NADPH OXIDASE 4 INHIBITORS
20180179194 ยท 2018-06-28
Assignee
Inventors
- Hamed Aissaoui (Allschwil, CH)
- Martin Bolli (Allschwil, CH)
- Christoph Boss (Allschwil, CH)
- Sylvia Richard-Bildstein (Allschwil, CH)
- Patrick Sieber (Allschwil, CH)
Cpc classification
C07D491/107
CHEMISTRY; METALLURGY
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
C07D417/12
CHEMISTRY; METALLURGY
A61P9/04
HUMAN NECESSITIES
A61P21/00
HUMAN NECESSITIES
A61P1/18
HUMAN NECESSITIES
C07D263/58
CHEMISTRY; METALLURGY
A61P1/16
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
International classification
C07D413/12
CHEMISTRY; METALLURGY
C07D491/107
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
Abstract
The invention relates to 2,5-disubstituted benzoxazole and benzothiazole derivatives of Formula (I)
##STR00001##
wherein L, X, Y, and ring (A) are as described in the description, their preparation and their use as pharmaceutically active compounds. Said compounds may be useful for the prevention or treatment of diseases or disorders associated with impaired reactive oxygen species (ROS) production, and/or for the prevention or treatment of various fibrotic diseases.
Claims
1. A compound of the Formula (I), ##STR00035## wherein ring (A) represents a non-aromatic 5- to 7-membered heterocyclic ring which is fused to the phenyl group; wherein said 5- to 7-membered heterocyclic ring contains one oxygen ring atom and optionally one further ring heteroatom independently selected from oxygen or nitrogen; wherein said 5- to 7-membered heterocyclic ring independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from: one oxo substituent attached to a ring carbon atom in alpha position to a ring oxygen and/or a ring nitrogen atom; and/or one C.sub.1-3-alkyl attached to a ring nitrogen atom having a free valency; or two fluoro substituents attached to the same ring carbon atom; L represents NHCO* or CONH*, wherein the asterisks (*) indicate the bond that is linked to the benzoxazole/the benzothiazole moiety; X represents O or S; and Y represents NR.sup.1R.sup.2 wherein R.sup.1 represents C.sub.1-4-alkyl; C.sub.2-4-alkyl which is mono-substituted with di-(C.sub.1-3-alkyl)amino, hydroxy or C.sub.1-3-alkoxy; C.sub.3-5-cycloalkyl-L.sup.1-, wherein L.sup.1 represents a direct bond or C.sub.1-3-alkylene; and wherein the C.sub.3-5-cycloalkyl optionally contains one oxygen ring atom, and wherein said C.sub.3-5-cycloalkyl is unsubstituted, or mono-substituted with methyl or fluoro; or a piperidin-3-yl, piperidin-4-yl or pyrrolidin-3-yl group, which groups are substituted on the ring nitrogen atom with C.sub.3-5-cycloalkyl, wherein said C.sub.3-5-cycloalkyl optionally contains one oxygen ring atom; and R.sup.2 represents hydrogen, C.sub.1-3-alkyl, or C.sub.3-5-cycloalkyl; or Y represents a saturated 4- to 7-membered monocyclic heterocyclyl selected from: morpholin-4-yl; 2-oxo-pyrrolidin-1-yl; 1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally mono-substituted in position 4 with oxetan-3-yl or C.sub.1-3-alkyl; or azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl independently is unsubstituted, or substituted with: two fluoro substituents attached to the same ring carbon atom; or one substituent selected from unsubstituted phenyl, or unsubstituted 5- or 6-membered heteroaryl; or one substituent selected from hydroxy; C.sub.1-3-alkoxy; COC.sub.1-4-alkoxy; di-(C.sub.1-3-alkyl)amino; and C.sub.1-3-alkyl which is mono-substituted with di-(C.sub.1-3-alkyl)amino, hydroxy, or C.sub.1-3-alkoxy; or two substituents, wherein one of said substituents is C.sub.1-4-alkyl, and the other is independently selected from hydroxy, or di-(C.sub.1-3-alkyl)amino; or one substituent selected from morpholin-4-yl; 1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl which is optionally mono-substituted in position 4 with C.sub.1-3-alkyl; one substituent selected from azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups independently are unsubstituted, or mono-substituted with hydroxy, or di-substituted with methyl and hydroxy; or Y represents saturated 7- to 11-membered fused, bridged, or spiro-bicyclic heterocyclyl containing at least one nitrogen atom, wherein said nitrogen atom is bound to the benzoxazole/the benzothiazole moiety, and wherein said heterocyclyl optionally contains one further ring heteroatom independently selected from oxygen, nitrogen and sulfur; wherein said heterocyclyl is unsubstituted, or substituted with: two oxo substituents at a ring sulfur ring atom; or one C.sub.1-3-alkyl substituent attached to a ring nitrogen atom having a free valency; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein the fragment ##STR00036## represents a group selected from: ##STR00037## wherein R.sup.a represents hydrogen, or C.sub.1-3-alkyl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1, wherein the fragment ##STR00038## represents ##STR00039## or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1; wherein L represents CONH*, wherein the asterisk (*) indicates the bond that is linked to the benzoxazole/the benzothiazole moiety; or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1; wherein X represents O; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1; wherein Y represents a group NR.sup.1R.sup.2, wherein R.sup.1 represents C.sub.1-4-alkyl; C.sub.2-4-alkyl which is mono-substituted with di-(C.sub.1-3-alkyl)amino; C.sub.3-5-cycloalkyl-L.sup.1-, wherein L.sup.1 represents a direct bond or C.sub.1-3-alkylene; and wherein the C.sub.3-5-cycloalkyl optionally contains one oxygen ring atom, and wherein said C.sub.3-5-cycloalkyl is unsubstituted, or mono-substituted with methyl or fluoro; or 1-(oxetan-3-yl)-piperidin-4-yl; and R.sup.2 represents hydrogen, C.sub.1-3-alkyl, or C.sub.3-5-cycloalkyl; or Y represents a group ##STR00040## wherein r and q both represent the integer 2; and Z represents O, SO.sub.2, or NR.sup.Y1, wherein R.sup.Y1 represents oxetan-3-yl or C.sub.1-3-alkyl; or r represents the integer 0, 1, 2, or 3; q represents the integer 1, 2, 3, or 4; and the sum of r and q is 2, 3, or 4; Z represents CH2, CHR.sup.Y2, or CR.sup.Y3R.sup.Y4; wherein R.sup.Y2 represents unsubstituted phenyl, or unsubstituted 5- or 6-membered heteroaryl; hydroxy; C.sub.1-3-alkoxy; COC.sub.1-4-alkoxy; di-(C.sub.1-3-alkyl)amino; or C.sub.1-3-alkyl which is mono-substituted with di-(C.sub.1-3-alkyl)amino, hydroxy, or C.sub.1-3-alkoxy; morpholin-4-yl; 1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl which is optionally mono-substituted in position 4 with C.sub.1-3-alkyl; or azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups independently are unsubstituted, or mono-substituted with hydroxy, or di-substituted with methyl and hydroxy; and R.sup.Y3 represents C.sub.1-4-alkyl; and R.sup.Y4 independently represents hydroxy, or di-(C.sub.1-3-alkyl)amino; or R.sup.Y3 and R.sup.Y4 both represent fluoro; or R.sup.Y3 and R.sup.Y4 together with the carbon atom to which they are attached to form a 4- to 6-membered saturated carbocyclic ring; or a 4- to 6-membered saturated heterocyclic ring, wherein said heterocyclic ring contains one ring heteroatom independently selected from oxygen, nitrogen and sulfur; and wherein said heterocyclic ring is unsubstituted, or substituted with: two oxo substituents at a ring sulfur ring atom; or one C.sub.1-3-alkyl substituent (especially methyl) attached to a ring nitrogen atom having a free valency; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1; wherein Y