5-HETEROARYL-PYRIDIN-2-AMINE COMPOUNDS AS NEUROPEPTIDE FF RECEPTOR ANTAGONISTS

Abstract

The present invention relates to novel aminopyridine derivatives of the general formula (I) and pharmaceutical compositions comprising these compounds, as well as their therapeutic use, particularly as neuropeptide FF (NPFF) receptor antagonists, including, e.g., for the treatment or prevention of pain, opioid-induced hyperalgesia, or addiction.

##STR00001##

Claims

1. A compound of the following formula (I) ##STR00192## wherein: R.sup.1 is selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —Br, —I, C.sub.1-5 haloalkyl, —CN, —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-3 alkylene)-cycloalkyl, and —(C.sub.0-3 alkylene)-heterocycloalkyl, wherein the cycloalkyl moiety in said —(C.sub.0-3 alkylene)-cycloalkyl and the heterocycloalkyl moiety in said —(C.sub.0-3 alkylene)-heterocycloalkyl are each optionally substituted with one or more groups R.sup.A; ring X is phenyl or a monocyclic heteroaryl having 5+n ring members, wherein said phenyl or said heteroaryl is optionally substituted with one or more groups R.sup.X; n is 0 or 1; R.sup.2 and R.sup.3 are mutually joined to form, together with ring X, a bicyclic or tricyclic heteroaryl, wherein said heteroaryl is optionally substituted with one or more groups R.sup.X, and wherein said heteroaryl is not 1H-indazol-4-yl or benzimidazolyl; or alternatively, R.sup.2 is ring Y, and R.sup.3 is hydrogen or R.sup.X; ring Y is phenyl or a monocyclic heteroaryl, wherein said phenyl or said monocyclic heteroaryl is optionally substituted with one or more groups R.sup.Y, and further wherein ring X and ring Y are not both phenyl; and each R.sup.A, each R.sup.X, and each R.sup.Y is independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —(C.sub.0-3 alkylene)-O—R.sup.B, —(C.sub.0-3 alkylene)-O—(C.sub.1-5 alkylene)-O—R.sup.B, —(C.sub.0-3 alkylene)-S—R.sup.B, —(C.sub.0-3 alkylene)-S—(C.sub.1-5 alkylene)-S—R.sup.B, —(C.sub.0-3 alkylene)-N(R.sup.B)—R.sup.B, —(C.sub.0-3 alkylene)-N(R.sup.B)—O—R.sup.B, halogen, C.sub.1-5 haloalkyl, —(C.sub.0-3 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-3 alkylene)-CN, —(C.sub.0-3 alkylene)-CO—R.sup.B, —(C.sub.1-3 alkylene)-COOH, —(C.sub.0-3 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-3 alkylene)-CO—O—(C.sub.1-5 haloalkyl), —(C.sub.0-3 alkylene)-O—CO—R.sup.B, —(C.sub.0-3 alkylene)-CO—N(R.sup.B)—R.sup.B, —(C.sub.0-3 alkylene)-N(R.sup.B)—CO—R.sup.B, —(C.sub.0-3 alkylene)-N(R.sup.B)—CO—O—R.sup.B, —(C.sub.0-3 alkylene)-O—CO—N(R.sup.B)—R.sup.B, —(C.sub.0-3 alkylene)-SO.sub.2—N(R.sup.B)—R.sup.B, —(C.sub.0-3 alkylene)-N(R.sup.B)—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-3 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-3 alkylene)-SO—(C.sub.1-5 alkyl), -L-carbocyclyl, and -L-heterocyclyl, wherein the carbocyclyl moiety in said -L-carbocyclyl and the heterocyclyl moiety in said -L-heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —O—R.sup.B, —(C.sub.1-5 alkylene)-O—R.sup.B, —S—R.sup.B, —S—(C.sub.1-5 alkylene)-S—R.sup.B, —N(R.sup.B)—R.sup.B, —N(R.sup.B)—O—R.sup.B, halogen, C.sub.1-5 haloalkyl, —O—(CO.sub.1-5 haloalkyl), —CN, —CO—R.sup.B, —CO—O—R.sup.B, —O—CO—R.sup.B, —CO—N(R.sup.B)—R.sup.B, —N(R.sup.B)CO—R.sup.B, —N(R.sup.B)—CO—R.sup.B, —O—CO—N(R.sup.B)—R.sup.B, —SO.sub.2—N(R.sup.B)—R.sup.B, —N(R.sup.B)—SO.sub.2˜(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl), wherein each L is independently a covalent bond or C.sub.1-5 alkylene, wherein one or more —CH.sub.2— units comprised in said C.sub.1-5 alkylene are each optionally replaced by a group independently selected from —O—, —N(R.sup.B)—, —CO—, —S—, —SO—, and —SO.sub.2—, and further wherein each R.sup.B is independently hydrogen, C.sub.1-5 alkyl or C.sub.1-5 haloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein R.sup.1 is selected from C.sub.1-5 alkyl, C.sub.1-3 haloalkyl, —NH.sub.2, —NH(C.sub.1-3 alkyl), —N(C.sub.1-3 alkyl)(C.sub.1-3 alkyl), and —(C.sub.0-3 alkylene)-cyclopropyl.

3. The compound of claim 1 or 2, wherein R.sup.1 is —NH.sub.2 or C.sub.1-5 alkyl.

4. The compound of any one of claims 1 to 3, wherein R.sup.2 and R.sup.3 are mutually joined to form, together with ring X, a bicyclic or tricyclic heteroaryl, wherein said bicyclic or tricyclic heteroaryl is optionally substituted with one or more groups R.sup.X, and further wherein said heteroaryl is not 1H-indazol-4-yl or benzimidazolyl.

5. The compound of any one of claims 1 to 4, wherein R.sup.2 and R.sup.3 are mutually joined to form, together with ring X, a bicyclic heteroaryl, wherein said bicyclic heteroaryl is optionally substituted with one or more groups R.sup.X, and further wherein said bicyclic heteroaryl is not 1H-indazol-4-yl or benzimidazolyl.

6. The compound of claim 5, wherein R.sup.2 and R.sup.3 are mutually joined to form, together with ring X, a bicyclic heteroaryl selected from quinolin-4-yl, quinolin-5-yl, quinolin-8-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-7-yl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-4-yl, pyrazolo[1,5-a]pyridin-7-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-7-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-7-yl, 1H-indol-1-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-7-yl, 2H-isoindol-1-yl, 2H-isoindol-7-yl, 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-7-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-7-yl, chroman-5-yl, chroman-8-yl, and 1,4-benzodioxan-5-yl, wherein said bicyclic heteroaryl is optionally substituted with one or more groups R.sup.X.

7. The compound of claim 5 or 6, wherein R.sup.2 and R.sup.3 are mutually joined to form, together with ring X, a quinolin-8-yl which is optionally substituted with one or more groups R.sup.X, such that the compound of formula (I) has the following structure: ##STR00193## wherein the quinolin-8-yl group comprised in this compound is optionally substituted with one or more groups R.sup.X.

8. The compound of any one of claims 1 to 7, wherein the number of substituents R.sup.X in the compound of formula (I) is 1, 2 or 3, and further wherein each R.sup.X is independently selected from C.sub.1-5 alkyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, and —CN.

9. The compound of any one of claims 1 to 8, wherein the number of substituents R.sup.X in the compound of formula (I) is 2 or 3, and further wherein each R.sup.X is independently selected from C.sub.1-5 alkyl, —OH, and halogen.

10. The compound of claim 1, wherein said compound is selected from: 6-ethyl-5-(5-fluoroquinolin-8-yl)pyridin-2-amine; 6-methyl-5-quinolin-8-yl-pyridin-2-ylamine; 5-benzo[b]thiophen-3-yl-6-ethyl-pyridin-2-ylamine; 6-ethyl-5-(6-methoxybenzothiophen-3-yl)pyridin-2-amine; 6-ethyl-5-(8-isoquinolyl)pyridin-2-amine; 5-benzo[b]thiophen-3-yl-6-propyl-pyridin-2-ylamine; 6-propyl-5-(8-quinolyl)pyridin-2-amine; 5-(8-isoquinolyl)-6-propyl-pyridin-2-amine; 5-benzo[b]thiophen-3-yl-6-isopropyl-pyridin-2-ylamine; 6-isopropyl-5-(8-quinolyl)pyridin-2-amine; 6-isopropyl-5-(8-isoquinolyl)pyridin-2-amine; 5-benzo[b]thiophen-3-yl-6-cyclopropyl-pyridin-2-ylamine; 6-cyclopropyl-5-(8-quinolyl)pyridin-2-amine; 6-cyclopropyl-5-(8-isoquinolyl)pyridin-2-amine; 3-(1-methylindol-3-yl)pyridine-2,6-diamine; tert-butyl 3-(2,6-diamino-3-pyridyl)indole-1-carboxylate; 3-(1H-indol-3-yl)pyridine-2,6-diamine; 3-pyrazolo[1,5-a]pyridin-3-ylpyridine-2,6-diamine; 3-(benzofuran-3-yl)pyridine-2,6-diamine; 3-(benzothiophen-3-yl)pyridine-2,6-diamine; 3-(5-fluoro-benzo[b]thiophen-3-yl)pyridine-2,6-diamine; 3-(7-fluoro-2-methylquinolin-8-yl)pyridine-2,6-diamine; 3-(1H-indol-4-yl)pyridine-2,6-diamine; 3-(1H-indol-7-yl)pyridine-2,6-diamine; 3-(1-methylindazol-7-yl)pyridine-2,6-diamine; 4-(2,6-diamino-3-pyridyl)-2-methyl-isoindolin-1-one; 3-(2,3-dihydrobenzofuran-7-yl)pyridine-2,6-diamine; 3-(benzothiophen-7-yl)pyridine-2,6-diamine; 3-(1,3-benzothiazol-4-yl)pyridine-2,6-diamine; 3-(8-quinolyl)pyridine-2,6-diamine; 3-isoquinolin-8-yl-pyridine-2,6-diamine; 3-(5-isoquinolyl)pyridine-2,6-diamine; 3-quinolin-5-yl-pyridine-2,6-diamine; 3-quinolin-4-yl-pyridine-2,6-diamine; 3-isoquinolin-4-yl-pyridine-2,6-diamine; 3-chroman-8-yl-pyridine-2,6-diamine; 3-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-pyridine-2,6-diamine; 3-dibenzothiophen-4-ylpyridine-2,6-diamine; 3-dibenzofuran-4-ylpyridine-2,6-diamine; 6-ethyl-5-(2-methylbenzothiophen-3-yl)pyridin-2-amine; 6-ethyl-5-(5-methylbenzothiophen-3-yl)pyridin-2-amine; 6-ethyl-5-(5-fluorobenzothiophen-3-yl)pyridin-2-amine; 6-ethyl-5-[2-(3-pyridyl)phenyl]pyridin-2-amine; 3-[2-(3-pyridyl)phenyl]pyridine-2,6-diamine; 3-[2-(6-morpholino-3-pyridyl)phenyl]pyridine-2,6-diamine; 6-ethyl-5-(quinolin-8-yl)pyridin-2-amine; 3-(2-(1-methyl-1H-pyrazol-5-yl)phenyl)pyridine-2,6-diamine; 3-(1-methyl-1H-indol-7-yl)pyridine-2,6-diamine; 3-(benzofuran-7-yl)pyridine-2,6-diamine; 3-(benzo[b]thiophen-4-yl)pyridine-2,6-diamine; 3-(6-fluoroquinolin-8-yl)pyridine-2,6-diamine; 3-(6-methylquinolin-8-yl)pyridine-2,6-diamine; 3-(5-(trifluoromethyl)quinolin-8-yl)pyridine-2,6-diamine; 3-(5-fluoroquinolin-8-yl)pyridine-2,6-diamine; 8-(2,6-diaminopyridin-3-yl)quinolin-2(1H)-one; 3-(7-fluoroquinolin-8-yl)pyridine-2,6-diamine; 3-(3-fluoroquinolin-8-yl)pyridine-2,6-diamine; 3-(5,7-difluoroquinolin-8-yl)pyridine-2,6-diamine; 3-(3-chloro-7-fluoroquinolin-8-yl)pyridine-2,6-diamine; 3-(3,5,7-trifluoroquinolin-8-yl)pyridine-2,6-diamine; 8-(2,6-diaminopyridin-3-yl)-7-fluoroquinolin-2-ol; 8-(2,6-diaminopyridin-3-yl)-7-chloroquinolin-2-ol; 8-(2,6-diaminopyridin-3-yl)-6,7-difluoroquinolin-2-ol; 6-ethyl-5-(7-fluoroquinolin-8-yl)pyridin-2-amine; 5-(chroman-8-yl)-6-ethylpyridin-2-amine; 6-isobutyl-5-(quinolin-8-yl)pyridin-2-amine; 6-(cyclobutylmethyl)-5-(quinolin-8-yl)pyridin-2-amine; 5-(7-fluoroquinolin-8-yl)-6-(3,3,3-trifluoropropyl)pyridin-2-amine; 5-(7-fluoroquinolin-8-yl)-6-isobutylpyridin-2-amine; 5-(7-fluoroquinolin-8-yl)-6-(4,4,4-trifluorobutyl)pyridin-2-amine; 6-(cyclopropylmethyl)-5-(7-fluoroquinolin-8-yl)pyridin-2-amine; 5-(7-fluoroquinolin-8-yl)-6-isopentylpyridin-2-amine; 6-ethyl-5-(6-fluoroquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(5-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(7-fluoro-2-methylquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(6-methylquinolin-8-yl)pyridin-2-amine; 5-(benzo[b]thiophen-4-yl)-6-ethylpyridin-2-amine; 5-(benzofuran-7-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(2-(6-(piperidin-1-yl)pyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(4-fluoro-2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(5-fluoro-2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-(5-methylpyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-(5-methylpyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-(6-fluoropyridin-3-yl)phenyl)pyridin-2-amine; 5-(2-(6-amino-2-ethylpyridin-3-yl)phenyl)pyridin-2-ol; 6-ethyl-5-(2-(6-methoxypyridin-3-yl)phenyl)pyridin-2-amine; 6-ethyl-5-(2-methylquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(4-methylquinolin-8-yl)pyridin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-amine; 6-ethyl-5-(7-methylquinolin-8-yl)pyridin-2-amine; 5-(2-ethoxyquinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(3-methylquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(5-methylquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(3-fluoroquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(7-methoxyquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(1,7-naphthyridin-8-yl)pyridin-2-amine; 6-ethyl-5-(quinoxalin-5-yl)pyridin-2-amine; 6-ethyl-5-(imidazo[1,2-a]pyridin-8-yl)pyridin-2-amine; 6-ethyl-5-(imidazo[1,2-a]pyridin-5-yl)pyridin-2-amine; 6-ethyl-5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine; 5-(7-(difluoromethoxy)quinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(7-fluoro-3-phenylquinolin-8-yl)pyridin-2-amine; 5-(5,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(7-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine; 5-(7-chloroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(6,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)-6,7-difluoroquinolin-3-ol; 6-ethyl-5-(5,6,7,8-tetrahydroacridin-4-yl)pyridin-2-amine; 6-ethyl-5-(2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridin-6-yl)pyridin-2-amine, 5-(2,3-dihydro-1H-cyclopenta[b]quinolin-5-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(2-phenylquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(pyridin-3-yl)quinolin-8-yl)pyridin-2-amine; 5-(2-cyclohexylquinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(2-(pyridin-2-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(1-methylcyclopropyl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(tetrahydro-2H-pyran-4-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(pyridin-4-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(imidazo[1,2-a]pyridin-6-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(pyrimidin-5-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(isoxazol-4-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(pyrazin-2-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(4-methylpyridin-3-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(2-methylpyridin-3-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-morpholinoquinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(2-morpholinoethoxy)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(2-(pyrrolidin-1-yl)quinolin-8-yl)pyridin-2-amine; 5-(2-(4,4-difluoropiperidin-1-yl)quinolin-8-yl)-6-ethylpyridin-2-amine; 5-(2-(1,4-oxazepan-4-yl)quinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(7-fluoro-2-(1,4-oxazepan-4-yl)quinolin-8-yl)pyridin-2-amine; 6-ethyl-5-(7-fluoro-2-morpholinoquinolin-8-yl)pyridin-2-amine; 5-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(2-(azepan-1-yl)-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)-N-cyclohexyl-N-ethyl-7-fluoroquinolin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)-N-ethyl-7-fluoro-N-isopropylquinolin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)-N,N-dimethylquinoline-2-carboxamide; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(pyrrolidin-1-yl)methanone; 6-ethyl-5-(2-(methoxymethyl)quinolin-8-yl)pyridin-2-amine; 5-(3,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(7-chloro-3-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(3,5,7-trifluoroquinolin-8-yl)pyridin-2-amine; 5-(3-chloro-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(3,7-dichloroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(3-chloro-5,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 5-(3-chloro-6,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 6-ethyl-5-(3,6,7-trifluoroquinolin-8-yl)pyridin-2-amine; 5-(3-bromo-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine; 8-(6-amino-2-ethylpyridin-3-yl)quinoline-7-carboxamide; 8-(6-amino-2-ethylpyridin-3-yl)quinoline-7-carbonitrile; 8-(6-amino-2-ethylpyridin-3-yl)quinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-1-methylquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-7-fluoroquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-5,7-difluoroquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-7-chloroquinolin-2(1H)-one; 8-(6-amino-2-ethylpyridin-3-yl)-6,7-difluoroquinolin-2(1H)-one; 6-ethyl-5-(1-methylindolin-7-yl)pyridin-2-amine; 7-(6-amino-2-ethylpyridin-3-yl)indolin-2-one; 6-ethyl-5-(indolin-7-yl)pyridin-2-amine; 6-ethyl-5-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)pyridin-2-amine; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(morpholino)methanone; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(1,4-oxazepan-4-yl)methanone; 8-(6-amino-2-ethylpyridin-3-yl)-N-cyclohexyl-N-ethylquinoline-2-carboxamide; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(azepan-1-yl)methanone; 8-(6-amino-2-ethylpyridin-3-yl)-N-ethyl-N-isopropylquinoline-2-carboxamide; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methanone; (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(4-phenylpiperidin-1-yl)methanone; 8-(6-amino-2-ethylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide; 8-(6-amino-2-ethylpyridin-3-yl)-N-benzylquinoline-2-carboxamide; 8-(6-amino-2-ethylpyridin-3-yl)-N-(oxetan-3-yl)quinoline-2-carboxamide; 6-ethyl-5-(7-fluorochroman-8-yl)pyridin-2-amine; 6-ethyl-5-(7-fluoro-2,2-dimethylchroman-8-yl)pyridin-2-amine; 6-ethyl-5-(8-fluoro-2,5-dihydrobenzo[b]oxepin-9-yl)pyridin-2-amine; and 6-ethyl-5-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-9-yl)pyridin-2-amine; or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 and a pharmaceutically acceptable excipient.

12. The compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 for use as a medicament.

13. The compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 for use in the treatment or prevention of pain.

14. The compound for use according to claim 13 or the pharmaceutical composition for use according to claim 13, wherein said pain is selected from acute pain, chronic pain, postsurgical pain, cancer pain, inflammatory pain, rheumatoid arthritis-associated pain, neuropathic pain, and diabetes-associated pain.

15. The compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 for use in the treatment or prevention of opioid-induced hyperalgesia.

16. The compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 for use in the treatment or prevention of addiction.

17. The compound for use according to claim 16 or the pharmaceutical composition for use according to claim 16, wherein said addiction is a substance addiction or a behavioral addiction.

18. The compound for use according to claim 16 or the pharmaceutical composition for use according to claim 16, wherein said addiction is selected from alcohol addiction, amphetamine addiction, cocaine addiction, methamphetamine addiction, methylphenidate addiction, nicotine addiction, and opioid addiction.

19. The compound for use according to any one of claims 13 to 15 or the pharmaceutical composition for use according to any one of claims 13 to 15, wherein the compound or the pharmaceutical composition is to be administered in combination with one or more opioid analgesics.

20. In vitro use of a compound as defined in any one of claims 1 to 10 as an NPFF receptor antagonist.

Description

[0324] The present invention is also described by the appended illustrative figure.

[0325] FIG. 1: Effect of exemplary compounds of formula (I) on morphine-induced hyperalgesia in a mouse model (see Example 181). The tested compounds are (A) Examples 31 and 32 as well as (B) Examples 56 and 143. The figure shows the mean time of tail withdrawal latency in each group of animals. The anti-hyperalgesia effect of the tested compounds was compared to vehicle-treated group using ANOVA test followed by the Bonferroni's test. The insert at the bottom shows the comparison between groups of the global Area Under Curve (AUC) over D0 to D8 period.

[0326] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

[0327] The compounds described in the following examples section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

EXAMPLES

[0328] All reagents were commercial grade and used without further purification. Reactions were typically run using anhydrous solvents under argon atmosphere. Organic layers were usually dried over sodium or magnesium sulphate or filtered through an Isolute® SPE Single Fritted column. Thin layer chromatography was carried out using pre-coated silica gel F-254 plate. Flash column chromatography was performed using a Biotage® isolera 4 system, with the Biotage® SNAP cartridge KP-Sil (50 μm) if not specified. In specific cases, a Biotage® SNAP cartridge KP-NH or Interchim PF-15SIHP-F0025 (15 μm or 20 μm) could be used.

[0329] Reactions were monitored and compounds were characterized using a Waters Acquity UPLC H-class system with a photodiode array detector (190-400 nm). An Acquity CSH C18 1.7 μM 2.1×30 mm column was used. The mobile phase consisted in a gradient of A and B: A was water with 0.025% of trifluoroacetic acid and B was acetonitrile with 0.025% of trifluoroacetic acid. Flow rate was 0.8 mL per min. All analyses were performed at 55° C. The UPLC system was coupled to a Waters SQD2 platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using positive electrospray ionization.

[0330] Preparative LC-MS were performed using a Waters HPLC system with a 2767 sample manager, a 2525 pump, a photodiode array detector (190-400 nm) enabling analytical and preparative modes. An Xselect CSH C18 3.5 μM 4.6×50 mm column was used in analytical mode and an Xselect CSH C18 5 μM 19×100 mm column in preparative mode. The mobile phase consisted in both cases in a gradient of A and B: A was water with 0.1% of formic acid and B was acetonitrile with 0.1% of formic acid. Flow rate was 1 mL per min in analytical mode and 25 mL per min in preparative mode. All LCMS analyses/purifications were performed at room temperature. The HPLC system was coupled with a Waters Acquity QDa detector. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using positive electrospray ionization.

[0331] All NMR experiments were recorded on a Bruker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual DMSO (2.50 ppm). Splitting patterns are designated as s (singlet); d (doublet); dd (doublet of doublet); t (triplet); dt (doublet of triplet); td (triplet of doublet); tt (triplet of triplet); q (quartet); quint (quintuplet); m (multiplet); bs (broad singlet).

I. Preparation of Synthetic Intermediates

General Methods

Method a: Heteroaromatic Bromination

[0332] At 0° C., to a solution of heteroaromatic (1.0 eq.) in DCM (C=0.2 M), N-bromosuccinimide (1.0 eq.) was added portion-wise. The mixture was stirred at rt until no more evolution was noticed by UPLC-MS (1 h, unless mentioned otherwise). The reaction mixture was concentrated and the residue was purified by flash chromatography.

Method b: Heteroaromatic Iodination

[0333] To a suspension of heteroaromatic (1.0 eq.) and solid K.sub.2CO.sub.3 (1.0 eq.) in THE (C=0.125 M), at 0° C., a solution of iodine (1.0 eq.) in THF (C=0.125 M) was added dropwise over the course of one hour. The mixture was stirred at rt until no more evolution was noticed by UPLC-MS (2 h, unless mentioned otherwise). The reaction mixture was hydrolysed, extracted thrice with EtOAc and the organic layer was dried and concentrated.

Method c: Heteroaromatic Halogenation/Miyaura Borylation

Step 1: Heteroaryl Halogenation

[0334] Under argon, at 0° C., to a solution of heteroaryl (1.0 eq.) in chloroform (C=0.2 M), bromine (1.1 eq.) was added dropwise. The mixture was stirred from 0° C. to rt for 2 h. The reaction mixture was diluted with a saturated aqueous Na.sub.2S.sub.2O.sub.3 solution and the aqueous layer was extracted with DCM. Combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated.

Step 2: Miyaura Borylation

[0335] In a sealed vial, a suspension of heteroaryl halide (1.0 eq.), bis(pinacolato)diboron (1.5 eq.) and KOAc (2.0 eq.) in dioxane (0.2 M) was degassed with argon bubbling for 15 min and P(tBu).sub.3 Pd G2 (10 mol %) or Xphos (20 mol %) followed by Pd.sub.2dba.sub.3 (10 mol %) were added in one portion. The reaction mixture was stirred for 17 h at 90° C., cooled to rt, filtered through a Celite® pad and the cake was washed with DCM. The filtrate was concentrated and the crude was purified by flash chromatography.

Method d: Heteroaromatic Miyaura Borylation

[0336] In a sealed vial, a suspension of heteroaromatic halide (1.0 eq.), bis(pinacolato)diboron (1.2 eq.), KOAc (2.0 eq.), in dioxane (C=0.2 M) was degassed with argon bubbling for 15 min and PdCl.sub.2dppf (5 mol %) was then added. The reaction mixture was stirred for 17 h at 90° C., cooled to rt, hydrolysed with NH.sub.4Cl and extracted with DCM thrice. The combined organic layers were dried. The crude was purified by flash chromatography.

Method e: Suzuki Coupling

[0337] In a sealed vial, to a solution of heteroaromatic halide (1.0 eq.) and heteroaryl boronic derivative (1.2-1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography.

Method f: Negishi Coupling/Heteroaromatic Halogenation

Step 1: Negishi Coupling

[0338] In a sealed vial under Argon, to a solution of 6-bromopyridin-2-amine (1.0 eq.) in THF (C=0.2 mL) was added Alkylzinc(II) bromide (0.5M in THF) (1.4 eq.) and Pd(dppf)Cl.sub.2 (0.1 eq.). The reaction mixture was heated at 90° C. until no more evolution was noticed by UPLC-MS (4 h, unless mentioned otherwise). The reaction mixture was filtered through a pad of Celite® and the cake washed with EtOAc. Filtrated was hydrolyzed with NaHCO.sub.3 sat. and extracted twice with EtOAc. Organic layers were washed with brine, dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography.

Step 2: Heteroaromatic Bromination

[0339] At 0° C., to a solution of heteroaromatic (1.0 eq.) in DCM (C=0.2 M), N-bromosuccinimide (1.0 eq.) was added portion-wise. The mixture was stirred at rt until no more evolution was noticed by UPLC-MS (1 h, unless mentioned otherwise). The reaction mixture was concentrated, and the residue was purified by flash chromatography.

Method g: Skraup reaction

[0340] Under Argon, to a suspension of aniline derivative (1.0 eq.), sodium 3-nitrobenzenesulfonate (2.0 eq.) and propane-1,2,3-triol (4.0 eq.) was added H.sub.2SO.sub.4 70% (C=0.70 M). The reaction mixture was heated at 135° C. for 2 h. After cooling to rt, the reaction mixture was poured on ice and neutralized with NaOH 6N. The obtained suspension was filtered over Celite® and washed with EtOAc. The filtrate was extracted with EtOAc. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method h: SNAr

[0341] In a sealed vial under Argon, to a solution of 2-chloroquinoline derivate (1.0 eq.) in DMA (C=0.2 M) was added amine (3.0 eq.). The reaction mixture was subjected to microwave irradiation at 150° C. for 15 min. A mixture 50/50 of NH.sub.4Cl sat/H.sub.2O was added to the reaction mixture and was extracted twice with EtOAc. Combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography to afford the corresponding 8-bromo-2-aminoquinoline.

Method i; Quinolone Formation

[0342] Under Argon, at 0° C., to a solution of aniline derivative (1.0 eq.) in THF (C=0.2 M) was added methyl 3,3-dimethoxypropanoate (1.2 eq.) followed by the addition dropwise of LiHMDS (1 M in THF, 2.5 eq.). The reaction mixture was stirred overnight allowing the ice bath coming back at rt. The reaction mixture was hydrolyzed at 0° C. with aqueous citric acid solution (20 wt. %) then extracted twice with DCM. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated.

[0343] To the obtained crude in DCM (C=0.2 M) at 0° C. was added H.sub.2SO.sub.4 conc. (15 eq.). The reaction mixture was stirred 2 h at rt. The reaction mixture was poured on an ice-water mixture, then extracted twice with DCM. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method j: Peptidic Couplinq

[0344] Under Argon, to a solution of 2-carboxylic acid (1.0 eq.) in DCM (C=0.2 M) was added BOP (1.3-1.5 eq.), DIPEA (1.5-3 eq.) and amine (1.3-1.5 eq.). The reaction mixture was stirred at rt for 2 h, then was diluted with DCM, washed with NaHCO.sub.3 sat., brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method k: Nitration of 8-Bromo Quinoline

[0345] Under Argon, at 0° C., to a solution of 8-bromoquinoline derivative (1.0 eq.) in DCM (C=0.6 M) was added tetrabutylammonium nitrate (1.5 eq.) and dropwise trifluoroacetic anhydride (15 eq.). The reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was hydrolyzed with NaHCO.sub.3 sat. then extracted thrice with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method l: Reduction of Nitro

[0346] Under Argon, to a suspension of nitro heteroaromatic derivate (1.0 eq.) in a mixture EtOH/THF/H.sub.2O (2/2/1, C=0.05 M) were added ammonium chloride (6.4 eq) and iron (6.0 eq.). The reaction mixture was stirred at 80° C. for 2 h. After cooling to rt, the reaction mixture was filtered over a Celite® pad and the cake was washed with THF and EtOH. The filtrate was concentrated. The obtained residue was diluted with EtOAc and washed with water, brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method m: Fluorination

[0347] Under Argon, at 0° C., to a suspension of 3-aminoheteroaryl derivative (1.0 eq.) in H.sub.2O (C=0.35 M) was added tetrafluoroboric acid (48 wt. % in H.sub.2O, 4.0 eq.) followed by the addition dropwise of a solution of sodium nitrite (1.5 eq.) in H.sub.2O (C=0.81 M). The reaction mixture was stirred 3 h allowing the ice bath coming back to rt. The obtained solid was filtered and washed with iPrOH/Et.sub.2O (2/8) and Et.sub.2O (4 times). The obtained light yellow solid was suspended in trifluorotoluene (C=0.35 M) and the suspension was heated at 120° C. for 1 h. The reaction mixture was hydrolyzed with NaHCO.sub.3 sat. then extracted thrice with EtOAc. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography to obtain the corresponding fluoro-heteroaromatic derivative.

Method n: Chlorination

[0348] Under Argon, at −5° C. to a solution of amino-heteroaromatic derivate (1.0 eq.) in HCl 37% (C=0.2 M) was added dropwise a solution of sodium nitrite (1.5 eq.) in H.sub.2O (C=0.65 M). The reaction mixture was stirred at −5° C. for 10 min then copper(I) chloride (4.0 eq.) was added. 5 min later, the ice bath was removed, and the reaction mixture was stirred 2 h at rt. The reaction mixture was diluted with H.sub.2O and basified with NaOH 1N until pH-7. The aqueous layer was extracted thrice with EtOAc. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography to obtain the corresponding chloro-heteroaromatic derivative.

Method o: Friedlander 1.SUP.st .Method

[0349] In a sealed vial under Argon, to a solution of (2-aminophenyl)methanol derivative (1.0 eq.) in dioxane (C=0.3 M) was added ketone (1.0-1.5 eq.), KOtBu (1.0-1.5 eq.) and benzophenone (1.0 eq.). The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography to obtain the corresponding quinoline derivative

Method P: Friedlander 2.SUP.nd .Method

[0350] In a sealed vial under Argon, to a solution of (2-amino-3-bromophenyl)methanol (1.0 eq.) in EtOH (C=0.3 M) was added MnO.sub.2 (5 eq.). The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to 0° C. followed by the addition of ketone (1.2 eq.) and dropwise a solution of KOH (1.4 eq.) in EtOH (C=1 M). The reaction mixture was stirred at 0° C. until no more evolution was noticed by UPLC-MS (1 h, unless mentioned otherwise). The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc. The organic layer was washed with NH.sub.4Cl sat., brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography to obtain the corresponding 8-bromo-2-alkyl/arylquinoline.

Synthetic Intermediate Syntheses

Compound Id: 5-bromo-6-ethyl-pyridin-2-amine

[0351] Compound 1d was prepared according to method a, starting from 6-ethylpyridin-2-amine (5.00 g, 41.0 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to afford compound 1d as a brown solid (6.87 g, 83%).

[0352] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.13 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.63 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.03 (bs, 2H, NH.sub.2); 6.23 (d, J 8.8 Hz, 1H, Ar); 7.44 (d, J 8.8 Hz, 1H, Ar). M/Z (M[.sup.8′Br]+H)+: 202.8.

Compound Le: 5-bromo-6-propyl-pyridin-2-amine

[0353] Compound 1e was prepared according to method a starting from 6-propylpyridin-2-amine (500 mg, 3.67 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 1e as an orange solid (511 mg, 64%).

[0354] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.91 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.61 (sex, J 7.6 Hz, 2H, CH.sub.2—CH.sub.2—CH.sub.3); 2.60 (t, J 7.6 Hz, 2H, CH.sub.2—CH.sub.2—CH.sub.3); 6.01 (bs, 2H, NH.sub.2); 6.23 (d, J 8.8 Hz, 1H, Ar); 7.44 (d, J 8.8 Hz, 1H, Ar). M/Z (M[.sup.79Br]+H)+: 217.6.

Compound 1f: 5-bromo-6-isopropyl-pyridin-2-amine

[0355] Compound 1f was prepared according to method a starting from 6-isopropylpyridin-2-amine (500 mg, 3.67 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 1f (568 mg, 71%).

[0356] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.12 (d, J 6.8 Hz, 6H, CH—(CH.sub.3).sub.2); 3.26 (sep, J 6.8 Hz, 1H CH—(CH.sub.3).sub.2); 5.99 (bs, 2H, NH.sub.2); 6.23 (d, J 8.4 Hz, 1H, Ar); 7.44 (d, J 8.4 Hz, 1H, Ar). M/Z (M[.sup.79Br]+H)+: 217.6.

[0357] Compound 1g: 5-bromo-6-cyclopropyl-pyridin-2-amine Compound 1g was prepared according to method a starting from 6-cyclopropylpyridin-2-amine (500 mg, 3.67 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 1g as an orange oil (618 mg, 78%).

[0358] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.86 (d, J 6.4 Hz, 4H, CH—CH.sub.2CyPr); 2.25 (quint, J 6.4 Hz, 1H CH—CH.sub.2CyPr); 5.92 (bs, 2H, NH.sub.2); 6.16 (d, J 8.4 Hz, 1H, Ar); 7.42 (d, J 8.4 Hz, 1H, Ar). M/Z (M[.sup.79Br]+H)+: 215.6.

Compound 1h: 3-iodopyridine-2,6-diamine

[0359] Compound 1h was prepared according to method b starting from 2,6-diaminopyridine (4.5 g, 41.2 mmol). The residue was triturated in MeOH. The precipitate was filtered, and the filtrate was concentrated. The resulting foam was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 80/20 to 0/100) to afford compound 1h as a pink solid (7.7 g, 79%).

[0360] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.40 (bs, 2H, NH.sub.2); 5.58 (d, J 8.4 Hz, 1H, Ar); 5.63 (bs, 2H, NH.sub.2); 7.37 (d, J 8.4 Hz, 1H, Ar). M/Z (M+H).sup.+: 236.5.

Compound 2a: 3-bromo-2-methyl-benzothiophene

[0361] Compound 2a was prepared according to method c step 1 starting from 2-methyl-benzothiophene (500 mg, 3.37 mmol) and was obtained without further purification as a beige oil (838 mg, quant. yield).

[0362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.54 (s, 3H, CH.sub.3); 7.41 (dt, J 8.4, 1.2 Hz, 1H, Ar); 7.48 (dt, J 8.4, 1.2 Hz, 1H, Ar); 7.66 (d, J 8.0 Hz, 1H, Ar); 7.96 (d, J 8.0 Hz, 1H, Ar).

Compound 2b: 3-bromo-5-methyl-benzothiophene

[0363] Compound 2b was prepared according to method c step 1 starting from 5-methyl-benzothiophene (337 mg, 2.68 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 2b as a light-yellow oil (537 mg, 88%).

[0364] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.48 (s, 3H, CH.sub.3); 7.29-7.34 (m, 1H, Ar); 7.55-7.58 (m, 1H, Ar); 7.93-7.98 (m, 2H, Ar).

Compound 2c: 3-bromo-5-fluoro-benzothiophene

[0365] Compound 2c was prepared according to method c step 1 starting from 5-fluorobenzothiophene (500 mg, 3.25 mmol) and was obtained without further purification as a beige solid (789 mg, quant. yield).

[0366] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 7.39 (dt, J 8.8, 2.4 Hz, 1H, Ar); 7.52 (dd, J 9.2, 2.4 Hz, 1H, Ar); 8.12-8.18 (m, 2H, Ar).

Compound 2d: 3-bromo-6-methoxy-benzothiophene

[0367] Compound 2d was prepared according to method c step 1 starting from 6-methoxybenzothiophene (400 mg, 2.44 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 90/10) to afford compound 2d as a light-yellow oil (492 mg, 83%).

[0368] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.8 (s, 3H, CH.sub.3); 7.00 (dd, J 8.8, 2.4 Hz, 1H, Ar); 7.51 (s, 1H, Ar); 7.54 (d, J 2.4 Hz, 1H, Ar); 7.68 (d, J 8.8 Hz, 1H, Ar).

Compound 3a: 2-(5-fluorobenzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0369] Compound 3a was prepared according to method c step 2 starting from 2-bromo-5-fluorobenzothiophene 2c (200 mg, 0.87 mmol), using P(tBu).sub.3 Pd G2 (45 mg, 0.09 mmol, 10 mol %) as catalyst. The crude was purified by flash chromatography (SiO.sub.2, DCM: 100%) to afford compound 3a as a brown oil (59 mg, 25%, contamination with the corresponding boronic acid, 20% by NMR).

Compound 3b: 2-(6-methoxybenzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0370] Compound 3b was prepared according to method c step 2 starting from 2-bromo-6-methoxybenzothiophene 2d (393 mg, 1.62 mmol), using Pd.sub.2dba.sub.3 and XPhos as catalyst. The crude was purified by flash chromatography (SiO.sub.2, DCM: 100%) to afford compound 3b as a yellow solid (252 mg, 54%).

[0371] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.32 (s, 12H, 2 O—(CH.sub.3).sub.2); 3.84 (s, 3H, Ar—O—CH.sub.3); 7.01 (dd, J 8.4, 2.4 Hz, 1H, Ar); 7.56 (d, J 2.4 Hz, 1H, Ar); 7.75-7.78 (m, 2H, Ar).

Compound 4a: 6-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0372] Compound 4a was prepared according to method d starting from 5-bromo-6-ethylpyridin-2-amine 1d (1.5 g, 7.46 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10) to afford compound 4a as a brown solid (570 mg, 31%).

