropylethylamine (1.5 eq., 0.81 mmol, 0.133 ml) and 2-methoxyethoxymethyl chloride (1.1 eq., 0.60 mmol, 0.0675 ml ) at 0°C. The resulting mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with saturated NH ₄ Cl, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 187 mg of the desired product.

MS(M+H)+=645.6.

Step 22-2, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(2methoxyethoxy)methoxy]benzonitrile:

To a solution in dichloromethane (5.0 ml) of tert-butyl-N-[1-(6-{3-cyano-2-[(2methoxyethoxy)methoxy]phenyl}-3-(3,5-difluorophenyl)quinoline-4 -yl)piperidin-4-yl]carbamate (187 mg, 0.29 mmol) was added trifluoroacetic acid (0.5 ml) and the resulting mixture was stirred at 0° C. for 0.5 h. An additional amount of 0.5 ml was added triperoxonane acid and the reaction solution was stirred at 0°C for 1 h, the Reaction solution was diluted with dichloromethane, washed with saturated NaHCO ₃ , dried with Na ₂ SO ₄ and concentrated. The resulting residue was purified by C18 reverse phase chromatography eluting with MeCN/water (0~40%). Pure fractions containing the desired product were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ .

MS(M+H) ⁺ =545.4.

Example 23 trans-3-{4-[Amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2(methoxymethoxy)benzonitrile (Compound No. 2-84)

Step 23-1, Preparation of trans-tert-butyl-N-(1-(6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5difluorophenyl)quinolin-4-yl}-3-methoxypiperidine -4-yl) carbamate:

To a solution in dioxane (6.6 ml) of trans-tert-butyl-N-{1-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]3-methoxypiperidin-4-yl}carbamate Pd(amphos)Cl ₂ ( 0.20 eq, 0.13 mmol, 97 mg), 2-methoxymethoxy-3-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (2.0 eq. , 1.36 mmol, 418 mg) and K ₂ CO ₃ (3.0 eq., 2.06 mmol, 284 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.66 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 273 mg of the desired product as a yellow foam. MS(M+H) ⁺ =631.5.

Step 23-2, preparation of trans-3-{4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2-(methoxymethoxy)benzonitrile:

To a solution in dichloromethane (5.0 ml) of trans-tert-butyl-N-(1-{6-[3-cyano-2-(methoxymethoxy)phenyl]3-(3,5-difluorophenyl)quinolin-4-yl }-3-methoxypiperidin-4-yl)carbamate (188 mg, 0.30 mmol) was added trifluoroacetic acid (0.23 ml) in 1.0 ml dichloromethane at 0°C. After 0.5 h, an additional amount of 0.5 ml trifluoroacetic acid was added and the reaction solution was stirred at 0°C for 1 h. The reaction solution was diluted with dichloromethane, washed with saturated NaHCO3, dried with Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with MeOH/DCM (0~10%) to obtain 24 mg of the desired product.

MS(M+H) ⁺ =531.1.

Example 24 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]6-(azetidine-1carbonyl)phenol (Compound No. 2-88)

- 187 040023

Stage 24-1, obtaining 2-(azetidine-1-carbonyl)-6-bromophenol:

To a DMF solution (5 ml) of 3-bromo-2-hydroxybenzoic acid (1.0 mmol, 217 mg) was added triethylamine (3.0 eq, 3.0 mmol, 0.415 ml), HATU (1.5 eq, 1.5 mmol, 570 mg) and azetidine HCl salt (1.5 eq., 1.5 mmol, 141 mg). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 95 mg of the desired product as a yellow foam.

MS (M+H)+=631.5.

Step 24-2, Preparation of tert-butyl-N-(1-(6-[3-(azetidine-1-carbonyl)-2-hydroxyphenyl]-3-(3-fluoro5-methylphenyl)quinolin-4-yl)piperidine -4-yl) carbamate:

Pd(amphos)Cl ₂ (0.10 eq., 0.02 mmol , 14 mg), tert-butyl-N-{1-[3-(3-fluoro-5-methylphenyl)-6-(tetramethyl1,3,2-dioxaborolan-2-yl)quinolin-4-yl]piperidin- 4-yl}carbamate (1.0 eq., 0.2 mmol, 112 mg) (prepared similarly to the compound described in example 13, step 13-3) and K ₂ CO ₃ (2.5 eq., 0.5 mmol, 67 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.20 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 40 mg of the desired product.

MS(M+H) ⁺ =611.4.

Step 24-3, Preparation of 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6(azetidine-1-carbonyl)phenol:

To a solution in dichloromethane (1.0 ml) of tert-butyl-N-(1-{6-3-[(azetidine-1-carbonyl)-2hydroxyphenyl]-3-(3-fluoro-5-methylphenyl)quinoline-4 -yl}piperidin-4-yl)carbamate (40 mg) was added trifluoroacetic acid (0.3 ml) and the resulting mixture was stirred at ambient temperature for 1 h. The reaction solution was concentrated and purified by reverse phase C18 chromatography, eluting MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 0.5 ml) to give 8 mg of the final compound as the HCl salt.

MS(M+H) ⁺ =511.5.

Example 25 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro-4-fluoro-2hydroxybenzonitrile (Compound No. 2-147)

Stage 25-1, obtaining 3-bromo-5-chloro-4-fluoro-2-hydroxybenzonitrile:

To a solution in dichloromethane (15 ml) of 4-chloro-2,5-difluorophenol (803 mg, 4.46 mmol) was added dropwise bromine (1.2 eq., 5.35 mmol, 0.28 ml) dichloromethane. The resulting mixture was heated at 40° C. in a stoppered tube for 2 hours. The reaction solution was diluted with dichloromethane, washed with brine, dried with Na ₂ SO ₄ and concentrated. The resulting residue was slurried in ethyl acetate/hexane (1:4) over 1 hour and filtered to give 940 mg of the desired product.

Stage 25-2, obtaining 3-bromo-5-chloro-4-fluoro-2-[(2-methoxyethoxy)methoxy]benzonitrile:

To a dichloromethane (40 ml) solution of 3-bromo-5-chloro-4-fluoro-2-hydroxybenzonitrile (940 mg, 3.76 mmol) was added N,N-diisopropylethylamine (1.5 eq., 5.64 mmol, 0.93 ml) and 2 methoxyethoxymethyl chloride (1.5 eq., 5.64 mmol, 0.64 ml) at 0°C. The resulting mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with saturated NH4Cl and dried over Na2SO4. The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-15%) to give 939 mg of the desired product as a white solid.

Step 25-3, Preparation of tert-butyl-N-[1-(6-(3-chloro-5-cyano-2-fluoro-6-[(2-methoxyethoxy)methoxy]phenyl}-3-(3.5 -difluorophenyl)quinolin-4-yl)piperidin-4-yl]carbamate:

To THF solution (2.0 ml) tert-butyl-N-{1-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan2-yl)quinolin-4-yl] piperidin-4-yl}carbamate (0.21 mmol, 121 mg, step 13-3) was added 3-bromo-5chloro-4-fluoro-2-[(2-methoxyethoxy)methoxy]benzonitrile (2.0 eq., 0.21 mmol, 142 mg), tris(dibenzylideneacetone) dipalladium/tri-tert-butylphosphonium tetrafluoroborate mixture (molar ratio: 1/1.2) (0.05 eq., 0.01 mmol, 14 mg), K ₃ PO ₄ -H ₂ O (3.0 eq., 0.63 mmol, 148 mg). N2 bubbled che

- 188 040023 cut the reaction solution for 5 min and add 0.2 ml of water. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl, NaHCO ₃ and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-40%) to give 24 mg of the desired product as a yellow solid.

MS(M+H)+=697.5.

Step 25-4, Preparation of 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro4-fluoro-2-hydroxybenzonitrile:

To a solution in dichloromethane (1.0 ml) tert-butyl-N-[1-(6-{3-chloro-2,5-difluoro-6-[(2methoxyethoxy)methoxy]phenyl}-3-(3,5-difluorophenyl )quinolin-4-yl)piperidin-4-yl]carbamate (24 mg) was added trifluoroacetic acid (0.3 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 chromatography with reverse phase eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 0.2 ml) to give 4.4 mg of the final compound as the HCl salt.

MS(M+H)+=509.2.

The following compounds were prepared in a manner similar to that described in Example 25, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-150 486.3 2-161 498.3 2-134 502.2

Example 26 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}-3-methoxyurea (Compound No. 2-139)

Step 26-1, Preparation of tert-butyl N-{1-[6-(2-amino-3,5-difluorophenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamate :

To a solution in dioxane (2.0 ml) tert-butyl-N-{1-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2dioxaborolan-2-yl)quinolin-4-yl ]piperidin-4-yl}carbamate (1.0 eq., 0.2 mmol, 112 mg, step 13-3) Pd(amphos)Cl ₂ (0.10 eq., 0.02 mmol, 14 mg) was added , 2-bromo-4,6-difluorophenylamine (0.4 mmol, 80 mg) and K ₂ CO ₃ (2.5 eq., 0.5 mmol, 67 mg). N2 was bubbled through the reaction solution for 5 minutes and 0.20 ml of water was added. The resulting mixture was heated at 100° C. for 1 hour and complete consumption of starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 29 mg of the desired product.

MS (M+H) += 567.4.

Step 26-2, Preparation of tert-butyl-N-(1-[6-(3,5-difluoro-2-isocyanatophenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4-yl } carbamate:

tert-Butyl N-{1-[6-(2-Amino-3,5-difluorophenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidin-4yl}carbamate (29 mg, 0.051 mmol ) was dissolved in 0.5 ml dichloromethane and then triethylamine (2.2 eq., 0.11 mmol, 0.016 ml) was added. The resulting mixture was added dropwise to a dichloromethane (0.5 ml) solution of triphosgene (0.4 eq., 0.02 mmol, 6.0 mg) at 0°C. After 15 min, the reaction solution was warmed to ambient temperature and stirred for 0.5 h. The crude reaction solution was used in the next step without further purification.

Step 26-3, Preparation of tert-butyl-N-[1-(6-{3,5-difluoro-2-[(methoxycarbamoyl)amino]phenyl}-3(3,5-difluorophenyl)quinolin-4-yl) piperidin-4-yl] carbamate:

To an anhydrous DMF solution (1.0 ml) of the O-methylhydroxylamine HCl salt (3.0 eq, 0.15 mmol, 13 mg) was added triethylamine (4.4 eq, 0.20 mmol, 0.032 ml). The resulting suspension was cooled to 0° C., and the crude reaction solution from Step 26-2 was added dropwise. The reaction solution was stirred at ambient temperature for 10 minutes and complete consumption of the starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ , concentrated and dried

- 189 040023 under high vacuum to obtain 23 mg of the desired product. This material was used in the next step without further purification.

MS(M+H)+=640.4.

Step 26-4, Preparation of 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6difluorophenyl}-3-methoxyurea:

To a solution in dichloromethane (1.0 ml) tert-butyl-N-[1-(6-{3,5-difluoro-2-[(methoxycarbamoyl)amino]phenyl}-3-(3,5-difluorophenyl)quinoline -4-yl)piperidin-4-yl]carbamate (23 mg) was added trifluoroacetic acid (0.3 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography. eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 0.5 ml) to give 8.0 mg of the final compound as the HCl salt.

MS(M+H) ⁺ =540.4.

The following compounds were prepared using methods similar to those described in Example 26 and substitution with appropriate reagents and substrates as required. Compound 2-215, 2-237 was prepared by treating the corresponding aniline intermediates with 3-methoxy-1-(4nitrophenyl)urea in dioxane as an alternative step of step 26-2.

Example 27 Methyl N-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]-6-cyanophenyl}carbamate (Compound No. 2-148)

- 190 040023

Step 27-1 Preparation of methyl-N-{2-[4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]- 6-cyanophenyl}carbamate:

Solution in dichloromethane (0.9 ml) tert-butyl-N-{1-[6-(3-cyano-2-isocyanatophenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl} carbamate (0.065 mmol, obtained similarly to example 26, step 26-2) was added to 1.0 ml of MeOH at 0°C and the resulting mixture was stirred at ambient temperature for 0.5 h. The reaction solution was concentrated and dried under high vacuum with obtaining 25 mg of the desired product. This material was used in the next step without further purification. MS(M+H)+=614.5.

Step 27-2, preparation of methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6yl]-6-cyanophenyl}carbamate:

To a solution in dichloromethane (1.0 ml) of methyl-N-{2-[4-(4-{[(tert-butoxy)carbonyl]amino}piperidin1-yl)-3-(3,5-difluorophenyl)quinolin- 6-yl]-6-cyanophenyl}carbamate (25 mg) was added trifluoroacetic acid (0.3 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography, eluting MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 0.5 ml) to give 5.8 mg of the final compound as the HCl salt.

MS(M+H)+=514.5.

The following compounds were prepared using methods similar to those described in Example 27 and substitution with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-165 537.5 2-167 526.3 2-171 504.3 2-173 519.4 2-125 515.5 2-180 550.5 2-184 520.4 2-197 521.4 2-123 543.4 2-205 546.4 2-209 503.4 2-214 489.4 2-218 540.2 2-235 551.2

Example 28 Methyl trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4yl]piperidine-3-carboxylate (Compound No. 2-143 )

Step 28-1, preparation of methyl trans-1-(6-bromo-3-chloroquinolin-4-yl)-4-{[(tert-butoxy)carbonyl]amino}piperidine-3-carboxylate:

From 6-bromo-3,4-dichloroquinoline (225.1 mg, 0.813 mmol) and methyl trans-(tert-butoxy)carbonyl]amino}piperidine-3-carboxylate (140.0 mg, 0.542 mmol) the title compound was obtained as light brown solid using a method similar to that described in example 4, step 4-1.

MS(M+1) ⁺ =499.8.