represents N(C.sub.1-3-alkyl)amino, N,N-di-(C.sub.1-3-alkyl)-amino, N-[2-(di-C.sub.1-3-alkyl)amino)-ethyl]-N(C.sub.1-3-alkyl)-amino, N(C.sub.1-4-alkyl)-N-(oxetan-3-yl)-amino, N(C.sub.3-5-cycloalkyl)-N-(oxetan-3-yl)-amino, N(C.sub.1-4-alkyl)-N-(oxetan-3-yl-methyl)-amino, N-(3-methyl-oxetan-3-yl)-N-methylamino, N-(3-fluoro-oxetan-3-yl-methyl)-N-methylamino, or N-methyl-((N-(oxetan-3-yl)-piperidin)-4-yl)-amino; or Y represents a saturated 4- to 7-membered monocyclic heterocyclyl selected from: morpholin-4-yl; 2-oxo-pyrrolidin-1-yl; 1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally mono-substituted in position 4 with oxetan-3-yl or C.sub.1-3-alkyl; or azetidin-1-yl which is unsubstituted, or substituted with: two fluoro substituents attached to the same ring carbon atom; or one phenyl or pyridinyl substituent, wherein said phenyl or pyridinyl is unsubstituted; or one substituent selected from hydroxy; C.sub.1-3-alkoxy; CO-C.sub.1-4-alkoxy; di-(C.sub.1-3-alkyl)amino; and C.sub.1-3-alkyl which is mono-substituted with di-(C.sub.1-3-alkyl)amino, hydroxy, or C.sub.1-3-alkoxy; or two substituents, wherein one of said substituents is C.sub.1-4-alkyl, and the other is independently selected from hydroxy, or di-(C.sub.1-3-alkyl)amino; or one substituent selected from morpholin-4-yl; 1,1-dioxidothiomorpholin-4-yl; one substituent selected from azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups independently are unsubstituted, or mono-substituted with hydroxy, or di-substituted with methyl and hydroxy; or pyrrolidin-1-yl, or piperidin-1-yl; wherein said pyrrolidin-1-yl, or piperidin-1-yl independently is unsubstituted, or substituted with: two fluoro substituents attached to the same ring carbon atom; or one substituent selected from hydroxy; C.sub.1-3-alkoxy; or di-(C.sub.1-3-alkyl)amino; or Y represents saturated 7- to 11-membered spiro-bicyclic heterocyclyl containing at least one nitrogen atom, wherein said nitrogen atom is bound to the benzoxazole/the benzothiazole moiety, and wherein said heterocyclyl optionally contains one further ring heteroatom independently selected from oxygen, nitrogen and sulfur; wherein said heterocyclyl is unsubstituted, or substituted with: two oxo substituents at a ring sulfur ring atom; or one C.sub.1-3-alkyl substituent attached to a ring nitrogen atom having a free valency; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1; wherein Y represents a group independently selected from the following groups A), B), C), or D): ##STR00041## or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1; wherein Y represents a group independently selected from the following groups A), B), C), or D): ##STR00042## ##STR00043## or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1, which is selected from the group consisting of: 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-116-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-dimethylamino-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-morpholin-4-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(3-methyl-oxetan-3-yl)-amino]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1,1-dioxo-116-thiomorpholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-[1,3]biazetidinyl-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.5] non-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro [3.4] oct-5-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.5] non-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.5] non-5-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5] non-7-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5] non-7-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-8-aza-spiro[4.5] dec-8-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-2-aza-spiro[3.5] non-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro [3.4] oct-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(4-hydroxy-piperidin-1-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-methyl-2,6-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; 1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylic acid tert-butyl ester; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxo-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide; (R)N-(2-(3-hydroxypiperidin-1-yl)benzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-isopropoxy-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-ethoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(3-fluoro-oxetan-3-ylmethyl)-methyl-amino]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-oxetan-3-yl-piperazin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-ylmethyl-amino)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-benzooxazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-1,7-diaza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-2,7-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2,2-dioxo-216-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-116-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide; 2-(4-Methyl-piperazin-1-yl)-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-Piperidin-1-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-Morpholin-4-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-Diethylamino-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-piperidin-1-yl-benzothiazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzothiazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzothiazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzothiazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-dimethylamino-benzothiazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzothiazol-5-yl]-amide; (S)N-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzothiazol-5-yl}-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [24(R)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-azetidin-1-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid (2-ethylamino-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyridin-2-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; Benzo[1,3]dioxole-5-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide; Chroman-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide; 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide; 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; 2-Piperidin-1-yl-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide; 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide; 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide; and 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxo1-5-ylamide; or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising, as active principle, one or more compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. A method to prevent or treat a disease or disorder selected from a fibrotic disease; pulmonary hypertension; hypertension; asthma; acute respiratory distress syndrome; myocardial infarction; acute heart failure; cardiac and skeletal myopathy including Barth syndrome; stroke; traumatic brain injury; neuropathic pain; ataxia telangiectasia; ocular diseases; and cancer; comprising administering to a patient in need thereof, the compound of claim 1, in free or pharmaceutically acceptable salt form.
17. A method of inhibition of myofibroblast differentiation in a subject, comprising administering to said subject an effective amount of the compound of claim 1, in free or pharmaceutically acceptable salt form.
Description
EXPERIMENTAL PART
[0434] The following examples illustrate the invention but do not at all limit the scope thereof.