[0373] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.06-1.21 (m, 3H, CH.sub.2.CH.sub.3); 1.26 (s, 12H, 2 O—C(CH.sub.3).sub.2); 2.77 (q, J 7.6 Hz, 2H, CH.sub.2CH.sub.3); 6.31 (d, J 8.4 Hz, 1H, Ar); 6.50 (bs, 2H, NH.sub.2); 7.62 (d, J 8.4 Hz, 1H, Ar). M/Z (M+H)+: 249.5.

Compound 5A: 5-(2-chlorophenyl)-6-ethyl-pyridin-2-amine

[0374] Compound 5a was prepared according to method e from 5-bromo-6-ethylpyridin-2-amine 1d (1.00 g, 4.97 mmol) and 2-chlorophenylboronic acid (1.16 g, 7.46 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 5a as an orange solid (1.00 g, 86%).

[0375] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.00 (t, J 7.6 Hz, 3H, CH.sub.3); 2.19-3.38 (m, 2H, CH.sub.2); 5.92 (s, 1H, NH.sub.2); 6.33 (d, J 8.4 Hz, 1H, Ar); 7.08 (d, J 8.4 Hz, 1H, Ar); 7.25-7.30 (m, 1H, Ar); 7.34-7.39 (m, 2H, Ar); 7.50-7.55 (m, 1H, Ar). M/Z (M[.sup.35Cl]+H).sup.+: 233.1.

Compound 5b: 3-(2-chlorophenyl)pyridine-2,6-diamine

[0376] Compound 5b was prepared according to method e from 2,6-diamino-3-iodopyridine 1h (1.0 g, 4.25 mmol) and 2-chlorophenylboronic acid (0.99 g, 6.38 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 5b as a smoothy brown solid (897 mg, 96%).

[0377] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.83 (s, 2H, NH.sub.2); 5.54 (s, 2H, 2 NH.sub.2); 5.79 (d, J 8.0 Hz, 1H, Ar); 6.91 (d, J 8.0 Hz, 1H, Ar); 7.26-7.38 (m, 3H, Ar); 7.48-7.53 (m, 1H, Ar). M/Z (M[.sup.35Cl]+H).sup.+: 220.6.

Compound 6: 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridine

[0378] Under Argon, to a solution of 5-bromo-6-ethylpyridin-2-amine 1d (5.30 g, 26.4 mmol, 1.0 eq.) in toluene (26 mL) was added hexane-2,5-dione (3.16 g, 3.25 mL, 27.7 mmol, 1.05 eq.) and 4-methylbenzenesulfonic acid (45.4 mg, 264 μmol, 0.01 eq.). The reaction mixture was heated at 135° C. for 18 h. The reaction mixture was concentrated, dissolved in toluene (26 mL) and heated at 135° C. for 20 h. The reaction mixture was concentrated to obtain a brown oil. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 95/5) to afford compound 6 (7.09 g, 96%) as an orange oil. M/Z (M[.sup.79Br]+H).sup.+: 281.0.

Compound 7: 6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0379] Under Argon, to a solution of compound 6 (7.09 g, 25.4 mmol, 1.0 eq.) in dioxane (63.5 mL) was added Bis(pinacolato)diboron (12.9 g, 50.8 mmol, 2.0 eq.) and potassium acetate (4.98 g, 50.8 mmol, 2.0 eq.). The reaction mixture was sparged with argon for 10 min then Pd(dppf)C.sub.2 (557 mg, 0.76 mmol, 0.03 eq.) was added. The reaction mixture was heated at 110° C. for 3 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (200 mL). Filtrate was hydrolyzed with NH.sub.4Cl sat. (200 mL) and extracted twice with EtOAc (200 mL). The organic layers were washed with brine (200 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 95/5) to afford to afford compound 7 (6.66 g, 80%) as a yellow oil. M/Z (M+H).sup.+: 327.0.

Compound 8: N-(6-amino-5-bromopyridin-2-yl)pivalamide

[0380] Under Argon, at −78° C., to a solution of 3-bromopyridine-2,6-diamine (1.20 g, 6.42 mmol, 1.0 eq.) in a mixture THE (9 mL)/DCM (9 mL) at −78° C. was added Et.sub.3N (1.16 mL, 8.35 mmol, 1.3 eq.) and pivaloyl chloride (833 μL, 6.74 mmol, 1.05 eq.) in solution in DCM (5 mL) over a period of 10 min. The reaction mixture was stirred 18 h allowing the bath coming back to room temperature. The reaction mixture was hydrolyzed with NaHCO.sub.3 sat. (100 mL) and extracted twice with EtOAc (100 mL). Combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtAOc: 100/0 to 50/50) to afford compound 8 (1.26 g, 4.65 mmol, 72%) as a light yellow solid. M/Z (M[.sup.81Br]+H).sup.+: 273.9.

Compound 9: N-(6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pivalamide

[0381] In a sealed tube under Argon, to a solution of N-(6-amino-5-bromopyridin-2-yl)pivalamide 8 (860 mg, 3.17 mmol, 1.0 eq.) in dioxane (6 mL), bis(pinacolato)diboron (1.61 g, 6.34 mmol, 2.0 eq.) and KOAc (622 mg, 6.34 mmol, 2.0 eq.) were added. The reaction mixture was sparged with Ar for 10 min then Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (129 mg, 159 μmol, 0.05 eq.) was added. The reaction mixture was heated at 110° C. for 4 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (100 mL). Filtrate was hydrolyzed with NH.sub.4Cl sat. (100 mL) and extracted twice with EtOAc (100 mL). The organic layers were washed with brine (200 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 9 (760 mg, 2.38 mmol, 75%) as a light yellow solid. M/Z (M+H).sup.+: 238.0.

Compound 10: 8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)quinoline-2-carboxylic Acid

[0382] In a sealed tube under Argon, to a solution of 8-bromoquinoline-2-carboxylic acid (600 mg, 2.38 mmol) and compound 7 (1.16 g, 3.57 mmol, 1.5 eq.) in DME (24 mL) was added a solution of K.sub.2CO.sub.3 1.2M in H.sub.2O (3.97 mL, 4.76 mmol, 2.0 eq.). The reaction mixture was sparged with argon for 10 min then SPhos Pd G2 (85.8 mg, 119 μmol, 0.05 eq.) was added. The reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (125 mL). Filtrate was hydrolyzed with HCl 0.05 N. (120 mL) until pH˜4-5 and extracted twice with EtOAc (100 mL). The organic layers were dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 10 (870 mg, 98%) as an orange gum. M/Z (M+H).sup.+: 372.1.

Compound 11: 6-isobutylpyridin-2-amine

[0383] Compound 11 was prepared according to method f step 1 starting from 6-bromopyrind-2-amine (2.00 g, 12.0 mmol) and isobutylzinc bromide (0.5 M in THF, 32 mL, 16 mmol, 1.4 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH 100/0 to 95/5) to afford compound 11 (1.10 g, 63%) as a brown oil. M/Z (M+H).sup.+: 151.2.

Compound 12: 5-bromo-6-isobutylpyridin-2-amine

[0384] Compound 12 was prepared according to method f step 2 starting from compound 11 (1.10 g, 7.30 mmol) and NBS (0.95 g, 7.0 mmol, 0.95 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 12 (1.21 g, 75%) as a brown solid. M/Z (M[.sup.81Br]+H).sup.+: 231.0.

Compound 13: 6-(cyclobutylmethyl)pyridin-2-amine

[0385] Compound 13 was prepared according to method f step 1 starting from 6-bromopyrind-2-amine (1.00 g, 5.80 mmol) and (cyclobutylmethyl)zinc bromide (0.5 M in THF, 25 mL, 12.5 mmol, 2.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH 100/0 to 95/5) to afford compound 13 (622 mg, 66%) as a brown oil. M/Z (M+H).sup.+: 163.1

Compound 14: 5-bromo-6-(cyclobutylmethyl)pyridin-2-amine

[0386] Compound 14 was prepared according to method f step 2 starting compound 13 (622 mg, 3.83 mmol) and NBS (682 mg, 3.83 mmol, 1.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 14 (100 mg, 11%) as a brown solid. M/Z (M[.sup.1Br]+H).sup.+: 243.0.

Compound 15: 6-(3,3,3-trifluoropropyl)pyridin-2-amine

[0387] Compound 15 was prepared according to method f step 1 starting from 6-bromopyrind-2-amine (1.00 g, 5.80 mmol) and (3,3,3-trifluoropropyl)zinc bromide (0.5 M in THF, 25 mL, 12.5 mmol, 2.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH 100/0 to 95/5) to afford compound 15 (417 mg, 38%) as an orange oil. M/Z (M+H).sup.+: 191.0

Compound 16: 5-bromo-6-(3,3,3-trifluoropropyl)pyridin-2-amine

[0388] Compound 16 was prepared according to method f step 2 starting from compound 14 (417 mg, 2.19 mmol) and NBS (371 mg, 2.08 mmol, 0.95 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 16 (467 mg, 84%) as a yellow solid. M/Z (M[.sup.79Br]+H).sup.+: 268.9.

Compound 17: 6-(4,4,4-trifluorobutyl)pyridin-2-amine

[0389] Compound 17 was prepared according to method f step 2 starting from 6-bromopyrind-2-amine (1.10 g, 6.40 mmol) and 4,4,4-trifluorobutyl)zinc bromide (0.5 M in THF, 25 mL, 12.5 mmol, 2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH 100/0 to 95/5) to afford compound 17 (1.05 g) as an orange oil. M/Z (M+H).sup.+: 191.0

Compound 18: 5-bromo-6-(4,4,4-trifluorobutyl)pyridin-2-amine

[0390] Compound 18 was prepared according to method f step 2 starting from compound 17 (1.05 g, 5.14 mmol) and NBS (824 mg, 4.63 mmol, 0.9 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 18 (914 mg, 51% over 2 steps) as a brown oil. M/Z (M[.sup.79Br]+H).sup.+: 284.9.

Compound 19: 6-(cyclopropylmethyl)pyridin-2-amine

[0391] Compound 19 was prepared according to method f step 1 starting from 6-bromopyrind-2-amine (1.00 g, 5.8 mmol) and (cyclopropylmethyl)zinc bromide (0.5 M in THF, 25 mL, 12.5 mmol, 2.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 19 (420 mg) as an orange oil. M/Z (M+H).sup.+: 149.2.

Compound 20: 5-bromo-6-(cyclopropylmethyl)pyridin-2-amine

[0392] Compound 20 was prepared according to method f step 2 starting from compound 19 (420 mg, 2.83 mmol, 1.0 eq.) and NBS (479 mg, 2.69 mmol, 0.95 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 20 (286 mg, 22% over 2 steps) as a red oil. M/Z (M[.sup.79Br]+H).sup.+: 227.0

Compound 21: 6-isopentylpyridin-2-amine

[0393] Compound 21 was prepared according to method f step1 starting from 6-bromopyrind-2-amine (1.00 g, 5.8 mmol) and isopentylzinc bromide (0.5 M in THF, 25 mL, 12.5 mmol, 2.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH 100/0 to 95/5) to afford compound 21 (620 mg, 65%) as a light orange oil. M/Z (M+H).sup.+: 165.2

Compound 22: 5-bromo-6-isopentylpyridin-2-amine

[0394] Compound 22 was prepared according to method f step1 starting from compound 21 (620 mg, 3.77 mmol) and NBS (707 mg, 3.97 mmol, 1.05 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 22 (807 mg, 88%) as an orange solid. M/Z (M[.sup.9Br]+H).sup.+: 243.0

Compound 23: 8-bromo-7-fluoroquinoline

[0395] Compound 23 was prepared according to method g starting from 2-bromo-3-fluoroaniline (4.00 g, 21.1 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 70/30) to afford compound 23 as a white solid (4.20 g, 88%). M/Z ([.sup.81Br]+H).sup.+: 228.0

Compound 24: 8-bromo-5,7-difluoroquinoline

[0396] Compound 24 was prepared according to method g starting from 2-bromo-3,5-difluoroaniline (2.50 g, 12.0 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 24 as a white solid (2.40 g, 82%). M/Z ([.sup.79Br]+H).sup.+: 243.8

Compound 25: 8-bromo-7-(trifluoromethyl)quinoline

[0397] Compound 25 was prepared according to method g starting from 2-bromo-3-(trifluoromethyl)aniline (500 mg, 2.08 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 25 as a beige solid (428 mg, 80%). M/Z ([.sup.79Br]+H).sup.+: 275.9

Compound 26: 8-bromo-7-chloroquinoline

[0398] Compound 26 was prepared according to method g starting from 2-bromo-3-chloroaniline (2.50 g, 12.0 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 26 as a white solid (2.42 g, 82%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 245.8

Compound 27: 8-bromo-6,7-difluoroquinoline

[0399] Compound 27 was prepared according to method g starting from 2-bromo-3,4-difluoroaniline (3.00 g, 14.4 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 75/25) to afford compound 27 as a beige solid (3.36 g, 95%). M/Z ([.sup.81Br]+H).sup.+: 245.8

Compound 28: 5-bromo-1,2,3,4-tetrahydroacridine

[0400] Compound 28 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (100 mg, 0.50 mmol) and cyclohexanone (51 μL, 0.50 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 28 (84 mg, 65%) as a yellow oil. M/Z (M[.sup.81Br]+H).sup.+: 261.9.

Compound 29: 6-bromo-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine

[0401] Compound 29 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (150 mg, 0.74 mmol) and 1-methylpiperidin-4-one (91 μL, 0.74 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100) to afford compound 29 (115 mg, 56%) as a yellow oil. M/Z (M[.sup.79Br]+H).sup.+: 276.9.

Compound 30: 5-bromo-2,3-dihydro-1H-cyclopenta[b]quinoline

[0402] In a sealed vial under Argon, to a solution of (2-amino-3-bromophenyl)methanol (150 mg, 0.74 mmol, 1.0 eq.) in dioxane (1.5 mL) was added cyclopentanol (67 μL, 0.74 mmol, 1.0 eq.), potassium tert-butoxide (167 mg, 1.48 mmol, 2.0 eq.) and benzophenone (271 mg, 1.48 mmol, 2.0 eq.). The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 30 (77 mg, 42%) as an orange solid. M/Z (M[.sup.81Br]+H).sup.+: 249.9.

Compound 31: 8-bromo-2-phenylquinoline

[0403] Compound 31 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (202 mg, 1.00 mmol) and acetophenone (120 mg, 1.00 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 31 (162 mg, 57%) as a yellow oil. M/Z (M[.sup.79Br]+H).sup.+: 284.0.

Compound 32: 8-bromo-2-(pyridin-3-yl)quinoline

[0404] Compound 32 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (202 mg, 1.00 mmol) and 3-acetylpyridine (110 μL, 1.00 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 32 (156 mg, 55%) as a colorless oil. M/Z (M[79Br]+H).sup.+: 285.0.

Compound 33: 8-bromo-2-cyclohexylquinoline

[0405] Compound 33 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-cyclohexylethan-1-one (125 mg, 0.99 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 33 (162 mg, 56%) as a colorless oil. M/Z (M[.sup.79Br]+H).sup.+: 290.0.

Compound 34: 8-bromo-2-(1-methylcyclopropyl)quinoline

[0406] Compound 34 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-(1-methylcyclopropyl)ethan-1-one (97 mg, 0.99 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 34 (145 mg, 53%) as a colorless oil. M/Z (M[.sup.79Br]+H).sup.+: 262.0

Compound 35: 8-bromo-2-(pyridin-2-yl)quinoline

[0407] Compound 35 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (202 mg, 1.00 mmol) and 2-acetylpyridine (118 μL, 1.00 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/80) to afford compound 35 (190 mg, 67%) as a brown solid. M/Z (M[.sup.79Br]+H).sup.+: 285.0

Compound 36: 8-bromo-2-(tetrahydro-2H-pyran-4-yl)quinoline

[0408] Compound 36 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-(tetrahydro-2H-pyran-4-yl)ethan-1-one (127 mg, 0.99 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 36 (100 mg, 34%) as a colorless oil. M/Z (M[.sup.81Br]+H).sup.+: 294.0.

Compound 37: 8-bromo-2-(pyridin-4-yl)quinoline

[0409] Compound 37 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (250 mg, 1.24 mmol) and 1-(pyridin-4-yl)ethan-1-one (225 mg, 1.86 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 20/80 to 0/100) to afford compound 37 (220 mg, 62%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 286.9.

Compound 38: 8-bromo-2-(imidazo[1,2-a]pyridin-6-yl)quinoline

[0410] Compound 38 was prepared according to method o starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-(imidazo[1,2-a]pyridin-6-yl)ethan-1-one (237 mg, 1.48 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 38 (100 mg, 31%) as a yellow solid. M/Z (M[.sup.61Br]+H).sup.+: 326.0.

Compound 39: 8-bromo-2-(pyrimidin-5-yl)quinoline

[0411] Compound 39 was prepared according to method p starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-(pyrimidin-5-yl)ethan-1-one (142 mg, 1.16 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 39 (250 mg, 88%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 287.9.

Compound 40: 8-bromo-2-(pyrazin-2-yl)quinoline

[0412] Compound 40 was prepared according to method p starting from (2-amino-3-bromophenyl)methanol (200 mg, 0.99 mmol) and 1-(pyrazin-2-yl)ethan-1-one (133 mg, 1.08 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOac: 100/0 to 70/30) to afford compound 40 (210 mg, 74%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 287.9.

Compound 41: 8-bromo-2-(4-methylpyridin-3-yl)quinoline

[0413] Compound 41 was prepared according to method p starting from (2-amino-3-bromophenyl)methanol (150 mg, 0.74 mmol) and 1-(4-methylpyridin-3-yl)ethan-1-one (120 mg, 0.89 mmol). The reaction mixture was stirred at 0° C. for 2 h and then heated at 80° C. for 20 h. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 41 (150 mg, 68%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 301.0.

Compound 42: 8-bromo-2-(2-methylpyridin-3-yl)quinoline

[0414] Compound 42 was prepared according to method p starting from (2-amino-3-bromophenyl)methanol (150 mg, 0.74 mmol) and 1-(2-methylpyridin-3-yl)ethan-1-one (120 mg, 0.89 mmol). The reaction mixture was stirred at 0° C. for 2 h and then heated at 80° C. for 20 h. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 42 (170 mg, 77%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 301.0.

Compound 43: 4-(8-bromoquinolin-2-yl)morpholine

[0415] In a sealed vial under Argon, to a solution of 8-bromo-2-chloroquinoline (100 mg, 0.41 mmol, 1.0 eq.) in DMA (2.0 mL) was added morpholine (72 μL, 0.83 mmol, 2.0 eq.). The reaction mixture was subjected to microwave irradiation at 150° C. for 15 min and was heated at 80° C. for 3 days. The reaction mixture was hydrolyzed with water (50 mL) and extracted twice with EtOAc (30 mL). The organic layers were washed brine (40 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 43 (103 mg, 85%) as a pink oil. M/Z (M[.sup.79Br]+H).sup.+: 293.1.

Compound 44: 4-(2-((8-bromoquinolin-2-yl)oxy)ethyl)morpholine

[0416] In a sealed vial under Argon, to a solution of 8-bromo-2-chloroquinoline (500 mg, 2.06 mmol, 1.0 eq.) in THF (9 mL) was added 2-morpholinoethan-1-ol (541 mg, 4.12 mmol, 2.0 eq.) and potassium tert-butoxide (347 mg, 3.09 mmol, 1.5 eq.). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was hydrolyzed with NH.sub.4Cl sat. (100 mL) and extracted twice with EtOAc (80 mL). The organic layers were washed with brine (150 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 44 (600 mg, 86%) as a light brown oil. M/Z (M[.sup.79Br]+H).sup.+: 337.1.

Compound 45: 8-bromo-2-(pyrrolidin-1-yl)quinoline

[0417] Compound 45 was prepared according to method h starting from 8-bromo-2-chloroquinoline (500 mg, 2.06 mmol) and pyrrolidine (440 mg, 6.19 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 45 as a pink solid (482 mg, 84%). M/Z ([.sup.81Br]+H).sup.+: 229.0

Compound 46: 8-bromo-2-(4,4-difluoropiperidin-1-yl)quinoline

[0418] In a sealed vial under Argon, to a suspension of 8-bromo-2-chloroquinoline (373 mg, 1.54 mmol, 1.0 eq.) in DMA (9 mL) was added 4,4-difluoropiperidine hydrochloride (364 mg, 2.31 mmol, 1.5 eq.) and Et.sub.3N (729 μL, 5.23 mmol, 3.4 eq.). The reaction mixture was subjected thrice to microwave irradiation at 150° C. for 25 min. The reaction mixture was hydrolyzed with water (50 mL) then extracted twice with EtOAc (50 mL). Organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtAOc: 100/0 to 80/20) to afford compound 46 (150 mg, 30%) as a red oil. M/Z (M[.sup.79Br]+H).sup.+: 327.0.

Compound 47: 4-(8-bromoquinolin-2-yl)-1,4-oxazepane

[0419] Compound 47 was prepared according to method h starting from 8-bromo-2-chloroquinoline (500 mg, 2.06 mmol) and 1,4-oxazepane (626 mg, 6.19 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 47 as a purple oil (588 mg, 93%). M/Z ([.sup.79Br]+H).sup.+: 307.0

Compound 48: 8-bromo-7-fluoroquinolin-2(1H)-one

[0420] Compound 48 was prepared according to method i starting from 2-bromo-3-fluoroaniline (600 mg, 3.16 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 48 as an orange solid (540 mg, 71%). M/Z ([.sup.81Br]+H).sup.+: 243.8

Compound 49: 8-bromo-5,7-difluoroquinolin-2(1H)-one

[0421] Compound 49 was prepared according to method i starting from 2-bromo-3,5-difluoroaniline (600 mg, 2.88 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 49 as an orange solid (347 mg, 46%). M/Z ([.sup.81Br]+H).sup.+: 261.8

Compound 50: 8-bromo-7-chloroquinolin-2(1H)-one

[0422] Compound 50 was prepared according to method i starting from 2-bromo-3-chloroaniline (600 mg, 2.91 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 50 as an orange solid (347 mg, 46%). M/Z ([.sup.79Br][.sup.35Cl]+H).sup.+: 258.8

Compound 51: 8-bromo-5,6-difluoroquinolin-2(1H)-one

[0423] Compound 51 was prepared according to method i starting from 2-bromo-3,4-difluoroaniline (600 mg, 2.88 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 51 as an orange solid (297 mg, 40%). M/Z ([.sup.79Br]+H).sup.+: 259.8

Compound 52: 8-bromo-2-chloro-7-fluoroquinoline

[0424] Under Argon, to a suspension of 8-bromo-7-fluoroquinolin-2(1H)-one 48 (1.17 g, 4.83 mmol, 1.0 eq.) in toluene (23 mL) was added DMF (0.56 mL, 7.25 mmol, 1.5 eq.). The reaction mixture was heated at 90° C. then POCl.sub.3 (451 μL, 4.83 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 90° C. for 1 h. The reaction mixture was hydrolyzed at 0° C. with NaOH 1N (100 mL) then extracted twice with EtOAc (150 mL). The organic layers were washed thrice with brine (150 mL), dried over magnesium sulfate, concentrated to afford compound 52 (1.11 g, 88%) as a brown solid and was used without further purification. M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+: 260.9.

Compound 53: 4-(8-bromo-7-fluoroquinolin-2-yl)-1,4-oxazepane

[0425] Compound 53 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and 1,4-oxazepane (175 mg, 1.73 mmol, 3.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 53 as a white solid (162 mg, 87%). M/Z ([.sup.79Br]+H).sup.+: 326.9

Compound 54: 4-(8-bromo-7-fluoroquinolin-2-yl)morpholine

[0426] Compound 54 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and morpholine (151 mg, 1.73 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/02) to afford compound 54 as a white solid (150 mg, 83%). M/Z ([.sup.79Br]+H).sup.+: 310.9

Compound 55: 3-(8-bromo-7-fluoroquinolin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

[0427] Compound 55 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (151 mg, 1.73 mmol). Starting from a chlorhydrate, Et.sub.3N (241 μL, 1.73 mmol) was added. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 55 as a beige solid (165 mg, 85%). M/Z ([.sup.81Br]+H).sup.+: 339.0

Compound 56: 2-(azepan-1-yl)-8-bromo-7-fluoroquinoline

[0428] Compound 56 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and azepane (171 mg, 1.73 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 56 as a beige solid (144 mg, 77%). M/Z ([.sup.81Br]+H).sup.+: 325.0

Compound 57: 8-bromo-N-cyclohexyl-N-ethyl-7-fluoroquinolin-2-amine

[0429] Compound 57 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and N-ethylcyclohexanamine (220 mg, 1.73 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 57 as a yellow oil (132 mg, 65%). M/Z ([.sup.81Br]+H).sup.+: 353.0

Compound 58: 8-bromo-N-ethyl-7-fluoro-N-isopropylquinolin-2-amine

[0430] Compound 58 was prepared according to method h starting from 8-bromo-2-chloro-7-fluoroquinoline 52 (150 mg, 0.58 mmol) and N-ethylpropan-2-amine (151 mg, 1.73 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 58 as a yellow oil (132 mg, 74%). M/Z ([.sup.81Br]+H).sup.+: 313.0.

Compound 59: 8-bromo-N,N-dimethylquinoline-2-carboxamide

[0431] Compound 59 was prepared according to method j starting from 8-bromo-2-carboxylic acid (500 mg, 1.98 mmol) and dimethylamine (2M in THF, 1.50 mL, 3.00 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to afford compound 59 as a white solid (540 mg, 71%). M/Z ([.sup.81Br]+H).sup.+: 281.0

Compound 60: (8-bromoquinolin-2-yl)(pyrrolidin-1-yl)methanone

[0432] Compound 60 was prepared according to method j starting from 8-bromo-2-carboxylic acid (500 mg, 1.98 mmol) and pyrrolidine (0.34 mL, 4.20 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to afford compound 60 as a light yellow solid (550 mg, 91%). M/Z ([.sup.79Br]+H).sup.+: 304.9

Compound 61: 8-bromo-N-(oxetan-3-yl)quinoline-2-carboxamide

[0433] Compound 61 was prepared according to method j starting from 8-bromo-2-carboxylic acid (125 mg, 0.50 mmol) and oxetan-3-amine (47 mg, 0.64 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 61 as a yellow oil (96 mg, 63%). M/Z ([.sup.79Br]+H).sup.+: 306.9

Compound 62: (8-bromoquinolin-2-yl)methanol

[0434] Under Argon, at 0° C., to a solution of 8-bromoquinoline-2-carboxylic acid (500 mg, 1.98 mmol, 1.0 eq.) in THF (15 mL) was added Et.sub.3N (332 μL, 2.38 mmol, 1.2 eq.) and dropwise isobutyl chloroformate (309 μL, 2.38 mmol, 1.2 eq.). The reaction mixture was stirred at 0° C. for 1 h. The formed precipitated was filtered off and washed with anhydrous THF (5 mL). Under Argon, at 0° C., to the filtrate was added dropwise a lithium borohydride solution (2M in THF, 2.58 mL, 5.16 mmol, 2.6 eq.). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was hydrolyzed at 0° C. with HCl 1N (20 mL) then extracted thrice with DCM (30 mL). Combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 62 (300 mg, 64%) as a colorless oil. M/Z (M[.sup.8′Br]+H).sup.+: 240.0.

Compound 63: 8-bromo-2-(methoxymethyl)quinoline

[0435] Under Argon, to a solution of (8-bromoquinolin-2-yl)methanol 62 (300 mg, 1.26 mmol, 1.0 eq.) in DCM (12 mL) were added DMAN (948 mg, 4.42 mmol, 3.5 eq.) and trimethyloxonium tetrafluoroborate (559 mg, 3.84 mmol, 3.0 eq.). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was hydrolyzed with HCl 1N (40 mL), then extracted twice with DCM (30 mL). The organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10) to afford compound 63 (178 mg, 56%) as a yellow oil. M/Z (M[.sup.81Br]+H).sup.+: 254.0

Compound 64: 8-bromo-7-(difluoromethoxy)quinoline

[0436] In a sealed tube under Argon, to a solution of 8-bromoquinolin-7-ol (100 mg, 0.45 mmol, 1 eq.) in DMF (2.2 mL) was added Cs.sub.2CO.sub.3 (291 mg, 0.89 mmol, 2.0 eq.) and sodium 2-chloro-2,2-difluoroacetate (170 mg, 1.12 mmol, 2.5 eq.). The reaction mixture was heated at 120° C. for 24 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (20 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 64 (73 mg, 60%) as a white solid. M/Z (M[.sup.81Br]+H).sup.+: 275.8.

Compound 65: 8-bromo-7-fluoro-3-iodoquinoline

[0437] In a sealed tube under Argon, to a solution of 8-bromo-7-fluoroquinoline 23 (1.00 g, 4.42 mmol, 1.0 eq.) in acetic acid (13 mL) was added NIS (1.09 g, 4.87 mmol, 1.1 eq.). The reaction mixture was heated at 100° C. for 1 hour, then NIS (498 mg, 2.21 mmol, 0.5 eq.) was added and heating at 100° C. was maintains for 1 h. The reaction mixture was poured over ice and extracted twice with EtOAc (100 mL). Combined organic layers were washed with brine (100 mL), dried and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 65 (720 mg 46%) as a white solid M/Z (M[.sup.81Br]+H).sup.+: 353.7.

Compound 66: 8-bromo-7-fluoro-3-phenylquinoline

[0438] In a sealed tube under Argon, to a suspension of 8-bromo-7-fluoro-3-iodoquinoline 65 (170 mg 0.48 mmol, 1.0 eq.) and phenylboronic acid (59 mg, 0.48 mmol, 1.0 eq.) in toluene (1.0 mL), EtOH (0.17 mL) and H.sub.2O (0.17 mL) was added Na.sub.2CO.sub.3 (102 mg, 0.96 mmol, 2.0 eq.). The reaction mixture was sparged with argon for 10 min before addition of Pd(PPh.sub.3).sub.4 (28 mg, 24 μmol, 0.05 eq.). The reaction mixture was heated at 90° C. for 5 h. The reaction mixture was hydrolyzed with water (50 mL) and extracted twice EtOAc (50 mL). The organic layers were washed with brine (80 mL), dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 66 (109 mg, 75%) as a yellow solid. M/Z (M[.sup.1Br]+H).sup.+: 303.9.

Compound 67: 7-bromo-1-methylindoline

[0439] Under Argon at 0° C., to a solution of 7-bromoindoline (150 mg, 0.76 mmol, 1.0 eq.) in THF (5 mL) was added tBuOK (127 mg, 1.14 mmol, 1.5 eq.). The reaction mixture was stirred at 0° C. for 1 h then iodomethane (161 mg, 1.14 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was hydrolyzed with water (20 mL) then extracted twice with EtOAc (20 mL). The organic layers were filtered through an hydrophobic cartridge and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 67 (105 mg, 65%) as a yellow liquid. M/Z (M[.sup.81Br]+H).sup.+: 213.9

Compound 68: 8-bromo-7-fluoro-3-nitroquinoline

[0440] Compound 68 was prepared according to method k starting from compound 23 (1.00 g, 4.40 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 68 as a yellow solid (650 mg). M/Z ([.sup.81Br]+H).sup.+: 272.1

Compound 69: 8-bromo-7-fluoroquinolin-3-amine

[0441] Compound 69 was prepared according to method l starting from 68 (650 mg). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 20/80) to afford compound 69 (330 mg, 31% over 2 steps) as an orange solid. M/Z (M[.sup.81Br]+H).sup.+: 242.8.

Compound 70: 8-bromo-3,7-difluoroquinoline

[0442] Compound 70 was prepared according to method m starting from 8-bromo-7-fluoroquinolin-3-amine 69 (330 mg, 1.37 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 70 as a white solid (286 mg, 80%). M/Z ([.sup.79Br]+H).sup.+: 243.8

Compound 71: 8-bromo-3-chloro-7-fluoroquinoline

[0443] Compound 71 was prepared according to method n starting from 8-bromo-7-fluoroquinolin-3-amine 69 (390 mg, 1.62 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 71 as a light yellow solid (286 mg, 80%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 263.9

Compound 72: 8-bromo-7-chloro-3-nitroquinoline

[0444] Compound 72 was prepared according to method k starting from compound 26 (1.00 g, 4.12 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 72 as a yellow solid (504 mg, 43%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 290.8.

Compound 73: 8-bromo-7-chloroquinolin-3-amine

[0445] Compound 73 was prepared according to method l starting from compound 72 (500 mg, 1.74 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 10/90) to afford compound 73 (373 mg, 95%) as a beige solid. M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 260.8.

Compound 74: 8-bromo-7-chloro-3-fluoroquinoline

[0446] Compound 74 was prepared according to method m starting from 8-bromo-7-chloroquinolin-3-amine 73 (290 mg, 1.13 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/DCM: 100/0 to 30/70) to afford compound 74 as a white solid (166 mg, 57%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 263.7.

Compound 75: 8-bromo-3,7-dichloroquinoline

[0447] Compound 75 was prepared according to method n starting from 8-bromo-7-chloroquinolin-3-amine 73 (370 mg, 1.44 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 75 as a white solid (307 mg, 77%). M/Z ([.sup.81Br][.sup.37Cl].sub.2+H).sup.+: 279.8

Compound 76: 8-bromo-5,7-difluoro-3-nitroquinoline

[0448] Compound 76 was prepared according to method k starting from compound 24 (640 mg, 2.62 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 76 as a white solid (295 mg, 39%). M/Z ([.sup.81Br]+H).sup.+: 290.8.

Compound 77: 8-bromo-5,7-difluoroquinolin-3-amine

[0449] Compound 77 was prepared according to method l starting from compound 76 (368 mg, 1.27 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 10/90) to afford compound 77 (293 mg, 89%) as a light yellow solid. M/Z ([.sup.81Br]+H).sup.+: 260.9.

Compound 78: 8-bromo-3,5,7-trifluoroquinoline

[0450] Compound 78 was prepared according to method m starting from 8-bromo-5,7-difluoroquinolin-3-amine 77 (400 mg, 1.54 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 78 as a white solid (166 mg, 57%). M/Z ([.sup.79Br]+H).sup.+: 261.9.

Compound 79: 8-bromo-3-chloro-5,7-difluoroquinoline

[0451] Compound 79 was prepared according to method n starting from 8-bromo-5,7-difluoroquinolin-3-amine 77 (290 mg, 1.12 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 79 as a white solid (243 mg, 78%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 281.7.

Compound 80: 8-bromo-6,7-difluoro-3-nitroquinoline & Compound 81: 8-bromo-6,7-difluoroquinolin-3-ol

[0452] Compound 80 & compound 81 were prepared according to method k starting from compound 27 (1.50 g, 6.15 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 80 as a white solid (660 mg, 37%) M/Z ([.sup.81Br]+H).sup.+: 290.8 and compound 81 as a yellow solid (144 mg, 9%) M/Z ([.sup.81Br]+H).sup.+: 261.9.

Compound 82: 8-bromo-6,7-difluoroquinolin-3-amine

[0453] Compound 82 was prepared according to method starting from compound 80 (660 mg, 2.28 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 10/90) to afford compound 82 (576 mg, 98%) as a light yellow solid. M/Z ([.sup.81Br]+H).sup.+: 260.8.

Compound 83: 8-bromo-3,6,7-trifluoroquinoline

[0454] Compound 83 was prepared according to method m starting from 8-bromo-6,7-difluoroquinolin-3-amine 82 (280 mg, 1.08 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 83 as a white solid (163 mg, 58%). M/Z ([.sup.81Br]+H).sup.+: 263.9.

Compound 84: 8-bromo-3-chloro-6,7-difluoroquinoline

[0455] Compound 84 was prepared according to method n starting from 8-bromo-6,7-difluoroquinolin-3-amine 82 (280 mg, 1.08 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 85/15) to afford compound 84 as a white solid (233 mg, 77%). M/Z ([.sup.81Br][.sup.37Cl]+H).sup.+: 281.8

Compound 85: 8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)-7-fluoroquinolin-3-amine

[0456] In a seal tube under Argon, to a solution of compound 7 (284 mg, 0.87 mmol, 1.5 eq.) and 8-bromo-7-fluoroquinolin-3-amine 69 (140 mg, 0.58 mmol, 1.0 eq.) in dioxane (2 mL) was added a solution of K.sub.2CO.sub.3 1.2M in water (968 μL, 1.16 mmol, 2.0 eq.). The reaction mixture was vacuum purged with argon (3 times) before addition of SPhos Pd G2 (21 mg, 0.03 mmol, 0.05 eq.). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture hydrolyzed with water (40 mL) and extracted twice with EtOAc (50 mL). The organic layers were washed brine (40 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 85 (189 mg, 90%) as a brown solid. M/Z (M+H).sup.+: 361.2.

Compound 86: 3-bromo-8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)-7-fluoroquinoline

[0457] Under Argon, at 0° C., to a suspension of copper(I) bromide (147 mg, 1.03 mmol, 2.0 eq.) in acetonitrile (2.0 mL) was added tert-butyl nitrite (136 μL, 1.03 mmol, 2.0 eq.) and a solution of compound 85 (185 mg, 0.51 mmol, 1.0 eq.) in acetonitrile (4.0 mL). The reaction mixture was heated at 60° C. for 1 h. The reaction mixture was hydrolyzed with NaHCO.sub.3 sat. (50 mL) then extracted thrice with EtOAc (50 mL). The organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 86 (47 mg, 19%) as a colorless oil. M/Z (M[.sup.81Br]+H).sup.+: 426.0

Compound 87: 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline

[0458] Under Argon, to a suspension of 8-bromo-1,2,3,4-tetrahydroquinoline hydrochloride (300 mg, 1.21 mmol, 1 eq.) in THE (12 mL) was added formaldehyde 40 wt % in water (831 μL, 12.1 mmol, 10 eq.) and NaBH.sub.3CN (758 mg, 12.1 mmol, 10 eq.). The reaction mixture was stirred at 25° C. for 40 h. The reaction mixture was hydrolyzed with NaOH 1N (100 mL) then extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 70/30) to obtain compound 87 (149 mg, 55%) as a colorless oil. M/Z (M[.sup.79Br]+H).sup.+: 225.9.

Compound 88: (7-fluoroquinolin-8-yl)boronic Acid

[0459] Under Argon and anhydrous atmosphere, at −78° C., to a solution of 8-bromo-7-fluoroquinoline (1.0 g, 4.4 mmol, 1.0 eq.) in THE (12 mL) was added dropwise n-butyllithium (1.6 M in hexanes, 3.0 mL, 4.90 mmol, 1.1 eq.). The reaction mixture was stirred at −78° C. for 30 min then isopropoxyboronic acid (2.7 mL, 13 mmol, 3.0 eq.) was added in one portion. The reaction mixture was stirred 45 min at −78° C. The reaction mixture was hydrolyzed with water (20 mL) and EtOAc (10 mL) was added. The obtained white solid was filtered and washed with water (30 mL) and iPr.sub.2O (15 mL) to afford compound 88 after an overnight drying under vacuum at 50° C. with P.sub.2O.sub.5 (618 mg, 73%) as a white solid. M/Z (M+H).sup.+: 192.0.