Step 28-2, preparation of methyl trans-4-{[(tert-butoxy)carbonyl]amino)-1-{3-chloro-6-[3-cyano-2(methoxymethoxy)phenyl]}quinolin-4-yl }piperidine-3-carboxylate:

From methyl trans-1-(6-bromo-3-chloroquinolin-4-yl)-4-{[(tert-butoxy)carbonyl]amino}piperidine-3carboxylate (108.0 mg, 0.217 mmol) and 2-( methoxymethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile (74.8 mg, 0.260 mmol) gave the title compound as a light brown gum using a method similar to that described in Example 12, step 12- 3.

- 191 040023

MS(M+1) ⁺ =581.1.

Step 28-3, preparation of methyl trans-4-([(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl) quinolin-4-yl}piperidine-3-carboxylate:

From methyl-trans-4-{[(tert-butoxy)carbonyl]amino}-1-{3-chloro-6-[3-cyano-2-(methoxymethoxy)phenyl]quinolin-4-yl}piperidin-3- carboxylate (125.9 mg, 0.217 mmol) and (3,5-difluorophenyl)boronic acid (51.4 mg, 0.326 mmol) the title compound was obtained as a light yellow gum using a method similar to that described in example 12, step 12 -4.

MS(M+1) ⁺ =659.5.

Step 28-4, preparation of methyl trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate:

From methyl-trans-4-{[(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3(3,5-difluorophenyl)quinolin-4-yl }piperidine-3-carboxylate (14.0 mg, 0.0213 mmol) was obtained as a yellow solid using a method similar to that described in example 5, stage 5-6.

MS(M+1) ⁺ =515.5.

The following compounds were prepared using methods similar to those described in Example 28 and substitution with appropriate reagents and substrates as required.

Example 29 trans-4-amino-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin4-yl}piperidine-3-carboxylic acid (compound no. 2 -145)

Step 29-1, obtaining trans-4-{[(tert-butoxy)carbonyl]amino)-1-{6-[3-cyano-2(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinoline- 4-yl}piperidine-3-carboxylic acid:

To a solution of methyl-trans-4-{[(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinoline-4 -yl}piperidine-3-carboxylate (106.0 mg, 0.161 mmol) in a mixed solvent of THF/MeOH/H ₂ O (3:1:1, 2 ml) at 0°C was added lithium hydroxide monohydrate (33.8 mg, 0.805 mmol). The mixture was stirred at ambient temperature for 4 hours. The mixture was neutralized with 1 N HCl (aq.) and concentrated to remove the organic solvent. The aqueous residue was diluted with water and acidified with 1 N HCl (aq) to pH 3. The solid was collected by vacuum filtration and washed with water to give the title compound (74.4 mg, 0.115 mmol, 71.4% yield) as a yellow solid.

(M + 1) ⁺ = 645.3.

Step 29-2, Preparation of trans-4-amino-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5difluorophenyl)quinolin-4-yl}piperidine-3-carboxylic acid:

From trans-4-{[(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5difluorophenyl)quinolin-4-yl}piperidine- 3-carboxylic acid (15.0 mg, 0.0233 mmol), the title compound was obtained as a yellow solid using a method similar to that described in example 5, step 5-6.

MS(M+1) ⁺ =501.2.

Example 3 0. trans-4-Amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4yl]piperidine-3-carboxamide (Compound No. 2-146)

Step 30-1, Preparation of tert-butyl-N-trans-3-carbamoyl-1-(6-[3-cyano-2-(methoxymethoxy)phenyl]3-(3,5-difluorophenyl)quinolin-4-yl} piperidin-4-yl] carbamate:

To a solution of trans-4-{[(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3(3,5-difluorophenyl)quinolin-4-yl} piperidine-3-carboxylic acid (30.0 mg, 0.0465 mmol) and 1[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (26, 5 mg, 0.0617 mmol) in DMF (2 ml) diisopropylethylamine (0.12 ml, 0.689 mmol) was added in a stoppered tube. After stirring at rt. ammonium chloride (24.9 mg, 0.465 mmol) was added over 5 minutes. The mixture was stirred at rt. all night long. The mixture was purified by column chromatography with

- 192 040023 reversed phase (neutralized with saturated NaHCO ₃ (aq.)) to obtain the title compound (19.4 mg, 0.0301 mmol, 64.7% yield) as a yellow solid. MS(M+1)+=644.1.

Step 30-2, preparation of trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxamide:

From tert-butyl-N-[trans-3-karbαmoyl-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl}piperidin-4 -yl]carbamate (19.4 mg, 0.0301 mmol) was obtained as a yellow solid using a method similar to that described in example 5, stage 5-6.

MS(M+1)+=500.3.

The following compounds were prepared in a manner similar to that described in Example 30, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-151 527.9

Example 31 trans-4-Amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-Nmethylpiperidine-3-carboxamide (Compound No. 2- 149)

Step 31-1, Preparation of tert-butyl-N-[trans-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5difluorophenyl)quinolin-4-yl}-3-{ [(4-methoxyphenyl)methyl](methyl)carbamoyl}piperidin-4-yl]carbamate:

From trans-4-{[(tert-butoxy)carbonyl]amino}-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl} piperidine-3-carboxylic acid (28.4 mg, 0.0441 mmol) and [(4methoxyphenyl)methyl](methyl)amine (8.7 mg, 0.0575 mmol) gave the title compound as a yellow solid using the method , similar to that described in example 24, stage 24-1.

MS(M+1)+= 778.4.

Step 31-2, Preparation of trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-N-methylpiperidine-3-carboxamide :

K tert-butyl-N-[trans-1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)quinolin-4yl}-3-{[(4-methoxyphenyl )methyl](methyl)carbamoyl}piperidin-4-yl]carbamate (28.0 mg, 0.0360 mmol) was added (methylsulfanyl)benzene (0.05 ml) and 2,2,2-trifluoroacetic acid (0.25 ml). The mixture was heated at 80° C. overnight. The mixture was concentrated in vacuo to dryness and the residue was purified by reverse phase column chromatography (neutralized with saturated NaHCO ₃ (aq.)) to give the title compound (15.9 mg, 0.0310 mmol, 86.1% yield) as a yellow solid .

MS(M+1)+=514.0.

Example 32 trans-6-[3-(3,5-Difluorophenyl)-4-{octahydro-1H-pyrido[3,4-b]morpholin-6-yl}quinolin6-yl]-4-fluoro-2 ,3-dihydro-1H-1,3-benzodiazol-2-one (compound no. 2-80)

Step 32-1, preparation of trans-tert-butyl-6-(6-bromo-3-chloroquinolin-4-yl)-octahydro-1Hpyrido[3,4-b]morpholine-1-carboxylate:

The title compound was obtained as a brown gum using a method similar to that described in example 4, stage 4-1.

MS(M+1)+=484.4.

Step 32-2, obtaining trans-tert-butyl-6-[3-chloro-6-(7-methyl-2-oxo-2,3-dihydro-1H-1,3benzodiazol-5-yl)quinoline-4- yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:

From trans-tert-butyl-6-(6-bromo-3-chloroquinolin-4-yl)-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (112 mg, 0.232 mmol) and (77 mg, 0.278 mmol) obtained the title compound as a yellow solid using a method similar to that described in Example 4, Step 4-3. MS(M+1)+=554.4.

Step 32-3, trans-tert-butyl-6-[3-(3,5-difluorophenyl)-6-(7-fluoro-2-oxo-2,3-dihydro-1H-1,3benzodiazol-5-yl )quinolin-4-yl]-octahydro-1 H-pyrido [3,4-N-morpholine-1-carboxylate:

From trans-tert-butyl-6-[3-chloro-6-(7-fluoro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)quinolin-4yl]-octahydro- 1H-pyrido[3,4-b]morpholine-1-carboxylate (123 mg, 0.223 mmol) and 3,-5-difluorophenylboronic acid (70 mg, 0.443 mmol) gave the title compound as a yellow solid using a method similar to that described in example 4, step 4-3.

- 193 040023

MS(M+1)+: 632.5.

Step 32-4, obtaining trans-6-[3-(3,5-difluorophenyl)-4-{octahydro-1H-pyrido[3,4-b]morpholin-6yl}quinolin-6-yl]-4-fluoro -2,3-dihydro-1H-1,3-benzodiazol-2-one:

From trans-tert-butyl-6-[3-(3,5-difluorophenyl)-6-(7-fluoro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5yl)quinoline-4 -yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (76 mg, 0.120 mmol) and HCl in dioxane (4.0 M, 3.0 mL) gave the title compound as a yellow solid substances using a method similar to that described in example 5, stage 5-6.

MS(M+1) ⁺ =532.1.

Example 33 trans-6-[3-(3,5-difluorophenyl)-4-{octahydro-1H-pyrido[3,4-b]morpholin-6-yl}quinolin6-yl]pyridine-2-carboxamide (No. connections 2-85)

Step 33-1, preparation of trans-1-benzyl-6-tert-butyloctahydro-1H-pyrido[3,4-b]morpholine-1,6-dicarboxylate:

To a dichloromethane (5.0 ml) solution of trans-tert-butyloctahydro-1H-pyrido[3,4-b]morpholine-6carboxylate (400 mg, 1.81 mmol) was added benzyloxycarbonyl-N-succinimide (1.3 eq. , 2.35 mmol, 583 mg) and the resulting mixture was stirred at ambient temperature overnight. The reaction solution was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0-40%) to give 540 mg of the desired product as a colorless oil.

MS(M+1) ⁺ =377.4.

Step 33-2, preparation of trans-benzyl octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:

HCl in dioxane (3.5 ml, 4.0 M) and the resulting mixture was stirred at ambient temperature for 2 hours. The resulting suspension was filtered and the solid was collected after washing with hexane to give 375.5 mg of the desired product as the HCl salt. MS(M+1) ⁺ =277.0.

Step 33-3, Preparation of trans-benzyl-6-(3-bromo-6-chloroquinolin-4-yl)-octahydro-1H-pyrido[3,4b]morpholine-1-carboxylate: To anhydrous DMSO (5.0 ml ) to a solution of 3-bromo-4,6-dichloroquinoline (1.2 eq., 1.44 mmol, 399 mg) was added N,N-diisopropylethylamine (1.0 ml) and the HCl salt of transbenzyl octahydro-1H-pyrido[3.4 -b]morpholine-1-carboxylate (1.20 mmol, 376 mg). N2 was bubbled through the reaction solution for 5 minutes and the resulting solution was heated at 130° C. overnight. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by C18 reverse phase chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated and dried under high vacuum to give 239 mg of the desired product.

MS (M+H) += 516.3.

Step 33-4, preparation of trans-benzyl-6-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1Hpyrido[3,4-b]morpholine-1-carboxylate:

From trans-benzyl-6-(3-bromo-6-chloroquinolin-4-yl)-octahydro-1 H-pyrido[3,4-b]morpholine-1-carboxylate (239 mg, 0.464 mmol) and 3,- 5-difluorophenylboronic acid (2.0 eq., 0.928 mmol, 147 mg) was obtained as a white solid using a method similar to that described in example 13, stage 13-2.

MS(M+1) ⁺ =550.5.

Step 33-5, Preparation of trans-benzyl-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2yl)quinolin-4-yl]-octahydro-1H-pyrido [3,4-b]morpholine-1-carboxylate:

From trans-benzyl-6-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (130 mg, 0.236 mmol) received the specified connection using a method similar to that described in example 13, stage 13-3. The reaction solution was diluted with ethyl acetate, washed with water, dried over Na ₂ SO ₄ and concentrated. This material was used in the next step without further purification.

MS(M+1) ⁺ =642.5.

Step 33-6, obtaining trans-benzyl-6-[6-(6-carbamoylpyridin-2-yl)-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1 H-pyrido [3, 4-b]morpholine-1-carboxylate:

From trans-benzyl-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]octahydro-1H-pyrido[3,4 -b]morpholine-1-carboxylate (0.118 mmol) and 6-bromopyridine-2-carboxylic acid amide (0.263 mmol, 55 mg) was obtained as a white solid using a method similar to that described in example 12, step 12-4.

- 194 040023

MS(M+1) ⁺ =636.4.

Step 33-7, obtaining trans-6-[3-(3,5-difluorophenyl)-4-{octahydro-1H-nirido[3,4-b]morpholin-6yl|quinolin-6-yl]pyridin-2- carboxamide:

Trans-benzyl-6-[6-(6-carbamoylpyridin-2-yl)-3-(3,5-difluorophenyl)quinolin-4-yl]octahydro-1Hpyrido[3,4-b]morpholine-1-carboxylate ( 30.4 mg) was combined with trifluoroacetic acid (0.5 ml) and thioanisole (0.1 ml), and the resulting mixture was stirred at 60° C. for 1 hour. The reaction solution was concentrated and purified by C18 reverse phase chromatography, eluting MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in ether (2.0 M, 0.5 ml) to give 23 mg of the desired product as the HCl salt.

MS(M+H) ⁺ =502.4.

The following compounds were prepared in a manner similar to that described in Example 33, substituting with appropriate reagents and substrates as required. Compound 2-251 was prepared using MOM-protected 2-bromo-3-hydroxyisonicotinonitrile. Compound 2-256 was prepared using 3,4-dimethoxybenzyl-protected 3-bromo-5-fluoropyridin-4-ol.

connection no. MS (M+H) ⁺ 2-100 535.4 2-245 477.4 2-247 488.4 2-249 477.4 2-251 500.4 2-252 557.3 2-255 475.2 2-256 493.3 2-257 505.2

Example 34 trans-2-[3-(3,5-Difluorophenyl)-4-{octahydro-1H-pyrido[3,4-b]morpholin-6-yl}quinolin6-yl]-6-fluorophenol (Compound No. 2-144)

Step 34-1, Preparation of trans-benzyl-6-[3-(3,5-difluorophenyl)-6-(3-fluoro-2-hydroxyphenyl)quinolin4-yl]-octahydro-1H-pyrido[3,4-b ]morpholine-1-carboxylate:

From trans-benzyl-6-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (Example 33, step 33-4) (50 mg, 0.09 mmol) and 3-fluoro-2-hydroxyphenylboronic acid (2.0 eq., 0.18 mmol, 28 mg) gave the title compound as a white solid using a method similar to described in example 12, stage 12-4.