[0435] All temperatures are stated in C. Compounds are characterized by .sup.1H-NMR (Bruker Avance II, 400 MHz UltraShield, 400 MHz (.sup.1H), 100 MHz (.sup.13C); or Bruker Avance III HD, Ascend 500 MHz (.sup.1H), 125 MHz (.sup.13C) magnet equiped with DCH cryoprobe); chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, p=pentuplet, hex=hexet, hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz), in case non-deuterated DMSO was used as a solvent, the resonance of the solvent at 2.5 ppm was suppressed; by LC-MS: Finnigan MSQ plus or MSQ surveyor (Dionex, Switzerland), with HP 1100 Binary Pump and DAD (Agilent, Switzerland), column: Zorbax SB-AQ, 5 m, 120 , 4.650 mm (Agilent), gradient: 5-95% acetonitrile in water containing 0.04% of trifluoroacetic acid, within 1 min, flow: 4.5 mL/min; t.sub.R is given in min, or by TLC (TLC-plates from Merck, Silica gel 60 F.sub.254); or by melting point. Compounds are purified by preparative HPLC (column: X-terra RP18, 5019 mm, 5 m, gradient: 10-95% MeCN in water containing 0.5% of formic acid).
[0436] Abbreviations (as used herein): [0437] abs absolute [0438] aq. aqueous [0439] BSA bovine serum albumin [0440] CC column chromatography on silica gel [0441] DCM dichloromethane [0442] DIPEA Wining's base, diethylisopropylamine [0443] DMA N,N-dimethylacetamide [0444] DMF dimethylformamide [0445] DMSO dimethylsulfoxide [0446] EA ethyl acetate [0447] EDC N-(3-dimethylaminopropyI)-N-ethyl-carbodiimide [0448] Et ethyl [0449] EtOH ethanol [0450] h hour(s) [0451] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b ] pyridinium 3-oxid hexafluorophosphate [0452] HBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate [0453] HOBt 1-hydroxy-benzotriazole [0454] HPLC high performance liquid chromatography [0455] HV high vacuum conditions [0456] LC-MS liquid chromatography-mass spectrometry [0457] KOtBu potassium tert.-butylate [0458] Lit. literature [0459] Me methyl [0460] MeCN acetonitrile [0461] MeOH methanol [0462] min minute(s) [0463] NEt.sub.3 triethylamine [0464] org. organic [0465] PPh.sub.3 triphenylphosphine [0466] PyBOP benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluoro-phosphate [0467] prep. preparative [0468] rt room temperature [0469] sat. saturated [0470] TBTU 2-(1H-benzotriazole-1-yl)-1,2,3,3-tetramethyluronium tetrafluoroborate [0471] tert. tertiary [0472] TFA trifluoroacetic acid [0473] THF tetrahydrofuran [0474] TLC thin layer chromatography [0475] t.sub.R retention time
[0476] Preparation of Building Blocks
5-Nitrobenzo[d]oxazole-2-thiol
[0477] To a solution of 2-amino-4-nitrophenol (10 g, 64.2 mmol) in abs. EtOH (150 mL) potassium ethyl xanthogenate (12.6 g, 77.1 mmol) was added. The mixture was stirred under reflux for 5 h before it was cooled to rt and concetrated. The residue was dissolved in water (300 mL) and treated with 1 M aq. HCl (75 mL) with vigorous stirring. The precipitate that formed was collected, washed with water (50 mL) and dried under HV for 2 days to give the title compound (or tautomer) (11.9 g) as a grey-beige solid; LC-MS: t.sub.R=0.71 min; [M+H].sup.+ =not detectable; .sup.1H NMR (400 MHz, D.sub.6-DMSO) 14.33 (s br, 1H), 8.21 (dd, J.sub.1=2.3 Hz, J.sub.2=8.9 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H).
2-Chloro-5-nitrobenzo[d]oxazole
[0478] To a suspension of 5-nitrobenzo[d]oxazole-2-thiol (5.9 g, 30 mmol) in thionyl chloride (54.7 mL, 751 mmol) DMF (0.04 mL, 0.456 mmol) was added. The mixture was heated to 65 C. and stirred for 1 h. The mixture was cooled to rt and concentrated. The residue was suspended in toluene (30 mL) and the solvent was again evaporated. The residue was then taken up in DCM (25 mL) and purified by CC eluting with heptane:EA 4:1 to give the title compound (4.4 g) as a beige solid; LC-MS: t.sub.R=0.78 min; [M+H].sup.+ =not detectable; .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.61 (d, J=2.3 Hz, 1H), 8.38 (dd, J.sub.1=2.3 Hz, J.sub.2=9.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H).
5-Nitrobenzo[d]oxazole-2-thiol
[0479] A mixture of 2-amino-4-nitrophenol (4.0 g, 26 mmol) and potassium xanthogenate (5.0 g, 31.2 mmol) in EtOH (100 mL) was refluxed for 24 h before it was stirred at rt for two additional days. The precipitat that formed was collected, washed with EtOH and dried to give the title compound (or tautomer) (5.3 g) as an orange solid; LC-MS: t.sub.R=0.71 min; [M+H].sup.+ =not detectable; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 7.85 (dd, J.sub.1=2.4 Hz, J.sub.2=8.6 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H).
5-Aminobenzo[d]oxazole-2-thiol
[0480] To a suspension of 5-nitrobenzo[d]oxazole-2-thiol (1.0 g, 5.1 mmol) in EtOH (38 mL,) and H.sub.2O (38 mL) at 80 C. was added NH.sub.4Cl (545 mg, 10.2 mmol), followed by Fe (1.40 g, 25 mmol). The resulting mixture was stirred at 80 C. for 1.5 h. The mixture was cooled to rt, filtered and the filtrate was concentrated. The precipitate that formed was collected, washed with water and dried to give the title compound (or tautomer) (640 mg) as a beige powder; LC-MS: t.sub.R=0.37 min; [M+H].sup.+=208.06; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 13.39 (s br, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.36-6.51 (m, 2H), 5.26 (s br, 2H).
Methyl 2-mercaptobenzo[d]oxazole-5-carboxylate
[0481] To a solution of methyl 3-amino-5-hydroxybenzoate (1.0 g, 5.98 mmol) in MeOH (13.5 mL) KOH (468 mg, 7.18 mmol) was added. The mixture was stirred at rt until all KOH had dissolved. Then CS.sub.2 (9.02 mL, 150 mmol) was added and the mixture was stirred at 60 C. for 16 h before it was cooled to 0 C. and diluted with EA (50 mL). 1M aq. HCl (8.6 mL) was added to acidify the mixture to pH 1. The organic layer was separated, washed with water (25 mL), dried over MgSO.sub.4, filtered and concentrated to give the title compound (or tautomer) (1.18 g) as a solid; LC-MS: t.sub.R=0.72 min; [M+H].sup.+=209.96; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 14.14 (s, 1H), 7.89 (dd, J.sub.1=1.7 Hz, J.sub.2=8.5 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 3.88 (s, 3H).