Compound 89: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one

[0460] In a sealed tube under Argon, to a solution of 8-bromoquinolin-2(1H)-one (200 mg, 0.89 mmol, 1.0 eq.) and Bis(pinacolato)diboron (453 mg, 1.79 mmol, 2.0 eq.) in 1,4-dioxane (4 mL) was added KOAc (175 mg, 1.79 mmol, 2.0 eq.). The reaction mixture was sparged with argon for 10 min before addition of Pd(dppf)Cl.sub.2 (33 mg, 0.05 Eq, 44.6 μmol). The reaction mixture was heated at 110° C. for 2 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (30 mL). Filtrate was hydrolyzed NH.sub.4Cl sat. (40 mL), then extracted twice with EtOAc (40 mL). Combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 89 (200 mg, 82%) as an orange solid. M/Z (M+H).sup.+: 272.1.

Compound 90: 5-(2-chloro-4-fluorophenyl)-6-ethylpyridin-2-amine

[0461] Compound 90 was prepared according to method e from 5-bromo-6-ethylpyridin-2-amine 1d (308 mg, 1.53 mmol) and (2-chloro-4-fluorophenyl)boronic acid (400 mg, 2.29 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to afford compound 90 as a beige solid (195 mg, 51%). M/Z (M[.sup.35Cl]+H).sup.+: 251.1.

Compound 91: 5-(2-chloro-5-fluorophenyl)-6-ethylpyridin-2-amine

[0462] Compound 91 was prepared according to method e from 5-bromo-6-ethylpyridin-2-amine 1d (500 mg, 2.49 mmol) and (2-chloro-5-fluorophenyl)boronic acid (650 mg, 3.73 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 91 as a beige solid (393 mg, 63%). M/Z (M[.sup.35Cl]+H).sup.+: 251.1.

Compound 92: 1-(allyloxy)-2-bromo-3-fluorobenzene

[0463] Under Argon, to a solution of 2-bromo-3-fluorophenol (1.13 mL, 10.5 mmol, 1.0 eq.) in Acetonitrile (27 mL) was added K.sub.2CO.sub.3 (1.74 g, 12.6 mmol, 1.2 eq.). The reaction mixture was heated at 80° C. then a solution of allyl bromide (1.45 mL, 16.8 mmol, 1.6 eq.) in acetonitrile (3.3 mL) was added. The reaction mixture was heated at 80° C. for 18 h. The reaction mixture was hydrolyzed with water (300 mL) and extracted twice with EtOAc (300 mL). The organic layers were washed with brine (300 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 92 as a colorless oil (2.25 g, 93%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 4.69 (dt, J 5.0, 1.6 Hz, 2H, O—CH.sub.2); 5.30 (dq, J 10.4, 1.6 Hz, 1H, CH═CH.sub.2); 5.46 (dq, J 17.2, 1.6 Hz, 1H, CH═CH.sub.2); 6.05 (ddt, J 17.2, 10.4, 5.0 Hz, 1H, CH═CH.sub.2); 6.94-6.98 (m, 2H, Ar); 7.34-7.40 (m, 1H, Ar).

Compound 93: 6-allyl-2-bromo-3-fluorophenol

[0464] In a MW vial under Argon, compound 92 (2.22 g, 9.60 mmol, 1.0 eq.) was stirred neat under microwave irradiation at 200° C. for 20 min. The reaction was further subjected to microwave irradiation at 200° C. for 15 min. The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 70/30) to afford compound 93 as a yellow oil (1.80 g). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 3.36 (d, J 6.4 Hz, 2H, Ph-CH.sub.2); 4.99-5.05 (m, 2H, CH═CH.sub.2); 5.87-5.97 (m, 1H, CH═CH.sub.2); 6.80 (t, J, 8.4 Hz, 1H, Ar); 7.07 (dd, J 8.4, 6.8 Hz, 1H, Ar), 9.52 (s, 1H, OH).

Compound 94: 2-bromo-3-fluoro-6-(3-hydroxypropyl)phenol

[0465] Under Argon, at 0° C., to a solution of compound 93 (500 mg, 2.16 mmol, 1.0 eq.) in THF (22 mL) was added dropwise borane dimethyl sulfide complex (0.82 mL, 8.66 mmol, 4.0 eq.). The reaction was stirred at 0° C. for 2 h. When borylation was complete (full conversion of the starting material was noticed by UPLC-MS), NaOH 2N (2.2 mL) was added dropwise at 0° C. then hydrogen peroxide (30 wt. % in water, 17.7 mL, 173 mmol, 80 eq.) was added dropwise. The reaction mixture was stirred at 25° C. for 45 min. The reaction mixture was hydrolyzed with HCl 1N (200 mL) until pH ˜1, then extracted twice with DCM (200 mL). The organic layer were washed with brine (200 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/EtOAc: 100/0 to 95/5) to afford compound 94 (520 mg, 97%) as a colorless oil. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.65 (tt, J 7.6, 6.4 Hz, 2H, Ph-CH.sub.2—CH.sub.2); 2.61 (t, J 7.6 Hz, 2H, Ph-CH.sub.2—CH.sub.2); 3.40 (t, J 6.4 Hz, 2H, O—CH.sub.2); 4.59 (bs, 1H, OH); 6.77 (t, J, 8.4 Hz, 1H, Ar); 7.10 (dd, J 8.4, 6.6 Hz, 1H, Ar), 9.44 (bs, 1H, Ph-OH).

Compound 95: 8-bromo-7-fluorochromane

[0466] Under Argon, at 0° C., to a solution of 2-bromo-3-fluoro-6-(3-hydroxypropyl)phenol 94 (250 mg, 1.00 mmol, 1.0 eq.) in THF (5 mL), diisopropyl-diazene-1,2-dicarboxylate (217 μL, 1.10 mmol, 1.1 eq.) and triphenylphosphine (290 mg, 1.10 mmol, 1.1 eq.) were added. The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was hydrolyzed with NaOH 1N (10 mL), then extracted twice with EtOAc (10 mL). The organic layers were washed with HCl 1N (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 95 (166 mg, 72%) as a colorless oil. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.92 (tt, J 6.4, 5.2 Hz, 2H, O—CH.sub.2—CH.sub.2); 2.75 (td, J 6.4, 0.8 Hz, 2H, Ph-CH.sub.2); 4.26 (t, J 5.2 Hz, 2H, O—CH.sub.2—CH.sub.2); 6.82 (t, J, 8.4 Hz, 1H, Ar); 7.10-7.13 (m, 1H, Ar).

Compound 96: 8-bromo-7-fluoro-2,2-dimethylchromane

[0467] Under Argon, to a solution of 2-bromo-3-fluorophenol (0.57 mL, 5.2 mmol, 10.0 eq.) in DCM (2.6 mL), 3-methylbut-2-en-1-yl acetate (73 μL, 0.52 mmol, 1.0 eq.) and indium(III) trifluoromethanesulfonate (29 mg, 0.52 mmol, 0.1 eq.) were added. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was hydrolyzed with NaOH 1N (50 mL) then extracted twice with Et.sub.2O (25 mL). The organic layers were washed twice with NaOH 1N (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated to afford compound 96 (88 mg, 65%) as a colorless oil which was used without further purification. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.31 (s, 6H, 2*CH.sub.3); 1.78 (t, J 6.8 Hz, 2H, Ph-CH.sub.2—CH.sub.2); 2.75 (t, J 6.8 Hz, 2H, Ph-CH.sub.2); 6.80 (t, J, 8.4 Hz, 1H, Ar); 7.11-7.15 (m, 1H, Ar).

Compound 97: 1-allyl-2-(allyloxy)-3-bromo-4-fluorobenzene

[0468] Under Argon, to a solution of 6-allyl-2-bromo-3-fluorophenol 93 (1.18 g, 5.11 mmol, 1.0 eq.) in acetonitrile (25 mL), K.sub.2CO.sub.3 (847 mg, 5.35 mmol, 1.2 eq.) was added. The reaction mixture was heated at 80° C., then a solution of allyl bromide (707 μL, 7.13 mmol, 1.6 eq.) in acetonitrile (4 mL) was added. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was hydrolyzed with water (40 mL) and extracted twice with EtOAc (40 mL). The organic layers were washed with brine (40 mL), dried over sodium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 97 as a colorless oil (1.45 g). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 3.39 (d, J 6.4 Hz, 2H, Ph-CH.sub.2); 4.46 (ddd, J 5.6, 1.6, 1.2 Hz, 2H, O—CH.sub.2); 5.02-5.10 (m, 2H, CH═CH.sub.2); 5.28 (m, 1H, CH═CH.sub.2); 5.44 (dq, J 17.2, 1.6 Hz, 1H, CH═CH.sub.2); 5.94 (ddt, J 16.8, 10.4, 6.4 Hz, 1H, CH═CH.sub.2); 6.11 (ddt, J 17.2, 10.4, 5.8 Hz, 1H, CH═CH.sub.2); 7.14 (t, J, 8.4 Hz, 1H, Ar); 7.25 (dd, J 8.4, 6.8 Hz, 1H, Ar).

Compound 98: 9-bromo-8-fluoro-2,5-dihydrobenzo[b]oxepine

[0469] Under Argon, to a solution of 1-allyl-2-(allyloxy)-3-bromo-4-fluorobenzene 97 (876 mg, 3.23 mmol, 1.0 eq.) in DCM (16 mL), Grubbs II catalyst (15 mg, 0.02 mmol, 0.006 eq.) was added. The reaction mixture was stirred at 25° C. for 22 h. The reaction mixture was filtered through a Celite® pad and the cake washed with DCM (100 mL). The organic layer was hydrolyzed with NaHCO.sub.3 sat. (100 mL) and extracted twice with DCM (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 98 (734 mg, 94% over 2 steps) as a colorless oil. .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 3.44-3.46 (m, 2H, Ph-CH.sub.2); 4.47-4.60 (m, 2H, O—CH.sub.2); 5.49-5.53 (m, 1H, CH═CH); 5.80-5.86 (m, 1H, CH═CH); 7.05 (t, J, 8.4 Hz, 1H, Ar); 7.23 (dd, J 8.4, 6.4 Hz, 1H, Ar).

II. Preparation of Selected Examples of the Invention

General Methods

Method 1: Suzuki Coupling

[0470] In a sealed vial, to a solution of aminopyridine halide 1 (1.0 eq.) and heteroaryl boronic derivative (1.2-1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 90° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. For specific examples, the corresponding hydrochloride salt was prepared.

Method 2: Suzuki Couplinq

[0471] In a sealed vial, to a solution of aminopyridine halide 1 (1.0 eq.) and heteroaryl boronic derivative (1.2-1.5 eq.) in dioxane (C=0.2 M) an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and SPhos Pd G2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 3: Suzuki Coupling

[0472] In a sealed vial, to a solution of aminopyridine halide 1 (1.0 eq.) and heteroaryl boronic derivative (1.2-1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and P(tBu).sub.3 Pd G2 (7 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 90° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, filtered on a Celite® pad and the cake was washed with MeOH. The filtrate was concentrated and purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 4: Suzuki Coupling

[0473] In a sealed vial, to a solution of aminopyridine halide 1 (1.0 eq.) and heteroaryl boronic derivative (1.2-1.5 eq.) in ethanol (C=0.2 M) an aqueous solution of Na.sub.2CO.sub.3 (1.2 M, 1.5 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and XPhos Pd G2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 90° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, filtered on a Celite® pad and the cake was washed with DCM/MeOH 9/1. The filtrate was concentrated and purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 5: Suzuki Coupling

[0474] In a sealed vial, to a solution of aminopyridine halide 1 (1.0 eq.), heteroaryl boronic derivative 3 (1.2-2.5 eq.) and CataCXium HI (0.1 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.5 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and Pd(OAc).sub.2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 120° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, filtered on a Celite® pad and the cake was washed with DCM/MeOH 9/1. The organic layer was washed with NH.sub.4Cl sat., the aqueous layer was extracted with DCM and two organic layers was washed with brine, dried over magnesium sulfate and concentrated. The crude residue was purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 6: Suzuki Coupling

[0475] In a sealed vial, to a suspension of heteroarylbromide (1.0 eq.) and boronate (1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and SPhos Pd G2 (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, filtered on a Celite® pad and the cake was washed with DCM/MeOH 9/1. The filtrate was concentrated and purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 7: Suzuki Coupling

[0476] In a sealed vial, to a suspension of heteroarylbromide (1.0 eq.) and boronate (1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added dropwise. The resulting suspension was degassed with argon bubbling for 15 min and PdCl.sub.2 dppf (5 mol %) was then added in one portion. The vial was sealed and the mixture was stirred at 90° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, filtered on a Celite® pad and the cake was washed with DCM/MeOH 9/1. The filtrate was concentrated and purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 8: Suzuki Coupling

[0477] In a sealed vial, to a solution of halide 5b (1.0 eq.), (hetero)aryl boronic derivative (1.2-1.5 eq.) and P(Cy).sub.3 (20 mol %) in dioxane (C=0.2 M), a solution of TBAF (1.0 M in THF, 2.0 eq.) was added dropwise. The resulting solution was degassed with argon bubbling for 15 min and Pd.sub.2(dba).sub.3 (10 mol %) was then added in one portion. The vial was sealed, and the mixture was stirred at 100° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was cooled to rt, hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography. For specific examples, the corresponding hydrochloride salt was prepared.

Method 9: Suzuki Coupling/Dimethylpyrrole Cleavage

[0478] Step 1: In a sealed vial, to a suspension of bromo (heteroaryl) (1.0 eq.) and boronic ester (1.1-1.5 eq.) in dioxane (C=0.2 M) was added dropwise an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.). The resulting suspension was sparged with argon for 10 min and SPhos Pd G2 (5 mol %) was added. The vial was sealed, and the reaction mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to afford the protected intermediate.

[0479] Step 2: Under Argon, to a suspension of the protected intermediate (1.0 eq.) in a mixture of EtOH/H.sub.2O: 2/1 (C=0.1 M) was added hydroxylamine hydrochloride (20.0 eq.) and triethylamine (3.6 eq.). The reaction mixture was heated at 90° C. until no more evolution was noticed by UPLC-MS (4 h, unless mentioned otherwise). The reaction mixture was hydrolyzed with HCl 1 M and extracted twice with Et.sub.2O. The aqueous layer was basified with NaOH 6N, and extracted thrice with DCM. Combined DCM layers were dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method 10 Peptidic Coupling/Dimethylpyrrole Cleavage

[0480] Step 1: Under Argon, to a solution of quinoline-2-carboxylic acid derivative (1.00 eq.) in DMF (C=0.1 M), BOP (1.3 eq.), N-ethyl-N-isopropylpropan-2-amine (3.0 eq.) and amine (1.1 eq.) were added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was hydrolyzed with NH.sub.4Cl sat. and extracted twice with EtOAc. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography to afford the protected intermediate.

[0481] Step 2: Under Argon, to a suspension of the protected intermediate (1 eq.) in a mixture of EtOH/H.sub.2O: 2/1 (C=0.1 M) was added hydroxylamine hydrochloride (20.0 eq.) and triethylamine (3.6 eq.). The reaction mixture was heated at 90° C. until no more evolution was noticed by UPLC-MS (4 h, unless mentioned otherwise). The reaction mixture was hydrolyzed with HCl 1 M and extracted twice with Et.sub.2O. The aqueous layer was basified with NaOH 6N and extracted thrice with DCM. Combined DCM layers were dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method 11: Suzuki Coupling/Pivaloyl Deprotection

[0482] Step 1: In a sealed vial, to a suspension of bromo (heteroaryl) (1.0 eq.) and boronic ester (1.1-1.5 eq.) in dioxane (C=0.2 M), an aqueous solution of K.sub.2CO.sub.3 (1.2 M, 2.0 eq.) was added. The resulting suspension was sparged with argon for 10 min and SPhos Pd G2 (5 mol %) was added. The vial was sealed, and the reaction mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture hydrolysed and then extracted thrice with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to afford the protected intermediate.

[0483] Step 2: In a MW vial under Argon, a solution of the protected intermediate (1 eq.) in a mixture dioxane/aqueous HCl 3N: 1/1 (C=0.1 M) was heated at 150° C. under MW irradiation for 30 min. The reaction mixture was neutralized with K.sub.2CO.sub.3 sat. until pH-9 and extracted twice with EtOAc. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Method 12: Suzuki Coupling/Dimethylpyrrole Cleavage

[0484] Step 1: In a sealed vial, to a suspension of bromo (heteroaryl) (1.0 eq.) and boronic ester (1.0-1.1 eq.) in toluene/EtOH/H.sub.2O: 6/1/1 (C=0.2 M), K.sub.2CO.sub.3 (2.0 eq.) was added. The resulting suspension was sparged with argon for 10 min and Pd(PPh.sub.3).sub.4 (5 mol %) was added. The vial was sealed, and the reaction mixture was stirred at 80° C. until no more evolution was noticed by UPLC-MS (overnight, unless mentioned otherwise). The reaction mixture was filtered through a pad of Celite® and the cake was washed with DCM. The reaction mixture was hydrolysed with NH.sub.4Cl sat. and then extracted thrice with DCM. The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The residue was purified by flash chromatography to afford the protected intermediate.

[0485] Step 2: Under Argon, to a suspension of the protected intermediate (1.0 eq.) in a mixture of EtOH/H.sub.2O: 2/1 (C=0.1 M) was added hydroxylamine hydrochloride (20.0 eq.) and triethylamine (3.6 eq.). The reaction mixture was heated at 90° C. until no more evolution was noticed by UPLC-MS (4 h, unless mentioned otherwise). The reaction mixture was hydrolyzed with HCl 1 M and extracted twice with Et.sub.2O. The aqueous layer was basified with NaOH 6N and extracted thrice with DCM. Combined DCM layers were dried over sodium sulfate and concentrated. The crude was purified by flash chromatography.

Example Syntheses

Example 1: 6-ethyl-5-(5-fluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0486] ##STR00013##

[0487] Example 1 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (60 mg, 0.30 mmol) and (5-fluoroquinolin-8-yl)boronic acid (87 mg, 0.46 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The resulting foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 1 as a white solid (24 mg, 26%).

[0488] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.37-2.46 (m, 2H, CH.sub.2—CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.58 (dd, J 9.9, 8.1 Hz, 1H, Ar); 7.71 (dd, J 8.5, 4.2 Hz, 1H, Ar); 7.77 (dd, J 8.1, 6.1 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 8.00 (bs, 2H, NH.sub.2); 8.59 (dd, J 8.5, 1.7 Hz, 1H, Ar); 8.97 (dd, J 4.2, 1.7 Hz, 1H, Ar); 14.20 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 268.1. Mp: 120-140° C.

Example 2: 6-Fluoro-5-quinolin-8-yl-pyridin-2-ylamine (hydrochloride)

[0489] ##STR00014##

[0490] Example 2 was prepared according to method 1 starting from 2-amino-5-bromo-6-fluoropyridine (100 mg, 0.58 mmol) and 8-quinolinyl boronic acid (150 mg, 0.87 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 2 as a yellow solid (93 mg, 58%).

[0491] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.50 (dd, J 8.2, 1.9 Hz, 1H, Ar); 7.64 (dd, J 10.2, 8.2 Hz, 1H, Ar); 7.79-7.89 (m, 3H, Ar); 8.19 (dd, J 7.9, 1.3 Hz, 1H, Ar); 8.84 (d, J 8.2 Hz, 1H, Ar); 9.02 (dd, J 4.7, 1.3 Hz, 1H, Ar) HCl salt signal not observed. M/Z (M+H).sup.+: 240.0. Mp>250° C.

Example 3: 6-Methyl-5-quinolin-8-yl-pyridin-2-ylamine (hydrochloride)

[0492] ##STR00015##

[0493] Example 3 was prepared according to method 1 starting from 2-amino-5-bromo-6-methylpyridine (100 mg, 0.58 mmol) and 8-quinolinyl boronic acid (150 mg, 0.87 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 3 as a brown solid (81 mg, 51%).

[0494] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 2.18 (s, 3H, CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.71 (dd, J 8.3, 4.4 Hz, 1H, Ar); 7.75-7.83 (m, 2H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 8.17 (dd, J 7.7, 1.8 Hz, 1H, Ar); 8.63 (dd, J 8.2, 1.3 Hz, 1H, Ar); 8.94 (dd, J 4.4, 1.8 Hz, 1H, Ar); 14.47 (s, 1H, HCl salt). M/Z (M+H).sup.+: 236.1. Mp>250° C.

Example 4: 5-Benzo[b]thiophen-3-yl-6-ethyl-pyridin-2-ylamine

[0495] ##STR00016##

[0496] Example 4 was prepared according to method 1 starting from 2-amino-5-bromo-6-ethylpyridine 1d (75 mg, 0.37 mmol) and benzo[b]thien-3-yl boronic acid (100 mg, 0.56 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 4 as a brown solid (53 mg, 56%).

[0497] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.01 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.36 (q, J 7.5 Hz, 2H, CH.sub.2—CH.sub.3); 5.98 (s, 2H, NH.sub.2); 6.39 (d, J 8.4 Hz, 1H, Ar); 7.23 (d, J 8.4 Hz, 1H, Ar); 7.36-7.41 (m, 3H, Ar); 7.57 (s, 1H, Ar); 8.01-8.04 (m, 1H, Ar). M/Z (M+H).sup.+: 255.7. Mp: 108-120° C.

Example 5: 6-Ethyl-5-(6-methoxybenzothiophen-3-yl)pyridin-2-amine

[0498] ##STR00017##

[0499] Example 5 was prepared according to method 1 starting from 2-amino-5-bromo-6-ethylpyridine 1d (100 mg, 0.50 mmol) and 2-(6-methoxybenzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3b (217 mg, 0.75 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc, 100/0 to 50/50). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 5 as a brown solid (49 mg, 34%).

[0500] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.16 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.70 (q, J 7.5 Hz, 2H, CH.sub.2—CH.sub.3); 3.82 (s, 3H, O—CH.sub.3); 6.10 (bs, 2H, NH.sub.2); 6.35 (d, J 8.4 Hz, 1H, Ar); 6.99 (dd, J 8.7, 2.4 Hz, 1H, Ar); 7.18 (s, 1H, Ar); 7.38 (d, J 8.4 Hz, 1H, Ar); 7.51 (d, J 2.4 Hz, 1H, Ar); 7.70 (d, J 8.7 Hz, 1H, Ar). M/Z (M+H).sup.+: 285.7. Mp: 151-155° C.

Example 6: 6-Ethyl-5-(8-isoquinolyl)pyridin-2-amine (hydrochloride)

[0501] ##STR00018##

[0502] Example 6 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (100 mg, 0.47 mmol) and 8-isoquinolinyl boronic acid (130 mg, 0.75 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 6 as a white solid (116 mg, 81%).

[0503] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.aH.sub.b—CH.sub.3); 2.32-2.40 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.52-2.59 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.81-7.84 (m, 2H, Ar); 8.12-8.29 (m, 3H, Ar+NH.sub.2); 8.32 (d, J 8.3 Hz, 1H, Ar); 8.40 (d, J 6.2 Hz, 1H, Ar); 8.69 (d, J 6.2 Hz, 1H, Ar); 9.33 (s, 1H, Ar); 14.56 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 250.8. Mp>250° C.

Example 7: 5-Benzo[b]thiophen-3-yl-6-propyl-pyridin-2-ylamine (hydrochloride)

[0504] ##STR00019##

[0505] Example 7 was prepared according to method 2 starting from 2-amino-5-bromo-6-propylpyridine 1e (93 mg, 0.43 mmol) and benzo[b]thien-3-yl boronic acid (129 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 97/3). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The resulting solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 7 as a white solid (81 mg, 62%).

[0506] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.70 (t, J 7.4 Hz, 3H, CH.sub.2—CH.sub.2—CH.sub.3); 1.50-1.59 (m, 2H, CH.sub.2—CH.sub.2—CH.sub.3); 2.52-2.56 (m, 2H, CH.sub.2—CH.sub.2—CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.40-7.50 (m, 3H, Ar); 7.83 (d, J 9.0 Hz, 1H, Ar); 7.83 (s, 1H, Ar); 8.03 (bs, 2H, NH.sub.2); 8.08-8.10 (m, 1H, Ar); 14.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 269.7. Mp: 175-190° C.

Example 8: 6-Propyl-5-(8-quinolyl)pyridin-2-amine (hydrochloride)

[0507] ##STR00020##

[0508] Example 8 was prepared according to method 2 starting from 2-amino-5-bromo-6-propylpyridine 1e (100 mg, 0.43 mmol) and 8-quinolinyl boronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 8 as a yellow solid (124 mg, 96%).

[0509] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.63 (t, J 7.4 Hz, 3H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 1.46-1.55 (m, 2H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 2.28-2.40 (m, 1H, CH.sub.aH.sub.b—CH.sub.2CH.sub.3); 2.52-2.56 (m, 1H, CH.sub.aH.sub.b—CH.sub.2CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.69 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.74-7.81 (m, 2H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 8.06 (bs, 2H, NH.sub.2); 8.16 (dd, J 7.4, 2.4 Hz, 1H, Ar); 8.60 (dd, J 8.4, 1.6 Hz, 1H, Ar); 8.92 (dd, J 4.3, 1.6 Hz, 1H, Ar); 14.43 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.5. Mp: 80-120° C.

Example 9: 5-(8-Isoquinolyl)-6-propyl-pyridin-2-amine (hydrochloride)

[0510] ##STR00021##

[0511] Example 9 was prepared according to method 2 starting from 2-amino-5-bromo-6-propylpyridine 1e (100 mg, 0.43 mmol) and 8-isoquinolinyl boronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH, 100/0 to 90/10). The obtained solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 9 as a yellow solid (97 mg, 75%).

[0512] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.67 (t, J 7.4 Hz, 3H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 1.46-1.60 (m, 2H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 2.26-2.33 (m, 1H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 2.52-2.56 (m, 1H, CH.sub.aH.sub.b—CH.sub.2—CH.sub.3); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.12-7.15 (m, 2H, Ar); 7.24-7.34 (m, 4H, Ar); 7.46-7.57 (m, 3H, Ar); 7.67 (d, J 9.0 Hz, 1H, Ar); 7.84 (bs, 2H, NH.sub.2); 13.74 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.8. Mp: 100-117° C.

Example 10: 5-Benzo[b]thiophen-3-yl-6-isopropyl-pyridin-2-ylamine (hydrochloride)

[0513] ##STR00022##

[0514] Example 10 was prepared according to method 1 starting from 2-amino-5-bromo-6-isopropylpyridine 1f (100 mg, 0.46 mmol) and benzo[b]thien-3-yl boronic acid (123 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 10 as a white solid (65 mg, 46%).

[0515] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.27 (d, J 6.9 Hz, 6H, CH(CH.sub.3).sub.2); 2.84 (sep, J 6.9 Hz, 1H, CH(CH.sub.3).sub.2); 6.95 (d, J 8.5 Hz, 1H, Ar); 7.38-7.52 (m, 3H, Ar); 7.74-7.85 (m, 2H, Ar); 8.06-8.12 (m, 1H, Ar); 8.37 (bs, 2H, NH.sub.2); 14.02 (s, 1H, HCl salt). M/Z (M+H).sup.+: 269.7. Mp>250° C.

Example 11: 6-Isopropyl-5-(8-quinolyl)pyridin-2-amine (hydrochloride)

[0516] ##STR00023##

[0517] Example 11 was prepared according to method 2 starting from 2-amino-5-bromo-6-isopropylpyridine if (100 mg, 0.46 mmol) and 8-quinolinyl boronic acid (112 mg, 0.65 mmol, 1.5 eq.). The hydrolysis induced the precipitation of the product which was collected by filtration. The resulting powder was further purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 11 as a yellow solid (70 mg, 51%).

[0518] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.24 (d, J 7.0 Hz, 3H, CH(CH.sub.3).sub.2); 1.25 (d, J 7.0 Hz, 3H, CH(CH.sub.3).sub.2); 2.62 (sep, J 7.0 Hz, 1H, CH(CH.sub.3).sub.2); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.70 (dd, J 8.1, 4.2 Hz, 1H, Ar); 7.74-7.81 (m, 3H, Ar); 8.14-8.21 (m, 1H, Ar); 8.43 (bs, 2H, NH.sub.2); 8.62 (d, J 8.1 Hz, 1H, Ar); 8.94 (dd, J 4.2, 1.6 Hz, 1H, Ar); 14.21 (s, 1H, HCl). M/Z (M+H).sup.+: 264.8. Mp>250° C.

Example 12: 6-Isopropyl-5-(8-isoquinolyl)pyridin-2-amine (hydrochloride)

[0519] ##STR00024##

[0520] Example 12 was prepared according to method 2 starting from 2-amino-5-bromo-6-isopropylpyridine 1f (100 mg, 0.46 mmol) and 8-isoquinolinyl boronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 12 as a yellow solid (88 mg, 64%).

[0521] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.16 (d, J 6.9 Hz, 3H, CH(CH.sub.3).sub.2); 1.21 (d, J 6.9 Hz, 3H, CH(CH.sub.3).sub.2); 2.52 (sep, J 6.9 Hz, 1H, CH(CH.sub.3).sub.2); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.73 (d, J 9.0 Hz, 1H, Ar); 7.77 (dd, J 7.1, 0.7 Hz, 1H, Ar); 8.10 (dd, J 8.2, 7.1 Hz, 1H, Ar); 8.27 (dt, J 8.2, 0.7 Hz, 1H, Ar); 8.37 (d, J 6.2 Hz, 1H, Ar); 8.50 (bs, 2H, NH.sub.2); 8.63 (d, J 6.2 Hz, 1H, Ar); 9.34 (s, 1H, Ar); 14.24 (s, 1H, HCl salt). M/Z (M+H).sup.+: 264.9. Mp>250° C.

Example 13: 5-Benzo[b]thiophen-3-yl-6-cyclopropyl-pyridin-2-ylamine (hydrochloride)

[0522] ##STR00025##

[0523] Example 13 was prepared according to method 2 starting from 2-amino-5-bromo-6-cyclopropylpyridine 1 g (100 mg, 0.47 mmol) and benzo[b]thien-3-yl boronic acid (126 mg, 0.71 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 13 as a beige solid (78 mg, 55%).

[0524] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.95 (bs, 2H, 2 CH.sub.aCH.sub.bCyPr); 1.20 (bs, 1H, 2 CH.sub.aCH.sub.bCyPr); 1.79-1.87 (m, 1H, CHCyPr); 6.85 (bs, 1H, Ar); 7.40-7.46 (m, 1H, Ar); 7.55-7.59 (m, 2H, Ar); 7.77 (bs, 1H, Ar); 7.86 (s, 1H, Ar); 8.06-8.40 (bs, 3H, Ar+NH.sub.2); 13.05 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 267.0. Mp: 210-220° C.

Example 14: 6-Cyclopropyl-5-(8-quinolyl)pyridin-2-amine (hydrochloride)

[0525] ##STR00026##

[0526] Example 14 was prepared according to method 2 starting from 2-amino-5-bromo-6-cyclopropylpyridine 1 g (100 mg, 0.47 mmol) and 8-quinolinyl boronic acid (115 mg, 0.69 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 14 as a beige solid (76 mg, 54%).

[0527] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.82 (bs, 2H, 2 CH.sub.aCH.sub.bCyPr); 1.14 (bs, 2H, 2 CH.sub.aCH.sub.bCyPr); 2.1.66-1.74 (m, 1H, 2 CHCyPr); 6.89 (d, J 9.0 Hz, 1H, Ar); 7.70 (dd, J 8.3, 4.4 Hz, 1H, Ar); 7.78 (d, J 7.2 Hz, 1H, Ar); 7.79 (d, J 9.0 Hz, 1H, Ar); 7.86 (dd, J 7.2, 1.4 Hz, 1H, Ar); 8.17 (dd, J 8.2, 1.4 Hz, 1H, Ar); 8.28 (bs, 2H, NH.sub.2); 8.63 (d, J 8.2 Hz, 1H, Ar); 8.93 (dd, J 4.4, 1.7 Hz, 1H, Ar); 13.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 262.0. Mp>250° C.

Example 15: 6-Cyclopropyl-5-(8-isoquinolyl)pyridin-2-amine (hydrochloride)

[0528] ##STR00027##

[0529] Example 15 was prepared according to method 1 starting from 2-amino-5-bromo-6-cyclopropylpyridine 1 g (100 mg, 0.47 mmol) and 8-isoquinolinyl boronic acid (112 mg, 0.71 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 15 as a beige solid (141 mg, 95%).

[0530] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 0.75-0.91 (m, 2H, 2 CH.sub.aH.sub.bCyPr); 1.20-1.34 (m, 2H, 2 CH.sub.aH.sub.bCyPr); 1.56-1.63 (m, 1H, CHCyPr); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.90 (dd, J 7.2, 0.8 Hz, 1H, Ar); 8.19 (dd, J 7.2, 0.8 Hz, 1H, Ar); 8.34 (d, J 8.3 Hz, 1H, Ar); 8.46 (bd, J 6.3 Hz, 3H, Ar+NH.sub.2); 8.70 (d, J 6.3 Hz, 1H, Ar); 9.45 (s, 1H, Ar); 13.38 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 262.0. Mp: 200-215° C.

Example 16: 3-(1-Methylindol-3-yl)pyridine-2,6-diamine

[0531] ##STR00028##

[0532] Example 16 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1-methylindol-3-yl boronic pinacol ester (167 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of H.sub.2O/ACN. The suspension was freeze dried to afford Example 16 as a white solid (38 mg, 37%).

[0533] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.80 (s, 3H, N—CH.sub.3); 4.99 (bs, 2H, NH.sub.2); 5.42 (bs, 2H, NH.sub.2); 5.83 (d, J 8.0 Hz, 1H, Ar); 7.04 (ddd, J 7.8, 6.9, 0.9 Hz, 1H, Ar); 7.14 (d, J 8.0 Hz, 1H, Ar); 7.16-7.19 (m, 1H, Ar); 7.32 (s, 1H, Ar); 7.41-7.47 (m, 2H, Ar). M/Z (M+H).sup.+: 239.8. Mp: 47-55° C.

Example 17: Tert-butyl 3-(2,6-diamino-3-pyridyl)indole-1-carboxylate

[0534] ##STR00029##

[0535] Example 17 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (200 mg, 0.85 mmol) and 1-N-Boc-indol-3-yl boronic pinacol ester (167 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was triturated in Et.sub.2O and then in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 17 as a yellow solid (35 mg, 12%).

[0536] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ:1.64 (s, 9H, tBu); 5.11 (bs, 2H, NH.sub.2); 5.56 (bs, 2H, NH.sub.2); 5.83 (d, J 8.0 Hz, 1H, Ar); 7.15 (d, J 8.0 Hz, 1H, Ar); 7.25 (ddd, J 7.9, 7.5, 1.0 Hz, 1H, Ar); 7.35 (ddd, J 7.9, 7.5, 1.0 Hz, 1H, Ar); 7.45 (dd, J 7.5, 1.0 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 8.11 (dd, J 7.9, 1.0 Hz, 1H, Ar). M/Z (M+H).sup.+: 325.6. Mp: 150-154° C.

Example 18: 3-(1H-indol-3-yl)pyridine-2,6-diamine

[0537] ##STR00030##

[0538] Example 18 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (200 mg, 0.85 mmol) and 1-N-Boc-indol-3-yl boronic pinacol ester (167 mg, 0.65 mmol, 1.5 eq.) and was obtained concomitantly with example 17. The obtained foam was triturated in Et.sub.2O and then in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 18 as a white solid (83 mg, 43%).

[0539] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.94 (bs, 2H, NH.sub.2); 5.40 (bs, 2H, NH.sub.2); 5.83 (d, J 7.8 Hz, 1H, Ar); 7.00 (ddd, J 7.7, 7.3, 1.0 Hz, 1H, Ar); 7.10 (ddd, J 7.7, 7.3, 1.0 Hz, 1H, Ar); 7.15 (d, J 7.8 Hz, 1H, Ar); 7.32 (d, J 72.4 Hz, 1H, Ar); 7.38-7.46 (m, 2H, Ar); 11.13 (bs, 1H, NH). M/Z (M+H).sup.+: 225.7. Mp: 152-155° C.

Example 19: 3-Pyrazolo[1,5-a]pyridin-3-ylpyridine-2,6-diamine

[0540] ##STR00031##

[0541] Example 19 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 3-pyrazolo[1,5-a]pyridin-3-yl boronic pinacol ester (124 mg, 0.51 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 19 as a white solid (44 mg, 45%).

[0542] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.02 (bs, 2H, NH.sub.2); 5.51 (bs, 2H, NH.sub.2); 5.84 (d, J 8.0 Hz, 1H, Ar); 6.88 (td, J 6.8, 1.1 Hz, 1H, Ar); 7.11 (d, J 8.0 Hz, 1H, Ar); 7.15-7.22 (ddd, J 8.9, 6.8, 1.1 Hz, 1H, Ar); 7.46 (dt, J 8.9, 1.1 Hz, 1H, Ar); 7.99 (s, 1H, Ar); 8.65 (dt, J 6.8, 1.1 Hz, 1H, Ar). M/Z (M+H).sup.+: 225.7. Mp: 195-200° C.

Example 20: 3-(Benzofuran-3-yl)pyridine-2,6-diamine

[0543] ##STR00032##

[0544] Example 20 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 3-benzofuran-3-yl boronic pinacol ester (124 mg, 0.51 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 20 as a white solid (53 mg, 56%).

[0545] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.17 (bs, 2H, NH.sub.2); 5.59 (bs, 2H, NH.sub.2); 5.85 (d, J 8.0 Hz, 1H, Ar); 7.22 (d, J 8.0 Hz, 1H, Ar); 7.27 (td, J 8.0, 1.2 Hz, 1H, Ar); 7.35 (ddd, J 8.0, 7.2, 1.2 Hz, 1H, Ar); 7.53-7.55 (m, 1H, Ar); 7.61 (dt, J 8.0, 1.2 Hz, 1H, Ar); 7.98 (s, 1H, Ar). M/Z (M+H).sup.+: 226.0 Mp: 109-112° C.

Example 21: 3-(Benzothiophen-3-yl)pyridine-2,6-diamine (hydrochloride)

[0546] ##STR00033##

[0547] Example 21 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and benzothiophen-3-yl boronic acid (90 mg, 0.51 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 21 as a white solid (52 mg, 44%).

[0548] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.09 (d, J 8.4 Hz, 1H, Ar); 6.87 (bs, 2H, NH.sub.2); 7.39-7.46 (m, 3H, Ar+NH.sub.2); 7.51-7.56 (m, 2H, Ar); 7.67 (s, 1H, Ar); 8.01-8.09 (m, 2H, Ar); 12.95 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 242.6 Mp: 35-38° C.

Example 22: 3-(5-Fluoro-benzo[b]thiophen-3-yl)pyridine-2,6-diamine

[0549] ##STR00034##

[0550] Example 22 was prepared according to method 3 using 5 mol % P(tBu).sub.3 Pd G2 instead of 7 mol %, starting from 2,6-diamino-3-iodopyridine 1h (47 mg, 0.20 mmol) and 3-(5-fluoro-benzothiophen-3-yl) boronic pinacol ester 3a (110 mg, 0.40 mmol, 2.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 30/70). The obtained brown oil was triturated twice in Et.sub.2O and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 22 as a brown powder (19 mg, 37%).