MS(M+1) ⁺ =626.4.

Step 34-2, Preparation of trans-2-[3-(3,5-difluorophenyl)-4-{octahydro-1H-nirido[3,4-b]morpholin-6yl}quinolin-6-yl]-6-fluorophenol :

From trans-benzyl-6-[3-(3,5-difluorophenyl)-6-(3-fluoro-2-hydroxyphenyl)quinolin-4-yl]octahydro-1Hpyrido[3,4-b]morpholine-1-carboxylate (30 mg) received the specified connection in the form of a white solid using a method similar to that described in example 33, stage 33-7.

MS(M+1) ⁺ =492.4.

Example 35 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-6-(methoxyiminomethyl)phenol (compound no. 2-243)

Stage 35-1, obtaining 3-bromo-2-(methoxymethoxy)benzaldehyde:

To a solution in dichloromethane (100 ml) of 3-bromo-2-hydroxybenzaldehyde (4.144 g, 20 mmol) was added

- 195 040023

Ν,N-diisopropylethylamine (1.5 eq., 30 mmol, 4.95 ml) and methoxymethyl chloride (1.5 eq., 30 mmol, 2.28 ml) at 0°C. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed with saturated NH4Cl and dried over Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0~25%) to give 4.575 g of the desired product.

MS(M+H)+= 245.2, 246.9.

Stage 35-2, obtaining 2-(methoxymethoxy)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde:

To an anhydrous solution in dioxane (30 ml) of 3-bromo-2-(methoxymethoxy)benzaldehyde (10 ml, 2.45 g) was added Pd(dppf)Cl ₂ (0.10 eq., 1.0 mmol, 731 mg) , bis(pinacolato)diborane (2.0 eq, 20 mmol, 5.08 g) and KOAc (3.0 eq, 30 mmol, 2.94 g). N2 was bubbled through the reaction solution for 5 minutes. The reaction solution was heated at 80° C. for 2 h. Additional Pd(dppf)Cl ₂ (0.05 eq., 0.5 mmol, 350 mg), bis(pinacolato)diborane (1.0 eq., 10 mmol, 2.5 g) and sparged with N2. The resulting solution was heated at 80° C. for 24 hours. The reaction solution was filtered through pads of celite and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~5%) to obtain 6.01 g of the title compound.

Step 35-3, Preparation of benzyl-trans-6-[3-(3,5-difluorophenyl)-6-[3-formyl-2-(methoxymethoxy)phenyl]quinolin-4-yl]-octahydro-1H-pyrido[ 3,4-b]morpholine-1-carboxylate:

From benzyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]octahydro-1H-pyrido[3,4 -b]morpholin-1-carboxylate (0.166 mmol) and 2-(methoxymethoxy)-3(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.33 mmol) gave the title compound as a white solid using a method similar to that described in example 12, step 124.

MS(M+1)+=680.4.

Step 35-4, Preparation of 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-2-hydroxybenzaldehyde :

Benzyl-trans-6-[3-(3,5-difluorophenyl)-6-[3-formyl-2-(methoxymethoxy)phenyl]quinolin-4-yl]octahydro-1H-pyrido[3,4-b]morpholine -1-carboxylate (30 mg, 0.044 mmol) was combined with trifluoroacetic acid (0.4 ml) and thioanisole (0.02 ml). The resulting mixture was heated at 60° C. for 1 hour and then cooled to ambient temperature. MTBE was added and the solid was crushed and collected after filtration. This material was used in the next step without purification.

MS(M+1) ⁺ =502.4.

Step 35-5, Preparation of 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-6-( methoxyiminomethyl)phenol:

From 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2hydroxybenzaldehyde (20 mg) was obtained the specified connection using a method similar to that described in example 18, stage 18-2.

MS(M+l)+=531.4.

The following compounds were prepared in a manner similar to that described in Example 35, substituting with appropriate reagents and substrates as required:

connection no. MS (M+H) ⁺ 2-221 527.3 2-253 505.4

Example 36 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}acetic acid (Compound No. 2-201)

Step 36-1, Preparation of 2-[4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3-(3,5difluorophenyl)quinolin-6-yl]-6-cyanophenylmethyl carbonate:

To a DCM solution (3.0 ml) of {1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5difluorophenyl)quinolin-4-yl]piperidin-4-yl}carbamic tert-butyl ester acid (167 mg, 0.30 mmol) pyridine (8.0 eq., 0.24 mmol, 0.19 ml) and methyl chloroformate (4.0 eq., 1.2 mmol, 0.090 ml) were added at 0°C . The resulting mixture was heated at the same temperature for 0.5 h and complete consumption of the starting material was observed by LCMS analysis. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried with Na ₂ SO ₄ . The organic layer was concentrated and purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 135 mg

- 196 040023 of the required product.

MS(M+H)+=615.4.

Step 36-2, Preparation of 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6cyanophenylmethyl carbonate:

To a solution in dichloromethane (2.0 ml) of 2-[4-(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)-3(3,5-difluorophenyl)quinolin-6-yl] -6-cyanophenylmethyl carbonate (135 mg) was added trifluoroacetic acid (20 eq., 4.4 mmol, 0.34 ml) and the resulting mixture was stirred at ambient temperature for 3 h. MTBE was added to the reaction solution and the solid was broken up. The collected solid was purified by reverse phase C18 chromatography eluting with MeCN/water (0~80%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with MTBE and dried over MgSO ₄ . The organic solution was concentrated with HCl in ether (2.0 M trifluoroacetic acid) to give 55 mg of the final compound as the TFA salt.

MS(M+H) ⁺ =515.4.

Example 37 3-{4-[cis-4-Amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6yl}-2-(2-methoxyethoxy)benzonitrile (No. connections 2-224)

Step 37-1, preparation of benzyl trans-4-amino-3-hydroxypiperidine-1-carboxylate:

Benzyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (40 g, 171.48 mmol, 1.00 eq.), ethanol (400 ml), ammonium ( 400 ml). The resulting solution was stirred overnight at 70° C. in an oil bath. The mixture was concentrated and then diluted with 700 ml of water. The organics were extracted with 3x300 ml ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 27 g (63%) of the desired product as a yellow oil.

MS(M+H) ⁺ =251.1.

Step 37-2, Preparation of benzyl trans-4-[[(tert-butoxy)carbonyl]amino]-3-hydroxypiperidine-1carboxylate:

In a 1 L round bottom flask were placed benzyl trans-4-amino-3-hydroxypiperidine-1-carboxylate (27 g, 107.87 mmol, 1.00 eq.), dichloromethane (300 ml), (Boc) ₂ O (23, 5 g, 107.67 mmol, 1.00 eq.), triethylamine (16.4 g, 162.07 mmol, 1.50 eq.). The resulting solution was stirred overnight at room temperature and concentrated. The residue was purified using a silica gel column eluting with ethyl acetate/petroleum ether (2:1). Fractions containing the desired product were combined and concentrated in vacuo. This resulted in the formation of 24 g (63%) of benzyl trans-4[[(tert-butoxy)carbonyl]amino]-3-hydroxypiperidine-1-carboxylate as a yellow oil.

MS(M+H) ⁺ =351.2.

Step 37-3, preparation of tert-butyl N-[trans-3-hydroxypiperidin-4-yl]carbamate:

In a 1 L round bottom flask, purged and maintained under an inert nitrogen atmosphere, was placed benzyl trans-4-[[(tert-butoxy)carbonyl]amino]-3-hydroxypiperidine-1-carboxylate (24 g, 68.49 mmol, 1.00 eq.), methanol (400 ml) and carbon-supported palladium (2.4 g, 10%). The resulting solution was stirred at room temperature under H ₂ for 2 hours. The solids were filtered off. The mixture was concentrated under vacuum. This resulted in the formation of 14.5 g (98%) of tert-butyl-N-[trans-3-hydroxypiperidin-4-yl]carbamate as a white solid.

MS(M+H) ⁺ =217.1.

Step 37-4, Preparation of N-[trans-1-(6-bromo-3-chloroquinolin-4-yl)-3-hydroxypiperidin-4yl]carbamate:

In a 250 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was placed 6-bromo-3,4-dichloroquinoline (8.5 g, 30.69 mmol, 1.00 eq.), NMP (80 ml), DIEA (7.9 g, 61.13 mmol, 2.00 eq.), tert-Butyl N-[trans-3-hydroxypiperidin-4-yl]carbamate (7.9 g, 36.53 mmol, 1.20 equiv.). The resulting solution was stirred overnight at 130°C in an oil bath, cooled to rt, and then diluted with 300 ml of water and extracted with 3x100 ml of ethyl acetate. The organic layers were combined and washed with 2x300 ml of brine, dried over anhydrous sodium sulfate and concentrated after filtration of the solids. The residue was purified using a silica gel column eluting with ethyl acetate/petroleum ether (1:2). Fractions containing the desired product were combined and concentrated in vacuo to give 9 g (64%) of the title compound as a white solid.

MS (M+H) ⁺ = 456.1.

Step 37-5, Preparation of tert-butyl N-[1-(6-bromo-3-chloroquinolin-4-yl)-3-oxopiperidin-4yl]carbamate:

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To a 500 ml 3-necked round bottom flask was placed tert-butyl-N-[trans-1-(6-bromo-3chloroquinolin-4-yl)-3-hydroxypiperidin-4-yl]carbamate (9 g, 19.70 mmol , 1.00 eq.), dichloromethane (150 ml), Dess-Martin periodinan (13 g, 1.50 eq.) was added in several portions. The resulting solution was stirred for 2 h at rt, then quenched with 10 ml of an aqueous solution of Na ₂ S ₂ O ₃ . The mixture was extracted with 3x200 ml dichloromethane and the combined organic layers were washed with 2x200 ml brine, dried over anhydrous sodium sulfate and concentrated after solids were removed by filtration to give 9 g (100%) of the title compound as a white solid.

MS(M+H)+=454.0.

Step 37-6, Preparation of tert-butyl M-[cis-1-(6-bromo-3-chloroquinolin-4-yl)-3-hydroxypiperidin-4yl]carbamate:

Into a 500 ml 3-necked round bottom flask, purged and maintained under an inert nitrogen atmosphere, was placed tert-butyl-N-[(1-(6-bromo-3-chloroquinolin-4-yl)-3-oxo-piperidin-4-yl ]carbamate (9 g, 19.79 mmol, 1.00 eq.), anhydrous oxolane (100 ml) The flask was cooled to -78°C, and then L-selectride (25.7 ml, 1.30 The resulting solution was stirred for 2 h at -60°C, then quenched by adding 30 ml of ethanol. The mixture was diluted with 200 ml of saturated aqueous NH ₄ Cl. Then the solids were filtered, the resulting solution was extracted with 3x200 ml of dichloromethane, and the combined organic layers dried over anhydrous sodium sulfate and concentrated after removal of solids The crude material was purified by prep HPLC on a C18 column to give 5 g (55%) of the title compound as a white solid.

MS(M+H)+=456.1.

Step 37-7, obtaining cis-4-amino-1-(6-bromo-3-chloroquinolin-4-yl)piperidin-3-ol:

In a 250 ml round bottom flask was placed tert-butyl-N-[cis-1-(6-bromo-3-chloroquinolin-4yl)-3-hydroxypiperidin-4-yl]carbamate (4.8 g, 10.51 mmol, 1.00 eq.), dichloromethane (50 ml). After that, trifluoroacetic acid (6 ml) was added dropwise with stirring at 0°C. The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated in vacuo to give 4.5 g (91%) of cis-4-amino-1-(6-bromo-3-chloroquinolin-4-yl)piperidin-3-ol as a yellow oil of the TFA salt.

MS (M+H) += 356.0.

Step 37-8, Preparation of benzyl-M-[(cis-1-(6-bromo-3-chloroquinolin-4-yl)-3-hydroxypiperidin-4yl]carbamate:

To cis-4-amino-1-(6-bromo-3-chloroquinolin-4-yl)piperidin-3-ol (4.5 g, 9.56 mmol, 1.00 eq.) in dichloromethane (80 ml) at 0° C., triethylamine (5 g, 49.41 mmol, 5.00 eq.) was added dropwise with stirring, and then Cbz-OSu (3 g, 1.20 eq.) was added in several portions. The resulting solution was stirred for a further 3 h at RT and then diluted with 300 ml H2O. The mixture was extracted with 3x100 ml dichloromethane and the combined organic layers were washed with 200 ml brine, dried over anhydrous sodium sulfate and concentrated under vacuum after solids filtration to give 3.57 g (76%) of the title compound as a light yellow solid.

MS(M+H)+=490.0.

Step 37-9, Preparation of benzyl-M-[cis-1-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl]-3hydroxypiperidin-4-yl]carbamate:

From benzyl N-[cis-1-(6-bromo-3-chloroquinolin-4-yl)-3-hydroxypiperidin-4-yl]carbamate (98 mg, 0.20 mmol) and 3-cyano-2-hydroxyphenylboronic acid (0.5 mg, 0.81 mmol) received the specified connection using a method similar to that described in example 7, stage 7-2. The reaction solution was diluted with ethyl acetate, washed with water and brine, dried over MgSO ₄ and concentrated. The crude material was used in the next step without further purification.

MS(M+1) ⁺ =529.2.