Methyl 2-chlorobenzo[d]oxazole-5-carboxylate
[0482] To a solution of methyl 2-mercaptobenzo[d]oxazole-5-carboxylate 1.08 g, 5.16 mmol) in DCM (5.5 mL) POCl.sub.3 (4.25 mL, 46.5 mmol) followed by PCl.sub.S (1.29 g, 6.19 mmol) was added. The mixture was stirred at rt for 8 h before it was concentrated. The remaining oil was cooled with an ice bath before sat. aq. NaHCO.sub.3 solution (50 mL) was added. When the evolution of gas had ceased the mixture was transferred to a separating funnel and extracted twice with DCM (250 mL). The combined organic extracts were dried over MgSO.sub.4, filtered and concentrated. The crude product was suspended in diethyl ether (10 mL). The suspension was stirred for 10 min before it was filtered. The filtrate was concentrated and dried to give the title compound (0.62 g) as a solid; LC-MS: t.sub.R=0.80 min; [M+H+CH.sub.3CN].sup.+=253.04; .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.40 (d, J=1.2 Hz, 1H), 8.15 (dd, J.sub.1=1.6 Hz, J.sub.2=8.7 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 3.99 (s, 3H).
5-Nitrobenzo[d]thiazole-2-thiol
[0483] To a solution of 2-fluoro-5-nitroaniline (3.12 g, 20 mmol) in DMF (15 mL) potassium ethyl xanthogenate (3.93 g, 24 mmol) was added. The mixture was stirred at 100 C. for 5 h before it was cooled to rt, diluted with water (25 mL) and 1 M aq. HCl (35 mL). The precipitate that formed was collected, washed with water (15 mL) and dried to give the title compound (or tautomer) (3.99 g) as a beige solid; LC-MS: t.sub.R=0.76 min; [M+H].sup.+ =not detectable; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 14.17 (s, 1H), 8.15 (dd, J.sub.1=2.2 Hz, J.sub.2=8.8 Hz, 1H), 7.99 (d, J=9.0 Hz), 7.97 (d, J=2.3 Hz).
2-Chloro-5-nitrobenzo[d]thiazole
[0484] Solid 5-nitrobenzo[d]thiazole-2-thiol (4.0 g, 18.8 mmol) was placed in a round bottom flask and cooled to 0 C. while SO.sub.2Cl.sub.2 (9.1 mL, 113 mmol) was slowly added at 0 C. Upon complete additions, the yellow suspension was stirred at 0 C. for 5 min, then at rt for 2 h. The mixture was poured onto ice/water (200 mL) and stirred for 1h. The precipitate that formed was collected, washed with water and dried under high vacuum. The material was slurried in EA (25 mL), vigorously stirred for 15 min and filtered. The filtrate was concentrated and dried. The obtained solid absorbed to silica gel and purified by CC eluting with heptane:EA 4:1 to give the title compound (2.02 g) as a solid; LC-MS: t.sub.R=0.84 min; [M+H].sup.+=214.51; .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.84 (d, J=2.2 Hz, 1H), 8.35 (dd, J.sub.1=2.2 Hz, J.sub.2=8.9 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H).
2-Chlorobenzo[d]thiazol-5-amine
[0485] To a solution of 2-chloro-5-nitrobenzo[d]thiazole (2.18 g, 10.2 mmol) in EtOH:acetic acid 91:9 (102 mL) iron powder (5.70 g, 102 mmol) was carefully added. The mixture was refluxed for 1.5 h before it was filtered. The filtrate was concentrated to about one third of the volume and the pH of the solution was adjusted to pH 8 by adding 10% aq. NaOH solution. The mixture was extracted with EA (150 mL). The organic extract was washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was suspended in EtOH (4 mL), filtered, washed with additional EtOH (0.5 mL) and dried to give the title compound (1.55 g) as a solid; LC-MS: t.sub.R=0.78 min; [M+H].sup.+=185.03; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 7.65 (d, J=8.7 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.79 (dd, J.sub.1=2.0 Hz, J.sub.2=8.7 Hz, 1H), 5.43 (s, 2H).
2-Chloro-benzothiazole-5-carbonyl chloride
[0486] To a mixture of 2-sulfanyl-1,3-benzothiazole-5-carboxylic acid (50.1 mg, 0.237 mmol), PCl.sub.5 (158 mg, 0.745 mmol) and POCl.sub.3 (0.446 mL, 4.74 mmol), DMF (0.042 mL, 0.524 mmol) was carefully added. The mixture became warm and the thick suspension was stirred at rt for 3 h to become a clear solution. The mixture was concentrated and diluted with DCM, solid material was filtered off and the filtrate was concentrated and dried to give the crude title compound (92 mg) as a pale yellow resin which was used without further purification; LC-MS: t.sub.R=0.91 min; [M+H].sup.+ =not detectable.
[0487] Preparation of Intermediates
[0488] Intermediate A1
4-(5-Aminobenzo[d]oxazol-2-yl)thiomorpholine 1,1-dioxide
[0489] a) To a solution of 2-chloro-5-nitrobenzo[d]oxazole (1.0 g, 5.0 mmol) and Et.sub.3N (2.1 mL, 15.1 mmol) in THF (25 mL) thiomorpholine 1,1-dioxide (715 mg, 5.29 mmol) was added. The mixture was stirred at 70 C. for 3 h before it was diluted with water (100 mL) and extracted with EA (200 mL) followed by DCM (100 mL). The combined org. extracts were dried over MgSO.sub.4, filtered and concentrated. The remaining solid was suspended in DCM (10 mL), filtered off, washed with additonal DCM (5 mL) and dried to give a first batch of the title compound (698 mg). The filtrate was concentrated and once more suspended in DCM (2 mL). Solid material was collected, washed with a small amount of DCM and dried to give a second batch of the title compound (460 mg). The obtained solid materials were combined; LC-MS: t.sub.R=0.69 min; [M+H].sup.+=297.98; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 8.15 (d, J=2.3 Hz, 1H), 8.04 (dd, J,=2.3 Hz, J.sub.2=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 4.08-4.16 (m, 4H), 3.35-3.42 (m, 4H).
[0490] b) To a solution of 4-(5-nitrobenzo[d]oxazol-2-yl)thiomorpholine 1,1-dioxide (1.10 g, 3.7 mmol) in acetic acid (25 mL) iron powder (2.07 g, 37 mmol) was added carefully. The mixture was stirred at 40 C. for 2 h before it was filtered. The filtrate is diluted with water (50 mL) and the pH was adjusted to 13-14 by adding 5 M aq. NaOH solution. The mixture was extracted twice with DCM (2100 mL), the combined org. extracts were dried over MgSO.sub.4, filtered and dried to give the title compound (908 mg) as a grey solid; LC-MS: t.sub.R=0.38 min; [M+H].sup.+=268.07; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 7.07 (d, J=8.5 Hz, 1H), 6.53 (d, J=2.1 Hz, 1H), 6.28 (dd, J,=2.2 Hz, J.sub.2=8.5 Hz, 1H), 4.84 (s, 2H), 3.98-4.05 (m, 4H), 3.26-3.32 (m, 4H). or alternatively:
[0491] b) To a mixture of 4-(5-nitrobenzo[d]oxazol-2-yl)thiomorpholine 1,1-dioxide (10 mg, 0.05 mmol) in degassed EA (0.5 mL) wet Pd/C (10 mg) was added before it was stirred under 4 bar of H.sub.2 at rt for 16 h. The catalyst was removed by filtration and the filtrate was concentrated and dried to give the title compound (5 mg).