[0551] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.02 (s, 2H, NH.sub.2); 5.63 (s, 2H, NH.sub.2); 5.84 (d, J 8.0 Hz, 1H, Ar); 7.09 (d, J 8.0 Hz, 1H, Ar); 7.20 (dd, J 10.1, 2.5 Hz, 1H, Ar); 7.27 (td, J 8.9, 2.5 Hz, 1H, Ar); 7.69 (s, 1H, Ar); 8.05 (dd, J 8.9, 5.0 Hz, 1H, Ar). M/Z (M+H).sup.+: 260.7 Mp: 116-118° C.

Example 23: 3-(7-fluoro-2-methylquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0552] ##STR00035##

[0553] Example 23 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (7-fluoro-2-methylquinolin-8-yl)boronic acid (218 mg, 1.06 mmol, 2.5 eq.). The crude HCl was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 93/7). The resulting foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 93/7). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 23 as a white solid (58 mg, 44%).

[0554] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 2.65 (s, 3H, CH.sub.3); 6.10 (d, J 8.5 Hz, 1H, Ar); 6.87 (bs, 2H, NH.sub.2); 7.48 (d, J 8.5 Hz, 1H, Ar); 7.47-7.58 (bd, 3H, Ar+NH.sub.2); 7.62 (t, J 9.1 Hz, 1H, Ar); 8.15 (dd, J 8.8, 6.5 Hz, 1H, Ar); 8.48 (bd, J 8.8 Hz, 1H, Ar); 13.05 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 269.1. Mp: 130-170° C.

Example 24: 3-(1H-Indol-4-yl)pyridine-2,6-diamine (hydrochloride)

[0555] ##STR00036##

[0556] Example 24 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and indole-4-boronic pinacol ester (158 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 24 as a white solid (48 mg, 43%).

[0557] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.10 (d, J 8.5 Hz, 1H, Ar); 6.20-6.23 (m, 1H, Ar); 6.69 (bs, 2H, NH.sub.2); 6.94 (dd, J 7.3, 0.8 Hz, 1H, Ar); 7.17 (dd, J 8.0, 7.3 Hz, 1H, Ar); 7.35-7.49 (m, 4H, NH.sub.2+2 Ar); 7.58 (d, J 8.5 Hz, 1H, Ar); 11.31 (s, 1H, HCl salt or NH); HCl salt or NH signal not observed. M/Z (M+H).sup.+: 225.8. Mp: 150-154° C.

Example 25: 3-(1H-indol-7-yl)pyridine-2,6-diamine

[0558] ##STR00037##

[0559] Example 25 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1H-indole-7-boronic pinacol ester (158 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained solid was dissolved in a mixture of H.sub.2O/ACN and the resulting solution was freeze dried to afford Example 25 as a white solid (43 mg, 45%).

[0560] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.92 (bs, 2H, NH.sub.2); 5.67 (bs, 2H, NH.sub.2); 5.89 (d, J 8.0 Hz, 1H, Ar); 5.65 (dd, J 2.9, 1.9 Hz, 1H, Ar); 7.20 (dd, J 7.5, 0.9 Hz, 1H, Ar); 7.03 (t, J 7.5 Hz, 1H, Ar); 7.14 (d, J 8.0 Hz, 1H, Ar); 7.23-7.26 (m, 1H, Ar); 7.48 (dt, J 7.5, 0.9 Hz, 1H, Ar); 10.58 (bs, 1H, NH). M/Z (M+H).sup.+: 225.7. Mp: 62-70° C.

Example 26: 3-(1-Methylindazol-7-yl)pyridine-2,6-diamine (hydrochloride)

[0561] ##STR00038##

[0562] Example 26 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1-methyl-1H-indazole-7-boronic acid (114 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 26 as a yellow solid (52 mg, 44%).

[0563] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.77 (s, 3H, N—CH.sub.3); 6.10 (d, J 8.5 Hz, 1H, Ar); 6.88 (bs, 2H, NH.sub.2); 7.13-7.23 (m, 2H, Ar); 7.51 (d, J 8.5 Hz, 1H, Ar); 7.54 (bs, 2H, NH.sub.2); 7.82 (dd, J 7.4, 1.7 Hz, 1H, Ar); 8.11 (s, 1H, Ar); 13.14 (s, 1H, HCl salt). M/Z (M+H).sup.+: 240.8. Mp: 198-204° C.

Example 27: 4-(2,6-Diamino-3-pyridyl)-2-methyl-isoindolin-1-one

[0564] ##STR00039##

[0565] Example 27 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 2-N-methyl-2,3-dihydroisoindol-1-one-4-boronic pinacol ester (178 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 27 as a beige powder (69 mg, 63%).

[0566] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.05 (s, 3H, N—CH.sub.3); 4.32 (bs, 2H, N—CH.sub.2); 5.04 (bs, 2H, NH.sub.2); 5.59 (bs, 2H, NH.sub.2); 5.81 (d, J 7.9 Hz, 1H, Ar); 7.05 (d, J 7.9 Hz, 1H, Ar); 7.42 (dd, J 7.5, 0.9 Hz, 1H, Ar); 7.49 (t, J 7.5 Hz, 1H, Ar); 7.58 (dd, J 7.5, 0.9 Hz, 1H, Ar). M/Z (M+H).sup.+: 255.7. Mp>250° C.

Example 28: 3-(2,3-Dihydrobenzofuran-7-yl)pyridine-2,6-diamine (hydrochloride)

[0567] ##STR00040##

[0568] Example 28 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 2,3-dihydro-1-benzofuran-7-yl-boronic acid (107 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 28 as a white solid (88 mg, 78%).

[0569] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.15 (t, J 8.7 Hz, 2H, O—CH.sub.2—CH.sub.2); 4.48 (t, J 8.7 Hz, 2H, O—CH.sub.2—CH.sub.2); 5.96 (d, J 8.5 Hz, 1H, Ar); 6.74 (bs, 2H, NH.sub.2); 6.83 (t, J 7.6 Hz, 1H, Ar); 6.93 (dd, J 7.6, 1.1 Hz, 1H, Ar); 7.16-7.20 (m, 1H, Ar); 7.31 (bs, 2H, NH.sub.2); 7.40 (d, J 8.5 Hz, 1H, Ar); 12.86 (s, 1H, HCl). M/Z (M+H).sup.+: 228.8. Mp>250° C.

Example 29: 3-(Benzothiophen-7-yl)pyridine-2,6-diamine (hydrochloride)

[0570] ##STR00041##

[0571] Example 29 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1-benzothiophen-7-yl boronic acid (116 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 29 as a white solid (74 mg, 62%).

[0572] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.09 (d, J 8.5 Hz, 1H, Ar); 6.91 (bs, 2H, NH.sub.2); 7.29 (dd, J 8.1, 0.8 Hz, 1H, Ar); 7.46-7.51 (m, 1H, Ar); 7.53 (bs, 2H, NH.sub.2); 7.54 (d, J 5.4 Hz, 1H, Ar); 7.61 (d, J 8.5 Hz, 1H, Ar); 7.78 (d, J 5.4 Hz, 1H, Ar); 7.92 (dd, J 8.1, 0.8 Hz, 1H, Ar); 13.09 (s, 1H, HCl salt). M/Z (M+H).sup.+: 242.8. Mp: 100-113° C.

Example 30: 3-(1,3-Benzothiazol-4-yl)pyridine-2,6-diamine (hydrochloride)

[0573] ##STR00042##

[0574] Example 30 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1-benzothiazole-4-boronic pinacol ester (170 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 30 as a white solid (74 mg, 61%).

[0575] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.09 (d, J 8.5 Hz, 1H, Ar); 6.88 (bs, 2H, NH.sub.2); 7.41-7.50 (m, 3H, Ar, NH.sub.2); 7.56 (t, J 8.0 Hz, 1H, Ar); 7.60 (d, J 8.0 Hz, 1H, Ar); 8.21 (dd, J 8.0, 1.2 Hz, 1H, Ar); 9.38 (s, 1H, Ar); 13.03 (s, 1H, HCl salt). M/Z (M+H).sup.+: 243.7. Mp>250° C.

Example 31: 3-(8-quinolyl)pyridine-2,6-diamine (hydrochloride)

[0576] ##STR00043##

[0577] Example 31 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (300 mg, 1.28 mmol) and 8-quinolylboronic acid (332 mg, 1.92 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was triturated in pentane and the collected precipitate dissolved in a mixture of aqueous 1N HCl/ACN. The solution was freeze dried to afford Example 31 as a white solid (297 mg, 85%).

[0578] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.11 (d, J 8.5 Hz, 1H, Ar); 6.84 (bs, 2H, NH.sub.2); 7.50-7.53 (m, 3H, Ar); 7.79-7.83 (m, 3H, Ar+NH.sub.2); 8.20 (dd, J 6.2, 2.8 Hz, 1H, Ar); 8.77 (d, J 4.6 Hz, 1H, Ar); 9.01 (dd, J 4.6, 1.2 Hz, 1H, Ar); 13.17 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 296.7. Mp: 182-192° C.

Example 32: 3-Isoquinolin-8-yl-pyridine-2,6-diamine hydrochloride (hydrochloride)

[0579] ##STR00044##

[0580] Example 32 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 8-isoquinolylboronic acid (111 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The resulting yellow powder was dissolved in a mixture of aqueous 1N HCl/ACN and the obtained solution was freeze dried to afford Example 32 as a white solid (58 mg, 49%).

[0581] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.15 (d, J 8.4 Hz, 1H, Ar); 6.99 (bs, 2H, NH.sub.2); 7.56 (d, J 8.4 Hz, 1H, Ar); 7.67 (bs, 2H, NH.sub.2); 7.81 (dd, J 7.2, 0.8 Hz, 1H, Ar); 8.16 (dd, J 8.4, 7.2 Hz, 1H, Ar); 8.30 (dd, J 8.4, 0.8 Hz, 1H, Ar); 8.45 (d, J 6.4 Hz, 1H, Ar); 8.68 (d, J 6.4 Hz, 1H, Ar); 9.40 (s, 1H, Ar); 13.27 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 237.8. Mp: 77-88° C.

Example 33: 3-(5-Isoquinolyl)pyridine-2,6-diamine

[0582] ##STR00045##

[0583] Example 33 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 5-isoquinolylboronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 95/5). The resulting foam was further purified flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained powder was dried under high vacuum at 70° C. to afford Example 33 as a white solid (25 mg, 25%).

[0584] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.86 (bs, 2H, NH.sub.2); 5.62 (bs, 2H, NH.sub.2); 5.88 (d, J 8.0 Hz, 1H, Ar); 7.01 (d, J 8.0 Hz, 1H, Ar); 7.46 (dd, J 6.0, 0.9 Hz, 1H, Ar); 7.62 (dd, J 7.1, 1.1 Hz, 1H, Ar); 7.70 (t, J 7.1 Hz, 1H, Ar); 7.07 (dt, J 8.0, 1.1 Hz, 1H, Ar); 8.44 (d, J 6.0 Hz, 1H, Ar); 9.33 (d, J 0.9 Hz, 1H, Ar). M/Z (M+H).sup.+: 237.7. Mp>250° C.

Example 34: 3-Quinolin-5-yl-pyridine-2,6-diamine

[0585] ##STR00046##

[0586] Example 34 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 5-quinolylboronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 95/5). The resulting foam was further purified flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained solid was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. to afford Example 34 as a yellow powder (31 mg, 30%).

[0587] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.85 (bs, 2H, NH.sub.2); 5.61 (bs, 2H, NH.sub.2); 5.87 (d, J 8.0 Hz, 1H, Ar); 7.01 (d, J 8.0 Hz, 1H, Ar); 7.45 (dd, J 7.1, 1.1 Hz, 1H, Ar); 7.48 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.77 (dd, J 8.4, 7.1 Hz, 1H, Ar); 7.95-8.01 (m, 2H, Ar); 8.89 (dd, J 4.2, 1.8 Hz, 1H, Ar). M/Z (M+H).sup.+: 237.8. Mp>250° C.

Example 35: 3-Quinolin-4-yl-pyridine-2,6-diamine

[0588] ##STR00047##

[0589] Example 35 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 4-quinolylboronic acid (112 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The resulting foam was further purified by trituration in MeOH. The obtained solid was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. to afford Example 35 as a yellow powder (55 mg, 54%).

[0590] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.06 (bs, 2H, NH.sub.2); 5.72 (bs, 2H, NH.sub.2); 5.88 (d, J 8.0 Hz, 1H, Ar); 7.05 (d, J 8.0 Hz, 1H, Ar); 7.37 (d, J 4.4 Hz, 1H, Ar); 7.50-7.57 (m, 1H, Ar); 7.70-7.77 (m, 2H, Ar); 8.02-8.06 (m, 1H, Ar); 8.85 (d, J 4.4 Hz, 1H, Ar). M/Z (M+H).sup.+: 237.8. Mp>250° C.

Example 36: 3-Isoquinolin-4-yl-pyridine-2,6-diamine

[0591] ##STR00048##

[0592] Example 36 was prepared according to method 4 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 3-isoquinolylboronic acid (88 mg, 0.51 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained solid was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. to afford Example 36 as a yellow powder (46 mg, 46%).

[0593] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.91 (bs, 2H, NH.sub.2); 5.63 (bs, 2H, NH.sub.2); 5.88 (d, J 8.0 Hz, 1H, Ar); 7.04 (d, J 8.0 Hz, 1H, Ar); 7.57-7.79 (m, 3H, Ar); 8.16 (d, J 7.6 Hz, 1H, Ar); 8.32 (s, 1H, Ar); 9.36 (s, 1H, Ar). M/Z (M+H).sup.+: 237. Mp: 180-185° C.

Example 37: 3-Chroman-8-yl-pyridine-2,6-diamine (hydrochloride)

[0594] ##STR00049##

[0595] Example 37 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (3,4-dihydro-2H-1-benzopyran-8-yl)boronic acid (116 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained solid was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 37 as a yellow powder (74 mg, 62%).

[0596] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.93 (tt, J 6.4, 5.0 Hz, 2H, O—CH.sub.2—CH.sub.2—CH.sub.2—Ar); 2.79 (t, J 6.4 Hz, 2H, O—CH.sub.2—CH.sub.2—CH.sub.2—Ar); 4.15 (t, J 5.0 Hz, 2H, O—CH.sub.2—CH.sub.2—CH.sub.2—Ar); 6.01 (d, J 8.5 Hz, 1H, Ar); 6.72 (bs, 2H, NH.sub.2); 6.88 (t, J 7.5 Hz, 1H, Ar); 6.95 (dd, J 7.5, 1.7 Hz, 1H, Ar); 7.08-7.12 (m, 1H, Ar); 7.29 (bs, 2H, NH.sub.2); 7.37 (d, J 8.5 Hz, 1H, Ar); 12.86 (s, 1H, HCl salt). M/Z (M+H).sup.+: 242.8. Mp: 110-124° C.

Example 38: 3-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-pyridine-2,6-diamine (hydrochloride)

[0597] ##STR00050##

[0598] Example 38 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)boronic acid (117 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The resulting foam was further purified flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained solid was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 38 as a yellow solid (31 mg, 30%).

[0599] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 4.26 (s, 4H, 2 O—CH.sub.2); 6.01 (d, J 8.5 Hz, 1H, Ar); 6.71 (dd, J 6.0, 3.2 Hz, 1H, Ar); 6.82 (bs, 2H, NH.sub.2); 6.86-6.90 (m, 2H, Ar); 7.32 (bs, 2H, NH.sub.2); 7.42 (d, J 8.5 Hz, 1H, Ar); 12.86 (s, 1H, HCl). M/Z (M+H).sup.+: 244.8. Mp: 99-110° C.

Example 39: 3-Dibenzothiophen-4-ylpyridine-2,6-diamine (hydrochloride)

[0600] ##STR00051##

[0601] Example 39 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 4-dibenzothiophenylboronic acid (148 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained solid was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 39 as a white solid (100 mg, 71%).

[0602] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.11 (d, J 8.5 Hz, 1H, Ar); 6.98 (bs, 2H, NH.sub.2); 7.44 (dd, J 7.4, 1.0 Hz, 1H, Ar); 7.49-7.68 (m, 6H, NH.sub.2+4 Ar); 7.97-8.02 (m, 1H, Ar); 8.35-8.46 (m, 2H, Ar); 13.09 (s, 1H, HCl salt). M/Z (M+H).sup.+: 292.7. Mp: 165-170° C.

Example 40: 3-Dibenzofuran-4-ylpyridine-2,6-diamine (hydrochloride)

[0603] ##STR00052##

[0604] Example 40 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 4-dibenzofuranylboronic acid (137 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained solid was triturated in pentane and the collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 40 as a white solid (88 mg, 66%).

[0605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 6.11 (d, J 8.5 Hz, 1H, Ar); 7.04 (bs, 2H, NH.sub.2); 7.38-7.56 (m, 6H, NH.sub.2+4 Ar); 5.65 (d, J 8.5 Hz, 1H, Ar); 7.70 (dd, J 8.2, 1.5 Hz, 1H, Ar); 8.15-8.21 (m, 2H, Ar); 13.02 (s, 1H, HCl salt). M/Z (M+H).sup.+: 276.7. Mp: 135-143° C.

Example 41: 6-Ethyl-5-(2-methylbenzothiophen-3-yl)pyridin-2-amine (hydrochloride)

[0606] ##STR00053##

[0607] Example 41 was prepared according to method 6 starting from 3-bromo-2-methyl-benzothiophene 2a (100 mg, 0.44 mmol) and ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 4a (144 mg, 0.66 mmol, 1.5 eq.). The crude was purified by preparative HPLC. The obtained solid was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 41 as a white solid (49 mg, 36%).

[0608] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.37 (s, 3H, Ar—CH.sub.3); 2.44 (q, J 7.6 Hz, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.45 (q, J 7.6 Hz, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.26-7.29 (m, 1H, Ar); 7.32-7.38 (m, 3H, Ar); 7.74 (d, J 9.0 Hz, 1H, Ar); 8.09 (bs, 2H, NH.sub.2); 14.33 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 269.8. Mp: 70-72° C.

Example 42: 6-Ethyl-5-(5-methylbenzothiophen-3-yl)pyridin-2-amine (hydrochloride)

[0609] ##STR00054##

[0610] Example 42 was prepared according to method 6 starting from 3-bromo-5-methyl-benzothiophene 2b (100 mg, 0.44 mmol) and ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 4a (144 mg, 0.66 mmol, s 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50). The obtained solid was further purified by preparative HPLC and then was dissolved in a mixture of aqueous 1N HCl/ACN. The resulting solution was freeze dried to afford Example 42 as a white solid (71 mg, 53%).

[0611] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.13 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39 (s, 3H, Ar—CH.sub.3); 2.56 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.27-7.29 (m, 2H, Ar); 7.79 (s, 1H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 7.96 (dd, J 8.0, 0.7 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 14.36 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 269.8. Mp: 64-88° C.

Example 43: 6-Ethyl-5-(5-fluorobenzothiophen-3-yl)pyridin-2-amine (hydrochloride)

[0612] ##STR00055##

[0613] Example 43 was prepared according to method 7 starting from 3-bromo-5-fluoro-benzothiophene 2c (100 mg, 0.43 mmol) and ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 4a (144 mg, 0.66 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50). The obtained solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 43 as a white solid (37 mg, 27%).

[0614] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.12 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.55 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.31-7.36 (m, 2H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 7.96 (s, 1H, Ar); 8.06 (bs, 2H, NH.sub.2); 8.12-8.15 (m, 1H, Ar); 14.31 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 273.8. Mp>250° C.

Example 44: 6-Ethyl-5-[2-(3-pyridyl)phenyl]pyridin-2-amine (hydrochloride)

[0615] ##STR00056##

[0616] Example 44 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethyl-pyridin-2-amine 5a (100 mg, 0.43 mmol) and 3-pyridylboronic acid (80 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained solid was triturated in pentane. The collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 44 as a beige solid (81.1 mg, 60%).

[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.04 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.79 (d, J 8.8 Hz, 1H, Ar); 7.42-7.48 (m, 1H, Ar); 7.56-7.69 (m, 4H, Ar); 7.79 (dd, J 8.0, 5.6 Hz, 1H, Ar); 7.99-8.24 (m, 3H, Ar+NH.sub.2); 8.67 (d, J 1.6 Hz, 1H, Ar); 8.72 (dd, J 5.2, 1.2 Hz, 1H, Ar); 14.32 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 276.8. Mp>250° C.

Example 45: 3-[2-(3-pyridyl)phenyl]pyridine-2,6-diamine (hydrochloride)

[0618] ##STR00057##

[0619] Example 45 was prepared according to method 8 starting from 3-(2-chlorophenyl)pyridine-2,6-diamine 5b (100 mg, 0.46 mmol) and 3-pyridylboronic acid (85 mg, 0.69 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 95/5). The obtained solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford to afford Example 45 as a brown solid (51 mg, 37%).

[0620] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 5.96 (d, J 8.4 Hz, 1H, Ar); 6.78 (s, 2H, NH.sub.2); 7.33-7.52 (m, 4H, Ar+NH.sub.2); 7.52-7.64 (m, 3H, Ar); 7.79 (dd, J 7.6, 5.6 Hz, 1H, Ar); 8.09 (d, J 8.0 Hz, 1H, Ar); 8.63-8.68 (m, 1H, Ar); 8.72 (d, J 4.8 Hz, 1H, Ar); 12.91 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 263.8. Mp: 100-135° C.

Example 46: 3-[2-(6-morpholino-3-pyridyl)phenyl]pyridine-2,6-diamine (hydrochloride

[0621] ##STR00058##

[0622] Example 46 was prepared according to method 8 starting from 3-(2-chlorophenyl)pyridine-2,6-diamine 5b (100 mg, 0.46 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-2-pyridyl]morpholine (200 mg, 0.69 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 46 as a yellow solid (77 mg, 43%).

[0623] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.54-3.62 (m, 4H, 2 N—CH.sub.2); 3.68-3.76 (m, 4H, 2 O—CH.sub.2); 5.97 (d, J 8.4 Hz, 1H, Ar); 6.76 (bs, 2H, NH.sub.2); 7.03-7.15 (m, 1H, Ar); 7.29-7.55 (m, 7H, Ar+NH.sub.2); 7.60 (d, J 8.8 Hz, 1H, Ar); 7.95 (d, J 2.0 Hz, 1H, Ar); 12.93 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 348.8. Mp: 180-210° C.

Example 47: 6-ethyl-5-(quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0624] ##STR00059##

[0625] Example 47 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (100 mg, 0.50 mmol) and quinolin-8-ylboronic acid (130 mg, 0.75 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained solid was triturated in pentane. The collected precipitate was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 47 as a white solid (100 mg, 70%).

[0626] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.3); 2.36-2.48 (m, 2H, CH.sub.2); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.68-7.71 (m, 1H, Ar); 7.75-7.82 (m, 3H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.17 (dd, J 7.6, 1.5 Hz, 1H, Ar); 8.61 (d, J 8.1 Hz, 1H, Ar); 8.93 (dd, J 4.3, 1.3 Hz, 1H, Ar); 14.41 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 250.8. Mp>250° C.

Example 48: 3-(2-(1-methyl-1H-pyrazol-5-yl)phenyl)pyridine-2,6-diamine (hydrochloride)

[0627] ##STR00060##

[0628] Example 48 was prepared according to method 8 starting from 3-(2-chlorophenyl)pyridine-2,6-diamine 5b (98 mg, 0.45 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (230 mg, 1.10 mmol, 2.4 eq.). The crude was purified twice by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3 then KPNH, CycloHex/EtOAc: 100/0 to 20/80). The obtained foam was triturated in pentane and the collected precipitate was dried under high vacuum at 70° C. overnight to afford Example 48 as a beige solid (7 mg, 5%).

[0629] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.58 (s, 3H, N—CH.sub.3); 5.88 (d, J 8.5 Hz, 1H, Ar); 6.05 (d, J 1.6 Hz, 1H, Ar); 6.82 (s, 2H, NH.sub.2); 7.18 (d, J 8.5 Hz, 1H, Ar); 7.35 (bd, 3H, Ar+NH.sub.2); 7.41 (dd, J 7.2, 1.4 Hz, 1H, Ar); 7.48 (dd, J 7.2, 1.4 Hz, 1H, Ar); 7.55 (quint d, J 7.2, 1.4 Hz, 1H, Ar); 12.73 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 266.0. Mp>250° C.

Example 49: 3-(1-methyl-1H-indol-7-yl)pyridine-2,6-diamine

[0630] ##STR00061##

[0631] Example 49 was prepared according to method 3 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (167 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained solid was further purified by preparative HPLC and the pure fractions were freeze dried to afford Example 49 as a white solid (21 mg, 20%).

[0632] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 3.47 (s, 3H, N—CH.sub.3); 5.32 (bs, 2H, NH.sub.2); 5.91 (d, J 8.0 Hz, 1H, Ar); 6.16 (bs, 2H, NH.sub.2); 6.45 (d, J 3.0 Hz, 1H, Ar); 6.84 (dd, J 7.2, 1.0 Hz, 1H, Ar); 7.04 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.15 (d, J 8.0 Hz, 1H, Ar); 7.23 (d, J 3.0 Hz, 1H, Ar); 7.54 (dd, J 8.0, 1.0 Hz, 1H, Ar). M/Z (M+H).sup.+: 239.1. Mp: 100-117° C.

Example 50: 3-(benzofuran-7-yl)pyridine-2,6-diamine (hydrochloride)

[0633] ##STR00062##

[0634] Example 50 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (75 mg, 0.32 mmol) and 2-(benzofuran-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 0.41 mmol, 1.3 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained foam was further purified flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 60/40). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 50 as a beige solid (40 mg, 48%).

[0635] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 6.09 (d, J 8.5 Hz, 1H, Ar); 6.95 (bs, 2H, NH.sub.2); 7.02 (d, J 2.2 Hz, 1H, Ar); 7.25 (dd, J 7.6, 1.2 Hz, 1H, Ar); 7.33 (t, J 7.7 Hz, 1H, Ar); 7.49 (bs, 2H, NH.sub.2); 7.61 (d, J 8.5 Hz, 1H, Ar); 7.69 (dd, J 7.7, 1.1 Hz, 1H, Ar); 8.00 (d, J 2.2 Hz, 1H, Ar); 12.86 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 226.1. Mp>250° C.

Example 51: 3-(benzo[b]thiophen-4-yl)pyridine-2,6-diamine (hydrochloride)

[0636] ##STR00063##

[0637] Example 51 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (75 mg, 0.32 mmol) and benzo[b]thiophen-4-ylboronic acid (74 mg, 0.41 mmol, 1.3 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 51 as a beige solid (60 mg, 68%).

[0638] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 6.09 (d, J 8.5 Hz, 1H, Ar); 6.79 (bs, 2H, NH.sub.2); 7.16 (dd, J 5.6, 0.7 Hz, 1H, Ar); 7.28 (dd, J 7.3, 0.9 Hz, 1H, Ar); 7.43-7.47 (m, 3H, Ar+NH.sub.2); 7.52 (d, J 8.5 Hz, 1H, Ar); 7.79 (d, J 5.6 Hz, 1H, Ar); 8.05 (d, J 8.1, 0.9 Hz, 1H, Ar); 12.88 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 242.1. Mp: 100-120° C.

Example 52: 3-(6-fluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0639] ##STR00064##

[0640] Example 52 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (6-fluoroquinolin-8-yl)boronic acid (163 mg, 0.85 mmol, 2.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of 1N H.sub.2O/ACN. The suspension was freeze dried to afford Example 52 as a yellow solid (108 mg, 88%).

[0641] H NMR (DMSO-d6, 400 MHz) δ: 6.08 (d, J 8.5 Hz, 1H, Ar); 6.87 (bs, 2H, NH.sub.2); 7.48 (bs, 2H, NH.sub.2); 7.53 (d, J 8.5 Hz, 1H, Ar); 7.67 (dd, J 8.3, 4.4 Hz, 1H, Ar); 7.69 (dd, J 9.2, 2.9 Hz, 1H, Ar); 7.90 (dd, J 9.2, 2.9 Hz, 1H, Ar); 8.51 (dd, J 8.3, 1.6 Hz, 1H, Ar); 8.88 (dd, J 4.4, 1.6 Hz, 1H, Ar); 13.00 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 255.1. Mp>250° C.

Example 53: 3-(6-methylquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0642] ##STR00065##

[0643] Example 53 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (6-methylquinolin-8-yl)boronic acid (159 mg, 0.85 mmol, 2.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 92/08). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of 1 N H.sub.2O/ACN. The suspension was freeze dried to afford Example 53 as a yellow solid (121 mg, 99%).

[0644] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 2.57 (s, 3H, CH.sub.3); 6.10 (d, J 8.5 Hz, 1H, Ar); 6.84 (bs, 2H, NH.sub.2); 7.52 (bd, J 8.5 Hz, 3H, Ar+NH.sub.2); 7.70 (bs, 1H, Ar); 7.77 (bs, 1H, Ar); 7.98 (bs, 1H, Ar); 8.69 (bs, 1H, Ar); 8.93 (dd, J 4.0 Hz, 1H, Ar); 13.04 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 251.1. Mp: 180-200° C.

Example 54: 3-(5-(trifluoromethyl)quinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0645] ##STR00066##

[0646] Example 54 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (75 mg, 0.32 mmol) and (5-(trifluoromethyl)quinolin-8-yl)boronic acid (116 mg, 0.48 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained foam was triturated in pentane and the collected precipitate was dissolved in a mixture of 1 N H.sub.2O/ACN. The suspension was freeze dried to afford Example 54 as a yellow solid (65 mg, 60%).

[0647] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 6.09 (d, J 8.5 Hz, 1H, Ar); 6.87 (bs, 2H, NH.sub.2); 7.47 (bs, 2H, NH.sub.2); 7.53 (d, J 8.5 Hz, 1H, Ar); 7.79 (dd, J 8.7, 4.2 Hz, 1H, Ar); 7.84 (d, J 7.6 Hz, 1H, Ar); 8.14 (d, J 7.6 Hz, 1H, Ar); 8.54 (dt, J 8.7, 1.6 Hz, 1H, Ar); 9.02 (dd, J 4.2, 1.6 Hz, 1H, Ar); 13.00 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 305.1. Mp>250° C.

Example 55: 3-(5-fluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0648] ##STR00067##

[0649] Example 55 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (100 mg, 0.43 mmol) and (5-fluoroquinolin-8-yl)boronic acid (163 mg, 0.85 mmol, 2.0 eq.). The 4 HCl crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained foam was triturated in Et.sub.2O (2×5 mL) and the collected precipitate was dissolved in a mixture of 1N H.sub.2O/ACN. The suspension was freeze dried to afford Example 55 as a yellow solid (26 mg, 21%).

[0650] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ: 6.07 (d, J 8.4 Hz, 1H, Ar); 6.74 (bs, 2H, NH.sub.2); 7.37 (bs, 2H, NH.sub.2); 7.49 (d, J 8.4 Hz, 1H, Ar); 7.54 (dd, J 9.9, 8.1 Hz, 1H, Ar); 7.70 (dd, J 8.4, 4.1 Hz, 1H, Ar); 7.71 (dd, J 8.1, 6.1 Hz, 1H, Ar); 8.59 (dd, J 8.4, 1.7 Hz, 1H, Ar); 8.97 (dd, J 4.2, 1.7 Hz, 1H, Ar); 12.77 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 255.1. Mp: 73-81° C.

Example 56: 8-(2,6-diaminopyridin-3-yl)quinolin-2(1H)-one (hydrochloride)

[0651] ##STR00068##

[0652] Example 56 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (170 mg, 0.73 mmol) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one 89 (237 mg, 0.87 mmol, 1.2 eq.). The HCl crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The resulting foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 56 as a white solid (72 mg, 34%).

[0653] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.03 (d, J 8.4 Hz, 1H, Ar); 6.51 (d, J 9.6 Hz, 1H, Ar); 6.76 (s, 2H, NH.sub.2); 7.24 (t, J 7.6 Hz, 1H, Ar); 7.32 (dd, J 7.6, 1.5 Hz, 1H, Ar); 7.35 (d, J 8.4 Hz, 1H, Ar); 7.38 (bs, 2H, NH.sub.2); 7.71 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.95 (d, J 9.6 Hz, 1H, Ar); 10.84 (s, 1H, NH); 12.64 (s, 1H, HCl salt). M/Z (M+H).sup.+: 253.0. Mp>250° C.

Example 57: 3-(7-fluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0654] ##STR00069##

[0655] Example 57 was prepared according to method 5 starting from 2,6-diamino-3-iodopyridine 1h (90 mg, 0.38 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (237 mg, 0.65 mmol, 1.7 eq.). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 57 as a yellow solid (53 mg, 48%).

[0656] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.10 (d, J 8.4 Hz, 1H, Ar); 6.88 (bs, 2H, NH.sub.2); 7.49 (d, J 8.4 Hz, 1H, Ar); 7.52 (bs, 2H, NH.sub.2); 7.65 (dd, J 8.4, 4.4 Hz, 1H, Ar); 7.71 (t, J 9.2 Hz, 1H, Ar); 8.22 (dd, J 9.2, 6.2 Hz, 1H, Ar); 8.60 (dd, J 8.4, 1.6 Hz, 1H, Ar); 13.00 (s, 1H, HCl salt). M/Z (M+H).sup.+: 255.0. Mp: 190-220° C.

Example 58: 3-(3-fluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0657] ##STR00070##

[0658] Protected intermediate of Example 58 was prepared according to method 11 step 1 starting from 8-bromo-3-fluoroquinoline (120 mg, 0.53 mmol) and compound 9 (203 mg, 0.64 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 20/80) to afford compound 99 (195 mg) as a yellow oil. M/Z (M+H).sup.+: 339.1

[0659] Example 58 was prepared according to method 11 step 2 starting from compound 99 (195 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 58 as a yellow solid (45 mg, 29% over 2 steps).

[0660] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) δ: 6.04 (d, J 8.4 Hz, 1H, Ar); 6.73 (bs, 2H, NH.sub.2); 7.39 (bs, 2H, NH.sub.2); 7.48 (d, J 8.4 Hz, 1H); 7.67 (dd, J 7.1, 1.6 Hz, 1H, Ar); 7.74 (dd, J 7.6, 7.4 Hz, 1H, Ar); 8.04 (dd, J 8.1, 1.6 Hz, 1H, Ar), 8.33 (dd, J 9.6, 2.9 Hz, 1H, Ar), 8.90 (d, J 2.9 Hz, 1H, Ar), 12.76 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 254.9. Mp: 114-116° C.

Example 59: 3-(5,7-difluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0661] ##STR00071##

[0662] Protected intermediate of Example 59 was prepared according to method 11 step 1 starting from 8-bromo-5,7-difluoroquinoline 24 (120 mg, 0.49 mmol) and compound 9 (204 mg, 0.63 mmol, 1.3 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 20/80) to afford compound 100 (161 mg, 92%) as a light brown oil. M/Z (M+H).sup.+: 357.1

[0663] Example 59 was prepared according to method 11 step 2 starting from compound 100 (161 mg, 0.45 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 59 as a yellow solid (68 mg, 49%).

[0664] .sup.1H NMR (300 MHz, DMSO): 6.05 (d, J 8.5 Hz, 1H, Ar); 6.81 (bs, 2H, NH.sub.2); 7.41 (bs, 2H, NH.sub.2); 7.46 (d, J 8.5 Hz, 1H, Ar); 7.65 (dd, J 8.4, 4.3 Hz, 1H, Ar); 1H, Ar); 7.73 (t, J 10.1 Hz, 1H, Ar); 8.54 (dd, J 8.4, 1.7 Hz, 1H, Ar); 8.95 (dd, J 4.3, 1.7 Hz, 1H, Ar); 12.47 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 273.25.

Example 60: 3-(3-chloro-7-fluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride)

[0665] ##STR00072##

[0666] Protected intermediate of Example 60 was prepared according to method 11 step 1 starting from 8-bromo-3-chloro-7-fluoroquinoline 71 (141 mg, 0.54 mmol) and compound 9 (224 mg, 0.70 mmol, 1.3 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 20/80) to afford compound 101 (131 mg, 65%) as a light brown oil. M/Z (M[.sup.35Cl]+H).sup.+: 373.2.

[0667] Example 60 was prepared according to method 11 step 2 starting from compound 101 (131 mg, 0.35 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 60 as a yellow solid (60 mg, 51%).

[0668] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.08 (d, J 8.5 Hz, 1H, Ar); 6.89 (bs, 2H, NH.sub.2); 7.48 (d, J 8.5 Hz, 1H, Ar); 7.50 (bs, 2H, NH.sub.2); 7.73 (t, J 9.1 Hz, 1H, Ar); 8.15 (dd, J 9.1, 6.1 Hz, 1H, Ar); 8.70 (d, J 2.4 Hz, 1H, Ar); 8.89 (d, J 2.4 Hz, 1H, Ar); 13.03 (bs, 1H, HCl salt). M/Z (M[.sup.35Cl]+H).sup.+: 365.2. Mp>250° C.

Example 61: 3-(3,5,7-trifluoroquinolin-8-yl)pyridine-2,6-diamine (hydrochloride) F

[0669] ##STR00073##

[0670] Protected intermediate of Example 61 was prepared according to method 11 step 1 starting from 8-bromo-3,5,7-trifluoroquinoline 78 (105 mg, 0.40 mmol) and compound 9 (175 mg, 0.55 mmol, 1.4 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 20/80) to afford compound 102 (110 mg, 72%) as a light brown oil. M/Z (M+H).sup.+: 357.1.

[0671] Example 61 was prepared according to method 11 step 2 starting from compound 102 (110 mg, 0.29 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 61 as a yellow solid (75 mg, 79%).

[0672] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.08 (d, J 8.5 Hz, 1H, Ar); 6.89 (bs, 2H, NH.sub.2); 7.50 (d, J 8.5 Hz, 1H, Ar); 7.50 (bs, 2H, NH.sub.2); 7.83 (t, J 10.0 Hz, 1H, Ar); 8.44 (dd, J 9.0, 2.8 Hz, 1H, Ar); 9.04 (d, J 2.8 Hz, 1H, Ar); 12.98 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 291.0. Mp>250° C.

Example 62: 8-(2,6-diaminopyridin-3-yl)-7-fluoroquinolin-2-ol (hydrochloride)

[0673] ##STR00074##

[0674] Protected intermediate of Example 62 was prepared according to method 11 step 1 starting from 8-bromo-7-fluorophenyl-2(1H)-one 48 (175 mg, 0.72 mmol) and compound 9 (346 mg, 1.08 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 103 (267 mg) as a light brown oil. M/Z (M+H).sup.+: 355.2.

[0675] Example 62 was prepared according to method 11 step 2 starting from compound 103 (267 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/2). The resulting foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 62 as a white solid (34 mg, 15% over 2 steps).