Step 37-10, Preparation of benzyl-M-[cis-1-{3-chloro-6-[3-cyano-2-(2-methoxyethoxy)phenyl]quinolin4-yl}-3-hydroxypiperidin-4-yl]carbamate :

From crude benzyl-N-[cis-1-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl]-3-hydroxypiperidin-4-yl]carbamate and methoxyethyl bromide (0.8 mmol, 0.125 ml) obtained the specified connection using a method similar to that described in example 10, stage 10-2.

MS(M+1) ⁺ =587.4.

Step 37-11, Preparation of benzyl-M-[cis-1-{6-[3-cyano-2-(2-methoxyethoxy)phenyl]-3-(3-fluoro-5methylphenyl)quinolin-4-yl}-3 -hydroxypiperidin-4-yl]carbamate:

From benzyl-N-[cis-1-{3-chloro-6-[3-cyano-2-(2-methoxyethoxy)phenyl]quinolin-4-yl}-3-hydroxypiperidin-4-yl]carbamate (0.078 mmol , 46 mg) and 3-fluoro-5-methylphenylboronic acid (0.235 mmol, 36 mg) was obtained the specified connection using a method similar to that described in example 12, stage 12-4.

MS(M+1) ⁺ =661.4.

Step 37-12, Preparation of 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3-fluoro-5methylphenyl)quinolin-6-yl}-2-(2-methoxyethoxy) benzonitrile:

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From benzyl-N-[cis-1-{6-[3-cyano-2-(2-methoxyethoxy)phenyl]-3-(3-fluoro-5-methylphenyl)quinolin-4yl}-3-hydroxypiperidin-4- yl]carbamate (0.05 mmol, 32 mg) was obtained the specified connection using a method similar to that described in example 33, stage 33-7.

MS(M+l) ⁺ =527.3.

The following compounds were prepared in a manner similar to that described in Example 37, substituting with appropriate reagents and substrates as required. Compound 2-220 was prepared from compound 2-219 using the alkylation conditions described in Steps 37-10 followed by deprotection as described in Steps 37-12.

connection no. MS (M+H) ⁺ 2-220 545.3 2-225 531.2 2-232 549.5

Example 38 cis-4-Amino-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methylphenyl)quinolin-4-yl)piperidin-3 -ol (compound no. 2-227)

Step 38-1, Preparation of tert-butyl N-[cis-1-[3-chloro-6-(3-fluoro-2-formylphenyl)quinolin-4-yl]-3hydroxypiperidin-4-yl]carbamate:

Into a 50 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was placed tert-butyl-N-[cis-1-(6-bromo-3-chloroquinolin-4-yl)-3-hydroxypiperidin-4-yl] carbamate (120 mg, 0.26 mmol, 1.00 eq., prepared in Example 37, step 37-6), tetrahydrofuran/H ₂ O (3 ml), (3-fluoro2-formylphenyl)boronic acid (177.6 mg , 1.06 mmol, 4.00 equiv.), K ₃ PO ₄ (168 mg, 0.79 mmol, 3.00 equiv.), Pd ₂ (dba) ₃ chloroform (14.4 mg, 0.05 equiv. .), P(t-Bu) ₃ (7.2 mg, 0.10 eq.). The resulting solution was stirred for 4 hours at 30° C. and then concentrated in vacuo. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:3) to give 100 mg (76%) of the title compound as a light yellow solid.

MS(M+1) ⁺ =500.2.

Step 38-2, Preparation of N-[cis-1-[6-(3-fluoro-2-formylphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4yl]-3-hydroxypiperidin-4-yl] carbamate:

In an 8 ml vessel, purged and maintained under an inert nitrogen atmosphere, was placed tert-butyl-N-[cis-1-[3-chloro-6-(3-fluoro-2-formylphenyl)quinolin-4-yl]-3-hydroxypiperidine -4-yl]carbamate (100 mg, 0.20 mmol, 1.00 eq.), (3-fluoro-5-methylphenyl)boronic acid (62 mg, 0.40 mmol, 2.00 eq.), Pd (amphos)Cl ₂ (9 mg, 0.05 eq.), K ₃ PO ₄ (65 mg, 0.31 mmol, 3.00 eq.), toluene/H ₂ O (2 ml). The resulting solution was stirred for 10 h at 100°C and then concentrated under vacuum. The residue was purified on a silica gel column eluting with ethyl acetate/petroleum ether (1:3) to give 60 mg (52%) of the title compound as a light yellow solid. MS(M+l) ⁺ =574.2.

Step 38-3, Preparation of tert-butyl-N-[cis-1-(6-[3-fluoro-2-[(hydroxyimino)methyl]phenyl]-3-(3fluoro-5-methylphenyl)quinolin-4-yl )-3-hydroxypiperidin-4-yl]carbamate:

tert-Butyl-N-[cis-1-[6-(3-fluoro-2-formylphenyl)-3-(3-fluoro-5methylphenyl)quinolin-4-yl]-3-hydroxypiperidin- 4-yl]carbamate (60 mg, 0.10 mmol, 1.00 eq.), methanol (2 ml), pyridine (41 mg, 0.52 mmol, 3.00 eq.), HO-NH2.HCl ( 15 mg, 2.00 eq.). The resulting solution was stirred for 2 h at RT and then concentrated in vacuo to give 80 mg (crude) of the title compound as a light yellow solid.

MS(M+1) ⁺ =589.3.

Step 38-4, obtaining cis-4-amino-1-(6-(3-fluoro-2-(hydroxyiminomethyl)phenyl|-3-(3-fluoro-5methylphenyl)quinolin-4-yl)piperidin-3-ol :

tert-Butyl-N-[cis-1-(6-[3-fluoro-2[(hydroxyimino)methyl]phenyl]3-(3-fluoro-5-methylphenyl)quinolin-4-yl )-3-hydroxypiperidin-4-yl]carbamate (80 mg, 0.14 mmol, 1.00 eq.), dichloromethane (1 ml), trifluoroacetic acid (0.25 ml). The resulting solution was stirred for 2 h at RT and then concentrated in vacuo. The crude material was purified by prep. HPLC to give 28.5 mg (40%) of the title product as a yellow solid.

MS(M+1) ⁺ =489.2.

Example 39 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpho-Folin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-4-hydroxypyridin-3 -carbonitrile (compound no. 2-254)

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Step 39-1, preparation of 5-bromo-4-hydroxypyridine-3-carbonitrile: Br ₂ (1.2 eq. , 1.2 mmol, 0.062 ml) in 1.0 ml HOAc. The resulting solution was heated at 90° C. for 4 hours. The reaction solution was concentrated and slurried into i-PrOH (3 ml) and filtered to give 100 mg of the desired product.

MS(M+1)+=199.l.

Step 39-2, Obtaining 5-bromo-4-oxo-1-(prop-2-en-1-yl)-1,4-dihydropyridine-3-carbonitrile:

To a DMF solution (1.0 ml) of 5-bromo-4-hydroxypyridine-3-carbonitrile (77 mg, 0.4 mmol) was added K ₂ CO ₃ (2.0 eq., 0.8 mmol, 110 mg) and allyl bromide (1.5 eq., 0.6 mmol, 0.052 ml). The resulting mixture was heated at 70° C. for 0.5 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ , concentrated and purified by silica gel chromatography eluting with ethyl acetate/DCM (0-50%) to give 35 mg of the desired product.

MS(M+H)+ = 239.1.

Step 39-3, obtaining benzyl-trans-6-{6-[5-cyano-4-oxo-1-(prop-2-en-1-yl)-1,4-dihydropyridin3-yl]-3-( 3,5-difluorophenyl)quinolin-4-yl}-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:

From 5-bromo-4-oxo-1-(prop-2-en-1-yl)-1,4-dihydropyridine-3-carbonitrile (0.07 mmol, 17 mg) and trans-benzyl-6-[3 -(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]octahydro1H-pyrido[3,4-b]morpholine-1-carboxylate (0, 1 mmol obtained in example 33, stage 33-5) received the specified connection using a method similar to that described in example 12, stage 12-4. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ , concentrated. The resulting crude material was used in the next step without purification.

MS(M+1)+: 674.5.

Step 39-4, obtaining benzyl-trans-6-[6-(5-cyano-4-hydroxypyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3 ,4-b]morpholine-1-carboxylate:

To THF solution (1.0 ml) of crude trans-6-{6-[5-cyano-4-oxo-1-(prop-2-en-1-yl)-1,4dihydropyridin-3-yl]-3 -(3,5-difluorophenyl)quinolin-4-yl}-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate was added Pd ₂ (dba) ₃ (0.1 eq., 0.007 mmol, 7.0 mg), dppb (0.2 eq, 0.014 mmol, 7.0 mg) and thiosalicylic acid (4.5 eq, 0.32 mmol, 50 mg). The resulting solution was stirred under N ₂ for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ , concentrated. The resulting crude material was used in the next step without purification.

MS(M+1)+=634.4.

Step 39-5, Preparation of 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl|-4-hydroxypyridine -3-carbonitrile: From crude benzyl-trans-6-[6(5-cyano-4-hydroxypyridin-3-yl)-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido [3,4b]morpholine-1-carboxylate received the specified connection using a method similar to that described in example 33, stage 33-7. MS(M+l)+=500.4.

Example 40 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-4-methylpyridin-3- ol (compound no. 2-258)

Stage 40-1, obtaining 2-bromo-3-(methoxymethoxy)-4-methylpyridine:

To a dichloromethane (3.0 ml) solution of 2-bromo-4-methylpyridin-3-ol (0.516 mmol, 100 mg) was added DIPEA (1.5 eq., 0.774 mmol, 0.13 ml) and chloromethyl methyl ether (1 .5 eq., 0.774 mmol, 0.06 ml) at 0°C. The resulting mixture was stirred at rt. for 1 h. The reaction solution was diluted with dichloromethane, washed with water, dried with Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-25%) to give 80 mg of the title product.

MS(M+H)+= 232.2.

Step 40-2, preparation of tert-butyl trans-6-(3-bromo-6-chloroquinolin-4-yl)-octahydro-1Hpyrido[3,4-b]morpholine-1-carboxylate:

To an anhydrous DMSO (8 ml) solution of 3-bromo-4,6-dichloroquinoline (5.78 mmol, 1.6 g) was added

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Ν,N-diisopropylethylamine (4.0 eq., 23.1 mmol, 3.82 ml) and tert-butyl-trans-octahydro-1H-pyrido[3,4b]morpholine-1-carboxylate (1.0 eq. , 5.78 mmol, 1.4 g). N ₂ was bubbled through the reaction solution for 5 minutes and the resulting solution was heated at 140° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 1.31 g of the title product as a white solid.

MS (M+H)+=482.2.

Step 40-3, preparation of tert-butyl trans-6-[6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]octahydro1H-pyrido[3,4-b]morpholine-1-carboxylate:

To a THF solution (25 ml) of tert-butyl trans-6-(3-bromo-6-chloroquinolin-4-yl)octahydro-1H-pyrido[3,4b]morpholine-1-carboxylate (2.05 g, 4 .24 mmol) was added 3,5-difluorophenylboronic acid (2.0 eq., 6.48 mmol, 1.34 g), a mixture of tris(dibenzylideneacetone)dipalladium/tri-tert-butylphosphonium tetrafluoroborate (molar ratio: 1/1.2 ) (0.05 eq., 0.21 mmol, 276 mg) and K ₃ ΡΟ ₄ ·Η ₂ Ο (4.0 eq., 17.0 mmol, 3.9 g). N2 was bubbled through the reaction solution for 5 minutes and 2.5 ml of water was added. The resulting mixture was stirred at ambient temperature for 1 hour and complete conversion to the desired product was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over MgSO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 1.80 g of the title product as a white solid. MS (M+H) += 516.3.

Step 40-4, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2dioxaborolan-2-yl)quinolin-4-yl]-octahydro-1H -pyrido[3,4-b]morpholine-1-carboxylate:

Pd ₂ (dba) ₃ (0.05 equiv., 0.01 mmol, 9.2 mg) and Xphos (0.10 equiv., 0.02 mmol, 9.6 mg), t-butyl-trans-6 [6-chloro-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (0.2 mmol, 103 mg), bis( pinacolato)diborane (2.0 eq., 0.4 mmol, 102 g) and KOAc (3.0 eq., 0.6 mmol, 59 mg) were added to anhydrous dioxane (2 ml).

N2 was bubbled through the reaction solution for 5 minutes. The reaction solution was heated at 100° C. for 1 hour, and complete consumption of the starting material was observed by LCMS analysis. The crude reaction solution was used in the next step without further processing.

MS(M+H)+=608.4.

Step 40-5, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-[3-(methoxymethoxy)-4methylpyridin-2-yl]quinolin-4-yl]-octahydro-1H -pyrido[3,4-b]morpholine-1-carboxylate:

To the crude solution from step 40-4 was added 2-bromo-3-(methoxymethoxy)-4-methylpyridine (3.0 eq., 0.6 mmol, 139 mg), Pd(Amphos)Cl ₂ (0.15 eq. , 0.03 mmol, 21 mg), K2CO3 (3.0 eq., 0.6 mmol, 83 mg) and H2O (0.2 ml). N2 was bubbled through the reaction solution for 5 minutes. The reaction solution was heated at 100° C. for 1 hour, and complete consumption of the starting material was observed by LCMS analysis. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 55 mg of the desired product.

MS(M+H)+=633.5.

Step 40-6, Preparation of 2-{4-ptrans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-methylpyridin- 3-ola:

To a solution in dichloromethane (1.0 ml) tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-[3(methoxymethoxy)-4-methylpyridin-2-yl]quinolin-4-yl ]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (55 mg) was added with TFA (0.25 ml). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 1.0 ml) to give 34 mg of the final compound as the HCl salt.

MS(M+H)+=489.4.

The following compounds were prepared in a manner similar to that described in Example 40, substituting with appropriate reagents and substrates as required. Compound 2-259 was prepared from 2-bromo-3[(3,4-dimethoxyphenyl)methoxy]pyridine and deprotection was achieved by heating in TFA at 90° C. in the presence of thioanisole.