[0492] Intermediates A2 to A38
[0493] The following 5-amino-benzo[d]oxazol derivatives were obtained in analogy to Intermediate A1:
TABLE-US-00001 LC-MS Intermediate Name t.sub.R [min] [M + H].sup.+ A2 2-(piperidin-1-yl)benzo[d]oxazol-5-amine 0.52 218.31 A3 2-(pyrrolidin-1-yl)benzo[d]oxazol-5-amine 0.46 204.29 A4 2-(4-methylpiperazin-1-yl)benzo[d]oxazol-5-amine 0.17 233.29 A5 2-morpholinobenzo[d]oxazol-5-amine 0.42 220.30 A6 N.sup.2,N.sup.2-diethylbenzo[d]oxazole-2,5-diamine 0.50 206.27 A7 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzo[d]oxazol-5-amine 0.42 232.24 A8 2-(4,4-difluoropiperidin-1-yl)benzo[d]oxazol-5-amine 0.54 254.24 A9 2-(3,3-difluoroazetidin-1-yl)benzo[d]oxazol-5-amine 0.46 267.26* A10 2-(3,3-difluoropyrrolidin-1-yl)benzo[d]oxazol-5-amine 0.50 240.24 A11 2-(3-methoxypyrrolidin-l-yl)benzo[d]oxazol-5-amine 0.45 234.12 A12 2-(4-methoxypiperidin-1-yl)benzo[d]oxazol-5-amine 0.49 248.29 A13 1-(5-aminobenzo[d]oxazol-2-yl)-3-methylazetidin-3-ol 0.40 220.24 A14 N.sup.2-(2-(dimethylamino)ethyl)-N.sup.2-methylbenzo[d]oxazole-2,5-diamine 0.18 234.93 A15 2-(4-(dimethylamino)piperidin-1-yl)benzo[d]oxazol-5-amine 0.29 261.33 A16 2-(6-oxa-1-azaspiro[3.3]heptan-l-yl)benzo[d]oxazol-5-amine 0.42 232.24 A17 2-(3,3-difluoropiperidin-1-yl)benzo[d]oxazol-5-amine 0.53 254.26 A18 2-(3-morpholinoazetidin-1-yl)benzo[d]oxazol-5-amine 0.24 275.16 A19 N.sup.2-methyl-N.sup.2-(3-methyloxetan-3-yl)benzo[d]oxazole-2,5-diamine 0.45 234.24 A20 4-(1-(5-aminobenzo[d]oxazol-2-yl)azetidin-3-yl)thiomorpholine 1,1-dioxide 0.43 323.00 A21 1-(5-aminobenzo[d]oxazol-2-yl)-3-methyl-[1,3-biazetidin]-3-ol 0.24 275.05 A22 2-(1-oxa-6-azaspiro[3.3]heptan-6-yl)benzo[d]oxazol-5-amine 0.44 232.11 A23 2-(2-oxa-6-azaspiro[3.4]octan-6-yl)benzo[d]oxazol-5-amine 0.44 246.15 A24 2-(6-oxa-2-azaspiro[3.5]nonan-2-yl)benzo[d]oxazol-5-amine 0.50 260.15 A25 2-(2-oxa-5-azaspiro[3.4]octan-5-yl)benzo[d]oxazol-5-amine 0.45 246.14 A26 2-(1-oxa-6-azaspiro[3.5]nonan-6-yl)benzo[d]oxazol-5-amine 0.46 260.15 A27 2-(2-oxa-5-azaspiro[3.5]nonan-5-yl)benzo[d]oxazol-5-amine 0.49 260.15 A28 2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)benzo[d]oxazol-5-amine 0.47 260.16 A29 2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzo[d]oxazol-5-amine 0.49 274.16 A30 2-(1-oxa-8-azaspiro[4.5]decan-8-yl)benzo[d]oxazol-5-amine 0.53 274.16 A31 2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzo[d]oxazol-5-amine 0.48 260.16 A32 2-(5-oxa-2-azaspiro[3.4]octan-2-yl)benzo[d]oxazol-5-amine 0.48 246.15 A33 1-(1-(5-aminobenzo[d]oxazol-2-yl)azetidin-3-yl)piperidin-4-ol 0.20 289.15 A34 2-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)benzo[d]oxazol-5-amine 0.34 273.18 A35 2-(5-oxa-2-azaspiro[3.5]nonan-2-yl)benzo[d]oxazol-5-amine 0.52 260.15 A36 2-(1-azaspiro[3.3]heptan-1-yl)benzo[d]oxazol-5-amine 0.55 230.18 A37 2-(7-oxa-1-azaspiro[3.5]nonan-1-yl)benzo[d]oxazol-5-amine 0.48 260.16 A38 tert-butyl 1-(5-aminobenzo[d]oxazol-2-yl)azetidine-3-carboxylate 0.60 290.15 *represents [M + H + CH.sub.3CN].sup.+.
[0494] Intermediate A5: .sup.1H NMR (500 MHz, D.sub.6-DMSO) : 7.04 (d, J=8.4 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.25 (dd, J,=2.2 Hz, J.sub.2=8.4 Hz, 1H), 4.81 (s, 2H), 3.67-3.73 (m, 4H), 3.48-3.55 (m, 4H).
[0495] Intermediate A39
1-(5-Aminobenzo[d]oxazol-2-yl)pyrrolidin-2-one
[0496] a) To a solution of 2-chloro-5-nitrobenzo[d]oxazole (800 mg, 4.03 mmol) in DCM (25 mL) were added ethyl 4-aminobutyrate hydrochloride (810 mg, 4.83 mmol) followed by DIPEA (1.59 mL, 9.27 mmol) at 0 C. The mixture was stirred at rt overnight before it was concentrated in vacuo, diluted with EA, washed with brine, dried over MgSO.sub.4, filtered and concentrated. The crude product was purified by CC eluting with heptane:EA 1:1 to give ethyl 4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoate (1.01 g) as a yellow powder, LC-MS: t.sub.R=0.77 min; [M+H].sup.+=294.1.