[0676] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.05 (d, J 8.6 Hz, 1H, Ar); 6.46 (d, J 9.6 Hz, 1H, Ar); 6.90 (bs, 2H, NH.sub.2); 7.14 (t, J 8.8 Hz, 1H, Ar); 7.36 (d, J 8.6 Hz, 1H, Ar); 7.47 (bs, 2H, NH.sub.2); 7.78 (dd, J 8.6, 6.2 Hz, 2H, Ar); 7.95 (d, J 9.6 Hz, 1H, Ar); 11.02 (s, 1H, NH or OH); 12.65 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 271.0. Mp: 210-230° C.

Example 63: 8-(2,6-diaminopyridin-3-yl)-7-chloroquinolin-2-ol (hydrochloride)

[0677] ##STR00075##

[0678] Protected intermediate of Example 63 was prepared according to method 11 step 1 starting from 8-bromo-7-chlorophenyl-2(1H)-one 50 (124 mg, 0.48 mmol) and compound 9 (230 mg, 0.72 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 104 (143 mg) as a light brown oil. M/Z (M[.sup.35Cl]+H).sup.+: 371.3.

[0679] Example 63 was prepared according to method 11 step 2 starting from compound 104 (143 mg), the crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 96/4). The resulting foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 63 as a white solid (50 mg, 32% over 2 steps).

[0680] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.00 (d, J 8.4 Hz, 1H, Ar); 6.32 (bs, 2H, NH.sub.2); 6.52 (d, J 9.6 Hz, 1H, Ar); 6.96 (bs, 2H, NH.sub.2); 7.18 (d, J 8.4 Hz, 1H, Ar); 7.37 (d, J 8.4 Hz, 1H, Ar); 7.72 (d, J 8.4 Hz, 1H, Ar); 7.97 (d, J 9.6 Hz, 1H, Ar); 10.41 (s, 1H, NH or OH); HCl salt signal not observed. M/Z (M[.sup.35Cl]+H).sup.+: 287.0. Mp>250° C.

Example 64: 8-(2,6-diaminopyridin-3-yl)-6,7-difluoroquinolin-2-ol (hydrochloride)

[0681] ##STR00076##

[0682] Protected intermediate of Example 64 was prepared according to method 11 step 1 starting from 8-bromo-6,7-difluorophenyl-2(1H)-one 51 (143 mg, 0.55 mmol) and compound 9 (263 mg, 0.82 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 105 (118 mg) as a light brown solid. M/Z (M+H).sup.+: 373.1.

[0683] Example 64 was prepared according to method 11 step 2 starting from compound 105 (118 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The resulting foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 64 as a white solid (23 mg, 13% over 2 steps).

[0684] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 6.06 (d, J 8.6 Hz, 1H, Ar); 6.54 (d, J 9.6 Hz, 1H, Ar); 6.95 (bs, 2H, NH.sub.2); 7.40 (d, J 8.6 Hz, 1H, Ar); 7.51 (bs, 2H, NH.sub.2); 7.88 (dd, J 10.6, 8.6 Hz, 2H, Ar); 7.92 (d, J 9.6 Hz, 1H, Ar); 11.05 (s, 1H, NH or OH); 12.68 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 289.1. Mp>250° C.

Example 65: 6-ethyl-5-(7-fluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0685] ##STR00077##

[0686] Example 65 was prepared according to method 2 starting from 5-bromo-6-ethylpyridin-2-amine 1d (150 mg, 0.75 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (171 mg, 0.90 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 65 as a beige solid (125 mg, 55%).

[0687] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.47 (m, 2H, CH.sub.2—CH.sub.3); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.62 (dd, J 8.2, 4.2 Hz, 1H, Ar); 7.74 (t, J 9.1 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 8.12 (bs, 2H, NH.sub.2); 8.25 (dd, J 9.1, 6.2 Hz, 1H, Ar); 8.55 (dd, J 8.4, 1.6 Hz, 1H, Ar); 8.91 (dd, J 4.2, 1.6 Hz, 1H, Ar); 14.43 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 268.1. Mp: 150-195° C.

Example 66: 5-(chroman-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0688] ##STR00078##

[0689] Example 66 was prepared according to method 2 starting from 5-bromo-6-ethylpyridin-2-amine 1d (125 mg, 0.62 mmol) and chroman-8-ylboronic acid (133 mg, 0.75 mmol, 1.2 eq.). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/02). The obtained foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/05). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried and triturated twice in Et.sub.2O (5 mL) to afford Example 66 as a white solid (93 mg, 52%).

[0690] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.13 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.88-1.94 (m, 2H, CH.sub.2—CH.sub.2—CH.sub.2); 2.52-2.55 (m, 2H, CH.sub.2—CH.sub.3); 2.80 (t, J 6.4 Hz, 2H, CH.sub.2); 4.09 (t, J 5.2 Hz, 2H, O—CH.sub.2); 6.87 (d, J 9.0 Hz, 1H, Ar); 6.90 (t, J 7.4 Hz, 1H, Ar); 6.96 (dd, J 7.4, 1.8 Hz, 1H, Ar); 7.14 (dd, J 7.4, 1.8 Hz, 1H, Ar); 7.68 (d, J 9.0 Hz, 1H, Ar); 7.88 (bs, 2H, NH.sub.2); 14.08 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 254.9. Mp: 180-192° C.

Example 67: 6-isobutyl-5-(quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0691] ##STR00079##

[0692] Example 67 was prepared according to method 2 starting from 5-bromo-6-isobutylpyridin-2-amine 12 (133 mg, 0.58 mmol) and quinolin-8-ylboronic acid (151 mg, 0.87 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The resulting foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 80/20). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 67 as a beige solid (85 mg, 45%).

[0693] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.6 (bs, 6H, 2 CH.sub.3); 1.78-1.88 (m, 1H, CH); 2.24 (bs, 1H, CH.sub.aH.sub.b); 2.53-2.59 (m, 1H, CH.sub.2H.sub.b); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.66 (dd, J 8.4, 4.4 Hz, 1H, Ar); 7.73-7.80 (m, 2H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 8.06 (bs, 2H, NH.sub.2); 8.15 (dd, J 7.6, 1.7 Hz, 1H, Ar); 8.57 (d, J 8.4, 1H, Ar); 8.91 (dd, J 4.4, 1.7 Hz, 1H, Ar); 14.42 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 278.2. Mp: 100-140° C.

Example 68: 6-(cyclobutylmethyl)-5-(quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0694] ##STR00080##

[0695] Example 68 was prepared according to method 2 starting from 5-bromo-6-(cyclobutylmethyl)pyridin-2-amine 14 (100 mg, 0.42 mmol) and quinolin-8-ylboronic acid (108 mg, 0.62 mmol, 1.5 eq.). The crude residue was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The resulting foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 80/20). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 68 as a beige solid (40 mg, 30%).

[0696] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.34 (bs, 2H, CH.sub.2); 1.44-1.52 (m, 1H, CH.sub.aH.sub.b); 1.53-1.65 (m, 1H, CH.sub.aH.sub.b); 1.73 (bs, 2H, CH.sub.2); 2.39-2.49 (m, 2H, CH.sub.2); 2.72 (bs, 1H, CH); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.66 (dd, J 8.3, 4.2 Hz, 1H, Ar); 7.74-7.80 (m, 2H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.15 (dd, J 7.2, 2.4 Hz, 1H, Ar); 8.56 (dd, J 8.4, 1.7, 1H, Ar); 8.91 (dd, J 4.2, 1.7 Hz, 1H, Ar); 14.30 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 290.2. Mp: 120-180° C.

Example 69: 5-(7-fluoroquinolin-8-yl)-6-(3,3,3-trifluoropropyl)pyridin-2-amine (hydrochloride)

[0697] ##STR00081##

[0698] Example 69 was prepared according to method 2 starting from 5-bromo-6-(3,3,3-trifluoropropyl)pyridin-2-amine 16 (110 mg, 0.41 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (156 mg, 0.82 mmol, 2.0 eq.). The crude residue was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/03). The resulting foam was further purified by flash CF.sub.3 chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 69 as a beige solid (27 mg, 18%).

[0699] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 2.59-2.68 (m, 4H, 2*CH.sub.2); 7.03 (d, J 9.0 Hz, 1H, Ar); 7.62 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.75 (t, J 9.2 Hz, 1H, Ar); 7.87 (d, J 9.0 Hz, 1H, Ar); 8.09 (bs, 2H, NH.sub.2); 8.26 (dd, J 9.2, 6.4 Hz, 1H, Ar); 8.55 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.92 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.56 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 336.0. Mp: 85-145° C.

[0700] Example 70: 5-(7-fluoroquinolin-8-yl)-6-isobutylpyridin-2-amine (hydrochloride)

##STR00082##

[0701] Example 70 was prepared according to method 2 starting from 5-bromo-6-isobutylpyridin-2-amine 12 (110 mg, 0.48 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (217 mg, 1.14 mmol, 2.0 eq.). The crude residue was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The resulting foam was further purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried. The obtained solid was triturated in Et.sub.2O (5 mL) to afford Example 70 as a beige solid (75 mg, 47%).

[0702] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.55 (d, J 6.6 Hz, 3H, CH.sub.3); 0.63 (d, J 6.6 Hz, 3H, CH.sub.3); 1.77-1.87 (m, 1H, CH); 2.26 (dd, J 14.0, 7.6 Hz, 1H, CH.sub.aH.sub.b); 2.40 (dd, J 14.0, 7.6 Hz, 1H, CH.sub.aH.sub.b); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.60 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.73 (t, J 9.2 Hz, 1H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 8.05 (bs, 2H, NH.sub.2); 8.24 (dd, J 9.2, 6.4 Hz, 1H, Ar); 8.53 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.90 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.26 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 296.1. Mp: 130-170° C.

Example 71: 5-(7-fluoroquinolin-8-yl)-6-(4,4,4-trifluorobutyl)pyridin-2-amine (hydrochloride)

[0703] ##STR00083##

[0704] Example 71 was prepared according to method 2 starting from 5-bromo-6-(4,4,4-trifluorobutyl)pyridin-2-amine 18 (110 mg, 0.39 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (89 mg, 0.47 mmol, 1.2 eq.). The crude F residue was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 71 as a beige solid (65 mg, 44%).

[0705] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.68-1.76 (m, 2H, CH.sub.2); 1.95-2.08 (m, 2H, CH.sub.2); 2.52-2.57 (m, 2H, CH.sub.2); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.61 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.74 (t, J 9.2 Hz, 1H, Ar); 7.83 (d, J 9.0 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.25 (dd, J 9.2, 6.4 Hz, 1H, Ar); 8.54 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.89 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.42 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 349.9. Mp: 70-130° C.

Example 72: 6-(cyclopropylmethyl)-5-(7-fluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0706] ##STR00084##

[0707] Example 72 was prepared according to method 2 starting from 5-bromo-6-(cyclopropylmethyl)pyridin-2-amine 20 (110 mg, 0.48 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (111 mg, 0.58 mmol, 1.2 eq.). The crude residue was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The resulting foam was further purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/02). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 72 as a beige solid (68 mg, 43%).

[0708] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.61-1.78 (m, 2H, CH.sub.2); 1.79-1.91 (m, 2H, CH.sub.2); 2.25-2.36 (m, 2H, CH.sub.2); 3.34 (quint, J 9.1 Hz, 1H, CH); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.61 (dd, J 8.2, 4.2 Hz, 1H, Ar); 7.72 (t, J 9.2 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 8.23 (dd, J 9.2, 6.4 Hz, 1H, Ar); 8.34 (bs, 2H, NH.sub.2); 8.53 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.90 (dd, J 4.2, 1.8 Hz, 1H, Ar); 13.83 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 294.1. Mp:170-207° C.

Example 73: 5-(7-fluoroquinolin-8-yl)-6-isopentylpyridin-2-amine (hydrochloride)

[0709] ##STR00085##

[0710] Example 73 was prepared according to method 2 starting from 5-bromo-6-isopentylpyridin-2-amine 22 (110 mg, 0.45 mmol) and (7-fluoroquinolin-8-yl)boronic acid 88 (104 mg, 0.54 mmol, 1.2 eq.). The crude residue was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 73 as a beige solid (62 mg, 39%).

[0711] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.45 (d, J 6.6 Hz, 3H, CH.sub.3); 0.50 (d, J 6.6 Hz, 3H, CH.sub.3); 1.17-1.27 (m, 1H, CH); 1.29-1.39 (m, 2H, CH.sub.2); 2.36-2.44 (m, 2H, CH.sub.2); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.61 (dd, J 8.4, 4.2 Hz, 1H, Ar); 7.73 (t, J 9.2 Hz, 1H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 8.03 (bs, 2H, NH.sub.2); 8.24 (dd, J 9.2, 6.4 Hz, 1H, Ar); 8.53 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.91 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.26 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 310.2. Mp: 100-140° C.

Example 74: 6-ethyl-5-(6-fluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0712] ##STR00086##

[0713] Example 74 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (60 mg, 0.30 mmol) and (6-fluoroquinolin-8-yl)boronic acid (110 mg, 0.60 mmol, 2.0 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 74 as an orange solid (21 mg, 23%).

[0714] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.3); 2.37-2.56 (m, 2H, CH.sub.2); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.65 (dd, J 8.5, 4.2 Hz, 1H, Ar); 7.76 (dd, J 9.0, 2.8 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.95 (dd, J 9.0, 2.8 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.48 (dd, J 8.5, 1.6 Hz, 1H, Ar); 8.86 (dd, J 4.2, 1.6 Hz, 1H, Ar); 14.40 (bs, 1H, NH.sub.3+). M/Z (M+H).sup.+: 268.2. Mp: 50-56° C.

##STR00087##

Example 75: 6-ethyl-5-(5-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0715] Example 75 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (60 mg, 0.30 mmol) and (5-(trifluoromethyl)quinolin-8-yl)boronic acid (110 mg, 0.45 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 93/7). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 75 as a beige solid (42 mg, 40%).

[0716] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.3); 2.36-2.44 (m, 1H, CH.sub.2); 2.50-2.57 (m, 1H, CH.sub.2); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.82 (dd, J 8.5, 4.2 Hz, 1H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 7.91 (d, J 7.5 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.20 (d, J 7.5 Hz, 1H, Ar); 8.56-8.62 (m, 1H, Ar); 9.04 (dd, J 4.2, 1.5 Hz, 1H, Ar); 14.30 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 318.2. Mp: 120-137° C.

Example 76: 6-ethyl-5-(7-fluoro-2-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0717] ##STR00088##

[0718] Example 76 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine Id (100 mg, 0.50 mmol) and (7-fluoro-2-methylquinolin-8-yl)boronic acid (255 mg, 1.24 mmol, 2.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/04). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 76 as a beige solid (99 mg, 62%).

[0719] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.09 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.4 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 2.57 (s, 3H, CH.sub.3); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.49 (d, J 8.4 Hz, 1H, Ar); 7.63 (t, J 9.1 Hz, 1H, Ar); 7.81 (d, J 9.1 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.16 (dd, J 9.0, 6.5 Hz, 1H, Ar); 8.40 (d, J 8.4 Hz, 1H, Ar); 14.27 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 282.1. Mp: 95-120° C.

Example 77: 6-ethyl-5-(6-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0720] ##STR00089##

[0721] Example 77 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (65 mg, 0.32 mmol) and (6-methylquinolin-8-yl)boronic acid (91 mg, 0.48 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH, 100/0 to 92/8). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 77 as a beige solid (68 mg, 70%).

[0722] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.48 (m, 2H, CH.sub.2—CH.sub.3); 2.56 (s, 3H, CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.60-7.63 (m, 2H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.91 (s, 1H, Ar); 8.01 (bs, 2H, NH.sub.2); 8.16 (d, J 8.4 Hz, 1H, Ar); 8.83 (dd, J 4.3, 1.7 Hz, 1H, Ar); 14.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.2. Mp: 100-140° C.

Example 78: 5-(benzo[b]thiophen-4-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0723] ##STR00090##

[0724] Example 78 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (75 mg, 0.37 mmol) and benzo[b]thiophen-4-ylboronic acid (86 mg, 0.48 mmol, 1.3 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 78 as a beige solid (74 mg, 69%).

[0725] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.40-2.46 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.54-2.59 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.14 (dd, J 5.6, 0.7 Hz, 1H, Ar); 7.29 (dd, J 7.2, 0.9 Hz, 1H, Ar); 7.47 (t, J 7.7 Hz, 1H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 7.83 (d, J 5.6 Hz, 1H, Ar); 7.96 (bs, 2H, NH.sub.2); 8.11 (dt, J 8.1, 0.9 Hz, 1H, Ar); 14.09 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 251.1. Mp: 80-140° C.

Example 79: 5-(benzofuran-7-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0726] ##STR00091##

[0727] Example 79 was prepared according to method 2 starting from 2-amino-5-bromo-6-ethylpyridine 1d (75 mg, 0.37 mmol) and 2-(benzofuran-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (180 mg, 0.75 mmol, 2.0 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH, 100/0 to 90/10). The resulting product was triturated in Et.sub.2O (2×2 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 79 as a beige solid (12 mg, 12%).

[0728] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.14 (t, J 7.6 Hz, 3H, CH.sub.3); 2.57 (q, J 7.6 Hz, 2H, CH.sub.2); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.06 (d, J 2.1 Hz, 1H, Ar); 7.26 (dd, J 7.7, 1.1 Hz, 1H, Ar); 7.37 (t, J 7.7 Hz, 1H, Ar); 7.75 (dd, J 7.7, 1.1 Hz, 1H, Ar); 7.89 (d, J 9.0 Hz, 1H, Ar); 7.89-8.19 (bs, 2H, NH.sub.2); 8.02 (d, J 2.1 Hz, 1H, Ar); 14.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 239.1.

Example 80: 6-ethyl-5-(2-(6-(piperidin-1-yl)pyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0729] ##STR00092##

[0730] Example 80 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethyl-pyridin-2-amine 5a (100 mg, 0.43 mmol) and 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (186 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 80 as a white solid (77 mg, 45%).

[0731] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.55-1.67 (m, 6H, 3 CH.sub.2); 2.41 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.61-3.64 (m, 4H, 2 CH.sub.2); 6.84 (d, J 9.0 Hz, 1H, Ar); 7.16 (bs, 1H, Ar); 7.36-7.38 (m, 1H, Ar); 7.5-7.59 (m, 4H, Ar); 7.68 (t, J 9.0 Hz, 1H, Ar); 7.80 (d, J 2.2 Hz, 1H, Ar); 8.09 (bs, 2H, NH.sub.2); 14.26 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 359.3. Mp: 50-80° C.

Example 81: 6-ethyl-5-(2-(6-(trifluoromethyl)pyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0732] ##STR00093##

[0733] Example 81 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethyl-pyridin-2-amine 5a (100 mg, 0.43 mmol) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (123 mg, 0.65 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 81 as a white solid (68 mg, 42%).

[0734] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.98 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.38 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.77 (d, J 9.0 Hz, 1H, Ar); 7.42-7.45 (m, 1H, Ar); 7.59-7.66 (m, 4H, Ar); 7.85-7.94 (m, 4H, Ar+NH.sub.2); 8.58 (d, J 1.7 Hz, 1H, Ar); 13.90 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 344.2. Mp>250° C.

Example 82: 6-ethyl-5-(4-fluoro-2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0735] ##STR00094##

[0736] Example 82 was prepared according to method 2 starting from 5-(2-chloro-4-fluorophenyl)-6-ethylpyridin-2-amine 90 (97 mg, 0.39 mmol) and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (170 mg, 0.58 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 0/100). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 82 as a beige solid (53 mg, 31%).

[0737] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.02 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.38 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.52-3.54 (m, 4H, 2 N—CH.sub.2); 3.69-3.71 (m, 4H, 2 O—CH.sub.2); 6.83 (d, J 9.0 Hz, 1H, Ar); 6.98 (d, J 9.1 Hz, 1H, Ar); 7.32-7.43 (m, 3H, Ar); 7.48 (dd, J 9.1, 2.4 Hz, 1H, Ar); 7.66 (d, J 9.0 Hz, 1H, Ar); 7.92 (d, J 2.4 Hz, 1H, Ar); 8.09 (bs, 2H, NH.sub.2); 14.25 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 379.2. Mp: 54-70° C.

Example 83: 6-ethyl-5-(5-fluoro-2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0738] ##STR00095##

[0739] Example 83 was prepared according to method 2 starting from 5-(2-chloro-5-fluorophenyl)-6-ethylpyridin-2-amine 91 (100 mg, 0.40 mmol) and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (174 mg, 0.60 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 83 as a beige solid (35 mg, 21%).

[0740] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.02 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.49-3.51 (m, 4H, 2 N—CH.sub.2); 3.68-3.71 (m, 4H, 2O—CH.sub.2); 6.83 (d, J 9.0 Hz, 1H, Ar); 6.95 (d, J 9.1 Hz, 1H, Ar); 7.28 (dd, J 9.4, 2.6 Hz, 1H, Ar); 7.38-7.44 (m, 2H, Ar); 7.28 (dd, J 8.6, 5.9 Hz, 1H, Ar); 7.69 (d, J 9.0 Hz, 1H, Ar); 7.92 (d, J 2.6 Hz, 1H, Ar); 8.07 (bs, 2H, NH.sub.2); 14.16 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 379.3. Mp: 85-100° C.

Example 84: 6-ethyl-5-(2-(6-morpholinopyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0741] ##STR00096##

[0742] Example 84 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (187 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was further purified by (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was triturated with Et.sub.2O (2×5 mL) and then dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 84 as a beige solid (26 mg, 15%).

[0743] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ:1.01 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.49-3.50 (m, 4H, CH.sub.2); 3.68-3.71 (m, 4H, CH.sub.2); 6.82 (d, J 9.1 Hz, 1H, Ar); 6.93 (d, J 8.9 Hz, 1H, Ar); 7.34-7.36 (m, 1H, Ar); 7.43 (dd, J 8.4, 2.4 Hz, 1H, Ar); 7.47-7.57 (m, 3H, Ar); 7.67 (d, J 9.1 Hz, 1H, Ar); 7.90 (d, J 2.4 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 14.03 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 361.2. Mp: 95-110° C.

Example 85: 6-ethyl-5-(2-(5-methylpyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0744] ##STR00097##

[0745] Example 85 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and (5-methylpyridin-3-yl)boronic acid (88 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was further purified by (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 85 as a beige solid (34 mg, 24%).

[0746] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.01 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.32-2.39 (m, 5H, CH.sub.2—CH.sub.3+CH.sub.3); 6.80 (d, J 9.0 Hz, 1H, Ar); 7.41-7.44 (m, 1H, Ar); 7.57-7.65 (m, 3H, Ar); 7.67 (d, J 9.0 Hz, 1H, Ar); 7.93 (bs, 1H, Ar); 8.07 (bs, 2H, NH.sub.2); 8.35 (bs, 1H, Ar); 8.55 (bs, 1H, Ar); 14.18 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 290.2. Mp: 120-150° C.

Example 86: 6-ethyl-5-(2-(5-methylpyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0747] ##STR00098##

[0748] Example 86 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and (6-methylpyridin-3-yl)boronic acid hydrate (100 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was further purified by (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 86 as a beige solid (32 mg, 23%).

[0749] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.03 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.38 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 2.64 (s, 3H, CH.sub.3); 6.81 (d, J 9.0 Hz, 1H, Ar); 7.42-7.44 (m, 1H, Ar); 7.58-7.65 (m, 4H, Ar); 7.67 (d, J 9.0 Hz, 1H, Ar); 7.93-7.96 (m, 1H, Ar); 8.12 (bs, 2H, NH.sub.2); 8.54 (bs, 1H, Ar); 14.29 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 290.2. Mp: 90-110° C.

Example 87: 6-ethyl-5-(2-(6-fluoropyridin-3-yl)phenyl)pyridin-2-amine (hydrochloride)

[0750] ##STR00099##

[0751] Example 87 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and (6-fluoropyridin-3-yl)boronic acid (91 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 87 as a beige solid (24 mg, 17%).

[0752] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.99 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.37 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.79 (d, J 9.0 Hz, 1H, Ar); 7.16 (ddd, J 8.4, 2.8, 0.6 Hz, 1H, Ar); 7.39-7.41 (m, 1H, Ar); 7.35-7.64 (m, 4H, Ar); 7.75 (td, J 8.2, 2.6 Hz, 1H, Ar); 7.96 (bs, 2H, NH.sub.2); 8.04 (d, J 2.6 Hz, 1H, Ar); 13.95 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 294.1. Mp>250° C.

Example 88: 5-(2-(6-amino-2-ethylpyridin-3-yl)phenyl)pyridin-2-ol (hydrochloride)

[0753] ##STR00100##

[0754] Example 88 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and (6-methoxypyridin-3-yl)boronic acid (99 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained product was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried. Two products were observed by UPLCMS, expected product and pyridinol suspected product. The mixture was dissolved in HCl 1M and was stirred at 25° C. for 2 days. The reaction mixture was subjected microwave irradiation at 150° C. for 5 min and was freeze dried. To finish conversion, the product was dissolved in HCl 1M and was subjected microwave irradiation at 150° C. for 5 min. The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 88 as a beige solid (56 mg, 40%).

[0755] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.42 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.27 (d, J 9.4 Hz, 1H, Ar); 6.85 (d, J 9.0 Hz, 1H, Ar); 7.16 (dd, J 9.4, 2.7 Hz, 1H, Ar); 7.21 (d, J 2.7 Hz, 1H, Ar); 7.43-7.53 (m, 3H, Ar); 7.66 (d, J 9.0 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 14.12 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 292.1. Mp: 95-120° C.

Example 89: 6-ethyl-5-(2-(6-methoxypyridin-3-yl)phenyl)pyridin-2-amine

[0756] ##STR00101##

[0757] Example 89 was prepared according to method 2 starting from 5-(2-chlorophenyl)-6-ethylpyridin-2-amine 5a (100 mg, 0.43 mmol) and ((6-methoxypyridin-3-yl)boronic acid (99 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam co-evaporated with EtOAc (2×20 mL) to afford Example 89 as a white solid (30 mg, 23%).

[0758] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.85 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.01-2.10 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.14-2.23 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 3.81 (s, 3H, CH.sub.3); 5.87 (bs, 2H, NH.sub.2); 6.26 (d, J 8.4 Hz, 1H, Ar); 6.69 (dd, J 8.6, 0.6 Hz, 1H, Ar); 7.08 (d, J 8.4 Hz, 1H, Ar); 7.24-7.26 (m, 1H, Ar); 7.37 (d, J 2.5 Hz, 1H, Ar); 7.39-7.46 (m, 3H, Ar); 7.91 (dd, J 2.5, 0.6 Hz, 1H, Ar). M/Z (M+H).sup.+: 306.2. Mp: 165-180° C.

Example 90: 6-ethyl-5-(2-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0759] ##STR00102##

[0760] Protected intermediate of Example 90 was prepared according to method 9 step 1 starting from 8-bromo-2-methylquinoline (100 mg, 0.45 mmol) and compound 7 (165 mg, 0.51 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 106 (88 mg, 59%) as a white solid. M/Z (M+H).sup.+: 342.2.

[0761] Example 90 was prepared according to method 9 step 2 starting from compound 106 (88 mg, 0.26 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 80/20). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 90 as a beige solid (93 mg, 58%).

[0762] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.41-2.46 (m, 2H, CH.sub.2—CH.sub.3); 2.61 (s, 3H, CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.53 (d, J 8.4 Hz, 1H, Ar); 7.64-7.71 (m, 2H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 8.07 (dd, J 7.7, 1.8 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.42 (d, J 8.4 Hz, 1H, Ar); 14.38 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.2. Mp: 110-150° C.

Example 91: 6-ethyl-5-(4-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0763] ##STR00103##

[0764] Protected intermediate of Example 91 was prepared according to method 9 step 1 starting from 8-bromo-4-methylquinoline (100 mg, 0.45 mmol) and compound 7 (176 mg, 0.54 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 85/15) to afford compound 107 (90 mg, 59%) as a white solid. M/Z (M+H).sup.+: 342.2.

[0765] Example 91 was prepared according to method 9 step 2 starting from compound 107 (90 mg, 0.26 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 40/60) and was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 91 as a beige solid (37 mg, 47%).

[0766] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.39 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.44-2.47 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.84 (s, 3H, CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.64-7.65 (m, 1H, Ar); 7.78 (d, J 9.0 Hz, 1H, Ar); 7.82-7.85 (m, 2H, Ar); 8.10 (bs, 2H, NH.sub.2), 8.34 (t, J 4.8 Hz, 1H, Ar); 8.83 (d, J 4.8 Hz, 1H, Ar); 14.45 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.1. Mp>250° C.

Example 92: 8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-amine (dihydrochloride)

[0767] ##STR00104##

[0768] Protected intermediate of Example 92 was prepared according to method 9 step 1 starting from 8-bromoquinolin-2-amine (100 mg, 0.45 mmol) and compound 7 (219 mg, 0.67 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 70/30) to afford compound 108 (79 mg, 51%) as a white solid. M/Z (M+H).sup.+: 343.2.

[0769] Example 92 was prepared according to method 9 step 2 starting from compound 108 (79 mg, 0.23 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 40/60). The resulting foam was triturated with Et.sub.2O (10 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 92 as a beige solid (38 mg, 49%).

[0770] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.28-2.37 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.52-2.57 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.15 (d, J 9.3 Hz, 1H, Ar); 7.57 (t, J 7.4 Hz, 1H, Ar); 7.65 (d, J 7.1 Hz, 1H, Ar); 7.72 (d, J 9.0 Hz, 1H, Ar); 8.02 (d, J 7.4, 1H, Ar); 8.05 (bs, 2H, NH.sub.2); 8.44 (d, J 9.3 Hz, 1H, Ar); 9.01 (bs, 1H, NH.sub.aNH.sub.b); 9.35 (bs, 1H, NH.sub.aNH); 12.92 (bs, 1H, HCl salt); 14.22 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 265.1. Mp: 200-250° C.

Example 93: 6-ethyl-5-(7-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0771] ##STR00105##

[0772] Protected intermediate of Example 93 was prepared according to method 9 step 1 starting from 8-bromo-7-methylquinoline (150 mg, 0.68 mmol) and compound 7 (331 mg, 1.01 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc, 100/0 to 70/30) to afford compound 109 (175 mg, 75%) as a yellow oil. M/Z (M+H).sup.+: 342.2.

[0773] Example 93 was prepared according to method 9 step 2 starting from compound 109 (175 mg, 0.51 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was triturated with Et.sub.2O (10 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 93 as a beige solid (52 mg, 54%).

[0774] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.98 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.24-2.30 (m, 2H, CH.sub.2—CH.sub.3); 2.32 (s, 3H, CH.sub.3); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.65-7.69 (m, 1H, Ar); 7.69 (d, J 9.0 Hz, 1H, Ar); 7.73 (d, J 8.4 Hz, 1H, Ar); 8.06 (bs, 2H, NH.sub.2); 8.11 (d, J 8.4 Hz, 1H, Ar); 8.62 (d, J 8.0 Hz, 1H, Ar); 8.88 (dd, J 4.4, 1.6 Hz, 1H, Ar); 14.35 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.1. Mp: 90-130° C.

Example 94: 5-(2-ethoxyquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0775] ##STR00106##

[0776] Protected intermediate of Example 94 was prepared according to method 9 step 1 starting from 8-bromo-2-ethoxyquinoline (150 mg, 0.60 mmol) and compound 7 (291 mg, 0.89 mmol, 1.5 eq.). The crude was purified by HCl flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 85/15). The obtained foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 90/10) to afford compound 110 (131 mg, 59%) as a white solid. M/Z (M+H).sup.+: 372.3 Example 94 was prepared according to method 9 step 2 starting from compound 110 (131 mg, 0.35 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The resulting compound was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 94 as a white solid (17 mg, 15%).

[0777] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.25 (t, J 7.1 Hz, 3H, O—CH.sub.2—CH.sub.3); 2.52-2.56 (m, 2H, CH.sub.2—CH.sub.3); 4.16-4.22 (m, 2H, O—CH.sub.2—CH.sub.3); 6.92 (d, J 9.0 Hz, 1H, Ar); 7.03 (d, J 8.9 Hz, 1H, Ar); 7.52 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.63 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.85 (d, J 9.0 Hz, 1H, Ar); 7.84-7.90 (bs, 2H, NH.sub.2); 7.98 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.31 (d, J 8.9 Hz, 1H, Ar); 14.02 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 294.0. Mp: 35-70° C.

Example 95: 6-ethyl-5-(3-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0778] ##STR00107##

[0779] Protected intermediate of Example 95 was prepared according to method 9 step 1 starting from 8-bromo-3-methylquinoline (150 mg, 0.68 mmol) and compound 7 (331 mg, 1.01 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to compound 111 (193 mg, 84%) as a beige solid. M/Z (M+H).sup.+: 342.2

[0780] Example 95 was prepared according to method 9 step 2 starting from compound 111 (193 mg, 0.57 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5) and was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 95 as a beige solid (128 mg, 76%).

[0781] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.48 (m, 2H, CH.sub.2—CH.sub.3); 2.52 (s, 3H, CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.68-7.74 (m, 2H, Ar); 7.79 (d, J 9.0 Hz, 1H, Ar); 8.05 (m, 3H, Ar+NH.sub.2); 8.35 (bs, 1H, Ar); 8.79 (d, J 2.2 Hz, 1H, Ar); 14.33 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.0. Mp>250° C.

Example 96: 6-ethyl-5-(5-methylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0782] ##STR00108##

[0783] Protected intermediate of Example 96 was prepared according to method 9 step 1 starting from 8-bromo-5-methylquinoline (150 mg, 0.68 mmol) and compound 7 (331 mg, 1.01 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 112 (216 mg, 94%) as a white solid. M/Z (M+H).sup.+: 342.2

[0784] Example 96 was prepared according to method 9 step 2 starting from compound 112 (216 mg, 0.63 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5) and was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 96 as a beige solid (161 mg, 85%).

[0785] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.34-2.48 (m, 2H, CH.sub.2—CH.sub.3); 2.75 (s, 3H, CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.61 (d, J 7.3 Hz, 1H, Ar); 7.68 (d, J 7.3 Hz, 1H, Ar); 7.71 (dd, J 8.5, 4.4 Hz, 1H, Ar); 7.77 (d, J 9.0 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.68 (dd, J 8.6, 1.5 Hz, 1H, Ar); 8.92 (dd, J 4.4, 1.5 Hz, 1H, Ar); 14.35 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 264.0. Mp>250° C.

Example 97: 6-ethyl-5-(3-fluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0786] ##STR00109##

[0787] Protected intermediate of Example 97 was prepared according to method 9 step 1 starting from 8-bromo-3-fluoroquinoline (150 mg, 0.66 mmol) and compound 7 (325 mg, 1.00 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 113 (280 mg) as a yellow oil. M/Z (M+H).sup.+: 346.2

[0788] Example 97 was prepared according to method 9 step 2 starting from compound 113 (280 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5).

[0789] The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10) and was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 97 as a beige solid (116 mg, 58% over 2 steps).

[0790] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.48 (m, 2H, CH.sub.2—CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.73 (dd, J 7.1, 1.6 Hz, 1H, Ar); 7.77 (d, J 8.0 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.12 (dd, J 8.0, 1.6 Hz, 1H, Ar); 8.38 (dd, J 9.4, 2.9 Hz, 1H, Ar); 8.92 (d, J 2.9 Hz, 1H, Ar); 14.18 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 267.9. Mp: 210-245° C.

Example 98: 6-ethyl-5-(7-methoxyquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0791] ##STR00110##

[0792] Protected intermediate of Example 98 was prepared according to method 9 step 1 starting from 8-bromo-7-methoxyquinoline (125 mg, 0.53 mmol) and compound 7 (257 mg, 0.79 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 114 (164 mg) as a light yellow oil. M/Z (M+H).sup.+: 358.3.

[0793] Example 98 was prepared according to method 9 step 2 starting from compound 114 (164 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5) and was triturated with Et.sub.2O (5 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 98 as a white solid (92 mg, 55% over 2 steps).

[0794] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.02 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.26-2.44 (m, 2H, CH.sub.2—CH.sub.3); 3.96 (s, 3H, CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.61-7.65 (m, 1H, Ar); 7.68 (d, J 9.0 Hz, 1H, Ar); 7.83 (d, J 9.2 Hz, 1H, Ar); 8.07 (bs, 2H, NH.sub.2); 8.32 (d, J 9.2 Hz, 1H, Ar); 8.71-8.74 (m, 1H, Ar); 8.88 (dd, J 4.6, 1.4 Hz, 1H, Ar); 14.40 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 280.2. Mp: 230-250° C.

Example 99: 6-ethyl-5-(2-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0795] ##STR00111##

[0796] Protected intermediate of Example 99 was prepared according to method 9 step 1 starting from 8-bromo-2-(trifluoromethyl)quinoline (125 mg, 0.45 mmol) and compound 7 (222 mg, 0.68 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford 8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)-2-(trifluoromethyl)quinoline 115 (169 mg, 94%) as a yellow oil. M/Z (M+H).sup.+: 396.2.

[0797] Example 99 was prepared according to method 9 step 2 starting from compound 115 (169 mg, 0.43 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtained foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 99 as a white solid (70 mg, 46%).

[0798] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.44 (bs, 2H, CH.sub.2—CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 7.88-7.93 (m, 2H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.05 (d, J 8.6 Hz, 1H, Ar); 8.26-8.30 (m, 1H, Ar); 8.84 (d, J 8.6 Hz, 1H, Ar); 14.14 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 318.0. Mp: 90-130° C.

Example 100: 6-ethyl-5-(1,7-naphthyridin-8-yl)pyridin-2-amine (hydrochloride)

[0799] ##STR00112##

[0800] Protected intermediate of Example 100 was prepared according to method 9 step 1 starting from 8-chloro-1,7-naphthyridine (125 mg, 0.76 mmol) and compound 7 (372 mg, 1.14 mmol, 1.5 eq.). The crude was purified by flash N chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to compound 116 (170 N mg, 68%) as a yellow oil. M/Z (M+H).sup.+: 396.2.

[0801] Example 100 was prepared according to method 9 step 2 starting from compound 116 (170 mg, 0.76 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 100 as an orange solid (124 mg, 83%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.58 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.85 (dd, J 8.4, 4.2 Hz, 1H, Ar); 8.00 (d, J 9.0 Hz, 1H, Ar); 8.04 (d, J 5.6 Hz, 1H, Ar); 8.09 (bs, 2H, NH.sub.2); 8.55 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.73 (d, J 5.6 Hz, 1H, Ar); 9.03 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.22 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 251.1. Mp: 160-200° C.

Example 101: 6-ethyl-5-(quinoxalin-5-yl)pyridin-2-amine (hydrochloride)

[0802] ##STR00113##

[0803] Protected intermediate of Example 101 was prepared according to method 9 step 1 starting from 5-bromoquinoxaline (115 mg, 0.55 mmol, 1.2 eq.) and compound 7 (150 mg, 0.46 mmol). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 117 (104 mg, 69%) as an orange solid. M/Z (M+H).sup.+: 329.1.

[0804] Example 101 was prepared according to method 9 step 2 starting from compound 117 (104 mg, 0.32 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 20/80). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 101 as a pink solid (47 mg, 52%).