- 201 040023

Example 41 N-[(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}pyridine -2-yl)methylidene1hydroxylamine (compound no. 2-264)

Step 41-1, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(2-formylpyridin-3yl)quinolin-4-yl]-octahydro-III-pyrido[3,4 -b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]-octahydro-1H-pyrido[3, 4-b]morpholine-1-carboxylate (0.2 mmol crude, example 40, step 40-4) and 3-bromo-2-formylpyridine (1.25 eq., 0.25 mmol, 50 mg) gave the title compound using a method similar to that described in example 40, step 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 64 mg of the desired product.

MS(M+1)+=587.5.

Step 41-2, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-3-yl}quinolin-4-yl]-octahydro -1H-pyrido[3,4-b]morpholine-1-carboxylate:

To a solution in dichloromethane (1.0 ml) of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(2-formylpyridin3-yl)quinolin-4-yl]octahydro-1H-pyrido[ 3,4-b]morpholine-1-carboxylate (64 mg) was added pyridine (8.0 eq., 0.88 mmol, 0.07 ml) and hydroxylamine HO salt (4.0 eq., 0.44 mmol, 32 mg). The resulting mixture was stirred at ambient temperature for 1 hour. By LCMS analysis, complete consumption of the starting material and formation of the desired product were observed. The reaction solution was used in the next step without further purification.

Step 41-3, Preparation of N-[(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl} pyridin-2-yl)methylidene]hydroxylamine:

TFA (0.75 ml) was added to the crude dichloromethane solution from step 41-4. The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 1.0 mL) to give 42 mg of the title compound as the HCl salt. MS (M+H) += 502.4.

The following compounds were prepared in a manner similar to that described in Example 41, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-260 505.3 2-266 531.3

Example 42 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-3-aminopyridin-4- carbonitrile (compound no. 2-262)

Step 42-1, Obtaining tert-butyl-trans-6-[6-(4-cyano-3-fluoropyridin-2-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H- pyrido[3,4-b]morfoline-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]-octahydro-1H-pyrido[3, 4-b]morpholine-1-carboxylate (0.3 mmol crude, example 40, step 40-4) and 2-chloro-3-fluoro-4-cyanopyridine (3.0 eq., 1.0 mmol, 156 mg ) received the specified connection using a method similar to that described in example 40, stage 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried

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Na ₂ SO ₄ and concentrated. The resulting residue was used in the next step without purification.

MS(M+1)+=602.5.

Step 42-2, Preparation of tert-butyl-trans-6-[6-(4-cyano-3-{[(2,4-dimethoxyphenyl)methyl]amino}pyridin-2-yl)-3 -(3.5 -difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1 carboxylate:

To a DMSO solution (3.0 ml) of crude tert-butyl-trans-6-[6-(4-cyano-3-fluoropyridin-2-yl)-3(3,5-difluorophenyl)quinolin-4-yl]- octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate DIPEA and 2,4-dimethoxybenzylamine (0.3 ml) were added. The resulting mixture was heated at 130° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 150 mg of the title compound.

MS(M+1) ⁺ =749.5.

Step 42-3, Preparation of 2-{4-ptrans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-3-aminopyridin- 4-carbonitrile:

tert-Butyl-trans-6-[6-(4-cyano-3-{[(2,4-dimethoxyphenyl)methyl]amino}pyridin-2-yl)-3-(3,5difluorophenyl)quinolin-4-yl ]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (150 mg) was combined with TFA (3.0 ml) and thioanisole (0.2 ml). The resulting mixture was heated at 60° C. for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over MgSO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 1.0 mL) to give 44 mg of the title compound as the HCl salt.

MS (M+H) ⁺ = 499.2.

The following compounds were prepared in a manner similar to that described in Example 42, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-282 495.4

Example 43 3-{4-[trans-Octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}pyridin-2-amine (No. connections 2-246)

Step 43-1, Preparation of tert-butyl-trans-6-[6-(2-aminopyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3,4 -b]morpholine-1-carboxylate: From tert-butyltrans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl] -octahydro-Hnirido[3,4-b]morpholine-1-carboxylate (0.2 mmol crude, example 40, step 40-4) and 3-bromo-2-aminopyridine (2.0 eq., 0.4 mmol, 71 mg) received the specified connection using a method similar to that described in example 40, stage 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The resulting residue was used in the next step without purification. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 70 mg of the title compound. MS(M+1) ⁺ =574.6.

Step 43-2, Preparation of 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}pyridin-2- amine:

To a solution in dichloromethane (1.0 ml) tert-butyl-trans-6-[6-(2-aminopyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido [3,4-b]morpholine-1-carboxylate (70 mg) was added with TFA (0.25 ml). The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in EtOEt (2.0 M, 1.0 mL) to give 44 mg of the title compound as the HCl salt.

MS(M+H) ⁺ =474.2.

The following compounds were prepared in a manner similar to that described in Example 43, substituting with appropriate reagents and substrates as required.

- 203 040023

connection no. MS (M+H) ⁺ 2-261 502.4 2-265 492.4 2-268 519.3 2-267 514.5 2-283 474.0 2-284 504.4

Example 44 5-{4-[trans-Octahydro-1H-n-irido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinoline

6-yl}-4-aminopyridine-3-carbonitrile (compound no. 2-244)

Step 44-1, Preparation of tert-butyl-trans-6-[6-(4-amino-5-cyanopyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl]octahydro-1H-pyrido[ 3,4-b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]octahydro-1H-pyrido[3,4 -b]morpholine-1-carboxylate (0.15 mmol crude, example 40, step 40-4) and 4-amino-5-bromonicotinonitrile (1.5 eq., 0.23 mmol, 47 mg) gave the title compound with using a method similar to that described in example 40, step 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was used in the next step without purification.

The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 53 mg of the desired product.

MS(M+1) ⁺ =599.4.

Step 44-2, Preparation of 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-aminopyridine -3-carbonitrile:

To a solution in dichloromethane (1.0 ml) tert-butyl-trans-6-[6-(4-amino-5-cyanopyridin-3-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro -1H-pyrido[3,4-b]morpholine-1-carboxylate (53 mg) TFA (0.25 ml) was added. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0~40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in ethyl ether (2.0 M, 1.0 ml) to give 44 mg of the final compound as the HCl salt. MS(M+H) ⁺ =499.4.

Example 45 2-{4-[trans-Octahydro-1H-n-irido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-4-[(methoxyimino) methyl]pyridine-3-amine (compound no. 2-269)

Step 45-1, Preparation of tert-butyl-trans-6-[6-(3-amino-4-formylpyridin-2-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-nirido [3,4-b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]-octahydro-1H-pyrido[3, 4-b]morpholine-1-carboxylate (0.15 mmol crude, example 40, step 40-4) and 3-amino-2-bromopyridine-4-carbaldehyde (2.0 eq., 0.30 mmol, 64 mg ) received the specified connection using a method similar to that described in example 40, stage 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with MeOH/DCM (0~3%) to obtain 60 mg of the desired product.

MS(M+1) ⁺ =602.5.

Step 45-2, Preparation of tert-butyl-trans-6-(6-{3-amino-4-[(methoxyimino)methyl]pyridin-2-yl}-3(3,5-difluorophenyl)quinolin-4-yl )-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:

To a solution in dichloromethane (1.0 ml) tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(2-formylpyridin3-yl)quinolin-4-yl]-octahydro-1H-pyrido [3,4-b]morpholine-1-carboxylate (60 mg) was added pyridine (8.0 eq., 0.80 mmol, 0.08 ml) and methoxyamine HCl salt (4.0 eq., 0.40 mmol , 32 mg). The resulting mixture

- 204 040023 stirred at rt. within 1 h. Using LCMS analysis, the complete consumption of the starting material and the formation of the desired product were observed. The reaction solution was used in the next step without further purification.

MS(M+1)+ = 631.5.

Step 45-3, Preparation of 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-[ (methoxyimino)methyl]pyridine-3-amine:

TFA (1.0 ml) was added to the crude dichloromethane solution from step 45-2. The resulting mixture was stirred at ambient temperature for 0.5 h. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in ethyl ether (2.0 M, 1.0 ml) to give 47 mg of the title compound as the HCl salt.

MS(M+H)+ = 531.4.

Example 46 connections 2-248)

Step 46-1, Preparation of 3-bromo-2-[(3,4-dimethoxyphenyl)methoxy]pyridine:

To a THF solution (5.0 ml) of 3-bromo-2-hydroxypyridine (2.0 mmol, 348 mg) was added PPh ₃ (1.5 eq., 3.0 mmol, 786 mg), 3,4-dimethoxybenzyl alcohol (1.2 eq., 2.4 mmol, 0.356 ml) and diisopropyl azodicarboxylate (DIAD) (1.2 eq., 2.4 mmol, 0.46 ml) at 0°C. The resulting mixture was then stirred at rt. for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with EtOAc/hexane (0~30%) to obtain 227 mg of the title compound.

MS (M+1)+= 324.0.

Step 46-2, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-{2-[(3,4-dimethoxyphenyl)methoxy]pyridin-3-yl}quinoline-4- yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]-octahydro-1H-pyrido[3, 4-b]morpholine-1-carboxylate (0.42 mmol, concentrated crude after treatment and drying with Na ₂ SO ₄ , example 40, step 40-4) and 3-bromo-2-[(3,4dimethoxyphenyl)methoxy] pyridine (1.66 equiv., 0.69 mmol, 227 mg) received the specified connection using a method similar to that described in example 40, stage 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was used in the next step without purification. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 86 mg of the title compound.

MS (M+1)+= 725.7.

Step 46-3, Preparation of 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}pyridin-2- ola:

tert-Butyl-(4aR,8aR)-6-[3-(3,5-difluorophenyl)-6-{2-[(3,4-dimethoxyphenyl)methoxy]pyridin-3yl}quinolin-4-yl]octahydro -1H-pyrido[3,4-b]morpholine-1-carboxylate (86 mg) was combined with TFA (1.5 ml) and thioanisole (0.3 ml). The resulting mixture was stirred at 90° C. for 22 hours. The reaction solution was concentrated and purified by reverse phase C18 chromatography eluting with MeCN/water (0-40%). Pure fractions were combined, neutralized with saturated NaHCO ₃ /NaCl, extracted with ethyl acetate and dried over Na ₂ SO ₄ . The organic solution was concentrated with HCl in ethyl ether (2.0 M, 1.0 ml) to give 18 mg of the title compound as the HCl salt.

MS(M+H)+=475.2.

Example 47 3-[5-(4-Aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2hydroxybenzonitrile (Compound No. 4-1)

Stage 47-1, obtaining 6-bromo-3-chloro-1,8-naphthyridin-4-ol:

.To a solution of 6-bromo-1,8-naphthyridin-4-ol (1.14 g, 5.07 mmol) in acetic acid (20 ml) was added NCS (0.81 g, 6.08 mmol). The mixture was heated at 100° C. for 1 h and then cooled to rt. solid

- 205 040023 material was collected by vacuum filtration and washed with acetic acid and water to give the title compound (0.73 g, 2.79 mmol, 55.1% yield) as a brown solid.

(M+1)+= 259.0.

Step 47-2, preparation of 6-bromo-3,4-dichloro-1,8-naphthyridine: To 6-bromo-3-chloro-1,8-naphthyridine-4ol (0.73 g, 2.79 mmol) was added POCl ₃ (3 ml) and the mixture was heated at 130°C for 25 min. The mixture was poured into ice and the solid was collected by vacuum filtration and washed with water to give the title compound (0.66 g, 2.36 mmol, 84.6% yield) as a brown solid.

(M+1) ⁺ = 279.0.

Step 47-3, Preparation of tert-butyl N-[1-(6-bromo-3-chloro-1,8-naphthyridin-4-yl)piperidin-4yl]carbamate:

To a mixture of 6-bromo-3,4-dichloro-1,8-naphthyridine (0.657 g, 2.364 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (0.916 g, 3.546 mmol) in a stoppered tube was added DMSO (8 ml) and DIEA (1.2 ml, 6.892 mmol). The mixture was heated at 130° C. overnight. The mixture was diluted with water and the solid was collected by vacuum filtration and washed with water. The crude solid was purified by silica gel column chromatography to give the title compound (0.92 g, 2.09 mmol, 88.3% yield) as a light orange solid.

(M + 1) ⁺ = 441.3.

Step 47-4, Preparation of tert-butyl-N-(1-{3-chloro-6-[3-cyano-2-(methoxymethoxy)phenyl]-1,8naphthyridin-4-yl|piperidin-4-yl)carbamate :

To a mixture of tert-butyl K-[1-(6-bromo-3-chloro-1,8-naphthyridin-4-yl)piperidin-4-yl]carbamate (0.275 g, 0.622 mmol), 2-methoxymethoxy-3 -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.216 g, 0.747 mmol), tris(dibenzylideneacetone)dipalladium/tri-tert-butylphosphonium tetrafluoroborate mixture (molar ratio : 1 / 1.2) (40.5 mg, 0.031 mmol) and K ₃ PO ₄ -H ₂ O (0.57 g, 2.49 mmol) in a stoppered tube were added THF (5 ml) and water (0. 5 ml). The mixture was sparged with N ₂ (gas) for 10 min and then stirred at rt. within 45 min. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (211.4 mg, 0.40 mmol, 64.8% yield) as a medium brown solid.

MS(M+1) ⁺ =524.4.