[0497] b) A suspension of ethyl 4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoate (1.01 g, 3.44 mmol) in EtOH (20 mL) and 1M aq. NaOH (5.2 mL) was stirred at rt overnight before it was cooled with an ice bath. 1 M aq. HCl was added (5.2 mL) and the mixture was concentrated and dried to give crude 4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoic acid (1.22 g) as a yellow powder, LC-MS: t.sub.R=0.60 min; [M+H].sup.+=266.14. This material was dissolved in DCM (25 mL) and SOCl.sub.2 (0.89 mL, 12.1 mmol) was added. The mixture was stirred at rt for 2 h before it was concentrated in vacuo, dissolved in pyridine (10 mL) and stirred at rt for 1 h. The mixture was again concentrated, diluted with DCM and washed with brine. The organic extract was separated and the precipitate that formed was removed by filtration (unreacted SM). The filtrate was dried over MgSO.sub.4, filtered and concentrated. The crude product was first purified by CC eluting with DCM:MeOH 10:1, then by prep. HPLC to give 1-(5-nitrobenzo[d]oxazol-2-yl)pyrrolidin-2-one (133 mg) as a white solid, LC-MS: t.sub.R=0.64 min; [M+H].sup.+=248.11; .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.50 (d, J=2.3 Hz, 1H), 8.25 (dd, J.sub.1=2.3 Hz, J.sub.2=8.9 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 4.17-4.23 (m, 2H), 2.76 (t, J=7.9 Hz, 2H), 2.30-2.39 (m, 2H).
[0498] c) To a solution of 1-(5-nitrobenzo[d]oxazol-2-yl)pyrrolidin-2-one (133 mg, 0.538 mmol) in EA (2 mL) Pd/C (7 mg, 10% Pd, 50% wet) was added. The mixture was stirred under 1 bar of H.sub.2 at rt for 18 h before the catalyst was removed by filtration. The filtrate was concentrated and dried to give 1-(5-aminobenzo[d]oxazol-2-yl)pyrrolidin-2-one (105 mg) as a white solid, LC-MS: t.sub.R=0.32 min; [M+H].sup.+=218.11.
TABLE-US-00002 LC-MS Intermediate Name t.sub.R [min] [M + H].sup.+ A40 2-Azetidin-1-yl-benzooxazol-5-ylamine 0.43 190.16 A41 1-(5-Amino-benzooxazol-2-yl)-piperidin-4-ol 0.54 234.15 A42 2-(2-Oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-ylamine 0.64 260.15 A43 1-(5-Amino-benzooxazol-2-yl)-azetidin-3-ol 0.50 206.15 A44 N.sup.2-Cyclopropyl-N.sup.2-oxetan-3-yl-benzooxazole-2,5-diamine 0.65 246.12 A45 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-ylamine 0.62 246.14 A46 2-(2-Oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-ylamine 0.66 260.14 A47 N.sup.2-Ethyl-benzooxazole-2,5-diamine 0.36 178.18 A48 2-(3-Pyridin-2-yl-azetidin-1-yl)-benzooxazol-5-ylamine 0.38 267.08
[0499] Intermediate B1
N-(2-Mercaptobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide
[0500] To a mixture of 5-aminobenzo[d]oxazole-2-thiol (540 mg, 3.25 mmol) in pyridine (27 mL) was added 2,3-dihydrobenzofuran-5-carbonyl chloride (593 mg, 3.25 mmol) at rt. The reaction mixture was stirred at rt for 1.5 h before another portion of 2,3-dihydrobenzofuran-5-carbonyl chloride (30 mg, 0.16 mmol) was added. Stirring was continued at rt for 1 h before the mixture was concentrated. The residue was treated with water, the resulting suspension was sonicated before the solid material was collected by filtration, washed and dried to give the title compound (890 mg) as a pink solid; LC-MS: t.sub.R=0.77 min; [M+H].sup.+=312.97; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 13.84 (s br, 1H), 10.21 (s, 1H), 7.93 (d, J=1.7 Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J.sub.1=1.3 Hz, J.sub.2=8.3 Hz, 1H), 7.55 (dd, J.sub.1=1.8 Hz, J.sub.2=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.27 (t, J=8.8 Hz, 2H).
[0501] Intermediate C1
2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylic acid
[0502] a) To a solution of methyl 2-chlorobenzo[d]oxazole-5-carboxylate (98.5 mg, 465 mol) in THF(1.5 mL) Et.sub.3N (195 L, 1.4 mmol) followed by 1-methylpiperazine (63 L, 559 mol) was added. The mixture was stirred at 65 C. for 16 h before it was cooled to rt and concentrated. The residue was dissolved in CH.sub.3CN (1 mL) and DMF (1 mL), filtered and the filtrate was separated by prep. HPLC to give methyl 2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate (80 mg) as a solid; LC-MS: t.sub.R=0.51 min; [M+H].sup.+=276.16; .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.04 (d, J=1.5 Hz, 1H), 7.83 (dd, J.sub.1=1.7 Hz, J.sub.2=8.4 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 3.77-3.82 (m, 4H), 2.57-2.62 (m, 4H), 2.41 (s, 3H).
[0503] b) To a solution of methyl 2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate (76 mg, 0.28 mmol) in THF (1 mL) and MeOH (1 mL) a 1 M aq. solution of NaOH (0.55 mL) was added. The mixture was stirred at rt for 18 h before it was neutralized by adding 1 M aq. HCl. The precipitate that formed was collected and dried to give the title compound (49 mg) as hydrochloride salt as a white solid; LC-MS: t.sub.R=0.43 min; [M+H].sup.+=262.11; .sup.1H NMR (400 MHz, DMSO) : 12.93 (s, 1H), 11.04 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.75 (dd, J.sub.1=1.7 Hz, J.sub.2=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.21-4.37 (m, 2H), 3.43-3.71 (m, 4H), 3.08-3.27 (m, 2H), 2.80 (s, 3H).
[0504] Intermediates C2 to C6
[0505] The following 2-aminobenzo[d]oxazole-5-carboxylic acid derivatives were obtained in analogy to Intermediate C1:
TABLE-US-00003 LC-MS Intermediate Name t.sub.R [min] [M + H].sup.+ C2 2-Piperidin-1-yl-benzooxazole-5-carboxylic acid 0.70 247.13 C3 2-Morpholin-4-yl-benzooxazole-5-carboxylic acid 0.61 249.11 C4 2-Diethylamino-benzooxazole-5-carboxylic acid 0.68 235.11 C5 2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic acid 0.61 233.16 C6 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazole- 0.60 261.04 5-carboxylic acid
[0506] Intermediate C2: .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 12.82 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.66 (dd, J,=1.7 Hz, J.sub.2=8.3 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 3.59-3.65 (m, 4H), 1.57-1.68 (m, 6H).
[0507] Intermediate C3: .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 12.86 (s, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.70 (dd, J,=1.6 Hz, J.sub.2=8.3 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 3.71-3.76 (m, 4H), 3.60-3.65 (m, 4H).
[0508] Intermediate C4: .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 12.80 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.65 (dd, J,=1.7 Hz, J.sub.2=8.3 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 3.56 (q, J=7.1 Hz, 4H), 1.22 (t, J=7.1 Hz, 7H).
[0509] Intermediate C5: .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 12.80 (s, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.65 (dd, J,=1.7 Hz, J.sub.2=8.3 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 3.54-3.60 (m, 4H), 1.95-2.01 (m, 4H).