[0805] 1H-NMR (DMSO-d6, 400 MHz) δ:1.06 (t, J 7.6 Hz, 3H, CH.sub.3); 2.39-2.45 (m, 2H, CH.sub.2); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.86 (dd, J 7.1, 1.3 Hz, 1H, Ar); 7.96-8.00 (m, 3H, Ar+NH.sub.2); 8.22 (dd, J 8.3, 1.3 Hz, 1H, Ar); 8.93 (d, J 1.8 Hz, 1H, Ar); 9.02 (d, J 1.8 Hz, 1H, Ar); 14.19 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 251.0. Mp>250° C.

Example 102: 6-ethyl-5-(imidazo[1,2-a]pyridin-8-yl)pyridin-2-amine (hydrochloride)

[0806] ##STR00114##

[0807] Protected intermediate of Example 102 was prepared according to method 9 step 1 starting from 8-bromoimidazo[1,2-a]pyridine (125 mg, 0.63 mmol) and compound 7 (202 mg, 0.63 mmol, 1.0 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to afford compound 118 (126 mg, 63%) as a light brown solid. M/Z (M+H).sup.+: 316.9.

[0808] Example 102 was prepared according to method 9 step 2 starting from compound 118 (126 mg, 0.40 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 96/4). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 102 as a beige solid (91 mg, 84%).

[0809] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.12 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.52-2.61 (m, 2H, CH.sub.2—CH.sub.3); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.59 (t, J 7.0 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.89 (d, J 7.0 Hz, 1H, Ar); 8.22 (d, J 1.9 Hz, 1H, Ar); 8.32 (bs, 2H, NH.sub.2); 8.48 (d, J 2.0 Hz, 1H, Ar); 8.99 (dd, J 7.0, 0.8 Hz, 1H, Ar); 14.78 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 239.0. Mp: 95-135° C.

Example 103: 6-ethyl-5-(imidazo[1,2-a]pyridin-5-yl)pyridin-2-amine (hydrochloride)

[0810] ##STR00115##

[0811] Protected intermediate of Example 103: Under Argon, to a solution of 5-bromoimidazo[1,2-a]pyridine (250 mg, 1.28 mmol) in DMF (6.5 mL), compound 7 (620 mg, 1.90 mmol, 1.5 eq.) and K.sub.2CO.sub.3 (703 mg, 4.0 Eq, 5.10 mmol) were added. The reaction mixture was sparged with argon for 10 min before addition of Pd(dppf)Cl.sub.2 (46.5 mg, 63.5 μmol, 0.05 eq.). The reaction mixture was heated at 110° C. for 2 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with DCM (70 mL). The organic layer was hydrolyzed with NH.sub.4Cl sat. (70 mL) and extracted twice with DCM (70 mL). The organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated. The crude was purified twice by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5) to obtain compound 119 (190 mg, 47%) as a light brown oil. M/Z (M+H).sup.+: 317.1.

[0812] Example 103 was prepared according to method 9 step 2 starting from compound 119 (190 mg, 0.60 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/2). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 103 as a beige solid (127 mg, 77%).

[0813] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.15 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.32-2.46 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.54-2.63 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 7.04 (d, J 9.1 Hz, 1H, Ar); 7.52 (dd, J 7.0, 1.2 Hz, 1H, Ar); 7.87 (d, J 9.1 Hz, 1H, Ar); 8.03 (dd, J 9.1, 7.0 Hz, 1H, Ar); 8.10 (t, J 9.1 Hz, 1H, Ar); 8.13 (dd, J 2.2, 0.5 Hz, 1H, Ar); 8.27 (d, J 2.2 Hz, 1H, Ar); 8.49 (bs, 2H, NH.sub.2); 14.96 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 239.0. Mp: 115-155° C.

Example 104: 6-ethyl-5-(pyrazolo[1,5-a]pyridin-7-yl)pyridin-2-amine (hydrochloride)

[0814] ##STR00116##

[0815] Protected intermediate of Example 104 was prepared according to method 9 step 1 starting from 7-bromopyrazolo[1,5-a]pyridine (150 mg, 0.76 mmol) and compound 7 (298 mg, 0.91 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 85/15) to afford compound 120 (140 mg, 58%) as yellow oil. M/Z (M+H).sup.+: 317.1.

[0816] Example 104 was prepared according to method 9 step 2 starting from compound 120 (140 mg, 0.44 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained product was triturated in Et.sub.2O (2×2 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 104 as an orange solid (73 mg, 60%).

[0817] 1H-NMR (DMSO-d6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.3); 2.52-2.53 (m, 2H, CH.sub.2); 6.76 (d, J 2.3 Hz, 1H, Ar); 6.96 (dd, J 6.7, 1.4 Hz, 1H, Ar); 6.99 (d, J 9.1 Hz, 1H Ar); 7.32 (dd, J 8.8, 6.8 Hz, 1H, Ar); 7.82 (dd, J 8.8, 1.3 Hz, 1H, Ar); 7.93 (d, J 9.1 Hz, 1H, Ar); 7.98 (d, J 2.3 Hz, 1H, Ar); 8.25 (bs, 2H, NH.sub.2); 14.52 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 238.9. Mp: 234-243° C.

Example 105: 5-(7-(difluoromethoxy)quinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0818] ##STR00117##

[0819] Protected intermediate of Example 105 was prepared according to method 9 step 1 starting from 8-bromo-7-(difluoromethoxy)quinoline 64 (129 mg, 0.47 mmol) and compound 7 (230 mg, 0.71 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 97/3) to afford compound 121 (82 mg) as yellow oil. M/Z (M+H).sup.+: 394.2

[0820] Example 105 was prepared according to method 9 step 2 starting from compound 121 (82 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 97/3). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 105 as a beige solid (35 mg, 21% over 2 steps).

[0821] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.02 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.29-2.40 (m, 2H, CH.sub.2—CH.sub.3); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.38 (t, J 73.3 Hz, 1H, CHF.sub.2); 7.61 (dd, J 8.3, 4.2 Hz, 1H, Ar); 7.72 (d, J 9.2 Hz, 1H, Ar); 7.74 (d, J 9.0 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.26 (d, J 9.2 Hz, 1H, Ar); 8.53 (dd, J 8.3, 1.6 Hz, 1H, Ar); 8.90 (dd, J 4.2, 1.6 Hz, 1H, Ar); 14.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 316.0. Mp: 120-160° C.

Example 106: 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0822] ##STR00118##

[0823] Protected intermediate of Example 106 was prepared according to method 9 step 1 starting from 8-bromo-1,2,3,4-tetrahydroquinoline hydrochloride (165 mg, 0.67 mmol) and compound 7 (262 mg, 0.80 mmol, 1.2 eq.) and using 3.0 eq. of K.sub.2CO.sub.3. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 122 (218 mg) as a colorless oil. M/Z (M+H).sup.+: 332.2

[0824] Example 106 was prepared according to method 9 step 2 starting from compound 122 (218 mg). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50).

[0825] The product was triturated in Et.sub.2O (4 mL) and pentane (4 mL). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 106 as a white solid (51 mg, 27% over 2 steps).

[0826] .sup.1H-NMR (D20, 400 MHz) δ: 1.17 (t, J 7.6 Hz, 3H, CH.sub.3); 2.06-2.16 (m, 2H, CH.sub.2); 2.46-2.55 (m, 1H, CH—H); 2.61-2.70 (m, 1H, CH—H); 3.00 (t, J 6.7 Hz, 2H, CH.sub.2); 3.33-3.39 (m, 1H, CH—H); 3.44-3.50 (m, 1H, CH—H); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.20 (d, J 7.5 Hz, 1H, Ar); 7.30 (t, J 7.5 Hz, 1H, Ar); 7.41 (d, J 7.7 Hz, 1H, Ar); 7.75 (d, J 9.0 Hz, 1H, Ar). M/Z (M+H).sup.+: 254.0. Mp: 147-160° C.

Example 107: 6-ethyl-5-(7-fluoro-3-phenylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0827] ##STR00119##

[0828] Protected intermediate of Example 107 was prepared according to method 9 step 1 starting from 8-bromo-7-fluoro-3-phenylquinoline 66 (105 mg, 0.35 mmol) and compound 7 (170 mg, 0.52 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 123 (129 mg) as a colorless oil. M/Z (M+H).sup.+: 422.2

[0829] Example 107 was prepared according to method 9 step 2 starting from compound 123 (129 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 80/20 to 40/60). Then, volatiles were removed under vacuum. The obtained solution was diluted in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 107 as a white solid (67 mg, 51% over 2 steps).

[0830] 1H-NMR (DMSO-d6, 400 MHz) δ: 1.08 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.37-2.48 (m, 2H, CH.sub.2—CH.sub.3); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.45-7.50 (m, 1H, Ar), 7.54-7.60 (m, 2H, Ar); 7.77 (t, J 9.1 Hz, 1H, Ar); 7.80-7.90 (m, 3H, Ar); 8.13 (bs, 2H, NH.sub.2); 8.30 (dd, J 9.1, 6.4 Hz, 1H, Ar); 8.82 (d, J 2.4 Hz, 1H, Ar); 9.26 (d, J 2.4 Hz, 1H, Ar); 14.43 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 344.1. Mp>250° C.

Example 108: 5-(5,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0831] ##STR00120##

[0832] Protected intermediate of Example 108 was prepared according to method 9 step 1 starting from 8-bromo-5,7-difluoroquinoline 24 (150 mg, 0.62 mmol) and compound 7 (301 mg, 0.92 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 124 (196 mg, 88%) as a white solid. M/Z (M+H).sup.+: 364.2.

[0833] Example 108 was prepared according to method 9 step 2 starting from compound 124 (190 mg, 0.52 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 108 as a beige solid (90 mg, 53%).

[0834] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ:1.06 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.47 (m, 2H, CH.sub.2—CH.sub.3); 6.98 (d, J 8.7 Hz, 1H, Ar); 7.70 (dd, 8.4, J 4.1 Hz 1H, Ar); 7.78-7.85 (m, 2H, Ar); 8.02 (bs, 2H, NH.sub.2); 8.60 (dd, J 8.4, 1.7 Hz, 1H, Ar); 8.98 (dd, J 4.1, 1.7 Hz, 1H, Ar); 14.10 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 285.9. Mp: 126-136° C.

Example 109: 6-ethyl-5-(7-(trifluoromethyl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0835] ##STR00121##

[0836] Protected intermediate of Example 109 was prepared according to method 9 step 1 starting from 8-bromo-7-(trifluoromethyl)quinoline 25 (125 mg, 0.45 mmol) and compound 7 (222 mg, 0.68 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 40/60) to afford compound 125 (145 mg, 81%) as a yellow oil. M/Z (M+H).sup.+: 396.2.

[0837] Example 109 was prepared according to method 9 step 2 starting from compound 125 (145 mg, 0.37 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 70/30). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 109 as a light yellow solid (100 mg, 77%).

[0838] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.98 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.13-2.32 (m, 2H, CH.sub.2—CH.sub.3); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.74-7.78 (m, 2H, Ar); 8.06 (d, J 8.8 Hz, 1H, Ar); 8.15 (bs, 2H, NH.sub.2); 8.38 (d, J 8.8 Hz, 1H, Ar); 8.62 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.99 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.47 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 318.1. Mp: 150-180° C.

Example 110: 5-(7-chloroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0839] ##STR00122##

[0840] Protected intermediate of Example 110 was prepared according to method 9 step 1 starting from 8-bromo-7-chloroquinoline 26 (435 mg, 1.79 mmol) and compound 7 (644 mg, 1.97 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2). The obtained foam was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford compound 126 (395 mg, 61%) as a yellow oil. M/Z (M[.sup.35Cl]+H).sup.+: 362.1.

[0841] Example 110 was prepared according to method 9 step 2 starting from compound 126 (145 mg, 0.37 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/2). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 110 as a beige solid (35 mg, 32%).

[0842] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.00 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.30-2.36 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.64 (dd, J 8.2, 4.2 Hz, 1H, Ar); 7.75 (d, J 9.0 Hz, 1H, Ar); 7.86 (d, J 8.8 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.19 (d, J 8.8 Hz, 1H, Ar); 8.54 (dd, J 8.4, 1.8 Hz, 1H, Ar); 8.90 (dd, J 4.2, 1.8 Hz, 1H, Ar); 14.38 (bs, 1H, HCl salt). M/Z (M[.sup.35Cl]+H).sup.+: 284.6. Mp: 140-180° C.

Example 111: 5-(6,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0843] ##STR00123##

[0844] Protected intermediate of Example 111 was prepared according to N method 9 step 1 starting from 8-bromo-6,7-difluoroquinoline 27 (125 mg, 0.51 mmol) and compound 7 (251 mg, 0.77 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to afford compound 127 (140 mg, 75%) as a yellow oil. M/Z (M+H).sup.+: 364.1.

[0845] Example 111 was prepared according to method 9 step 2 starting from compound 127 (140 mg, 0.39 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 97/3). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 111 as a beige solid (62 mg, 50%).

[0846] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.47 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.65 (dd, J 8.3, 4.2 Hz, 1H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 8.19 (bs, 2H, NH.sub.2); 8.24 (dd, J 10.8, 9.0 Hz, 1H, Ar); 8.50 (dd, J 8.3, 1.6 Hz, 1H, Ar); 8.89 (dd, J 4.3, 1.6 Hz, 1H, Ar); 14.52 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 286.0. Mp: 150-190° C.

Example 112: 8-(6-amino-2-ethylpyridin-3-yl)-6,7-difluoroquinolin-3-ol (hydrochloride)

[0847] ##STR00124##

[0848] Protected intermediate of Example 112 was prepared according to method 9 step 1 starting from 8-bromo-6,7-difluoroquinolin-3-ol 81 (170 mg, 0.65 mmol) and compound 7 (320 mg, 0.98 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 128 (115 mg) as an orange solid. M/Z (M+H).sup.+: 380.2.

[0849] Example 112 was prepared according to method 9 step 2 starting from compound 128 (115 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 112 as a white solid (30 mg, 14% over 2 steps).

[0850] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39-2.46 (m, 2H, CH.sub.2—CH.sub.3); 6.98 (d, J 9.1 Hz, 1H, Ar); 7.66 (d, J 2.8 Hz, 1H, Ar); 7.82 (d, J 9.1 Hz, 1H, Ar); 8.04 (dd, J 11.4, 8.8 Hz, 1H, Ar); 8.15 (bs, 2H, NH.sub.2); 8.55 (d, J 2.8 Hz, 1H, Ar); 10.72 (bs, 1H, OH); 14.44 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 302.1. Mp: 204-210° C.

Example 113: 6-ethyl-5-(5,6,7,8-tetrahydroacridin-4-yl)pyridin-2-amine (hydrochloride)

[0851] ##STR00125##

[0852] Protected intermediate of Example 113 was prepared according to method 9 step 1 starting from 5-bromo-1,2,3,4-tetrahydroacridine 28 (83 mg, 0.32 mmol) and compound 7 (150 mg, 0.47 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to HCl 80/20) to afford compound 129 (112 mg) as a colorless oil. M/Z (M+H).sup.+: 382.2

[0853] Example 113 was prepared according to method 9 step 2 starting from compound 129 (112 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 113 as a light yellow solid (65 mg, 60% over 2 steps).

[0854] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.3), 1.78-1.94 (m, 4H, 2*CH.sub.2), 2.36-2.47 (m, 2H, CH.sub.2—CH.sub.3), 2.90-3.04 (m, 4H, 2*CH.sub.2), 6.94 (d, J 9.1 Hz, 1H, Ar), 7.60-7.68 (m, 2H, Ar), 7.79 (d, J 9.1 Hz, 1H, Ar), 8.00 (t, J 4.5 Hz, 1H, Ar), 8.04 (bs, 2H, NH.sub.2), 8.23 (bs, 1H, Ar), 14.28 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 304.1. Mp: 160-172° C.

Example 114: 6-ethyl-5-(2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridin-6-yl)pyridin-2-amine (dihydrochloride)

[0855] ##STR00126##

[0856] Protected intermediate of Example 114 was prepared according to method 9 step 1 starting from 6-bromo-2-methyl-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine 29 (110 mg, 0.40 mmol) and compound 7 (194 mg, 0.60 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10) to afford compound 130 (150 mg) as a colorless oil. M/Z (M+H).sup.+: 397.3

[0857] Example 114 was prepared according to method 9 step 2 starting from compound 130 (150 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 80/20). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 114 as a yellow solid (102 mg, 44% over 2 steps).

[0858] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.12 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.36-2.46 (m, 2H, CH.sub.2—CH.sub.3), 2.95 (d, J 4.4 Hz, 3H, N—CH.sub.3), 3.17 (dt, J 17.5, 3.2 Hz, 1H, CH.sub.2), 3.38-3.60 (m, 2H, CH.sub.2), 3.72-3.81 (m, 1H, CH.sub.2), 4.53 (dd, J 15.6, 8.4 Hz, 1H, N—CH.sub.2), 4.73 (d, J 15.6 Hz, 1H, N—CH.sub.2), 6.95 (d, J 9.0 Hz, 1H, Ar), 7.65-7.74 (m, 2H, Ar), 7.80 (d, J 9.0 Hz, 1H, Ar), 8.07 (dd, J 7.7, 1.9 Hz, 1H, Ar), 8.12 (bs, 2H, NH.sub.2), 8.34 (s, 1H, Ar), 11.56-11.94 (m, 1H, HCl salt), 14.52 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 319.1. Mp: 197-211° C.

Example 115: 5-(2,3-dihydro-1H-cyclopenta[b]quinolin-5-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0859] ##STR00127##

[0860] Protected intermediate of Example 115 was prepared according to method 9 step 1 starting from 5-bromo-2,3-dihydro-1H-cyclopenta[b]quinoline 30 (130 mg, 0.52 mmol) and compound 7 (256 mg, 0.79 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 131 (215 mg) as a colorless oil. M/Z (M+H).sup.+: 368.2.

[0861] Example 115 was prepared according to method 9 step 2 starting from compound 131 (215 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 115 as a yellow solid (127 mg, 74% over 2 steps).

[0862] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.10 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.13 (qt, J 7.5 Hz, 2H, CH.sub.2—CH.sub.2—CH.sub.2); 2.35-2.47 (m, 2H, CH.sub.2—CH.sub.3); 3.00 (t, J 7.5 Hz, 2H, Ar—CH.sub.2—CH.sub.2); 3.08 (t, J 7.5 Hz, 2H, Ar—CH.sub.2—CH.sub.2); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.59-7.66 (m, 2H, Ar); 7.79 (d, J 9.0 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.01 (dd, J 6.5, 2.9 Hz, 1H, Ar); 8.25 (s, 1H, Ar); 14.17 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 290.1. Mp: 153-169° C.

Example 116: 6-ethyl-5-(2-phenylquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0863] ##STR00128##

[0864] Protected intermediate of Example 116 was prepared according to method 9 step 1 starting from 8-bromo-2-phenylquinoline 31 (162 mg, 0.57 mmol) and compound 7 (279 mg, 0.85 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 0/100) to afford compound 132 (140 mg, 61%) as a colorless oil. M/Z (M+H).sup.+: 404.1

[0865] Example 116 was prepared according to method 9 step 2 starting from compound 132 (140 mg, 0.35 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 116 as a beige solid (40 mg, 35%).

[0866] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.53-2.60 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.44-7.54 (m, 3H, Ar); 7.70 (dd, J 7.6, 7.2 Hz, 1H, Ar); 7.76 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.94 (d, J 9.0 Hz, 1H, Ar); 8.05 (bs, 2H, NH.sub.2); 8.08-8.14 (m, 3H, Ar), 8.23 (d, J 8.6 Hz, 1H, Ar); 8.26 (d, J 8.6 Hz, 1H, Ar); 14.30 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 326.2.

Example 117: 6-ethyl-5-(2-(pyridin-3-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0867] ##STR00129##

[0868] Protected intermediate of Example 117 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyridin-3-yl)quinoline 32 (156 mg, 0.55 mmol) and compound 7 (268 mg, 0.82 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 0/100 then DCM/EtOAc: 100/0 to 25/75) to afford compound 133 (50 mg) as a colorless oil. M/Z (M+H).sup.+: 405.1

[0869] Example 117 was prepared according to method 9 step 2 starting from compound 133 (50 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 117 as a beige solid (20 mg, 10% over 2 steps).

[0870] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.53-2.60 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.72-7.79 (m, 2H, Ar); 7.81 (dd, J 7.1, 1.6 Hz, 1H, Ar); 7.96 (d, J 9.0 Hz, 1H, Ar); 8.05 (bs, 2H, NH.sub.2); 8.17 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.35 (d, J 8.7 Hz, 1H, Ar); 8.63-8.70 (m, 2H, Ar); 8.77 (dd, J 5.0, 1.6 Hz, 1H, Ar); 9.33 (d, J 1.6 Hz, 1H, Ar); 14.20 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 327.2.

Example 118: 5-(2-cyclohexylquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0871] ##STR00130##

[0872] Protected intermediate of Example 118 was prepared according to method 9 step 1 starting from 8-bromo-2-cyclohexylquinoline 33 (160 mg, 0.55 mmol) and compound 7 (271 mg, 0.83 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/EtOAc: 100/0 to 25/75) to afford compound 134 (140 mg, 62%) as a colorless oil. M/Z (M+H).sup.+: 410.3 N NH.sub.2

[0873] Example 118 was prepared according to method 9 step 2 starting from compound 134 (140 mg, 0.34 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 80/20 to 40/60). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 118 as a light yellow solid (40 mg, 32%).

[0874] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.3); 1.14-1.27 (m, 1H, CHaHb); 1.30-1.53 (m, 4H, 2*CH.sub.2); 1.64-1.72 (m, 1H, CHaHb); 1.72-1.80 (m, 2H, CH.sub.2); 1.81-1.89 (m, 2H, CH.sub.2); 2.53-2.62 (m, 2H, CH.sub.2—CH.sub.3); 2.75-2.84 (m, 1H, CH); 6.90 (d, J 9.0 Hz, 1H, Ar); 7.54 (d, J 8.6 Hz, 1H, Ar); 7.60-7.71 (m, 2H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 8.04 (dd, J 7.8, 1.5 Hz, 1H, Ar); 8.37 (d, J 8.6 Hz, 1H, Ar); 14.14 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 332.3. Mp: 137-142° C.

Example 119: 6-ethyl-5-(2-(pyridin-2-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0875] ##STR00131##

[0876] Protected intermediate of Example 119 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyridin-2-yl)quinoline 35 (195 mg, 0.68 mmol) and compound 7 (385 mg, 1.03 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 0/100, then DCM/EtOAc: 100/0 to 50/50) to afford compound 135 (110 mg, 40%) as a yellow oil. M/Z (M+H).sup.+: 405.3

[0877] Example 119 was prepared according to method 9 step 2 starting from compound 135 (110 mg, 0.27 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 119 as a light yellow solid (25 mg, 28%).

[0878] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.5 Hz, 3H, CH.sub.3); 2.53-2.62 (m, 2H, CH.sub.2); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.51 (ddd, J 7.6, 4.9, 1.2 Hz, 1H, Ar); 7.73-7.82 (m, 2H, Ar); 7.93-8.01 (m, 2H, Ar); 8.05 (bs, 2H, NH.sub.2); 8.16 (dd, J 8.0, 1.6 Hz, 1H, Ar); 8.20 (d, J 8.0 Hz, 1H, Ar); 8.58-865 (m, 2H, Ar); 8.73-8.77 (m, 1H, Ar); 14.24 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 327.2. Mp: 111-116° C.

Example 120: 6-ethyl-5-(2-(1-methylcyclopropyl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0879] ##STR00132##

[0880] Protected intermediate of Example 120 was prepared according to method 9 step 1 starting from 8-bromo-2-(1-methylcyclopropyl)quinoline 34 (140 mg, 0.53 mmol) and compound 7 (261 mg, 0.80 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/DCM: 100/0 to 0/100) to afford compound 136 (160 mg, 79%) as a colorless oil. M/Z (M+H).sup.+: 382.2

[0881] Example 120 was prepared according to method 9 step 2 starting from compound 136 (160 mg, 0.42 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90110). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 80/20 to 40/60). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 120 as a light yellow solid (28 mg, 53%).

[0882] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.84 (d, J 2.8 Hz, 2H, CH.sub.2—CH.sub.2); 1.03 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.06-1.15 (m, 2H, CH.sub.2—CH.sub.2); 1.48 (s, 3H, CH.sub.3); 2.53-2.62 (m, 2H, CH.sub.2—CH.sub.3); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.53 (d, J 8.7 Hz, 1H, Ar); 7.60 (dd, J 7.9, 7.3 Hz, 1H, Ar); 7.68 (dd, J 6.9, 1.5 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.94 (bs, 2H, NH.sub.2); 8.02 (dd, J 8.2, 1.5 Hz, 1H, Ar); 8.33 (d, J 8.7 Hz, 1H, Ar); 14.11 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 304.2. Mp: 90-95° C.

Example 121: 6-ethyl-5-(2-(tetrahydro-2H-pyran-4-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0883] ##STR00133##

[0884] Protected intermediate of Example 121 was prepared according to method 9 step 1 starting from 8-bromo-2-(tetrahydro-2H-pyran-4-yl)quinoline 36 (100 mg, 0.34 mmol) and compound 7 (148 mg, 0.51 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 0/100) to afford compound 137 (70 mg, 50%) as a colorless oil. M/Z (M+H).sup.+: 382.2

[0885] Example 121 was prepared according to method 9 step 2 starting from compound 137 (70 mg, 0.17 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 121 as a light yellow solid (25 mg, 39%).

[0886] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 1.64-1.79 (m, 4H, 2*CH.sub.2—CH); 2.40-2.48 (m, 2H, CH.sub.2—CH.sub.3); 3.02-3.12 (m, 1H, CH); 3.44 (td, J 11.2, 3.0 Hz, 2H, 2*CHaHb-O); 3.87-3.95 (m, 2H, 2*CHaHb-O); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.57 (d, J 8.5 Hz, 1H, Ar); 7.61-7.73 (m, 2H, Ar); 7.84 (d, J 9.0 Hz, 1H, Ar); 8.05 (dd, J 7.8, 1.6 Hz, 1H, Ar); 8.07 (bs, 2H, NH.sub.2); 8.40 (d, J 8.6 Hz, 1H, Ar); 14.36 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 334.2. Mp: 175-185.

Example 122: 6-ethyl-5-(2-(pyridin-4-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0887] ##STR00134##

[0888] Protected intermediate of Example 122 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyridin-4-yl)quinoline 37 (130 mg, 0.46 mmol) and compound 7 (223 mg, 0.68 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 138 (230 mg) as a yellow oil. M/Z (M+H).sup.+: 405.3.

[0889] Example 122 was prepared according to method 9 step 2 starting from compound 138 (230 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained foam was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 122 as a light yellow solid (130 mg, 79% over 2 steps).

[0890] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.55-2.62 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.81-7.87 (m, 2H, 2*Ar); 7.94 (d, J 9.0 Hz, 1H, Ar); 8.15 (bs, 2H, NH.sub.2); 8.22 (dd, J 7.7, 2.0 Hz, 1H, Ar); 8.44 (d, J 6.4 Hz, 2H, 2*Ar); 8.50 (d, J 8.7 Hz, 1H, Ar); 8.76 (d, J 8.7 Hz, 1H, Ar); 8.95 (d, J 6.4 Hz, 2H, 2*Ar); 14.47 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 327.2. Mp>250° C.

Example 123: 6-ethyl-5-(2-(imidazo[1,2-a]pyridin-6-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0891] ##STR00135##

[0892] Protected intermediate of Example 123 was prepared according to method 9 step 1 starting from 8-bromo-2-(imidazo[1,2-a]pyridin-6-yl)quinoline 38 (100 mg, 0.31 mmol) and compound 7 (151 mg, 0.46 mmol, 1.5 eq.). The N crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10) to afford compound 139 (135 mg) as a light yellow solid. M/Z (M+H).sup.+: 444.3.

[0893] Example 123 was prepared according to method 9 step 2 starting from compound 139 (135 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtain solid was triturated in H.sub.2O (6 mL) and filtered. The obtained solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried and then triturated in CyHex (15 mL) to afford Example 123 as a light yellow solid (50 mg, 39% over 2 steps).

[0894] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.09 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.56-2.64 (m, 2H, CH.sub.2—CH.sub.3); 7.02 (d, J 9.0 Hz, 1H, Ar); 7.77-7.84 (m, 2H, 2*Ar); 7.95 (d, J 9.0 Hz, 1H, Ar); 8.09 (d, J 9.5 Hz, 1H, Ar); 8.13 (bs, 2H, NH.sub.2); 8.18 (d, J 8.0 Hz, 1H, Ar); 8.21 (d, J 1.1 Hz, 1H, Ar); 8.30 (d, J 8.6 Hz, 1H, Ar); 8.39 (d, J 1.1 Hz, 1H, Ar); 8.46 (d, J 9.6 Hz, 1H, Ar); 8.72 (d, J 8.6 Hz, 1H, Ar); 9.71 (s, 1H, Ar); 14.48 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 366.2. Mp: 70-75° C.

Example 124: 6-ethyl-5-(2-(pyrimidin-5-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride) & Example 125: 6-ethyl-5-(2-(isoxazol-4-yl)quinolin-8-yl)pyridin-2-amine

[0895] ##STR00136##

[0896] Protected intermediate of Example 124 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyrimidin-5-yl)quinoline 39 (120 mg, 0.42 mmol) and compound 7 (205 mg, 0.63 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 140 (150 mg) as a light yellow solid. M/Z (M+H).sup.+: 406.3.

[0897] Example 124 & Example 125 was prepared according to method 9 step 2 starting from compound 140 (150 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The first obtained compound was triturated in CyHex (15 mL), then dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 124 as a yellow solid (20 mg, 13% over 2 steps). The second obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried. The desired was unstable in this condition. The product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). Combined clean fractions were basified with NaHCO.sub.3 sat. until pH ˜8. The aqueous layer was extracted with EtOAc (2×50 mL). Combined organic layers were dried over sodium sulfate and concentrated to afford Example 125 as a white solid (20 mg, 15% over 2 steps).

[0898] Example 124: .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.55-2.63 (m, 2H, CH.sub.2—CH.sub.3); 7.00 (d, J 9.0 Hz, 1H, Ar); 7.77 (t, J 7.5 Hz, 1H, Ar); 7.83 (dd, J 7.5, 1.5 Hz, 1H, Ar); 7.97 (d, J 9.0 Hz, 1H, Ar); 8.01 (bs, 2H, NH.sub.2); 8.17 (dd, J 7.5, 1.5 Hz, 1H, Ar); 8.38 (d, J 8.7 Hz, 1H, Ar); 8.68 (d, J 8.7 Hz, 1H, Ar); 9.28 (s, 1H, Ar); 9.45 (s, 2H, 2*Ar); 14.10 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 328.2. Mp: 115-120° C.

##STR00137##

[0899] Example 125: .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.97 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.27-2.31 (m, 2H, CH.sub.2—CH.sub.3); 5.86 (bs, 2H, NH.sub.2); 6.40 (d, J 8.3 Hz, 1H, Ar); 7.28 (d, J 8.3 Hz, 1H, Ar); 7.62-7.64 (m, 2H, 2*Ar); 7.94-7.97 (m, 2H, 2*Ar); 8.48 (d, J 8.6 Hz, 1H, Ar); 8.81 (s, 1H, Ar); 9.55 (s, 1H, Ar). M/Z (M+H).sup.+: 317.1. Mp: 178-182° C.

Example 126: 6-ethyl-5-(2-(pyrazin-2-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0900] ##STR00138##

[0901] Protected intermediate of Example 126 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyrazin-2-yl)quinoline 40 (120 mg, 0.42 mmol) and compound 7 (205 mg, 0.63 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to HCl 80/20) to afford compound 141 (180 mg) as a light yellow solid. M/Z (M+H).sup.+: 406.3.

[0902] Example 126 was prepared according to method 9 step 2 starting from compound 141 (180 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). 1M HCl (3 mL) was added to the combined clean fractions and freeze dried to afford Example 126 as a white solid (65 mg, 43% over 2 steps).

[0903] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.55-2.63 (m, 2H, CH.sub.2—CH.sub.3); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.79 (t, J 7.5 Hz, 1H, Ar); 7.84 (dd, J 7.5, 1.6 Hz, 1H, Ar); 7.97 (d, J 9.0 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.19 (dd, J 7.5, 1.6 Hz, 1H, Ar); 8.54 (d, J 8.6 Hz, 1H, Ar); 8.68 (d, J 8.6 Hz, 1H, Ar); 8.75 (d, J 2.5 Hz, 1H, Ar); 8.80 (dd, J 2.6, 1.5 Hz, 1H, Ar); 9.34 (d, J 1.5 Hz, 1H, Ar); 14.08 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 328.2. Mp>250° C.

Example 127: 6-ethyl-5-(2-(4-methylpyridin-3-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0904] ##STR00139##

[0905] Protected intermediate of Example 127 was prepared according to method 9 step 1 starting from 8-bromo-2-(4-methylpyridin-3-yl)quinoline 41 (120 mg, 0.40 mmol) and compound 7 (196 mg, 0.60 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 142 (170 mg) as a light yellow oil. M/Z (M+H).sup.+: 419.3.

[0906] Example 127 was prepared according to method 9 step 2 starting from compound 142 (170 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/05). The obtained compound was triturated in H.sub.2O (15 mL), then dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 127 as a white solid (65 mg, 42% over 2 steps).

[0907] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 2.47 (s, 3H, CH.sub.3); 2.53-2.64 (m, 2H, CH.sub.2—CH.sub.3); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.78-7.84 (m, 3H, 3*Ar); 7.89 (d, J 9.0 Hz, 1H, Ar); 8.00 (d, J 8.6 Hz, 1H, Ar); 8.03 (bs, 2H, NH.sub.2); 8.22 (dd, J 7.7, 1.8 Hz, 1H, Ar); 8.69 (d, J 8.6 Hz, 1H, Ar); 8.73 (d, J 5.7 Hz, 1H, Ar); 8.92 (s, 1H, Ar); 14.33 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 341.2. Mp: 180-188° C.

Example 128: 6-ethyl-5-(2-(2-methylpyridin-3-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0908] ##STR00140##

[0909] Protected intermediate of Example 128 was prepared according to method 9 step 1 starting from 8-bromo-2-(2-methylpyridin-3-yl)quinoline 42 (120 mg, 0.40 mmol) and compound 7 (196 mg, 0.60 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 143 (210 mg) as a yellow oil. M/Z (M+H).sup.+: 419.3.

[0910] Example 128 was prepared according to method 9 step 2 starting from compound 143 (210 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained compound was triturated in CyHex (10 mL), then dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 128 as a white solid (85 mg, 57% over 2 steps).

[0911] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.6 Hz, CH.sub.2—CH.sub.3); 2.54-2.60 (m, 2H, CH.sub.2—CH.sub.3); 2.62 (s, 3H, CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.78-7.84 (m, 3H, 3*Ar); 7.88 (d, J 9.0 Hz, 1H, Ar); 7.98 (d, J 8.6 Hz, 1H, Ar); 8.02 (bs, 2H, NH.sub.2); 8.21 (dd, J 8.0, 1.9 Hz, 1H, Ar); 8.45-8.47 (m, 1H, Ar); 8.69 (d, J 8.6 Hz, 1H, Ar); 8.73 (dd, J 5.3, 1.0 Hz, 1H, Ar); 14.28 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 341.2. Mp: 200-205° C.

Example 129: 6-ethyl-5-(2-morpholinoquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0912] ##STR00141##

[0913] Protected intermediate of Example 129 was prepared according to method 9 step 1 starting from 4-(8-bromoquinolin-2-yl)morpholine 43 (150 mg, 0.51 mmol) and compound 7 (250 mg, 0.77 mmol, 1.5 eq.). XPhos PdG2 was used instead of SPhos PdG2.

[0914] The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 144 (159 mg, 75%) as an orange solid. M/Z (M+H).sup.+: 413.2 N

[0915] Example 129 was prepared according to method 9 step 2 starting from compound 144 (159 mg, 0.39 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 60/40). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 129 as a white solid (53 mg, 37%).

[0916] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.52-2.55 (m, 2H, CH.sub.2—CH.sub.3); 3.49 (t, J 4.8 Hz, 4H, 2*N—CH.sub.2); 3.65 (t, J 4.8 Hz, 4H, 2*O—CH.sub.2); 6.90 (d, J 9.0 Hz, 1H, Ar); 7.28 (d, J 9.2 Hz, 1H, Ar); 7.33 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.50 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.82 (dd, J 8.0, 1.5 Hz, 1H, Ar); 7.83 (d, J 9.0 Hz, 1H, Ar); 7.87 (bs, 2H, NH.sub.2); 8.15 (d, J 9.2 Hz, 1H, Ar); 13.91 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 335.1. Mp: 100-150° C.

Example 130: 6-ethyl-5-(2-(2-morpholinoethoxy)quinolin-8-yl)pyridin-2-amine (dihydrochloride)

[0917] ##STR00142##

[0918] Protected intermediate of Example 130 was prepared according to method 9 step 1 starting from 4-(2-((8-bromoquinolin-2-yl)oxy)ethyl)morpholine 44 (150 mg, 0.45 mmol) and compound 7 (218 mg, 0.67 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 10/90) to afford compound 145 (123 mg, 61%) as a yellow oil. M/Z (M+H).sup.+: 457.3.

[0919] Example 130 was prepared according to method 9 step 2 starting from compound 145 (123 mg, 0.27 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and resulting solutions were freeze dried to afford Example 130 as a beige solid (5 mg, 4%).

[0920] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.09 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.52-2.60 (m, 2H, CH.sub.2—CH.sub.3); 3.09-3.19 (m, 2H, O—CH.sub.2—CH.sub.2); 3.42-3.49 (m, 4H, 2*N—CH.sub.2); 3.75-3.82 (m, 2H, O—CH.sub.2); 3.93-3.96 (m, 2H, O—CH.sub.2); 4.55-4.59 (m, 2H, O—CH.sub.2—CH.sub.2); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.13 (d, J 8.8 Hz, 1H, Ar); 7.57 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.67 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.87 (d, J 9.0 Hz, 1H, Ar); 7.96-8.11 (bs, 2H, NH.sub.2); 8.03 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.40 (d, J 8.8 Hz, 1H, Ar); 10.98 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 379.1.

Example 131: 6-ethyl-5-(2-(pyrrolidin-1-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0921] ##STR00143##

[0922] Protected intermediate of Example 131 was prepared according to method 9 step 1 starting from 8-bromo-2-(pyrrolidin-1-yl)quinoline 45 (150 mg, 0.54 mmol) and compound 7 (265 mg, 0.81 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 146 (236 mg) as a colorless oil. M/Z (M+H).sup.+: 397.3.

[0923] Example 131 was prepared according to method 9 step 2 starting from compound 146 (236 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in EtOAc (30 mL) and was washed with H.sub.2O, dried over magnesium sulfate and concentrated. The obtained foam was triturated in Et.sub.2O (5 mL). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 131 as a white solid (99 mg, 52% over 2 steps).