Step 47-5, Preparation of tert-butyl-N-(1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5difluorophenyl)-1,8-naphthyridin-4-yl}piperidine -4-yl) carbamate:

To a mixture of tert-butyl N-(1-{3-chloro-6-[3-cyano-2-(methoxymethoxy)phenyl]-1,8-naphthyridin-4yl}piperidin-4-yl)carbamate (106.8 mg, 0.20 mmol), 3,5-difluorophenylboronic acid (64.4 mg, 0.41 mmol), Pd[t-Bu ₂ P(4-NMe ₂ C ₆ H ₄ )] ₂ Cl ₂ ) (14 .4 mg, 0.02 mmol) and K ₂ CO ₃ (84.6 mg, 0.61 mmol) in a stoppered tube were added dioxane (3 ml) and water (0.3 ml). The mixture was sparged with N ₂ (gas) for 10 minutes and then heated at 100° C. for 50 minutes. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (104.8 mg, 0.17 mmol, 85.3% yield) as a brown gum.

MS(M+1) ⁺ =602.6.

Step 47-6, Preparation of 3-[5-(4-aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]2-hydroxybenzonitrile:

To a solution of tert-butyl-K-(1-{6-[3-cyano-2-(methoxymethoxy)phenyl]-3-(3,5-difluorophenyl)-1,8naphthyridin-4-yl}piperidin-4-yl )carbamate (104.8 mg, 0.17 mmol) in DCM (0.8 ml) TFA (0.2 ml) was added. The mixture was stirred at rt. over 1 h. The mixture was concentrated and purified by reverse phase C ₁₈ column chromatography to give the title compound (55.5 mg, 0.12 mmol, 69.5% yield) as a yellow solid.

MS(M+1) ⁺ =458.2.

The following compounds were prepared in a manner similar to that described in Example 47, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 4-2 454.0 4-3 472.0 4-4 470.4

Example 48 3-[3-(3-Fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6-yl]-2hydroxybenzonitrile (Comp. No. 2-270 )

- 206 040023

Step 48-1, preparation of benzyl 3-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}morpholine-4carboxylate:

To a dichloromethane (5.0 ml) solution of tert-butyl-3-(morpholin-3-yl)azetidine-1-carboxylate (200 mg, 0.82 mmol) was added N-(benzyloxycarbonyloxy)succinimide (1.5 eq. , 1.24 mmol, 310 mg). The resulting mixture was stirred at ambient temperature overnight. The reaction solution was diluted with dichloromethane, washed with water, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to obtain 286 mg of the title compound as a colorless oil.

MS(M+1)+= 377.5.

Step 48-2, obtaining benzyl-3-(azetidin-3-yl)morpholine-4-carboxylate:

Benzyl 3-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}morpholine-4-carboxylate (286 mg) was combined with HCl in dioxane (4.0 M, 4.0 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated to give 200 mg of the title compound as the HCl salt.

MS(M+1) ⁺ =277.1.

Step 48-3, Preparation of benzyl 3-[1-(3-bromo-6-chloroquinolin-4-yl)azetidin-3-yl]morpholine-4carboxylate: From benzyl-3-(azetidin-3-yl)morpholin- 4-carboxylate (0.72 mmol) and 3-bromo-4,6-dichloroquinoline (1.40 eq., 1.0 mmol) the title compound was prepared using a method similar to that described in Example 40, step 40-2.

MS(M+1) ⁺ =516.2.

Step 48-4, Preparation of benzyl 3-{1-[6-chloro-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]azetidin-3yl}morpholine-4-carboxylate:

From benzyl 3-[1-(3-bromo-6-chloroquinolin-4-yl)azetidin-3-yl]morpholine-4-carboxylate (50 mg) the title compound was obtained using a method similar to that described in Example 40, step 403. The crude reaction material was worked up, dried, concentrated and used in the next step without further purification. MS(M+1) ⁺ =546.5.

Step 48-5, Preparation of benzyl-3-{1-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]azetidin-3-yl}morpholine -4-carboxylate:

From crude benzyl 3-{1-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4yl]azetidin-3-yl}morpholine-4-carboxylate and 3 -cyano-2-hydroxyphenylboronic acid (5.0 eq., 0.5 mmol, 75 mg) was obtained as a white solid using a method similar to that described in example 12, stage 12-4. The crude reaction material was worked up, dried, concentrated and used in the next step without further purification.

MS(M+1) ⁺ =629.4.

Step 48-6, Preparation of 3-[3-(3-fluoro-5-methylphenyl)-4-[3-(morpholin-3-yl)azetidin-1-yl]quinolin-6yl}-2-hydroxybenzonitrile:

From crude benzyl 3-{1-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4yl]azetidin-3-yl}morpholine-4-carboxylate (50 mg) received the specified connection using a method similar to that described in example 33, stage 33-7.

MS(M+1) ⁺ =495.5.

The following compounds were prepared in a manner similar to that described in Example 48, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-271 499.3

Example 49 2-{4-[trans-Octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-4-ethynylpyridin-3- amine (compound no. 2-277)

Step 49-1, Preparation of tert-butyl-trans-6-[6-(3-amino-4-chloropyridin-2-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido [3,4-b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4yl]-octahydro-1H-pyrido[3, 4-b]morpholine-1-carboxylate (0.275 mmol crude, example 40, step 40-4) and 2-bromo-4-chloropyridine-3-aminopyridine (2.0 eq., 0.55 mmol, 120 mg) were obtained the specified connection using a method similar to that described in example 40, stage 40-5. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to obtain 82 mg of the desired product.

- 207 040023

MS(M+1)+=608.3.

Step 49-2, tert-Butyl-trans-6-(6-{3-amino-4-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}-3-(3,5difluorophenyl)quinolin-4-yl )-octahydro-III-pyrido[3,4-b]morpholine-1-carboxylate:

To a solution in toluene of tert-butyl-trans-6-[6-(3-amino-4-chloropyridin-2-yl)-3-(3,5difluorophenyl)quinolin-4-yl]-octahydro-1H-pyrido[3 ,4-b]morpholine-1-carboxylate (26 mg, 0.041 mmol) and 1-tributylstannyl-2-trimethylsilylacetylene (3.0 eq., 0.123 mmol, 0.048 ml) were added Pd(Amphos)Cl ₂ (0.2 eq. ., 5.9 mg). N2 was bubbled through the reaction solution for 5 minutes and heated at 100° C. for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/hexane (0-50%) to give 16 mg of the title compound.

MS(M+1)+=670.6.

Step 49-3, Preparation of 2-{4-ptrans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}-4-ethynylpyridine- 3-amines:

To a solution of THF/MeOH (2:1, 3.0 ml) was added tert-butyl-trans-6-(6-{3-amino-4-[2(trimethylsilyl)ethynyl]pyridin-2-yl}-3- (3,5-difluorophenyl)quinolin-4-yl)octahydro-1H-pyrido[3,4b]morpholine-1-carboxylate (16 mg, 0.024 mmol) and K ₂ CO ₃ (3.0 eq., 10 mg) at 0°C. The resulting mixture was stirred at the same temperature for 0.5 hours. The mixture was filtered and concentrated. The resulting residue was dissolved in dichloromethane (1.0 ml) and TFA (0.2 ml) was added. The reaction mixture was stirred at ambient temperature for 0.5 h. The mixture was concentrated and purified by reverse phase C18 column chromatography to give the title compound.

MS(M+1)+ = 498.4.

The following compounds were prepared in a manner similar to that described in Example 49, substituting with appropriate reagents and substrates as required.

connection no. MS (M+H) ⁺ 2-272 512.4 2-274 498.3

Example 50 2-yl)-3-methoxyurea (compound no. 2-273)

Step 50-1, Preparation of tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-{2-[(methoxycarbamoyl)amino]pyridin-3-yl}quinolin-4-yl]-octahydro -1H-pyrido[3,4-b]morpholine-1-carboxylate:

From tert-butyl-trans-6-[6-(2-aminopyridin-3-yl)-3-(3,5-difluorophenyl)quinolin-4-yl]-octahydro-1Hpyrido[3,4-b]morpholine- 1-carboxylate (92 mg, 0.16 mmol, example 43, step 43-1) was obtained using a method similar to that described in example 26, step 26-3.

MS(M+1)+=647.3.

Step 50-2, preparation of 1-(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5difluorophenyl)quinolin-6-yl}pyridine -2-yl)-3-methoxyureas:

From tert-butyl-trans-6-[3-(3,5-difluorophenyl)-6-{2-[(methoxycarbamoyl)amino]pyridin-3-yl}quinolin-4-yl]-octahydro-1H-pyrido[ 3,4-b]morpholine-1-carboxylate (43 mg) received the specified connection using a method similar to that described in example 26, stage 26-4.

MS(M+1)+=547.4.

Example 51 Chiral SFC Separation of Compounds 2-19 - 2-190 and 2-193

Two enantiomers of 3-{4-[trans-Oktahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile (2 -19, 2.1 g) are 3-{4-[(4αS,8αS)-octahydro1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin- 6-yl}-2-hydroxybenzonitrile (2-190) and 3-{4-[(4αR,8αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3, 5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile (2-193). The two enantiomers were separated by chiral SFC using the conditions described below.

Thar SFC 350, column: CHIRALPAK AD-H, 50x250 mm, 5 µm; mobile phase A: CO2; mobile phase B: MeOH containing 0.1% diethylamine; flow rate: 150 g/min; gradient: 50% B; injection volume: 1 ml (57.5 mg/ml in MeOH); processing cycle: 4 min; detector: 220 nm. This resulted in a combination of peak 1 (enantiomer A; Rt=1.924 min; 837.7 mg) as a light yellow solid and peak 2 (enantiomer B, Rt=3.493 min; 830.1 mg) as a light yellow solid. substances.

MS (M+1)+= 499.2 for both compounds 2-190 and 2-193.

- 208 040023

Example A-1. Parenteral pharmaceutical composition

To obtain a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof was dissolved in sterile water and then mixed with 10 ml of 0 .9% sterile saline. A suitable buffer is optionally added as well as an optional acid or base to adjust the pH. The mixture was formulated into a unit dosage form suitable for administration by injection.

Example A-2. oral solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, was added to water (with optional solubilizer(s), optional buffer(s), and taste masking excipients) to give 20 mg/ml solution.

Example A-3. oral tablet

A tablet is prepared by mixing 20-50% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose and 1-10% by weight of magnesium stearate or other suitable excipients. substances. Tablets were obtained by direct compression. The total weight of the compressed tablets was maintained at 100-500 mg.

Example A-4. oral capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof was mixed with starch or other suitable powder mixture. The mixture was included in a dosage unit for oral delivery, such as a hard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin) and the capsule is capped.

Example A-5. Gel composition for topical application

To prepare a pharmaceutical gel composition for topical application, a compound of formula (I) or a pharmaceutically acceptable salt thereof was mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate and purified with USP alcohol. The resulting gel mixture is then included in containers, such as tubes, which are suitable for topical application.

Example B-1.

SSTR assays Functional assays for SSTR2 agonists

Overview: All five SSTR subtypes are G-protein coupled receptors (GPCRs) that result in a decrease in intracellular cyclic AMP (cAMP) when activated by an agonist. Thus, measurement of intracellular cAMP levels can be used to determine whether compounds of the present invention are SSTR subtype agonists (John Kelly, Troy Stevens, W. Joseph Thompson, and Roland Seifert, Current Protocols in Pharmacology, 2005, 2.2.1-2.2 ). Analysis of intracellular cAMP in association with SSTR2 is described below. Human SSTR assays 1, 3, 4, and 5 follow the same protocols as SSTR2.

cAMP assay protocol

Four days prior to analysis, 5,000 Chinese hamster ovary cells (Cho-Κι, ATCC #CCL-61) stably expressing human SSTR2 were plated into each well of a 96-well tissue culture plate treated with Ham's F12 growth medium (ThermoFisher #10 -080-CM) supplemented with 10% donor bovine serum (Gemini Bio-Products No. 100-506), 100 U/ml penicillin; 100 µg/ml streptomycin; 2 mM L-glutamine (Gemini Bio-Products no. 400-110) and 0.2 mg/ml hygromycin B (GoldBio no. 31282-04-9). Cells were cultured at 37°C, 5% CO ₂ and 95% humidity. On the day of analysis, the medium was aspirated and the cells were treated with 50 μl of 1.6 μM NKH477 (Sigma No. N3290) together with various dilutions of compounds of the present invention in assay buffer [1x Hank's balanced salt solution (ThermoFisher No. SH3058802), 0.5 mM HEPES pH 7.4, 0.1% bovine serum albumin, 0.2 mM 3-isobutyl-1-methixanthine (IBMX, VWR No. 200002-790)]. Cells were incubated for 20 min at 37°C (final concentration of the compounds of the present invention is typically 0-10,000 nM). Cells were treated with 50 μl lysis buffer (HRTF cAMP kit, Cisbio). The lysate was transferred to 384-well plates, cAMP detection kit and imaging antibodies were added and incubated for 1-24 hours at room temperature. The time resolved fluorescent signal was read using a Tecan M1000 Pro multiplate reader. Intracellular cAMP concentrations were calculated from regression with a standard curve and plotted against the concentration of compounds of the present invention and EC ₅₀ compounds were calculated using standard methods. All data manipulations were performed in GraphPad Prism v6.

An exemplary biological activity of the compounds is shown in the following table.

- 209 040023 by assessing the inhibition of cAMP activities by human SST2R, where A means < 10 nM; B means >10 nM and <100 nM; C means >100 nM and <1000 nM; D means >1000 nM.

connection no. ECso 1-1 A 1-2 A 1-3 WITH 1-4 A 1-5 A 1-6 A 1-7 A 1-8 A 1-9 IN 1-10 A 1-11 A 1-12 A 1-13 A 1-14 A 1-15 IN 1-16 A

connection no. ECso 1-17 A 1-18 A 1-19 A 1-20 IN 1-21 A 1-22 A 1-23 A 1-24 A 1-25 A 1-26 A 1-27 A 1-28 A 1-29 A 1-30 A 1-31 A 1-32 A

- 210 040023

- 211 040023

- 212 040023

- 213 040023

2-247 A 2-248 A 2-249 A 2-250 A 2-251 C 2-251 A 2-252 A 2-253 A 2-254 IN 2-255 IN 2-256 IN 2-257 IN 2-258 A 2-259 A 2-260 A 2-261 IN 2-262 A 2-263 A 2-264 A 2-265 A 2-266 A 2-267 IN

2-268 IN 2-269 A 2-270 A 2-271 IN 2-272 A 2-273 A 2-274 A 2-275 A 2-277 A 2-282 A 2-283 IN 3-1 A 3-2 A 3-3 A 3-4 A 3-5 A 3-9 A 3-10 A 4-1 IN 4-2 A 4-3 A 4-4 A

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are within the spirit and scope of this application and the scope of the appended claims.