[0510] Intermediate C6: .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 12.88 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.72 dd, J.sub.1=1.7 Hz, J.sub.2=8.3 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 5.22 (d, J=7.7 Hz, 2H), 4.67 (d, J=7.7 Hz, 2H), 4.04 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H).
[0511] Intermediate D1
2-(Piperidin-1-yl)benzo[d]thiazol-5-amine
[0512] a) To a solution of 2-chloro-5-nitrobenzo[d]thiazole (200 mg, 931 mol) in THF (1.5 mL) Et.sub.3N (0.195 mL, 1.4 mmol) followed by piperidine (0.138 mL, 1.4 mmol) was added. The mixture was stirred at 65 C. for 1 h before it was diluted with EA (50 mL) and washed with water (50 mL). The organic extract was dried over MgSO.sub.4, filtered and concentrated to give 5-nitro-2-(piperidin-1-yl)benzo[d]thiazole (250 mg) as a solid; LC-MS: t.sub.R=0.92 min; [M+H].sup.+=264.18.
[0513] b) To a solution of 5-nitro-2-(piperidin-1-yl)benzo[d]thiazole (245 mg, 0.93 mmol) in EtOH (15 mL) Pd/C (125 mg, 10% Pd, 50% water wet) was added. The mixture was stirred under 1 atm of H.sub.2 for 4 days before the catalyst was removed by filtration and the filtrate was evaporated. The crude product was purified by prep. HPLC to give the title compound (73 mg) as a solid; LC-MS: t.sub.R=0.54 min; [M+H].sup.+=234.17; .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.33 (d, J=8.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.49 (dd, J.sub.1=2.2 Hz, J.sub.2=8.3 Hz, 1H), 3.77 (s br, 2H), 3.56-3.64 (m, 4H), 1.67-1.77 (m, 6H).
[0514] Intermediates D2 to D17
[0515] The following 5-amino-benzo[d]thiazol derivatives were obtained in analogy to Intermediate D1:
TABLE-US-00004 LC-MS Intermediate Name t.sub.R [min] [M + H].sup.+ D2 2-Morpholin-4-yl-benzothiazol-5-ylamine 0.46 236.16 D3 2-(4-Methyl-piperazin-1-yl)-benzothiazol-5-ylamine 0.27 249.19 D4 2-Pyrrolidin-1-yl-benzothiazol-5-ylamine 0.48 220.11 D5 N2,N2-Diethyl-benzothiazole-2,5-diamine 0.52 222.13 D6 N2,N2-Dimethyl-benzothiazole-2,5-diamine 0.42 194.12 D7 2-(3,3-Difluoro-azetidin-1-yl)-benzothiazol-5-ylamine 0.52 241.95 D8 2-(3,3-Difluoro-pyrrolidin-1-yl)-benzothiazol-5-ylamine 0.54 256.10 D9 2-(3,3-Difluoro-piperidin-1-yl)-benzothiazol-5-ylamine 0.57 270.10 D10 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazol-5-ylamine 0.47 248.12 D11 2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-ylamine 0.45 248.12 D12 2-(1,1-Dioxo-1l6-thiomorpholin-4-yl)-benzothiazol-5-ylamine 0.43 284.04 D13 N2-(2-Dimethylamino-ethyl)-N2-methyl-benzothiazole-2,5-diamine 0.33 251.15 D14 2-(3-Methoxy-pyrrolidin-1-yl)-benzothiazol-5-ylamine 0.48 250.12 D15 2-(4-Methoxy-piperidin-1-yl)-benzothiazol-5-ylamine 0.52 264.15 D16 1-(5-Amino-benzothiazol-2-yl)-3-methyl-azetidin-3-ol 0.44 236.11 D17 2-(4-Dimethylamino-piperidin-1-yl)-benzothiazol-5-ylamine 0.35 277.14
[0516] Intermediate D2: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.37 (d, J=8.3 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.54 (dd, J.sub.1=2.2 Hz, J.sub.2=8.3 Hz, 1H), 3.83-3.87 (m, 4H), 3.60-3.66 (m, 4H).
[0517] Intermediate D3: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.36 (d, J=8.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.52 (dd, J,=2.2 Hz, J.sub.2=8.3 Hz, 1H), 3.70 (s br, 2H), 3.63-3.68 (m, 4H), 2.51-2.61 (m, 4H), 2.39 (s, 3H).
[0518] Intermediated D9: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.36 (d, J=8.3 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.54 (dd, J,=2.2 Hz, J.sub.2=8.4 Hz, 1H), 3.88 (t, J=11.4 Hz, 2H), 3.62-3.68 (m, 2H), 2.07-2.19 (m, 2H), 1.92-2.00 (m, 2H).
[0519] Intermediate D10: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.38 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 6.57 dd, J.sub.1=1.8 Hz, J.sub.2=8.5 Hz, 1H), 5.48 (d, J=7.7 Hz, 2H), 4.75 (d, J=7.7 Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H).
[0520] Intermediate E1
N-(2-Chlorobenzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide
[0521] To a solution of 2,3-dihydrobenzo[b]furan carboxylic acid (1.27 g, 7.5 mmol) in DMF (22.5 mL) TBTU (2.48 g, 7.5 mmol) followed by DIPEA (3.93 mL, 22.5 mmol) was added. The mixture was stirred at rt for 15 min before 2-chlorobenzo[d]thiazol-5-amine (1.52 g, 7.5 mmol) was added. Stirring is continued at 55 C. for 18 h. The mixture was concentrated, diluted with DCM (250 mL) and washed with sat. aq. NaHCO.sub.3 solution (125 mL). The organic extract was separated and concentrated. The crude product was purified by CC eluting with a gradient of heptane:EE 1:2 to pure EA to give the title compound (980 mg) as a solid; LC-MS*: t.sub.R=1.01 min; [M+H].sup.+=330.95 (*=0.5% NH.sub.4OH instead of TFA in eluting solvent.); .sup.1H NMR (400 MHz, DMSO) : 10.32 (s, 1H), 8.50 (d, J=1.9 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.87 dd, J.sub.1=2.0 Hz, J.sub.2=8.8 Hz, 1H), 7.83 dd, J.sub.1=1.9 Hz, J.sub.2=8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.65 (t, J=8.8 Hz, 2H), 3.28 (t, J=8.7 Hz, 2H).
[0522] Intermediate E2
2-Chloro-N-(2,3-dihydrobenzofuran-5-yl)benzo[d]thiazole-5-carboxamide
[0523] A solution of 2,3-dihydro-1-benzofuran-5-amine (33.7 mg, 0.237 mmol) and DIPEA (0.21 mL, 1.18 mmol) in DCM (1 mL) was cooled to 0 C. before crude 2-chloro-benzothiazole-5-carbonyl chloride (92 mg, 0.237 mmol) dissolved in DCM (1 mL) was added. The mixture was stirred at rt for 30 min. The mixture was diluted with DCM (5 mL) and washed with water (5 mL). the organic extract was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude title compound (69 mg) as a pale yellow resin; LC-MS: t.sub.R=0.86 min; [M+H].sup.+=330.97; .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.28 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.07 dd, J.sub.1=1.5 Hz, J.sub.2=8.5 Hz, 1H), 7.70 (s,1H), 7.45 dd, J.sub.1=1.7 Hz, J.sub.2=8.5 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.21 (t, J=8.7 Hz, 2H).