[0924] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, 80° C.) δ: 1.09 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.93-1.96 (m, 4H, CH.sub.2); 2.59 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.40-3.43 (m, 4H, CH.sub.2); 6.91 (d, J 9.0 Hz, 1H, Ar); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.26 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.46 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.77 (dd, J 8.0, 1.4 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.68-7.97 (m, 2H, NH.sub.2); 8.05 (d, J 9.0 Hz, 1H, Ar). HCl salt signal not observed. M/Z (M+H).sup.+: 319.0. Mp>250° C.

Example 132: 5-(2-(4,4-difluoropiperidin-1-yl)quinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0925] ##STR00144##

[0926] Protected intermediate of Example 132 was prepared according to method 9 step 1 starting from 8-bromo-2-(4,4-difluoropiperidin-1-yl)quinoline 46 (150 mg, 0.46 mmol) and compound 7 (224 mg, 0.69 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20). The obtain foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 80/20) to afford compound 147 (143 mg, 70%) as a transparent oil. M/Z (M+H).sup.+: 447.3.

[0927] Example 132 was prepared according to method 9 step 2 starting from compound 147 (143 mg, 0.32 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtained foam was triturated with Et.sub.2O (10 mL). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 132 as a white solid (85 mg, 66%).

[0928] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.91-1.98 (m, 4H, 2*CH.sub.2); 2.54-2.61 (m, 2H, CH.sub.2—CH.sub.3); 3.71 (t, J 5.4 Hz, 4H, 2*N—CH.sub.2); 6.91 (d, J 9.0 Hz, 1H, Ar); 7.35 (t, J 7.6 Hz, 1H, Ar); 7.39 (d, J 9.2 Hz, 1H, Ar); 7.52 (dd, J 7.2, 1.4 Hz, 1H, Ar); 7.82-7.89 (m, 4H, Ar+NH.sub.2); 8.17 (d, J 9.2 Hz, 1H, Ar); 13.99 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 369.1. Mp: 120-141° C.

Example 133: 5-(2-(1,4-oxazepan-4-yl)quinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0929] ##STR00145##

[0930] Protected intermediate of Example 133 was prepared according to method 9 step 1 starting from 4-(8-bromoquinolin-2-yl)-1,4-oxazepane 47 (125 mg, 0.41 mmol) and compound 7 (199 mg, 0.61 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 148 (138 mg, 79%) as a pink oil. M/Z (M+H).sup.+: 427.2.

[0931] Example 133 was prepared according to method 9 step 2 starting from compound 148 (138 mg, 0.32 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 50/50). The obtain compound was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated in Et.sub.2O (10 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 133 as a beige solid (28 mg, 23%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, 80° C.) δ: 1.04 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.77-1.80 (m, 2H, CH.sub.2); 3.51-3.55 (m, 4H, 2*N—CH.sub.2); 3.61-3.63 (m, 2H, CH.sub.2); 3.68-3.71 (m, 4H, 2*O—CH.sub.2); 6.89 (d, J 9.0 Hz, 1H, Ar); 7.17 (d, J 9.2 Hz, 1H, Ar); 7.27 (dd, J 8.0, 7.2 Hz, 1H, Ar); 7.48 (dd, J 7.2, 1.5 Hz, 1H, Ar); 7.78 (dd, J 8.0, 1.5 Hz, 1H, Ar); 7.82 (d, J 9.0 Hz, 1H, Ar); 7.89 (bs, 2H, NH.sub.2); 8.09 (d, J 9.2 Hz, 1H, Ar); 14.09 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 349.2. Mp: 50-90° C.

Example 134: 6-ethyl-5-(7-fluoro-2-(1,4-oxazepan-4-yl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0932] ##STR00146##

[0933] Protected intermediate of Example 134 was prepared according to method 9 step 1 starting from 4-(8-bromo-7-fluoroquinolin-2-yl)-1,4-oxazepane 53 (125 mg, 0.38 mmol) and compound 7 (199 mg, 0.61 mmol, 1.6 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford 149 (107 mg, 63%) as an orange oil. M/Z (M+H).sup.+: 445.2.

[0934] Example 134 was prepared according to method 9 step 2 starting from compound 149 (107 mg, 0.24 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 97/03). The obtain compound was further purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The product was solubilized in EtOAc (20 mL), washed with H.sub.2O (2×30 mL), brine (30 mL) and dried over magnesium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 134 as a beige solid (24 mg, 25%). .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.02 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.74-1.79 (m, 2H, CH.sub.2); 2.42-2.48 (m, 2H, CH.sub.2—CH.sub.3); 3.48-3.55 (m, 2H, N—CH.sub.2); 3.61-3.65 (m, 2H, N—CH.sub.2); 3.67-3.76 (m, 4H, 2*O—CH.sub.2); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.14 (d, J 9.2 Hz, 1H, Ar); 7.20 (t, J 9.2 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.86 (dd, J 8.9, 6.6 Hz, 1H, Ar); 8.00 (bs, 2H, NH.sub.2); 8.10 (d, J 9.2 Hz, 1H, Ar); 14.26 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 367.1. Mp: 100-150° C.

Example 135: 6-ethyl-5-(7-fluoro-2-morpholinoquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0935] ##STR00147##

[0936] Protected intermediate of Example 135 was prepared according to method 9 step 1 starting from 4-(8-bromo-7-fluoroquinolin-2-yl)morpholine 54 (125 mg, 0.40 mmol) and compound 7 (197 mg, 0.60 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 150 (201 mg) as a transparent oil. M/Z (M+H).sup.+: 431.2.

[0937] Example 135 was prepared according to method 9 step 2 starting from compound 150 (201 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 97/3). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 135 as a white solid (83 mg, 53% over 2 steps).

[0938] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.42-2.48 (m, 2H, CH.sub.2—CH.sub.3); 3.49-3.52 (m, 4H, 2*N—CH.sub.2); 3.63-3.65 (m, 4H, 2*O—CH.sub.2); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.23-7.29 (m, 2H, Ar); 7.79 (d, J 9.0 Hz, 1H, Ar); 7.90 (dd, J 8.8, 6.5 Hz, 1H, Ar); 7.98 (bs, 2H, NH.sub.2); 8.16 (d, J 9.2 Hz, 1H, Ar); 14.13 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 353.2. Mp: 100-146° C.

Example 136: 5-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0939] ##STR00148##

[0940] Protected intermediate of Example 136 was prepared according to method 9 step 1 starting from 3-(8-bromo-7-fluoroquinolin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

[0941] 55 (125 mg, 0.37 mmol) and compound 7 (181 mg, 0.56 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 151 (192 mg) as a transparent oil. M/Z (M+H).sup.+: 457.3.

[0942] Example 136 was prepared according to method 9 step 2 starting from compound 151 (192 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 99/1). The product was dissolved in HCl 1M (30 mL) and was washed with Et.sub.2O (2×40 mL). The aqueous layer was basified with NaOH 6M and was extracted with Et.sub.2O (2×40 mL), dried over magnesium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried and triturated twice in Et.sub.2O (2 mL) to afford Example 136 as a white solid (41 mg, 27% over 2 steps).

[0943] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.58-1.67 (m, 2H, CH.sub.2); 1.77-1.81 (m, 2H, CH.sub.2); 2.45 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 2.97 (dt, J 12.6, 3.0 Hz, 2H, 2*N—CH.sub.aH.sub.b); 3.88 (d, J 12.6 Hz, 2H, 2*N—CH.sub.aH.sub.b); 4.39 (d, J 3.1 Hz, 2H, 2*CH); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.15 (d, J 9.2 Hz, 1H, Ar); 7.24 (t, J 9.0 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.88 (dd, J 8.9, 6.6 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 8.13 (d, J 9.2 Hz, 1H, Ar); 14.07 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 379.2. Mp: 140-172° C.

Example 137: 5-(2-(azepan-1-yl)-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0944] ##STR00149##

[0945] Protected intermediate of Example 137 was prepared according to method 9 step 1 starting from 2-(azepan-1-yl)-8-bromo-7-fluoroquinoline 56 (125 mg, 0.39 mmol) and compound 7 (189 mg, 0.58 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 152 (165 mg) as a transparent oil. M/Z (M+H).sup.+: 443.2

[0946] Example 137 was prepared according to method 9 step 2 starting from compound 152 (165 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 99/01). The obtain foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 137 as a white solid (75 mg, 48% over 2 steps).

[0947] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.01 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.41 (m, 4H, 2*CH.sub.2); 1.61 (m, 4H, 2*CH.sub.2); 2.46 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 3.55-3.59 (m, 4H, 2*N—CH.sub.2); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.06 (d, J 9.2 Hz, 1H, Ar); 7.17 (t, J 9.0 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.83 (dd, J 9.0, 6.7 Hz, 1H, Ar); 7.96 (bs, 2H, NH.sub.2); 8.06 (d, J 9.2 Hz, 1H, Ar); 14.18 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 365.2. Mp: 110-145° C.

Example 138: 8-(6-amino-2-ethylpyridin-3-yl)-N-cyclohexyl-N-ethyl-7-fluoroquinolin-2-amine (hydrochloride)

[0948] ##STR00150##

[0949] Protected intermediate of Example 138 was prepared according to method 9 step 1 starting from 8-bromo-N-cyclohexyl-N-ethyl-7-fluoroquinolin-2-amine 57 (132 mg, 0.38 mmol) and compound 7 (184 mg, 0.56 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 153 (173 mg) as an orange oil. M/Z (M+H).sup.+: 471.3 N NH.sub.2

[0950] Example 138 was prepared according to method 9 step 2 starting from compound 153 (173 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/2). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 138 as a white solid (71 mg, 44% over 2 steps).

[0951] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, 80° C.) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.08 (t, J 6.9 Hz, 3H, N—CH.sub.2—CH.sub.3); 1.12-1.24 (m, 2H, CH.sub.2); 1.45-1.54 (m, 2H, CH.sub.2); 1.59-1.64 (m, 2H, CH.sub.2); 1.75-1.78 (m, 2H, CH.sub.2); 2.45-2.47 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.53-2.55 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 3.38-3.42 (m, 4H, 2*CH.sub.2); 4.15 (tt, J 11.8, 3.6 Hz, 1H, CH.sub.2—CH—CH.sub.2); 6.98 (dd, J 9.0, 2.2 Hz, 2H, Ar); 7.13 (t, J 9.0 Hz, 1H, Ar); 7.76 (d, J 9.0 Hz, 1H, Ar); 7.81 (dd, J 8.8, 6.6 Hz, 1H, Ar); 7.91 (bs, 2H, NH.sub.2); 8.03 (d, J 9.2 Hz, 1H, Ar); HCl salt signal not observed. M/Z (M+H).sup.+: 393.3. Mp: 160-210° C.

Example 139: 8-(6-amino-2-ethylpyridin-3-yl)-N-ethyl-7-fluoro-N-isopropylquinolin-2-amine (hydrochloride)

[0952] ##STR00151##

[0953] Protected intermediate of Example 139 was prepared according to method 9 step 1 starting from 8-bromo-N-ethyl-7-fluoro-N-isopropylquinolin-2-amine 58 (132 mg, 0.42 mmol) and compound 7 (208 mg, 0.64 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 85/15) to afford compound 154 (159 mg) as an orange oil. M/Z (M+H).sup.+: 431.2

[0954] Example 139 was prepared according to method 9 step 2 starting from compound 154 (159 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtain product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 80/20 to 40/60). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 139 as a white solid (68 mg, 41% over 2 steps).

[0955] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.03 (m, 6H, 2*CH.sub.2—CH.sub.3); 1.10 (dd, J 6.7, 1.8 Hz, 6H, 2*CH.sub.3); 2.42-2.48 (m, 2H, CH.sub.2—CH.sub.3); 3.35 (qd, J 7.0, 1.2 Hz, 2H); 4.50 (quint, J 6.7 Hz, 1H, CH.sub.3—CH—CH.sub.3); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.04 (d, J 9.4 Hz, 1H, Ar); 7.17 (t, J 9.0 Hz, 1H, Ar); 7.80 (d, J 9.0 Hz, 1H, Ar); 7.83 (dd, J 8.9, 6.6 Hz, 1H, Ar); 8.01 (bs, 2H, NH.sub.2); 8.08 (d, J 9.2 Hz, 1H, Ar); 14.33 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 353.2. Mp: 214-229° C.

Example 140: 8-(6-amino-2-ethylpyridin-3-yl)-N,N-dimethylquinoline-2-carboxamide (hydrochloride)

[0956] ##STR00152##

[0957] Protected intermediate of Example 140 were prepared according to method 9 step 1 starting from 8-bromo-N,N-dimethylquinoline-2-carboxamide 59 (150 mg, 0.54 mmol) and compound 7 (263 mg, 0.81 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 65/35) to afford compound 155 (200 mg, 93%) as a colorless oil. M/Z (M+H).sup.+: 399.3

[0958] Example 140 was prepared according to method 9 step 2 starting from compound 155 (201 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and resulting solutions were freeze dried to afford Example 140 as a beige solid (79 mg, 45%).

[0959] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ:1.05 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.47 (m, 2H, CH.sub.2—CH.sub.3); 2.89 (s, 3H, N—(CH.sub.3).sub.2); 3.00 (s, 3H, N—(CH.sub.3).sub.2); 6.94 (d, J 8.9 Hz, 1H, Ar); 7.74 (d, J 8.1 Hz, 1H, Ar); 7.76-7.81 (m, 2H, Ar); 7.83 (d, J 9.0 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 8.16 (dd, J 7.1, 2.4 Hz, 1H, Ar); 8.59 (d, J 8.2 Hz, 1H, Ar); 14.10 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 321.0. Mp: 103-113° C.

Example 141: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(pyrrolidin-1-yl)methanone (hydrochloride)

[0960] ##STR00153##

[0961] Protected intermediate of Example 141 was prepared according to method 9 step 1: starting from (8-bromoquinolin-2-yl)(pyrrolidin-1-yl)methanone 60 (125 mg, 0.41 mmol) and compound 7 (200 mg, 0.61 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 156 (150 mg) as a transparent oil. M/Z (M+H).sup.+: 425.3.

[0962] Example 141 was prepared according to method 9 step 2 starting from compound 156 (110 mg). The crude was purified by flash chromatography (KPNH DCM/MeOH: 100/0 to 98/2). The obtain foam was triturated in Et.sub.2O (10 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 141 as a beige solid (79 mg, 50% over 2 steps).

[0963] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz, 80° C.) δ: 1.03 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.75-1.82 (m, 4H, CH.sub.2); 2.35-2.46 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.52-2.54 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 3.45 (t, J 7.6 Hz, 2H, N—CH.sub.2), 3.50 (t, J 7.6 Hz, 2H, N—CH.sub.2); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.77-7.85 (m, 3H, Ar); 7.96 (d, J 8.6 Hz, 1H, Ar); 8.00 (bs, 2H, NH.sub.2); 8.16 (dd, J 7.5, 2.1 Hz, 1H, Ar); 8.59 (d, J 8.6 Hz, 1H, Ar); 14.27 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 347.1. Mp: 100-125° C.

Example 142: 6-ethyl-5-(2-(methoxymethyl)quinolin-8-yl)pyridin-2-amine (hydrochloride)

[0964] ##STR00154##

[0965] Protected intermediate of Example 142 was prepared according to method 9 step 1 starting from 8-bromo-2-(methoxymethyl)quinoline 63 (130 mg, 0.52 mmol) and compound 7 (202 mg, 0.62 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 157 (113 mg, 59%) as a colorless oil. M/Z (M+H).sup.+: 372.2

[0966] Example 142 was prepared according to method 9 step 2 starting from compound 157 (113 mg, 0.30 mmol). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 142 as a white solid (83 mg, 85%).

[0967] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.10 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 2.37-2.47 (m, 2H, CH.sub.2—CH.sub.3); 3.36 (s, 3H, O—CH.sub.3); 4.56 (s, 2H, CH.sub.2-0); 6.94 (d, J 9.2 Hz, 1H, Ar); 7.64 (d, J 8.2 Hz, 1H, Ar); 7.67-7.75 (m, 2H, Ar); 7.82 (d, J 8.9 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.09 (dd, J 7.5, 2.1 Hz, 1H, Ar); 8.48 (d, J 8.3 Hz, 1H, Ar); 14.30 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 294.1. Mp: 210-225° C.

Example 143: 5-(3,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0968] ##STR00155##

[0969] Protected intermediate of Example 143 was prepared according to method 9 step 1 starting from 8-bromo-3,7-difluoroquinoline 70 (110 mg, 0.45 mmol) and compound 7 (221 mg, 0.68 mmol, 1.5 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 158 (144 mg) as a colorless oil. M/Z (M+H).sup.+: 364.2

[0970] Example 143 was prepared according to method 9 step 2 starting from compound 158 (144 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 143 as a white solid (94 mg, 64% over 2 steps).

[0971] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.34-2.46 (m, 2H, CH.sub.2—CH.sub.3), 6.98 (d, J 8.9 Hz, 1H, Ar), 7.76-7.83 (m, 2H, Ar), 8.06 (bs, 2H, NH.sub.2), 8.23 (dd, J 9.2, 6.2 Hz, 1H, Ar), 8.44 (dd, J 9.2, 2.7 Hz, 1H, Ar), 8.96 (d, J 2.7 Hz, 1H, Ar), 14.31 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 286.0. Mp: 245-250° C.

Example 144: 5-(7-chloro-3-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0972] ##STR00156##

[0973] Protected intermediate of Example 144 was prepared according to method 9 step 1 starting from 8-bromo-7-chloro-3-fluoroquinoline 74 (125 mg, 0.48 mmol) and compound 7 (204 mg, 0.62 mmol, 1.3 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 159 (134 mg) as a colorless oil. M/Z (M[.sup.37Cl]+H).sup.+: 382.1

[0974] Example 144 was prepared according to method 9 step 2 starting from compound 159 (134 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 144 as a white solid (76 mg, 46% over 2 steps).

[0975] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.99 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.28-2.36 (m, 2H, CH.sub.2—CH.sub.3); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.74 (d, J 9.0 Hz, 1H, Ar); 7.92 (d, J 8.8 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.18 (d, J 8.8 Hz, 1H, Ar); 8.44 (dd, J 9.1, 2.8 Hz, 1H, Ar); 8.95 (d, J 2.9 Hz, 1H, Ar); 14.15 (bs, 1H, HCl salt). M/Z [(M[.sup.35Cl]+H).sup.+]: 302.0. Mp>250° C.

Example 145: 6-ethyl-5-(3,5,7-trifluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0976] ##STR00157##

[0977] Protected intermediate of Example 145 was prepared according to method 9 step 1 starting from 8-bromo-3,5,7-trifluoroquinoline 78 (110 mg, 0.42 mmol) and compound 7 (178 mg, 0.55 mmol, 1.3 eq.). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 160 (140 mg) as a colorless oil. M/Z (M+H).sup.+: 382.2

[0978] Example 145 was prepared according to method 9 step 2 starting from compound 160 (140 mg), the crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 94/6). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 145 as a white solid (101 mg, 71% over 2 steps).

[0979] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.45 (m, 2H, CH.sub.2—CH.sub.3); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.78 (d, J 9.0 Hz, 1H, Ar); 7.91 (t, J 10.0 Hz, 1H, Ar); 7.99 (bs, 2H, NH.sub.2); 8.48 (dd, J 8.8, 2.9 Hz, 1H, Ar); 9.04 (d, J 2.9 Hz, 1H, Ar); 14.12 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 304.0. Mp: 110-120° C.

Example 146: 5-(3-chloro-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0980] ##STR00158##

[0981] Protected intermediate of Example 146 was prepared according to modified method 12 step 1 from compound 7 (175 mg, 0.54 mmol, 1.1 eq.) and 8-bromo-3-chloro-7-fluoroquinoline 71 (125 mg, 0.48 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 161 (103 mg, 57%) as a yellow oil. M/Z (M[.sup.35Cl]+H).sup.+: 380.1.

[0982] Example 146 was prepared according to method 12 step 2 starting from compound 161 (103 mg, 0.27 mmol). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 97/3). The obtained foam was triturated in Et.sub.2O (5 mL) and pentane (5 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 146 as a white solid (23 mg, 25%).

[0983] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.46 (m, 2H, CH.sub.2—CH.sub.3); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.79-7.83 (m, 2H, Ar); 8.03 (bs, 2H, NH.sub.2); 8.22 (dd, J 9.2, 6.2 Hz, 1H, Ar); 8.75 (d, J 2.5 Hz, 1H, Ar); 8.91 (d, J 2.5 Hz, 1H, Ar); 14.22 (bs, 1H, HCl salt). M/Z (M[.sup.35Cl]+H).sup.+: 302.0. Mp: 145-170° C.

Example 147: 5-(3,7-dichloroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0984] ##STR00159##

[0985] Protected intermediate of Example 147 was prepared according to modified method 12 step I from compound 7 (147 mg, 0.45 mmol, 1.0 eq.) and 8-bromo-3,7-dichloroquinoline 75 (125 mg, 0.45 mmol, 1.0 eq.). The crude residue was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 162 (111 mg) as a white solid. M/Z (M[.sup.37Cl].sub.2+H).sup.+: 399.2

[0986] Example 147 was prepared according to method 12 step 2 starting from compound 162 (111 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92/8). The obtained compound was solubilized in HCl 1N (50 mL) and extracted twice with Et.sub.2O (50 mL). The organic layer was discarded. The aqueous layer was basified with NaOH 6M (25 mL) and extracted thrice with DCM (30 mL). Combined organic layers were dried over sodium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 147 as a white solid (61 mg, 38% over 2 steps).

[0987] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.00 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.28-2.37 (m, 2H, CH.sub.2—CH.sub.3); 6.99 (d, 9.0 Hz, 1H, Ar); 7.75 (d, 9.0 Hz, 1H, Ar); 7.93 (d, 9.0 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.16 (d, 9.0 Hz, 1H, Ar); 8.75 (d, 2.5 Hz, 1H, Ar); 8.90 (d, 2.5 Hz, 1H, Ar); 14.25 (bs, 1H, HCl salt). M/Z [(M[.sup.35Cl].sub.2+H).sup.+: 318.0. Mp: 145-160° C.

Example 148: 5-(3-chloro-5,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[0988] ##STR00160##

[0989] Protected intermediate of Example 148 was prepared according to modified method 12 step 1 from 8-bromo-3-chloro-5,7-difluoroquinoline 79 (110 mg, 0.40 mmol, 1.0 eq.) and compound 7 (142 mg 0.44 mmol, 1.1 eq.) The crude residue was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/DCM: 100/0 to 0/100) to obtain compound 163 (80 mg) as a colorless oil. M/Z (M[.sup.37Cl]+H).sup.+: 400.2

[0990] Example 148 was prepared according to method 12 step 2 starting from compound 163 (80 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 92:08). The obtained compound was solubilized in HCl 1N (50 mL), extracted twice with Et.sub.2O (50 mL). The organic layer was discarded. The aqueous layer was basified with NaOH 6M (25 mL) and extracted thrice with DCM (30 mL). Combined organic layers were dried over sodium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford 148 as a white solid (58 mg, 40% over 2 steps).

[0991] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.45 (m, 2H, CH.sub.2—CH.sub.3); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.78 (d, J 9.0 Hz, 1H, Ar); 7.91 (t, J 10.0 Hz, 1H, Ar); 8.00 (bs, 2H, NH.sub.2); 8.73 (d, J 2.5 Hz, 1H, Ar); 8.99 (d, J 2.5 Hz, 1H, Ar); 14.11 (bs, 1H, HCl salt). M/Z [(M[.sup.35Cl]+H).sup.+]: 320.0. Mp:112-130° C.

Example 149: 5-(3-chloro-6,7-difluoroquinolin-8-yl)-6-ethylpyridin-2-amine hydrochloride

[0992] ##STR00161##

[0993] Protected intermediate of Example 149 was prepared according to modified method 12 step 1 from 8-bromo-3-chloro-6,7-difluoroquinoline 84 (110 mg, 0.40 mmol, 1.0 eq.) and compound 7 (142 mg, 0.44 mmol, 1.1 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to obtain compound 164 (110 mg) as a colorless oil. M/Z (M[.sup.35Cl]+H).sup.+: 398.2.

[0994] Example 149 was prepared according to method 12 step 2 starting from compound 164 (110 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1 N HCL/ACN and the resulting solution was freeze dried to afford Example 149 as a white solid (55 mg, 38% over 2 steps).

[0995] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.37-2.47 (m, 2H, CH.sub.2—CH.sub.3); 6.99 (d, J 9.0 Hz, 1H, Ar); 7.83 (d, J 9.0 Hz, 1H, Ar); 8.12 (bs, 2H, NH.sub.2); 8.20 (dd, J 10.8, 8.9 Hz, 1H, Ar); 8.69 (d, J 2.4 Hz, 1H, Ar); 8.90 (d, J 2.4 Hz, 1H, Ar); 14.30 (bs, 1H, HCl salt).

[0996] M/Z (M[.sup.35Cl]+H).sup.+: 320.0. Mp: 140-150° C.

Example 150: 6-ethyl-5-(3,6,7-trifluoroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[0997] ##STR00162##

[0998] Protected intermediate of Example 150 was prepared according to method 9 step 1 starting from 8-bromo-3,6,7-trifluoroquinoline 83 (120 mg, 0.46 mmol) and compound 7 (224 mg, 0.69 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 75/25) to afford compound 165 (153 mg) as a colorless oil. M/Z (M+H).sup.+: 382.2

[0999] Example 150 was prepared according to method 9 step 2 starting from compound 165 (153 mg). The crude was purified by flash chromatography (15 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 94/6). The obtained foam was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 150 as a white solid (95 mg, 61% over 2 steps).

[1000] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.06 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.37-2.47 (m, 2H, CH.sub.2—CH.sub.3); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.81 (d, J 9.0 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 8.21 (dd, J 10.8, 8.9 Hz, 1H, Ar); 8.40 (dd, J 9.3, 2.8 Hz, 1H, Ar); 8.95 (d, J 2.8 Hz, 1H, Ar); 14.32 (bs, 1H, HCl salt). M/Z (M+H)*304.0. Mp: 120-130° C.

Example 151: 5-(3-bromo-7-fluoroquinolin-8-yl)-6-ethylpyridin-2-amine (hydrochloride)

[1001] ##STR00163##

[1002] Example 151 was prepared according to method 9 step 2 starting from 3-bromo-8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)-7-fluoroquinoline 86 (47 mg, 0.11 mmol, 1.0 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/50). The obtain product was suspended in ACN (2 mL)/H.sub.2O (6 mL) and HCl 1M (2 mL) was added. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 151 (25 mg, 59%) as a light yellow solid.

[1003] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.04 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 2.35-2.44 (m, 2H, CH.sub.2—CH.sub.3); 6.98 (d, J 9.0 Hz, 1H, Ar); 7.77-7.84 (m, 2H, Ar); 8.04 (bs, 2H, NH.sub.2); 8.21 (dd, J 9.2, 6.2 Hz, 1H, Ar); 8.90 (d, J 2.4 Hz, 1H, Ar); 8.96 (d, J 2.4 Hz, 1H, Ar); 14.14 (bs, 1H, HCl salt). M/Z (M[.sup.81Br]+H).sup.+: 348.0.

Example 152: 8-(6-amino-2-ethylpyridin-3-yl)quinoline-7-carboxamide (hydrochloride)

[1004] ##STR00164##

[1005] Protected intermediate of Example 152: In a MW tube under Argon, to a solution of 7-chloro-8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)quinoline 126 (100 mg, 0.28 mmol) in DMA (2.1 mL), zinc cyanide (49 N mg, 0.42 mmol, 1.5 eq.) was added. The reaction mixture was sparged with argon for 10 min and Pd(PtBu.sub.3).sub.2 (14 mg, 0.028 mmol, 0.1 eq.) was added. The reaction mixture was subjected to microwave irradiation at 150° C. for 15 min. The mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (40 mL). The filtrate was hydrolyzed with NaHCO.sub.3 sat. (40 mL) and extracted thrice with EtOAc (40 mL). The organic layers were washed with brine (40 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 166 (90 mg) as a yellow oil. M/Z (M+H).sup.+: 353.2.

[1006] Example 152 was prepared according to method 9 step 2 starting from compound 166 (90.0 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 90/10) to obtain a white solid. The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 152 as a beige solid (18 mg, 19% over 2 steps).

[1007] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.98 (t, J 7.6 Hz, 3H, CH.sub.3); 2.21-2.40 (m, 2H, CH.sub.2); 6.91 (d, J 9.0 Hz, 1H, Ar); 7.49 (bs, 1H, CO—N—H—H); 7.64 (dd, J 8.2, 4.2 Hz, 1H, Ar); 7.70 (d, J 9.0 Hz, 1H, Ar); 7.76 (d, J 8.3 Hz, 1H, Ar); 7.90 (bs, 1H, CO—N—H—H); 7.95 (bs, 2H, NH.sub.2); 8.18 (d, J 8.5 Hz, 1H, Ar); 8.52 (dd, J 8.3, 1.8 Hz, 1H, Ar); 8.90 (dd, J 5.9, 1.8 Hz, 1H, Ar); 14.11 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 293.1. Mp: 150-164° C.

Example 153: 8-(6-amino-2-ethylpyridin-3-yl)quinoline-7-carbonitrile

[1008] ##STR00165##

[1009] Intermediate of Example 153 was prepared according to method 9 step 2 starting from compound 7-chloro-8-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)quinoline 126 (150 mg, 0.42 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 20/80) to obtain 5-(7-chloroquinolin-8-yl)-6-ethylpyridin-2-amine 167 (60 mg, 51%) as a beige solid. M/Z (M[.sup.35Cl]+H).sup.+: 284.1.

[1010] Example 153: In a MW vial under Argon, to a solution of compound 167 (50 mg, 0.18 mmol) in DMA (1.4 mL) was added zinc cyanide (31 mg, 0.26 mmol, 1.5 eq.). The reaction mixture was sparged with argon for 10 min and Pd(PtBu.sub.3).sub.2 (9 mg, 0.02 mmol, 0.1 eq.) was added. The reaction mixture was subjected twice to microwave irradiation at 180° C. for 15 min. Pd(PtBu.sub.3).sub.2 (9.0 mg, 17.6 μmol, 0.1 eq.) was added and the reaction mixture was subjected to microwave irradiation at 150° C. for 15 min. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOAc (40 mL). The filtrate was hydrolyzed with NaHCO.sub.3 sat. (40 mL) and extracted thrice with EtOAc (40 mL). The organic layers were washed with brine (40 mL), dried over magnesium sulfate and concentrated. The organic layer was washed with NaHCO.sub.3 sat. (40 mL), brine (40 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 95/5). The obtain foam was further purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 20/80) to obtain a yellow solid. The obtained solid was triturated twice in Et.sub.2O (3 mL) to afford Example 153 as a yellow solid (18 mg, 16% over 2 steps).

[1011] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.92 (t, J 7.6 Hz, 3H, CH.sub.3); 2.06-2.20 (m, 2H, CH.sub.2); 6.04 (s, 2H, NH.sub.2); 6.41 (d, J 8.3 Hz, 1H, Ar); 7.21 (d, J 8.3 Hz, 1H, Ar); 7.70 (dd, J 8.3, 4.0 Hz, 1H, Ar); 7.97 (d, J 8.6 Hz, 1H, Ar); 8.17 (d, J 8.6 Hz, 1H, Ar); 8.53 (dd, J 8.3, 1.6 Hz, 1H, Ar); 8.96 (dd, J 4.2, 1.8 Hz, 1H, Ar). M/Z (M+H).sup.+: 275.1. Mp: 226-228° C.

Example 154: 8-(6-amino-2-ethylpyridin-3-yl)quinolin-2(1H)-one (hydrochloride)

[1012] ##STR00166##

[1013] Protected intermediate of 154 was prepared according to method 9 step 1 starting from 8-bromoquinolin-2(1H)-one (125 mg, 0.56 mmol) and compound 7 (273 mg, 0.84 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 168 (207 mg) as a light yellow oil. M/Z (M+H).sup.+: 344.2

[1014] Example 154 was prepared according to method 9 step 2 starting from compound 168 (207 mg). The crude was purified by flash chromatography (KPNH, DCM/MeOH: 100/0 to 98/2).

[1015] The obtained product was triturated twice in Et.sub.2O (3 mL), then dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 154 as a white solid (96 mg, 57% over 2 steps).

[1016] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.27-2.36 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.42-2.48 (m, 1H, CH.sub.aH—CH.sub.3); 6.53 (d, J 9.6 Hz, 1H, Ar); 6.91 (d, J 9.0 Hz, 1H, Ar); 7.27 (t, J 7.5 Hz, 1H, Ar); 7.37 (dd, J 7.5, 1.4 Hz, 1H, Ar); 7.66 (d, J 9.0 Hz, 1H, Ar); 7.76 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.98 (d, J 9.6 Hz, 1H, Ar); 7.99 (brs, 2H, NH.sub.2); 10.91 (s, 1H, NH); 14.16 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 266.0. Mp>250° C.

Example 155: 8-(6-amino-2-ethylpyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (hydrochloride)

[1017] ##STR00167##

[1018] In a sealed vial under Argon, a solution of Example 154 (free base, 30 mg, 0.11 mmol) in MeOH (1.0 mL) was sparged with Ar during 10 min before addition of Pd/C (10 wt. %, 10 mg). The reaction mixture was stirred under H.sub.2 atmosphere at 25° C. for 4 days. The mixture was filtered through a pad of Celite® and the cake was washed with MeOH (50 mL). The filtrate was concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/05) The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 155 as a white solid (11 mg, 33%).

[1019] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.13 (t, J 7.5 Hz, 3H, CH.sub.3); 2.49-2.66 (m, 2H, CH.sub.2); 2.67-2.71 (m, 2H, CH.sub.2); 3.09 (t, J 7.7 Hz, 2H, CH.sub.2); 6.96 (d, J 9.0 Hz, 1H, Ar); 7.18-7.25 (m, 2H, Ar); 7.41-7.43 (m, 1H, Ar); 7.72 (d, J 9.0 Hz, 1H, Ar). M/Z (M+H).sup.+: 268.1. Mp: 233-237° C.

Example 156: 8-(6-amino-2-ethylpyridin-3-yl)-1-methylquinolin-2(1H)-one (hydrochloride)

[1020] ##STR00168##

[1021] Protected intermediate of Example 156: Under Argon, to a solution of compound 168 (354 mg, 1.03 mmol, 1 eq.) in THF (15 mL) potassium 2-methylpropan-2-olate (200 mg, 1.78 mmol, 1.7 eq.) and iodomethane (252 mg, 1.78 mmol, 1.7 eq.) were added. The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was hydrolyzed with water (125 mL) and extracted twice with EtOAc (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to obtain compound 169 (313 mg, 85%) as a yellow oil. M/Z (M+H).sup.+: 458.2

[1022] Example 156 was prepared according to method 9 step 2 starting from compound 169 (313 mg, 0.88 mmol, 1 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4) to obtain compound 170 (217 mg, 88%) as white solid. M/Z (M+H).sup.+: 280.0.

[1023] 50 mg of compound 170 were dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 156 as a white solid. M/Z (M+H).sup.+: 280.0.

[1024] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.40-2.60 (m, 2H, CH.sub.2—CH.sub.3); 3.27 (s, 3H, N—CH.sub.3); 6.83 (d, J 9.2 Hz, 1H, CH); 7.03 (d, J 9.2 Hz, 1H, CH); 7.49-7.57 (m, 2H, Ar); 7.89 (dd, J 7.5, 1.9 Hz, 1H, Ar); 7.92 (d, J 9.3 Hz, 1H, Ar); 8.12 (d, J 9.3 Hz, 1H, Ar). NH.sub.2 and HCl salt signals not observed. M/Z (M+H).sup.+: 280.0. Mp: 132-145° C.

Example 157: 8-(6-amino-2-ethylpyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (hydrochloride)

[1025] ##STR00169##

[1026] Under Argon, to a solution of 8-(6-amino-2-ethylpyridin-3-yl)-1-methylquinolin-2(1H)-one 170 (167 mg, 0.60 mmol, 1 eq.) in methanol (5 mL) was sparged sparged with argon for 10 min before addition of palladium on charcoal 10 wt. % (63.6 mg, 0.06 mmol, 0.1 eq.). The reaction mixture was stirred under H.sub.2 atmosphere at 25° C. for 16 h. The mixture was filtered through a pad of Celite® and the cake was washed with MeOH (50 mL). The filtrate was concentrated. The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained product was in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 157 (142 mg, 75%) as a white solid.

[1027] .sup.1H-NMR (DMSO, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.44-2.47 (m, 2H, CH.sub.2—CH.sub.3); 2.52-2.61 (m, 2H, Ar—CH.sub.2); 2.66 (s, 3H, N—CH.sub.3); 2.88 (t, J 6.9 Hz, 2H, C═O—CH.sub.2); 6.93 (d, J 9.1 Hz, 1H, Ar); 7.08 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.16 (t, J 7.6 Hz, 1H, Ar); 7.33 (dd, J 7.3, 1.4 Hz, 1H, Ar); 7.81 (d, J 9.1 Hz, 1H, Ar); 8.00 (bs, 2H, NH.sub.2); 13.92 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 282.1.

Example 158: 8-(6-amino-2-ethylpyridin-3-yl)-7-fluoroquinolin-2(1H)-one (hydrochloride)

[1028] ##STR00170##

[1029] Protected intermediate of Example 158 was prepared according to method 9 step 1 starting from 8-bromo-7-fluoroquinolin-2(1H)-one 48 (125 mg, 0.52 mmol) and compound 7 (253 mg, 0.76 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 171 (185 mg) as a colorless oil. M/Z (M+H).sup.+: 382.2

[1030] Example 158 was prepared according to method 9 step 2 starting from compound 171 (185 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 158 as a white solid (65 mg, 39% over 2 steps).

[1031] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.29-2.38 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.40-2.48 (m, 1H CH.sub.aH.sub.b—CH): 6.49 (d, J 9.6 Hz, 1H, Ar); 6.94 (d, J 9.0 Hz, 1H, Ar); 7.21 (t, J 8.9 Hz, 1H, Ar); 7.69 (d, J 9.0 Hz, 1H, Ar); 7.85 (dd, J 8.9, 6.2 Hz, 1H, Ar); 7.98 (d, J 9.6 Hz, 1H, Ar); 8.06 (bs, 2H, NH.sub.2); 11.07 (s, 1H, NH or OH); 14.27 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 284.1. Mp: 172-208° C.

Example 159: 8-(6-amino-2-ethylpyridin-3-yl)-5,7-difluoroquinolin-2(1H)-one (hydrochloride)

[1032] ##STR00171##

[1033] Protected intermediate of Example 159 was prepared according to method 9 step 1 starting from 8-bromo-5,7-difluoroquinolin-2(1H)-one 49 (157 mg, 0.60 mmol) and compound 7 (295 mg, 0.91 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 172 (106 mg, 46%) as a colorless oil. M/Z (M+H).sup.+: 382.2

[1034] Example 159 was prepared according to method 9 step 2 starting from compound 172 (106 mg, 0.28 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/05). The obtained product was solubilized in HCl 1 N (20 mL) and extracted twice with Et.sub.2O (40 mL). The aqueous layer was basified with NaOH 6N and was extracted thrice with DCM (40 mL). The DCM layers were dried over magnesium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 159 as a white solid (48 mg, 51%).