Claims (17)

CLAIM 1. A compound of formula (A2), or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof where each R ^a is independently -OCH ₃ , -OCF ₃ , -CH ₂ OH or -CH ₂ CH ₂ OH; each R ^b is independently —OCH ₃ or —OCF ₃ ; m is 1 or 2; n is 0, 1 or 2; R ^B is hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ , -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -C(CH3)3, -CH2OH, -CH2CN, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, -CO2H, -CO2CH3 , -CO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHOCH3, -C(=O)N(CH3)2, - SO2N(CH3)2, -C(=NOCH3)H, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -NH2, -NHCH3, -N (CH3)2, - 214 040023 -NHCO2CH3, -NHSO2CH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, CH(CF3)NH2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) (CH ₂ CH ₃ ), -C (CH ₃ ) ₃ , -CH2OH, -CH2CN, -CH2F, -CHF2, -CF ₃ , pyrrolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, -CN, -OH, -OCH ₃ , -OCH2CH3, -OCF ₃ , -OCH ₂ OCH ₃ , -OCH ₂ OCH ₂ CH ₃ , -OCH2CH2OH, -C(=O)NHOCH ₃ , -C(=NOH)H, -C(=NOCH ₃ )H, -CH2C(=O)NH2, -NH2, NHCO2CH3, NHSO2CH3, NH(C=O)NHCH ₃ , NH(C=O)NHOCH ₃ or CH(CF ₃ )NH ₂ ; or if one R ^c and one R ^d are on adjacent atoms of ring B, then the adjacent R ^c and R ^d groups are taken together with the intermediate atoms to which they are attached to form a 5- or 6-membered monocyclic heterocycle containing at least 1 atom N, O or S and a total of 1-2 N atoms, 0-2 O atoms and 0-1 S atoms in the heterocycle; p is 1 or 2; q is 0, 1 or 2; X is CR ^f or N; Y is CR ^f or N; Z is CR ^f or N; R ^e is hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCH2CH3 or -OCF3; each R ^f is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3, -OCH2CH3 or - OCF3; R ¹ is hydrogen; R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl or tert- butyl or oxetanyl; R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH ₃ )2, -OCH2CH3, -OCF3, -CH ₃ , -CH ₂ CH ₃ , -CH2F , -CHF2 or -CF ₃ , -CN, -C(=O)OCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ or -C(=O)N(CH ₃ ) ₂ ; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form azetinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or azepanyl. 2. The compound of claim 1, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, wherein each R ^a is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN , -OH, -OCH3, -OCF3, -CH2OH or -CH2CH2OH; each R ^b is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH3 or -OCF3; each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, -C(=O)NH2, - C(=NOCH3)H, -SO2N(CH3)2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, C1, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -OCH ₂ OCH ₃ , -CH2OH, -OCH2CH2OH, -C(=O)NHOCH ₃ , NH2, NHCO2CH3, NH(C=O)NHOCH ₃ or CH ₂ (C=O)NH ₂ ; or if one R ^c and one R ^d are on adjacent ring B atoms, then the adjacent R ^c and R ^d groups are taken together with the intermediates to which they are attached to form a 5-membered monocyclic heterocycle. 3. A compound according to claim 1 or 2, wherein the compound has the following structure, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof R ¹ .R ² N 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, where each R ^a is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3, -OCF3, -CH2OH or -CH2CH2OH; each R ^b is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, or -OCF3; each R ^c is independently hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, -NH2, -C(=O)NH2, - C(=NOCH3)H, -SO2N(CH3)2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CN, -OH, -OCH3, -OCF3, -OCH2OCH3, -CH2OH, -OCH2CH2OH, -C(=O)NHOCH3, -NH2, -NHCO2CH3, - 215 040023 -NH(C=O)NHOCH ₃ or -CH ₂ (C=O)NH ₂ ; R ^e is hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3 or -OCF3; each R ^f is hydrogen; R ¹ is hydrogen; R ² is hydrogen; R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH ₃ , -NH2, -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₂ CH ₃ , -OCF ₃ , -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N( CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl. 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, where each R ^a is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OSN ₃ , -OCF ₃ , -CH2OH or -CH2CH2OH; each R ^b is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; each R ^c is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ , -NH2, -C(=O)NH2 or -C(=NOCH3)H; each R ^d is independently hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , or -NH2; X is CR ^f ; Y is CR ^f and Z is CR ^f or X is N; Y is CR ^f and Z is CR ^f ; or X is CR ^f ; Y is N and Z is CR ^f ; or X is CR ^f ; Y is CR ^f and Z is N; R ^e is hydrogen, F, or Cl; each R ^f is hydrogen; R ¹ is hydrogen; R ² is hydrogen; R ⁵ is hydrogen or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form morpholinyl. 6. A compound according to any one of claims 1 to 3, wherein the compound is characterized by the following structure of formula (AVb), or its pharmaceutically acceptable salt, diastereomeric mixture, or individual enantiomers wherein ^RB represents R ¹ is hydrogen; R ² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, isopropyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, tert- butyl or oxetanyl; R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, - CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or azepanyl. 7. The compound according to claim 6 or its pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers, where R ^a is hydrogen, F, Cl, Br, -CH3, -CH2F, -CHF2, -CF3, -CN, -OH, -OCH3, -OCF3, - 216 040023 -CH2OH or -CH2CH2OH; R ^b is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; each R ^c is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -NH2, -C(=O)NH2, -C(=NOCH ₃ )H, -SO2N(CH ₃ )2, azetidinyl or pyrrolidinyl; each R ^d is independently hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ , -OCF ₃ , -OCH ₂ OCH ₃ , -CH2OH , -OCH2CH2OH, -C(=O)NHOCH ₃ , -NH2, -NHCO2CH3, -NH(C=O)NHOCH3 or -CH2(C=O)NH2; R ^e is hydrogen, F, Cl, Br, -CH ₃ , -CH2F, -CHF2, -CF ₃ , -CN, -OH, -OCH ₃ or -OCF ₃ ; R ¹ is hydrogen; R ² is hydrogen; R ⁵ is hydrogen, F, Cl, Br, -OH, -OCH3, -NH ₂ , -NHCH3, -N(CH ₃ ) ₂ , -OCH2CH3, -OCF3, -CH3, -CH2CH3, -CH2F, -CHF2 , -CF3, -CN, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3 or -C(=O)N(CH3)2; or R ² and R ⁵ are taken together with the intermediates to which they are attached to form piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl. 8. A compound according to claim 6 or 7, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, wherein R ^a is hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -CH2OH, -CH2CH2OH, -OCH ₃ , or -OCF3; R ^b is hydrogen, F, Cl, -CH ₃ , -CF ₃ , -CN, -OH, -OCH ₃ , or -OCF ₃ ; each R ^c is independently hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -NH2, -OCH3, -OCF3, -CONH2, or -C(=NOCH3)H; each R ^d is independently hydrogen, F, Cl, -CH3, -CF3, -CN, -OH, -NH2, -OCH3, or -OCF3; R ^e is hydrogen; R ¹ is hydrogen; R ² is hydrogen; R ⁵ is hydrogen or R ² and R ⁵ are taken together with the intermediate atoms to which they are attached to form morpholinyl. 9. The compound that is 1-1: 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-2: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dimethylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-4: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-5: 3-{4-[trans-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}5-fluorobenzamide; 1-6: 3-{4-[cis-4-amino-3-fluoropiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl}-5fluorobenzamide; 1-7: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-8: 5-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro1H-1,3 -benzodiazol-2-one; 1-9: 4-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro1H-1,3 -benzodiazol-2-one; 1-10: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl}-5-fluorobenzamide; 1-11: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-12: 3-[4-(4-Aminopiperidin-1-yl)-7-chloro-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2hydroxybenzonitrile; 1-13: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-14: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-15: 3-[4-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)cinnolin-3-yl]-5-fluorobenzamide; 1-16: 5-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2,3-dihydro-1H-1,3benzodiazol-2 -He; 1-17: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-18: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-19: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-chloro-5-fluorophenyl)cinnolin-6-yl]-2-hydroxybenzo- 217 040023 nitrile; 1-20: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-21: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-2-hydroxybenzonitrile; 1-22: 3-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile; 1-23: 6-[4-(4-Aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-4-fluoro-2,3-dihydro1H-1,3 -benzodiazol-2-one; 1-24: 4-[4-(4-Aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6-fluoro-2,3-dihydro1H-1,3 -benzodiazol-2-one; 1-25: 3-[7-Chloro-3-(3-fluoro-5-methylphenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin-6yl]-5-fluorobenzamide ; 1-26: 3-{4-[trans-4-amino-3-hydroxypiperidin-1-yl]-7-chloro-3-(3-fluoro-5-methylphenyl)cinnolin-6yl}-5-fluorobenzamide; 1-27: 3-[4-(4-aminopiperidin-1-yl)-7-chloro-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluoro-2-hydroxybenzonitrile; 1-28: 6-[4-(4-Aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-4-fluoro-2,3-dihydro-III1,3-benzodiazol -2-he; 1-29: 2-[4-(4-aminopiperidin-1-yl)-3-(3-chloro-5-methylphenyl)cinnolin-6-yl]-6-fluorophenol; 1-30: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-dichlorophenyl)cinnolin-6-yl]-5-fluorobenzamide; 1-31: 3-[3-(3,5-dichlorophenyl)-4-{4-[(oxetan-3-yl)amino]piperidin-1-yl}cinnolin-6-yl]-5-fluorobenzamide; 1-32: 3-[3-(3,5-dichlorophenyl)-4-{4-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}cinnolin-6-yl]-5fluorobenzamide; 1-33: 3-[3-(3,5-dichlorophenyl)-4-{4-[(2-fluoroethyl)amino]piperidin-1-yl}cinnolin-6-yl]-5-fluorobenzamide; 2-1: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-2: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile; 2-3: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile; 2-4: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}benzonitrile; 2-5: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile; 2-6: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]phenol; 2-7: 6-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]pyridine-2-carboxamide; 2-8: 4-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1H-1,3benzodiazol-2 -He; 2-9: 5-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2,3-dihydro-1H-1,3benzodiazol-2 -He; 2-10: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile; 2-16: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-hydroxybenzonitrile; 2-19: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}2-hydroxybenzonitrile; 2-20: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6yl}-2-hydroxybenzonitrile ; 2-56: 2-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}acetic acid; 2-57: 4-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenoxy}butanoic acid; 2-58: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitrile; 2-59: 3-{4-[(3R,4R)-4-amino-3-fluoropiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile; 2-60: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile; 2-61: 3-{4-[(3S,4R)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2hydroxybenzonitrile; 2-62: 3-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy) benzonitrile; 2-63: 3-{4-[cis-4-amino-3-hydroxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-5-fluoro-2hydroxybenzonitrile; - 218 040023 2-65: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2-hydroxyethoxy)benzonitrile; 2-66: 3-{4-[(3R,4S)-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-hydroxybenzonitrile; 2-67: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(1,3-dihydroxypropan2-yl)oxy]benzamide ; 2-68: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(2-methoxyethoxy)phenyl]quinolin-6-yl]-2-hydroxybenzonitrile; 2-69: 3-[4-(4-Aminopiperidin-1-yl)-3-[3-fluoro-5-(oxetan-3-yloxy)phenyl]quinolin-6-yl]-2-hydroxybenzonitrile; 2-70: 3-[4-(4-aminopiperidin-1-yl)-3-{3-fluoro-5-[(1E)-(methoxyimino)methyl]phenyl}quinolin-6-yl]2-hydroxybenzonitrile; 2-72: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(2-methoxyethoxy)benzonitrile; 2-73: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(oxetan-3-yloxy)benzonitrile; 2-74: 1-[3-(3,5-difluorophenyl)-6-[5-fluoro-4-(oxetan-3-yloxy)pyridin-3-yl]quinolin-4-yl]piperidin-4-amine ; 2-75: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-(azetidin-1-yl)pyridine3-carbonitrile; 2-76: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-(azetidin-1-yl)pyridine3-carboxamide; 2-77: 2-amino-3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]benzonitrile; 2-78: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(methoxymethoxy)benzonitrile; 2-79: 3-[4-(4-Aminopiperidin-1-yl)-3-{3-[(ethoxyimino)methyl]-5-fluorophenyl}quinolin-6-yl]-2hydroxybenzonitrile; 2-80: 6-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-fluoro- 2,3-dihydro-1H-1,3-benzodiazol-2-one; 2-81: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-[-(methoxyimino)methyl]phenol; 2-83: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}carbamate; 2-84: 3-{4-[trans-4-amino-3-methoxypiperidin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(methoxymethoxy)benzonitrile; 2-85: 6-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}pyridine-2-carboxamide; 2-86: N{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}methanesulfonamide; 2-87: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-[(2-methoxyethoxy)methoxy]benzonitrile; 2-88: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-(azetidine-1-carbonyl)phenol; 2-92: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine3-carbonitrile; 2-94: cis-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3carbonitrile; 2-99: 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,5-difluoro-2-hydroxybenzonitrile; 2-100: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4,5- difluoro-2-hydroxybenzonitrile; 2-115: 2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-[(methoxyimino)methyl]phenol; 2-116: 2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-fluoro-6-[(methoxyimino)methyl]phenol ; 2-123: methyl-N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6-trifluorophenyl}carbamate; 2-125: methyl-N-{3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-cyanopyridin-4-yl}carbamate; 2-126: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}quinolin-4-yl]piperidin-4-amine; 