[1035] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.09 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.31-2.40 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.41-2.47 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.55 (d, J 9.6 Hz, 1H, Ar); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.31 (t, J 9.8 Hz, 1H, Ar); 7.68 (d, J 9.0 Hz, 1H, Ar); 8.02 (d, J 9.6 Hz, 1H, Ar); 8.08 (bs, 2H, NH.sub.2); 11.29 (s, 1H, NH or OH); 14.22 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 302.0. Mp>250° C.

Example 160: 8-(6-amino-2-ethylpyridin-3-yl)-7-chloroquinolin-2(1H)-one (hydrochloride)

[1036] ##STR00172##

[1037] Protected intermediate of Example 160 was prepared according to method 9 step 1 starting from 8-bromo-7-chloroquinolin-2(1H)-one 50 (125 mg, 0.48 mmol) and compound 7 (174 mg, 0.53 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 173 (114 mg) as a yellow oil. M/Z (M[.sup.35Cl]+H).sup.+: 378.2.

[1038] Example 160 was prepared according to method 9 step 2 starting from compound 173 (114 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained product was solubilized in HCl 1N (20 mL) and extracted twice with Et.sub.2O (40 mL). The aqueous layer was basified with NaOH 6N and was extracted thrice with DCM (40 mL). The DCM layers were dried over magnesium sulfate and concentrated. dried over magnesium sulfate and concentrated. The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 160 as a white solid (25 mg, 16% over 2 steps).

[1039] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.08 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.25-2.31 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.34-2.44 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.54 (dd, J 9.6, 1.7 Hz, 1H, Ar); 6.93 (d, J 9.0 Hz, 1H, Ar); 7.43 (d, J 8.4 Hz, 1H, Ar); 7.63 (d, J 9.0 Hz, 1H, Ar); 7.80 (d, J 8.4 Hz, 1H, Ar); 7.99 (d, J 9.6 Hz, 1H, Ar); 8.04 (bs, 2H, NH.sub.2); 11.00 (s, 1H, NH or OH); 14.16 (bs, 1H, HCl salt). M/Z (M[.sup.35Cl]+H).sup.+: 300.0. Mp>250° C.

Example 161: 8-(6-amino-2-ethylpyridin-3-yl)-6,7-difluoroquinolin-2(1H)-one (hydrochloride)

[1040] ##STR00173##

[1041] Protected intermediate of Example 161 was prepared according to method 9 step 1 starting from 8-bromo-6,7-difluoroquinolin-2(1H)-one 51 (125 mg, 0.48 mmol) and compound 7 (235 mg, 0.72 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 40/60) to afford compound 174 (120 mg) as a brown oil. M/Z (M+H).sup.+: 380.1.

[1042] Example 161 was prepared according to method 9 step 2 starting from compound 174 (120 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 91/9). (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 91/9). The obtained product was triturated twice in Et.sub.2O (5 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 161 as a white solid (31 mg, 19% over 2 steps).

[1043] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.10 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.32-2.41 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.42-2.48 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 6.57 (d, J 9.6 Hz, 1H, Ar); 6.95 (d, J 9.0 Hz, 1H, Ar); 7.72 (d, J 9.0 Hz, 1H, Ar); 7.93-7.98 (m, 2H, Ar); 8.11 (bs, 2H, NH.sub.2); 11.13 (s, 1H, NH or OH); 14.27 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 302.0. Mp>250° C.

Example 162: 6-ethyl-5-(1-methylindolin-7-yl)pyridin-2-amine (hydrochloride)

[1044] ##STR00174##

[1045] Protected intermediate of Example 162 was prepared according to method 9 step 1 starting from 7-bromo-1-methylindoline 67 (105 mg, 0.50 mmol) and compound 7 (242 mg, 0.74 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 95/5) to afford compound 175 (125 mg) as a transparent oil. M/Z (M+H).sup.+: 332.2.

[1046] Example 162 was prepared according to method 9 step 2 starting from compound 175 (125 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 162 as a pink solid (80 mg, 57% over 2 steps).

[1047] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.36 (s, 3H, N—CH.sub.3); 2.54-2.61 (m, 2H, CH.sub.2—CH.sub.3); 2.97 (t, J 8.3 Hz, 2H, Ar—CH.sub.2); 3.30-3.40 (m, 2H, N—CH.sub.2); 6.79-6.83 (m, 2H, 2 Ar); 6.90 (d, J 9.0 Hz, 1H, Ar); 7.17 (d, J 6.8 Hz, 1H, Ar); 7.76 (d, J 9.0 Hz, 1H, Ar); 8.05 (bs, 2H, NH.sub.2); 14.90 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 254.1. Mp>250° C.

Example 163: 7-(6-amino-2-ethylpyridin-3-yl)indolin-2-one (hydrochloride)

[1048] ##STR00175##

[1049] Protected intermediate of Example 163 was prepared according to method 9 step 1 starting from 7-bromoindolin-2-one (150 mg, 0.71 mmol) and compound 7 (346 mg, 1.06 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 90/10 to 70/30) to afford compound 176 (200 mg, 85%) as a yellow solid. M/Z (M+H).sup.+: 332.2.

[1050] Example 163 was prepared according to method 9 step 2 starting from compound 176 (100 mg, 0.30 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 90/10). The obtained product was triturated in H.sub.2O (5 mL). The obtained solid was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 163 as a white solid (43 mg, 49%).

[1051] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 2.39-2.47 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 2.54-2.60 (m, 1H, CH.sub.aH.sub.b—CH.sub.3); 3.49-3.62 (m, 2H, CH.sub.2—CO); 6.88 (d, J 9.0 Hz, 1H, Ar); 7.01-7.06 (m, 2H, 2*Ar); 7.26-7.28 (m, 1H, Ar); 7.66 (d, J 9.0 Hz, 1H, Ar); 7.93 (bs, 2H, NH.sub.2); 10.25 (s, 1H, NH); 14.17 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 254.0. Mp>250° C.

Example 164: 6-ethyl-5-(indolin-7-yl)pyridin-2-amine (hydrochloride)

[1052] ##STR00176##

[1053] Protected intermediate of Example 164 was prepared according to method 9 step 1 starting from 7-bromoindoline (120 mg, 0.61 mmol) and compound 7 (297 mg, 0.91 mmol, 1.5 eq.). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 177 (165 mg) as a light yellow solid. M/Z (M+H).sup.+: 318.2

[1054] Example 164 was prepared according to method 9 step 2 starting from compound 177 (165 mg). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 95/05 to 55/45). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 164 as a white solid (75 mg, 45% over 2 steps).

[1055] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.19 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 2.57-2.66 (m, 2H, CH.sub.2—Ar); 3.39 (t, J 7.8 H, 2H, CH.sub.2—CH.sub.3); 3.83 (m, 2H, CH.sub.2—NH); 6.98 (d, J 9.1 Hz, 1H, Ar); 7.33 (d, J 7.1 Hz, 1H, Ar); 7.50 (t, J 7.7 Hz, 1H, Ar); 7.59 (dd, J 7.7, 0.9 Hz, 1H, Ar); 7.78 (d, J 9.1 Hz, 1H, Ar). M/Z (M+H).sup.+: 240.0. Mp: 175-183° C.

Example 165: 6-ethyl-5-(1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)pyridin-2-amine (hydrochloride)

[1056] ##STR00177##

[1057] Protected intermediate of Example 165 was prepared according to method 9 step 1 starting from 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoline 87 (150 mg, 0.66 mmol) and compound 7 (260 mg, 0.80 mmol, 1.2 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 178 (203 mg) as a yellow oil. M/Z (M+H).sup.+: 346.2

[1058] Example 165 was prepared according to method 9 step 2 starting from compound 178 (203 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/04). The obtained product was further purified by preparative HPLC (H.sub.2O (0.5 wt. % HCOOH)/CH.sub.3CN (0.5 wt. % HCOOH): 90/10 to 50/40). Clean fractions were combined, HCl 1M in H.sub.2O was added and the obtained solution was freeze dried to afford Example 165 as a yellow solid (87 mg, 44% over 2 steps).

[1059] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.16 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 2.26-2.36 (m, 1H, Ar—CH—H); 2.39-2.49 (m, 2H, CH.sub.2—CH.sub.2); 2.64 (m, 1H, Ar—CH—H); 3.16-3.20 (m, 2H, CH.sub.2—CH.sub.2—CH.sub.2); 3.66-3.69 (m, 2H, CH.sub.2—NMe); 7.04 (d, 1H, J 9.1 Hz, Ar); 7.29 (dd, J 6.9, 2.0 Hz, 1H, Ar); 7.54-7.61 (m, 2H, Ar); 7.93 (d, 1H, J 9.1 Hz, Ar). NH.sub.2 and HCl salt signals not observed. M/Z (M+H).sup.+: 268.1. Mp: 155-165° C.

Example 166: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(morpholino)methanone (hydrochloride)

[1060] ##STR00178##

[1061] Protected intermediate of Example 166 was prepared according to method 10 step 1 starting from compound 10 (150 mg, 0.40 mmol) and morpholine (39 mg, 0.44 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 179 (131 mg, 74%) as a yellow oil. M/Z (M+H).sup.+: 441.2.

[1062] Example 166 was prepared according to method 10 step 2 starting from compound 179 (131 mg, 0.30 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained solid was triturated in Et.sub.2O (2×2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 166 as a white solid (51 mg, 43%).

[1063] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.07 (t, J 7.6 Hz, 3H, CH.sub.3); 2.46-2.67 (m, 2H, CH.sub.2); 3.45-3.58 (m, 2H, CH.sub.2); 3.63-3.65 (m, 2H, CH.sub.2); 3.80-3.89 (m, 4H, 2*CH.sub.2); 7.01 (d, J 9.0 Hz, 1H, Ar); 7.77 (d, J 8.5 Hz, 1H, Ar); 7.82-7.89 (m, 3H, Ar); 8.18 (dd, J 7.8, 1.9 Hz, 1H, Ar); 8.65 (d, J 8.5 Hz, 1H, Ar). NH.sub.2 and HCl salt not observed. M/Z (M+H).sup.+: 363.2. Mp: 130-135° C.

Example 167: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(1,4-oxazepan-4-yl)methanone (hydrochloride)

[1064] ##STR00179##

[1065] Protected intermediate of Example 167 was prepared according to method 10 step 1 starting from compound 10 (150 mg, 0.40 mmol) and 1,4-oxazepane (45 mg, 0.44 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 180 (109 mg, 59%) as a yellow solid. M/Z (M+H).sup.+: 455.2.

[1066] Example 167 was prepared according to method 10 step 2 starting from compound 180 (109 mg, 0.24 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated twice in Et.sub.2O (2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 167 as a white solid (69 mg, 70%).

[1067] .sup.1H-NMR (D.sub.2O, 400 MHz) δ:1.05 (t, J 7.7 Hz, 3H, CH.sub.3); 1.65-1.71 (m, 1H, C—H—H); 2.04-2.10 (m, 1H, C—H—H); 2.45-2.64 (m, 2H, CH.sub.2); 3.49-3.54 (m, 2H, CH.sub.2); 3.60-3.62 (m, 1H, C—H—H); 3.78 (t, J 5.4 Hz, 1H, C—H—H); 3.81-3.96 (m, 4H, 2*CH.sub.2); 7.00 (dd, J 9.1, 7.1 Hz, 1H, Ar); 7.75 (d, J 8.5 Hz, 1H, Ar); 7.81-7.88 (m, 3H, Ar); 8.16-8.18 (m, 1H, Ar); 8.62 (d, J 8.5 Hz, 1H, Ar). NH.sub.2 and HCl salt not observed. M/Z (M+H).sup.+: 377.2. Mp: 120-131° C.

Example 168: 8-(6-amino-2-ethylpyridin-3-yl)-N-cyclohexyl-N-ethylquinoline-2-carboxamide (hydrochloride)

[1068] ##STR00180##

[1069] Protected intermediate of Example 168 was prepared according to method 10 step I starting from compound 10 (180 mg, 0.49 mmol) and N-ethylcyclohexanamine (68 mg, 0.53 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 181 (155 mg, 67%) as a yellow oil. M/Z (M+H).sup.+: 481.3

[1070] Example 168 was prepared according to method 10 step 2 starting from compound 181 (155 mg, 0.33 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was triturated twice in Et.sub.2O (2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 168 as a white solid (58 mg, 41%).

[1071] .sup.1H-NMR (DMSO-d.sub.6+D.sub.2O, 400 MHz) presence of rotamer δ: 0.65-0.71 (m, 1.4H, CH.sub.2); 0.76 (t, J 7.1 Hz, 0.6H, CH.sub.3); 0.88-0.96 (m, 0.6H, CH.sub.2); 0.99 (t, J 7.7 Hz, 0.6H, CH.sub.3); 1.02 (t, J 7.7 Hz, 2.4H, CH.sub.3); 1.11 (t, J 7.1 Hz, 2.4H, CH.sub.3); 1.25-1.78 (m, 8H, 4*CH.sub.2); 2.36-2.42 (m, 2H, CH.sub.2); 3.09 (m, 0.6H, CH); 3.30-3.37 (m, 2.4H, CH+CH.sub.2); 6.87-6.90 (m, 1H, Ar); 7.61-7.65 (m, 1H, Ar); 7.74-7.78 (m, 3H, Ar); 8.06-8.12 (m, 1H, Ar); 8.51-8.55 (m, 1H, Ar). NH.sub.2 and HCl salt not observed. M/Z (M+H).sup.+: 403.3. Mp: 142-148° C.

Example 169: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(azepan-1-yl)methanone (hydrochloride)

[1072] ##STR00181##

[1073] Protected intermediate of Example 169 was prepared according to method 10 step 1 starting from compound 10 (180 mg, 0.49 mmol) and azepane (53 mg, 0.53 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 60/40) to afford compound 182 (144 mg, 66%) as an orange solid. M/Z (M+H).sup.+: 481.3

[1074] Example 169 was prepared according to method 10 step 2 starting from compound 182 (144 mg, 0.32 mmol). The crude was purified by flash chromatography (KPNH, CyHex/EtOAc: 100/0 to 30/70). The obtained foam was triturated twice in Et.sub.2O (2 mL). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 169 as a white solid (54 mg, 41%).

[1075] .sup.1H-NMR (D.sub.2O, 400 MHz) δ: 1.05 (t, J 7.6 Hz, 3H, CH.sub.3); 1.47-1.54 (m, 4H, 2*CH.sub.2); 1.61-1.67 (m, 2H, CH.sub.2); 1.78-1.84 (m, 2H, CH.sub.2); 2.43-2.64 (m, 2H, CH.sub.2); 3.32-3.34 (m, 2H, CH.sub.2); 3.61-3.74 (m, 2H, CH.sub.2); 6.98 (d, J 9.0, 1 H, Ar); 7.70 (d, J 8.5 Hz, 1H, Ar); 7.80-7.87 (m, 3H, Ar); 8.15 (dd, J 8.1, 1.6 Hz, 1H, Ar); 8.60 (d, J 8.5 Hz, 1H, Ar). NH.sub.2 and HCl salt not observed. M/Z (M+H).sup.+: 375.2. Mp: 140-144° C.

Example 170: 8-(6-amino-2-ethylpyridin-3-yl)-N-ethyl-N-isopropylquinoline-2-carboxamide (hydrochloride)

[1076] ##STR00182##

[1077] Protected intermediate of Example 170 was prepared according to method 10 step 1 starting from compound 10 (180 mg, 0.49 mmol) and ethylpropan-2-amine (47 mg, 0.53 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 183 (126 mg, 59%) as a yellow oil. M/Z (M+H).sup.+: 441.3

[1078] Example 170 was prepared according to method 10 step 2 starting from compound 183 (126 mg, 0.29 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated twice in Et.sub.2O (2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 170 as a white solid (54 mg, 47%).

[1079] .sup.1H-NMR (D.sub.2O, 400 MHz) presence of rotamer δ: 0.94-0.97 (m, 0.75H, CH.sub.3); 1.03-1.14 (m, 7.25H, CH.sub.3); 1.28-1.35 (m, 4H, CH.sub.3); 2.46-2.64 (m, 2H, CH.sub.2); 3.18-3.34 (m, 0.5H, CH); 3.46-3.51 (m, 1.5H, CH+CH.sub.2); 3.89-3.95 (m, 0.75H, CH.sub.2); 4.51-4.57 (m, 0.25H, CH); 6.97 (d, J 9.0 Hz, 1H, Ar); 7.67-7.71 (m, 1H, Ar); 7.80-7.86 (m, 3H, Ar); 8.17 (dd, J 7.8, 2.0 Hz, 1H, Ar); 8.62 (d, J 8.5 Hz, 1H, Ar). NH.sub.2 and HCl salt not observed. M/Z (M+H).sup.+: 363.3. Mp: 121-125° C.

Example 171: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methanone (hydrochloride)

[1080] ##STR00183##

[1081] Protected intermediate of Example 171 was prepared according to method 10 step 1 starting from compound 10 (145 mg, 0.39 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (64 mg, 0.43 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 40/60) to afford compound 184 (139 mg, 76%) as a yellow oil. M/Z (M+H).sup.+: 467.3

[1082] Example 171 was prepared according to method 10 step 2 starting from compound 184 (139 mg, 0.30 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained foam was triturated twice in Et.sub.2O (2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 171 as a white solid (72 mg, 57%).

[1083] .sup.1H-NMR (D.sub.2O, 400 MHz) presence of rotamer δ: 1.00 (t, J 7.5, 1.5H, CH.sub.3); 1.07 (t, J 7.5, 1.5H, CH.sub.3); 1.69-1.88 (m, 3H, CH.sub.2+CH—H); 1.98-2.07 (m, 1H, CH—H); 2.45-2.70 (m, 2H, CH.sub.2); 3.23 (d, J 13.1 Hz, 1H, CH—H); 3.29 (d, J 13.1 Hz, 0.5H, CH—H); 3.37 (d, J 13.1 Hz, 0.5H, CH—H); 3.58 (d, J 12.8 Hz, 0.5H, CH—H); 3.77 (d, J 12.8 Hz, 0.5H, CH—H); 4.21 (dd, J 13.1, 6.8 Hz, 1H, CH); 4.32 (t, J 7.3 Hz, 1H, CH—H); 4.61 (d, J 7.3 Hz, 1H, CH—H); 7.00 (d, J 9.2 Hz, 1H, Ar); 7.75 (d, J 8.2 Hz, 1H, Ar); 7.78-7.89 (m, 4H, Ar); 8.17 (d, J 8.0 Hz, 1H, Ar); 8.62 (t, J 7.3 Hz, 1H, Ar). M/Z (M+H).sup.+: 389.2. Mp: 150-160° C.

Example 172: (8-(6-amino-2-ethylpyridin-3-yl)quinolin-2-yl)(4-phenylpiperidin-1-yl)methanone (hydrochloride)

[1084] ##STR00184##

[1085] Protected intermediate of Example 172 was prepared according to method 10 step 1 starting from compound 10 (145 mg, 0.39 mmol) and 4-phenylpiperidine (69 mg, 0.43 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 40/60) to afford compound 185 (177 mg, 88%) as a yellow oil. M/Z (M+H).sup.+: 515.3

[1086] Example 172 was prepared according to method 10 step 2 starting from compound 185 (177 mg, 0.34 mmol), the crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 97/3). The obtained foam was triturated twice in pentane (2 mL). The obtained product was dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 172 as a white solid (85 mg, 52%).

[1087] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) presence of rotamer δ: 0.98 (m, 1.5H, CH.sub.3); 1.14 (m, 1.5H, CH.sub.3); 1.36-1.58 (m, 3H, CH.sub.2+CH—H); 1.88 (d, J 12.5 Hz, 1H, CH—H); 2.38-2.45 (m, 2H, CH.sub.2—CH.sub.3); 2.77-2.90 (m, 2H, CH); 2.97-3.06 (m, 1H, CH); 3.90 (d, J 13.0 Hz, 1H, CH—H); 4.63 (d, J 13.0 Hz, 1H, CH—H); 6.83-7.01 (m, 1H, Ar); 7.17 (d, J 7.2 Hz, 2H, Ar); 7.23 (t, J 7.2 Hz, 1H, Ar); 7.34-7.42 (m, 2H, Ar); 7.78-7.81 (m, 4H, Ar); 7.86 (bs, 2H, NH.sub.2); 8.15-8.18 (m, 1H, Ar); 8.61 (d, J 8.5 Hz, 1H, Ar); 13.97-14.14 (m, 1H, HCl salt). M/Z (M+H).sup.+: 437.2. Mp>250° C.

Example 173: 8-(6-amino-2-ethylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)quinoline-2-carboxamide (hydrochloride)

[1088] ##STR00185##

[1089] Protected intermediate of Example 173 was prepared according to method 10 step 1 starting from compound 10 (145 mg, 0.39 mmol) and tetrahydro-2H-pyran-4-amine (43 mg, 0.43 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 186 (152 mg, 86%) as a yellow oil. M/Z (M+H).sup.+: 455.2

[1090] Example 173 was prepared according to method 10 step 2 starting from compound 186 (152 mg, 0.33 mmol), the crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was triturated twice in pentane (2 mL). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 173 as a white solid (88 mg, 64%).

[1091] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.3); 1.43-1.52 (m, 2H, CH.sub.2); 1.81-1.85 (m, 2H, CH.sub.2); 2.52-2.54 (m, 2H, CH.sub.2); 3.44-3.51 (m, 2H, CH.sub.2); 3.77 (td, J 11.6, 4.2 Hz, 2H, CH.sub.2); 3.95-4.05 (m, 1H, CH); 6.98 (d, J 9.1 Hz, 1H, Ar); 7.91-8.06 (m, 6H, NH+NH.sub.2+Ar); 8.17-8.21 (m, 2H, Ar); 8.69 (d, J 8.6 Hz, 1H, Ar); 14.13 (s, 1H, HCl salt). M/Z (M+H).sup.+: 377.2. Mp: 112-125° C.

Example 174: 8-(6-amino-2-ethylpyridin-3-yl)-N-benzylquinoline-2-carboxamide (hydrochloride)

[1092] ##STR00186##

[1093] Protected intermediate of Example 174 was prepared according to method 10 step 1 starting from compound 10 (145 mg, 0.39 mmol) and phenylmethanamine (46 mg, 0.43 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 70/30) to afford compound 187 (140 mg, 78%) as an orange oil. M/Z (M+H).sup.+: 461.3

[1094] Example 174 was prepared according to method 10 step 2 starting from compound 187 (140 mg, 0.30 mmol). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 96/4). The obtained foam was triturated in Et.sub.2O (2 mL) and in pentane (2 mL). The obtained product was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 174 as a white solid (74 mg, 58%).

[1095] 1H-NMR (D.sub.2O, 400 MHz) δ: 0.91 (t, J 7.7 Hz, 3H, CH.sub.3); 2.35-2.42 (m, 2H, CH.sub.2); 4.46-4.57 (m, 2H, CH.sub.2); 6.71 (d, J 9.0 Hz, 1H, Ar); 7.29-7.31 (m, 2H, Ar); 7.42-7.48 (m, 3H, Ar); 7.54 (d, J 9.0 Hz, 1H, Ar); 7.73-7.78 (m, 2H, Ar); 8.02-8.07 (m, 2H, Ar); 8.47 (d, J 8.6 Hz, 1H, Ar). M/Z (M+H).sup.+: 383.2. Mp: 102-114° C.

Example 175: 8-(6-amino-2-ethylpyridin-3-yl)-N-(oxetan-3-yl)quinoline-2-carboxamide

[1096] ##STR00187##

[1097] Protected intermediate of Example 175 was prepared according to method 9 step 1 starting from 8-bromo-N-(oxetan-3-yl)quinoline-2-carboxamide 61 (96 mg, 0.31 mmol) and compound 7 (112 mg, 0.34 mmol, 1.1 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 50/50) to afford compound 188 (111 mg, 83%) as a yellow oil. M/Z (M+H).sup.+: 427.2.

[1098] Example 175 was prepared according to method 9 step 2 starting from compound 188 (111 mg, 0.26 mmol), the crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained product was triturated in pentane (5 mL) and filtered to afford Example 175 as a beige solid (32 mg, 35%).

[1099] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.01 (t, J 7.5 Hz, 3H, CH.sub.3); 2.28-2.33 (m, 2H, CH.sub.2—CH.sub.3); 4.38 (t, J 6.4 Hz, 2H, 2*CH.sub.aH.sub.b—O); 4.81 (t, J 7.1 Hz, 2H, 2*CH.sub.aH.sub.b—O); 4.94-5.02 (m, 1H, CH); 5.96 (bs, 2H, NH.sub.2); 6.45 (d, J 8.3 Hz, 1H, Ar); 7.38 (d, J 8.3 Hz, 1H, Ar); 7.74-7.79 (m, 2H, Ar); 8.05-8.09 (m, 1H, Ar); 8.09 (d, J 8.6 Hz, 1H, Ar); 8.38 (d, J 7.3 Hz, 1H, Ar); 8.62 (d, J 8.6 Hz, 1H, Ar). M/Z (M+H).sup.+: 349.2. Mp: 156-162° C.

Example 176: 6-ethyl-5-(7-fluorochroman-8-yl)pyridin-2-amine (hydrochloride)

[1100] ##STR00188##

[1101] Protected intermediate of Example 176 was prepared according to method 9 step 1 starting from 8-bromo-7-fluorochromane 95 (163 mg, 0.71 mmol) and compound 7 (345 mg, 1.06 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 98/02). The obtained foam was further purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 189 (281 mg) as a colorless oil. M/Z (M+H).sup.+: 351.2.

[1102] Example 176 was prepared according to method 9 step 2 starting from compound 189 (281 mg). The crude was purified by flash chromatography (SiO.sub.2, DCM/MeOH: 100/0 to 95/5). The obtained foam was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 30/70). The obtained foam was triturated twice in Et.sub.2O (5 mL), then dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 176 as a white solid (138 mg, 63% over 2 steps).

[1103] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.11 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.67-1.92 (m, 2H, O—CH.sub.2—CH.sub.2); 2.47 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 2.77 (t, J 6.4 Hz, 2H, Ph-CH.sub.2); 4.10 (dd, J 5.6, 4.4 Hz, 2H, O—CH.sub.2—CH.sub.2); 6.82 (dd, J, 9.2, 8.4 Hz, 1H, Ar); 6.90 (d, J 9.2 Hz, 1H, Ar); 7.19 (dd, J 8.4, 6.8 Hz, 1H, Ar); 7.69 (d, J 9.2 Hz, 1H, Ar); 7.96 (bs, 2H, NH.sub.2); 14.16 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 273.1. Mp: 85-95° C.

Example 177: 6-ethyl-5-(7-fluoro-2,2-dimethylchroman-8-yl)pyridin-2-amine (hydrochloride)

[1104] ##STR00189##

[1105] Protected intermediate of Example 177 was prepared according to method 9 step 1 starting from 8-bromo-7-fluoro-2,2-dimethylchromane 96 (85 mg, 0.33 mmol) and compound 7 (160 mg, 0.49 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10). The obtained F product was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 90/10) to afford compound 190 (99 mg) as a yellow oil. M/Z (M+H).sup.+: 379.3.

[1106] Example 177 was prepared according to method 9 step 2 starting from compound 190 (99 mg). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 30/70). The obtained foam was triturated twice in Et.sub.2O (3 mL), then dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 177 as a white solid (35 mg, 31% over 2 steps).

[1107] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.10 (t, J 7.6 Hz, 1H, CH.sub.2—CH.sub.3); 1.20 (s, 6H, 2*CH.sub.3); 1.76 (t, J 6.8 Hz, 2H, Ph-CH.sub.2—CH.sub.2); 2.45 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 2.77 (t, J 6.8 Hz, 2H, Ph-CH.sub.2); 6.80 (dd, J, 9.2, 8.4 Hz, 1H, Ar); 6.90 (d, J 8.8 Hz, 1H, Ar); 7.22 (dd, J 8.4, 6.8 Hz, 1H, Ar); 7.65 (d, J 8.8 Hz, 1H, Ar); 7.94 (bs, 2H, NH.sub.2); 14.11 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 301.1. Mp: 80-90° C.

Example 178: 6-ethyl-5-(8-fluoro-2,5-dihydrobenzo[b]oxepin-9-yl)pyridin-2-amine (hydrochloride)

[1108] ##STR00190##

[1109] Protected intermediate of Example 178 was prepared according to method 9 step 1 starting from 9-bromo-8-fluoro-2,5-dihydrobenzo[b]oxepine 98 (380 mg, 1.56 mmol) and compound 7 (765 mg, 2.34 mmol, 1.5 eq.). The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20). The obtained product was further purified by flash chromatography (20 μm Interchim® SiO.sub.2, CyHex/EtOAc: 100/0 to 80/20) to afford compound 191 (265 mg, 47%) as a yellow oil. M/Z (M+H).sup.+: 363.3.

[1110] Example 178 was prepared according to method 9 step 2 starting from compound 191 (262 mg, 0.72 mmol). The crude was purified by flash chromatography (20 μm Interchim® SiO.sub.2, DCM/MeOH: 100/0 to 98/2) to afford 6-ethyl-5-(8-fluoro-2,5-dihydrobenzo[b]oxepin-9-yl)pyridin-2-amine 192 (203 mg, 99%) as a white solid. 40 mg of 192 were dissolved in a mixture of aqueous 1N HCl/ACN and the resulting solution was freeze dried to afford Example 178 as a white solid (38 mg).

[1111] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 1.13 (t, J 7.6 Hz, 1.5 H one rotamer of CH.sub.2—CH.sub.3); 1.14 (t, J 7.6 Hz, 1.5 H other rotamer of CH.sub.2—CH.sub.3); 2.52-2.56 (m, 2H, CH.sub.2—CH.sub.3); 2.97-3.05 (m, 1H, Ph-CH.sub.2); 3.41-3.48 (m, 1H, Ph-CH.sub.2); 5.21 (ddt, J 10.4, 6.8, 1.2 Hz, 1H, O—CH.sub.2); 5.27-5.37 (m, 2H, O—CH.sub.2+CH═CH); 6.02 (dddd, J 17.2, 10.4, 6.4; 2.0 Hz, 1H, CH═CH); 6.81 (dd, J 10.0, 8.4 Hz, 1H, Ar); 6.91-6.92 (m, 1H, Ar); 7.27-7.30 (m, 1H, Ar); 7.74 (d, J 9.2 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 14.13 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 285.0. Mp: 43-52° C.

Example 179: 6-ethyl-5-(8-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepin-9-yl)pyridin-2-amine (hydrochloride)

[1112] ##STR00191##

[1113] Under Argon, to a solution of 6-ethyl-5-(8-fluoro-2,5-dihydrobenzo[b]oxepin-9-yl)pyridin-2-amine 192 (163 mg, 0.57 mmol, 1.0 eq.) in EtOH (2.9 mL) was added Pd/C 10 wt. % (61 mg, 0.06 mmol, 0.1 eq.). The reaction mixture was sparged with H.sub.2 for 5 min, then stirred under H.sub.2 atmosphere at 25° C. for 22 h. The reaction mixture was filtered through a pad of Celite® and the cake was washed with EtOH (20 mL). The filtrate was concentrated to dryness. The crude was purified by flash chromatography (SiO.sub.2, CyHex/EtOAc: 100/0 to 20/80). The obtained foam was dissolved in a mixture of aqueous 1 N HCl/ACN and the resulting solution was freeze dried to afford Example 179 as a white solid (58 mg, 31%).

[1114] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ: 0.89 (t, J 7.4 Hz, 1.5 H, one rotamer of CH.sub.2—CH.sub.3); 0.89 (t, J 7.4 Hz, 1.5 H, other rotamer of CH.sub.2—CH.sub.3); 1.10-1.17 (m, 3H, O—CH.sub.2—CH.sub.2—CH.sub.2+O—CH.sub.2—CH.sub.2—CH.sub.2); 1.62-1.75 (m, 2H, O—CH.sub.2—CH.sub.2—CH.sub.2+Ph-CH.sub.2); 2.52-2.60 (m, 2H, CH.sub.2—CH.sub.3); 2.84-2.94 (m, 1H, Ph-CH.sub.2); 3.28-3.32 (m, 1H, O—CH.sub.2); 4.78-4.86 (m, 1H, O—CH.sub.2); 6.77 (dd, J 10.0, 8.4 Hz, 1H, Ar); 6.91-6.92 (m, 1H, Ar); 7.26 (m, 1H, Ar); 7.73 (d, J 9.2 Hz, 1H, Ar); 7.97 (bs, 2H, NH.sub.2); 14.15 (bs, 1H, HCl salt). M/Z (M+H).sup.+: 287.1. Mp: 47-65° C.

III. Biological Experiments

Example 180: Human NPFFR1 Evaluation Using BRET Biosensors (IC.SUB.50.)

[1115] Compounds of the present invention were tested successively for their agonist and antagonist activities on human NPFFR1 (hNPFFR1) receptor transiently over-expressed in HEK-293 T cells. Compounds exert agonist activity if, by themselves in absence of neuropeptide RFRP-3 (also named NPVF) they activate hNPFFR1; and they exert antagonist activity if they decrease the action of RFRP-3 on the receptor.

[1116] The assay used to measure compound activity is based on BRET (Bioluminescence Resonance Energy Transfer) biosensors and is designed to monitor the plasma membrane translocation of protein that interacts with specific Ga subunit. The specific effector (luciferase tagged: BRET donor) recruited at the membrane will be in close proximity to a plasma membrane anchor (GFP tagged: BRET acceptor) to induce a BRET signal. Biosensors are described in the patent application WO 2016/041093 A1 (Biosensors for monitoring biomolecule localization and trafficking in cells).

Cell Culture and Transfection

[1117] HEK-293 T cells are maintained in Dulbecco's Modified Eagle's Medium supplemented with 10% Foetal Calf Serum, 1% Penicillin/Streptomycin at 37° C./5% CO.sub.2.

[1118] Cells are co-transfected using polyethylenimine (25 kDa linear) with four DNA plasmids encoding: hNPFFR1, GαoB, a Gi family specific intracellular effector fused to luciferase (BRET donor), a plasma membrane effector fused to GFP (BRET acceptor). After transfection, cells are cultured for 48 h at 37° C./5% CO.sub.2.

BRET Assay

[1119] Receptor activity is detected by changes in BRET signal.

[1120] On the day of the assay, cells are detached using trypsin 0.05%, resuspended in assay buffer (1.8 mM CaCl.sub.2, 1 mM MgCl.sub.2, 2.7 mM KCl, 137 mM NaCl, 0.4 mM NaH.sub.2PO.sub.4, 5.5 mM D-Glucose, 11.9 mM NaHCO.sub.3, 25 mM Hepes) and seeded in 384 well plate at a density of 20,000 cells per well. Then, plates are equilibrated 3.5 hours at 37° C. before adding compounds.

[1121] Compounds and luciferase substrate are added to the cells using an automated device (Freedom Evo®, Tecan) and BRET readings are collected on EnVision (PerkinElmer) with specific filters (410 nm BW 80 nm, 515 nm BW 30 nm).

[1122] Agonist and antagonist activities of compounds are consecutively evaluated on the same cell plate. Agonist activity is first measured after 10 minutes incubation with compound alone on the cells. Then, cells are stimulated by an EC80 RFRP-3 concentration and luminescence is recorded for additional 10 minutes. EC80 RFRP-3 concentration is the concentration giving 80% of the maximal RFRP-3 response. Agonist or antagonist activities are evaluated in comparison to basal signals evoked by assay buffer or EC80 RFRP-3 alone, respectively.

IC.SUB.50 .Determination

[1123] For IC.sub.50 determination, a dose-response test is performed using 20 concentrations (ranging over 6 logs) of each compound. Dose-response curves are fitted using the sigmoidal dose-response (variable slope) analysis in GraphPad Prism software (GraphPad Software) and IC.sub.50 of antagonist activity is calculated. Dose-response experiments are performed in duplicate, in two independent experiments.

[1124] According to the biological test procedure, the following compounds showed IC.sub.50 values in the ranges as detailed below:

[1125] IC.sub.50>1000 nM: Examples 2, 5, 16, 17, 18, 19, 27, 35, 36, 48, 54, 75, 100, 102, 103, 152, 156, 157

[1126] IC.sub.50 between 100 nM and 1000 nM: Examples 3, 4, 7, 10, 12, 13, 14, 15, 20, 21, 22, 24, 26, 28, 29, 30, 33, 34, 38, 41, 42, 43, 44, 45, 50, 69, 78, 79, 80, 81, 82, 83, 85, 86, 87, 88, 89, 91, 92, 96, 101, 104, 106, 107, 112, 114, 120, 130, 131, 140, 153, 154, 155, 158, 159, 161, 162, 163, 164, 165, 172

[1127] IC.sub.50<100 nM: Examples 1, 6, 8, 9, 11, 23, 25, 31, 32, 37, 39, 40, 46, 47, 49, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 76, 77, 84, 90, 93, 94, 95, 97, 98, 99, 105, 108, 109, 110, 111, 113, 115, 116, 117, 118, 119, 121, 122, 123, 124, 125, 126, 127, 128, 129, 132, 133, 134, 135, 136, 137, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 160, 166, 167, 168, 169, 170, 171, 173, 174, 176, 177, 178, 179

Example 181: In Vivo Evaluation on Morphine-Induced Hyperalgesia Model in the Mouse

[1128] This method, which detects opioid-induced hyperalgesia, follows those well-known by one skilled in the art and described in the literature (Elhabazi K et al., J Vis Exp. 2014; (89):e51264). The procedure applied to the compounds of the invention is as follows:

[1129] Nociceptive thresholds are assessed using the tail immersion test (TIT). After TIT, mice are treated daily during 8 consecutive days with morphine (10 mg/kg, sub-cutaneous s.c.) +/− tested compounds (10 mg/kg, s.c.) 20 min before morphine injection for example 31 and 32 and twice a day for examples 56 and 143 (20 min before morphine injection, and in the afternoon).

[1130] Mice used were male C57/B16N 8 weeks old at the beginning of the experiment. During TIT the tail of the animal is immersed two-thirds in a water bath at 47° C. and the withdrawal latency is recorded in seconds. The cutoff is 25 seconds, to avoid tissue damage. After TIT mice received an injection depending on their group then are replaced to their home cages.

Data Analysis

[1131] FIGS. 1A and 1B show the mean time of tail withdrawal latency in each group of animals. The anti-hyperalgesia effect of the tested compounds was compared to vehicle-treated group using ANOVA test followed by the Bonferroni's test. The insert at the bottom shows the comparison between groups of the global Area Under Curve (AUC) over D0 to D8 period.

Results

[1132] As illustrated in FIGS. 1A and 1B, examples 31, 32, 56 and 143 administered at 10 mg/kg s.c. showed a significant blockade of morphine-induced hyperalgesia.

[1133] These results demonstrate that the compounds of formula (I) can be used in the therapeutic or prophylactic treatment of opioid-induced hyperalgesia, including in particular morphine-induced hyperalgesia, and further that the therapeutic use of an opioid analgesic (such as morphine) in combination with a compound of formula (I) according to the invention is advantageous as it allows to prevent or reduce the development of opioid-induced hyperalgesia.