2-129: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(methoxyimino)methyl]phenyl}quinolin-4-yl]piperidin- 219 040023 4-amine; 2-132: 1-{6-[3-(1-amino-2,2,2-trifluoroethyl)phenyl]-3-(3,5-difluorophenyl)quinolin-4-yl}piperidine-4amine; 2-134: 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-chloro-3,4-difluorophenol; 2-139: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,6-difluorophenyl}-3-methoxyurea; 2-141: 6-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-chloro-2,3-dihydro-III1,3-benzodiazol -2-he; 2-142: 5-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2,3-dihydro-1,3-benzoxazol-2-one ; 2-143: methyltrans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylate; 2-144: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}6-fluorophenol; 2-145: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxylic acid; 2-146: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]piperidine-3-carboxamide; 2-147: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-chloro-4-fluoro-2-hydroxybenzonitrile; 2-148: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenyl}carbamate; 2-149: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-N-methylpiperidine-3-carboxamide; 2-150: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-3,4,6-trifluorophenol; 2-151: trans-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl]-N,Ndimethylpiperidine-3-carboxamide; 2-152: 1-[3-(3,5-difluorophenyl)-6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}quinolin-4yl]piperidine-4-amine; 2-161: 1-[3-(3-fluoro-5-methoxyphenyl)-6-(2,3,5-trifluoro-6-hydroxyphenyl)quinolin-4-yl]piperidin4-ol; 2-164: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-4,6-difluorophenyl}-3-methoxyurea ; 2-165: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-4,6difluorophenyl}carbamate; 2-166: 1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methoxyphenyl)quinolin-4-yl)piperidine-4-amine; 2-167: methyl-N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-cyanophenyl}carbamate; 2-168: 1-(6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-(3-fluoro-5-methylphenyl)quinolin-4yl)piperidine-4-amine; 2-169: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-amine; 2-170: methyl-(trans)-4-amino-1-[6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4yl]piperidine-3-carboxylate; 2-171: methyl-M-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4-yl} carbamate; 2-172: 1-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-4yl}-3-methoxyurea ; 2-173: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-fluorophenyl}carbamate; 2-174: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-fluorophenyl}-3-methoxyurea; 2-175: N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methoxyphenyl)quinolin-6-yl]-6-fluorophenyl}azetidine-1-carboxamide; 2-176: 1-(6-{5-fluoro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-[3-fluoro-5-(trifluoromethyl)phenyl]quinolin-4-yl)piperidine -4-amine; 2-177: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]pyridine-3-carbonitrile; 2-178: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2-amine; 2-179: 2-amino-3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4,5-difluoroben - 220 040023 zonitrile; 2-180: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyano-3,4difluorophenyl} carbamate; 2-181: 3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4-amine; 2-182: methyl-N-{3-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2-yl} carbamate; 2-183: 1-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoropyridin-2yl}-3-methoxyurea ; 2-184: methyl-N-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4-yl} carbamate; 2-185: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-cyanophenyl}carbamate; 2-186: 1-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-chloropyridin-4yl}-3-methoxyurea ; 2-187: 4-amino-5-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]pyridine-3carbonitrile; 2-189: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-cyanophenyl}-3methoxyurea; 2-190: 3-{4-[(4αS,8αS)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl} -2 -hydroxybenzonitrile; 2-191: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyano-3,4-difluorophenyl}-3 -methoxy-3-methylurea; 2-192: 1-(6-{5-chloro-4-[(hydroxyimino)methyl]pyridin-3-yl}-3-(3,5-difluorophenyl)quinolin-4yl)piperidine-4-amine; 2-193: 3-{4-[(4αR,8αR)-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin6-yl}-2 -hydroxybenzonitrile; 2-194: 3-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-5-fluoro-2-(methoxymethoxy)benzonitrile; 2-195: 1-[3-(3,5-difluorophenyl)-6-{3-[(hydroxyimino)methyl]pyridin-2-yl}quinolin-4-yl]piperidin-4-amine; 2-196: 1-[3-(3,5-difluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-3-yl}quinolin-4-yl]piperidin-4-amine; 2-197: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl}carbamate; 2-198: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl}3-methoxy- 3-methylurea; 2-199: 1-{2-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl} 3,3- dimethylurea; 2-200: 1-[3-(3,5-difluorophenyl)-6-{6-[(hydroxyimino)methyl]pyridin-2-yl}quinolin-4-yl]piperidin-4-amine; 2-201: 2-[4-(4-Aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-cyanophenylmethyl carbonate; 2-202: 1-[3-(3,5-difluorophenyl)-6-{3-fluoro-2-[(hydroxyimino)methyl]-6-methylphenyl}quinolin-4yl]piperidine-4-amine; 2-203: 1-[3-(3,5-difluorophenyl)-6-{2-[(hydroxyimino)methyl]pyridin-4-yl}quinolin-4-yl]piperidin-4-amine; 2-204: 3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-2-(2-methoxyethoxy)benzonitrile; 2-205: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-cyano3,4-difluorophenyl}carbamate ; 2-206: 1 - {2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-cyano-3,4-difluorophenyl} -3-methoxy-3-methylurea; 2-207: 1-(2-{4-[cis-4-amino-3-methoxypiperidin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-4,6difluorophenyl) -3-methoxyurea; 2-209: methyl N-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-fluorophenyl}carbamate; 2-210: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-fluorophenyl}-3methoxy-3-methylurea ; 2-213: 4-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-2-[(methoxyimino)methyl]phenol; - 221 040023 2-215: 1-{3-[4-(4-Aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-methyliiridin-2yl}-3-methoxyurea ; 2-216: 1-{2-[4-(4-aminopiperidin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl} 3-(propane -2-yloxy)urea; 2-217: trans-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methylphenyl)quinolin-4yl)-3-methoxypiperidine-4-amine ; 2-218: methyl-I-(2-{4-[trans-4-amino-3-methoxyiiieridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin6-yl}-6-cyanophenyl) carbamate; 2-219: cis-3-{4-[4-Amino-3-hydroxyiiyeridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5fluoro-2-hydroxybenzonitrile; 2-220: cis-3-{4-[4-amino-3-hydroxyiiyeridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-5fluoro-2-(2- methoxyethoxy)benzonitrile; 2-221: 2-{4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6yl}-6-[ (methoxyimino)methyl]phenol; 2-222: 1-{2-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-cyanophenyl}-3methoxyurea; 2-223: 1-{3-[4-(4-aminoiiyeridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluorophenyl}-3methoxyurea; 2-224: cis-3-{4-[4-amino-3-hydroxyiiyeridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}-2-(2methoxyethoxy)benzonitrile; 2-225: cis-3-{4-[4-amino-3-hydroxyiiyeridin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-2-(2methoxyethoxy)benzonitrile; 2-226: 1-{3-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]iiridin-2-yl}-3methoxyurea; 2-227: cis-4-amino-1-(6-{3-fluoro-2-[(hydroxyimino)methyl]phenyl}-3-(3-fluoro-5-methylphenyl)quinolin-4-yl)iiieridin- 3-ol; 2-228: 1-{2-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl}3-ethoxyurea; 2-230: N-{2-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl}-2-methoxyacetamide ; 2-231: 3-[4-(4-aminoiieridin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-(cyanomethoxy)benzonitrile; 2-232: cis-3-{4-[4-Amino-3-hydroxyiiyeridin-1-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}-5-fluoro-2(2-methoxyethoxy )benzonitrile; 2-233: 1-{2-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4,6-difluorophenyl}3-(2 ,2,2-trifluoroethoxy)urea; 2-234: 3-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-5-fluoro-K-(2-methoxyethyl)iiridin- 2-amine; 2-235: methyl-K-(2-{4-[trans-4-amino-3-methoxyiiieridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin6-yl}-4,6- difluorophenyl) carbamate; 2-236: 1-(2-{4-[trans-4-amino-3-methoxyiiieridin-1-yl]-3-(3-fluoro-5-methylphenyl)quinolin-6-yl}4,6-difluorophenyl )-3-methoxyurea; 2-237: 1-{2-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-4-cyano-6-fluorophenyl}-3 -methoxyurea; 2-23 8: 1-{2-[4-(4-aminoiieridin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-cyanophenyl}-3(2,2, 2-trifluoroethoxy)urea; 2-239: 1-{3-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-methyliiridin-2yl}-3-methoxyurea ; 2-240: 1 - {4-[4-(4-aminoiiyeridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]phenyl}-3-methoxyurea; 2-241: 2-[4-(4-aminoiieridin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-6-bromo-3,4-difluorophenol; 2-242: 5-[4-(4-aminoiieridin-1-yl)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl]-6-[(2-methoxyethyl)amino]iiridin-3 -carbonitrile; 2-243: 2-{4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}6-[( 1 E)-(methoxyimino)methyl]phenol; 2-244: 5-{4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-aminoiiridin- 3-carbonitrile; 2-246: 3-{4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}iiridin-2-amine; 2-247: 2-{4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-methyliiridin- 3-amine; 2-248: 3 - {4-[trans-octahydro-1H-iirido[3,4-b]morpholin-6-yl] -3 -(3,5-difluorophenyl)quinolin-6- 222 040023 yl} pyridin- 2-ol; 2-250: 2-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-4-methylpyridin-3-amine; 2-251: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}3-hydroxypyridine- 4-carbonitrile; 2-252: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-[( 2-methoxyethyl)amino]pyridine-3-carbonitrile; 2-254: 5-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-hydroxypyridine- 3-carbonitrile; 2-256: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-fluoropyridin- 4-ol; 2-258: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-methylpyridine- 3 -ol; 2-259: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-fluoropyridin- 2-ol; 2-261: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}3-fluoropyridin- 4-carbonitrile; 2-262: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}3-aminopyridin- 4-carbonitrile; 2-263: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}pyridin-3-ol; 2-264: N-[(3-{4-[trans-octahydro-III-pyrudo[3,4-b]morpholine-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}pyridine- 2-yl)methylidene]hydroxylamine; 2-265: 2-{4-[trans-octahydro-1H-pyrudo[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-fluoropyridine- 3-amine; 2-266: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-[( methoxyimino)methyl]pyridine-4-amine; 2-267: 3-{4-[trans-octahydro-1H-pyrudo[3,4-b]morpholine-6-yl]-3-(3,5-difluorophenyl)quinolin-6-ul}5-cyclopropylpyridine- 4-amine; 2-269: 2-{4-[trans-octahydro-1H-pyrudo[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-[( methoxyimino)methyl]pyridine-3-amine; 2-272: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-(prop -1-yn-1-yl)pyridine-4-amine; 2-273: 1-(3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}pyridine-2 -yl)-3-methoxyurea; 2-274: 3-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}5-ethynylpyridin- 4-amine; 2-275: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-chloropyridine- 3-amine; 2-283: 2-{4-[trans-octahydro-1H-pyrudo[3,4-b]morpholine-6-yl]-3-(3,5-difluorophenyl)quinolin-6yl}pyridine-3-amine; 2-284: 2-{4-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-3-(3,5-difluorophenyl)quinolin-6-yl}4-methoxypyridin- 3-amine; 3-1: 3-[8-(4-aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluorobenzamide; 3-2: 3-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-5-fluoro-2-hydroxybenzonitrile; 3-3: 4-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-6-fluoro-2,3dihydro- 1H-1,3-benzodiazol-2-one; 3-4: 5-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-2,3-dihydro-1H1, 3-benzodiazol-2-one; 3-5: 6-[8-(4-Aminopiperidin-1-yl)-7-(3-fluoro-5-methylphenyl)-1,5-naphthyridin-2-yl]-4-fluoro-2,3dihydro- 1H-1,3-benzodiazol-2-one; 3-9: 6-[8-(4-Aminopiperidin-1-yl)-7-(3,5-difluorophenyl)-1,5-naphthyridin-2-yl]-4-fluoro-2,3-dihydro1H- 1,3-benzode iazol-2-one; 3-10: 6-{8-[trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl]-7-(3,5-difluorophenyl)-1,5-naphthyridin-2-yl }-4-fluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one; 4-1: 3-[5-(4-Aminopiperidin-1-yl)-6-(3,5-difluorophenyl)-1,8-naphthyridin-3-yl]-2-hydroxybenzonitrile; 4-2: 3-[5-(4-Aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-2-hydroxybenzonitrile; 4-3: 3-[5-(4-Aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-1,8-naphthyridin-3-yl]-5-fluoro-2-hydroxybenzonitrile; - 223 040023 4-4: 3-[5-(4-aminopiperidin-1-yl)-6-(3-chloro-5-methylphenyl)-1,8-naphthyridin-3-yl]-2-hydroxybenzonitrile; or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof. 10. Connection of the following structure: or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition containing a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, and at least one pharmaceutically acceptable excipient. 12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is formulated for administration to a mammal via intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. 13. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment or lotion. 14. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, for the treatment of a disease or condition in a mammal for which modulation of somatostatin receptor subtype 2 (SSTR2) activity is effective, wherein the disease or condition is is an acromegaly, a neuroendocrine tumor, an ocular disease or condition, a neuropathy, a nephropathy, a respiratory disease or condition, a cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof. 15. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, for the treatment of acromegaly, neuroendocrine tumor, or combinations thereof. 16. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, for modulating somatostatin 2 receptor subtype (SSTR2) activity in a mammal with acromegaly or a neuroendocrine tumor. 17. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, diastereomeric mixture or individual enantiomers thereof, to agonize somatostatin 2 receptor subtype (SSTR2) activity in a mammal with acromegaly or a neuroendocrine tumor.