[0524] Intermediate E3
N-Benzo[d][1,3]dioxo1-5-yl)-2-chlorobenzo[d]thiazole-5-carboxamide
[0525] The title compound was prepared in analogy to Intermediate E2; LC-MS: t.sub.R=0.86 min; [M+H].sup.+=332.98; .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.34 (s, 1H), 8.56 (d, J=1.3 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.06 (dd, J.sub.1=1.6 Hz, J.sub.2=8.5 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 7.23 (dd, J.sub.1=2.0 Hz, J.sub.2=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.03 (s, 2H).
[0526] Intermediate E4
2-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d]thiazole-5-carboxamide
[0527] The title compound was prepared in analogy to Intermediate E2; LC-MS: t.sub.R=0.87 min; [M+H].sup.+=346.90; .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.28 (s, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.06 (dd, J.sub.1=1.6 Hz, J.sub.2=8.5 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.24 (dd, J.sub.1=2.4 Hz, J.sub.2=8.8 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.19-4.32 (m, 4H).
EXAMPLE 1
2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide
[0528] To a solution of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (18.5 mg, 113 mol) in DCM (2 mL) 1-chloro-N,N-2-trimethylpropenylamine (17 L, 124 mol) was added. The mixture was stirred at rt for 15 min before DIPEA (96 L, 563 mol) and 4-(5-aminobenzo[d]oxazol-2-yl)thiomorpholine 1,1-dioxide (30.1 mg, 113 mmol) was added. Stirring was continued at rt for 30 min. The mixture was diluted with DMF (2 mL) and separated using prep. HPLC (column: XBridge Prep C18, 3075 mm, 10 m, gradient of MeCN in water containing 0.5% of 15 M aq. NH.sub.4OH) to give the title compound (30 mg) as a white solid; LC-MS: t.sub.R=0.73 min; [M+H].sup.+ =414.05; .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.03 (s, 1H), 7.88 (s, 1H), 7.77-7.82 (m, 2H), 7.38-7.46 (m, 2H), 6.88 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H), 4.04-4.11 (m, 4H), 3.32-3.39 (m, 4H), 3.26 (t, J=8.7 Hz, 2H).
EXAMPLES 2 to 41
[0529] The following Example compounds were prepared in analogy to Example 1 starting from the appropriate Intermediates A2 to A39 and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid, 2,3-dihydrobenzofuran-5-carboxylic acid, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid, benzo[d][1,3]dioxole-5-carboxylic acid, or chromane-6-carboxylic acid.
TABLE-US-00005 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 2 2,3-Dihydro-benzofuran-5-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide 0.78 364.26 3 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide 0.71 350.29 4 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-l-yl)-benzooxazol-5-yl]-amide 0.59 379.23 5 2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide 0.76 366.25 6 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide 0.75 352.29 7 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.86 400.20 8 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.82 372.10 9 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.93 386.04 10 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.84 380.04 11 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.89 394.09 12 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.78 366.04 13 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzooxazol-5-yl}-amide; 0.60 381.08 compound with formic acid 14 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-dimethylamino-piperidin-1-yl)-benzooxazol-5-yl]-amide; 0.78 406.95 compound with formic acid 15 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 0.75 378.23 16 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.85 400.21 17 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-morpholin-4-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.59 421.02 18 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(3-methyl-oxetan-3-yl)amino]-benzooxazol-5-yl}-amide 0.78 380.20 19 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1,1-dioxo-1l6-thiomorpholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}- 0.70 469.10 amide 20 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-[1,3]biazetidinyl-1-yl)-benzooxazol-5-yl]-amide 0.61 421.20 21 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 0.74 378.20 22 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzooxazol-5-yl]-amide 0.70 392.20 23 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 0.77 406.11 24 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 0.76 392.11 25 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 0.75 406.11 26 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.5]non-5-yl)-benzooxazol-5-yl]-amide 0.84 406.12 27 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.76 406.09 28 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.73 420.13 29 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-benzooxazol-5-yl]-amide 0.80 420.12 30 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 0.76 406.11 31 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide 0.78 392.11 32 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(4-hydroxy-piperidin-1-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide 0.58 435.15 33 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-methyl-2,6-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 0.61 419.14 34 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 0.82 406.12 35 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 0.83 376.10 36 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 0.75 406.11 37 1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl)-azetidine-3-carboxylic acid tert-butyl ester 0.88 436.11 38 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxo-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.66 364.15 39 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide 0.73 429.90 40 Chroman-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide 0.77 427.97 41 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(1,1-dioxo- 0.75 442.94 thiomorpholin-4-yl)-benzooxazol-5-yl]-amide
EXAMPLE 3
[0530] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.01 (s, 1H), 7.83 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.27-7.33 (m, 2H), 6.85 (d, J=8.1 Hz, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.50-3.55 (m, 4H), 3.23 (t, J=8.3 Hz, 2H), 1.91-1.99 (m, 4H).
EXAMPLE 5
[0531] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.04 (s, 1H), 7.84 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.35 (s, 2H), 6.85 (dd, J.sub.1=2.2 Hz, J.sub.2=8.3 Hz, 1H), 4.56-4.65 (m, 2H), 3.51-3.69 (m, 8H), 3.19-3.27 (m, 2H).
EXAMPLE 6
[0532] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.01 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.63 (s, 1H), 7.23-7.33 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 4.60 (t, J=8.7 Hz, 2H), 3.50 (q, J=6.7 Hz, 4H), 3.23 (t, J=8.6 Hz, 2H), 1.18 (t, J=6.9 Hz, 6H).
EXAMPLE 15
[0533] .sup.1H NMR (400 MHz, DMSO) : 10.04 (s, 1H), 7.89 (s, 1H), 7.78-7.83 (m, 2H), 7.43 (s, 2H), 6.89 (d, J=8.4 Hz, 1H), 5.22 (d, J=7.5 Hz, 2H), 4.61-4.69 (m, 4H), 4.02 (t, J=7.3 Hz, 2H), 3.27 (t, J=8.7 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H).
EXAMPLE 23
[0534] .sup.1H NMR (400 MHz, DMSO) : 10.02 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.34-7.43 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.65 (t, J=8.7 Hz, 2H), 3.87-3.95 (m, 4H), 3.68 (s, 2H), 3.51-3.56 (m, 2H), 3.27 (t, J=8.6 Hz, 2H), 1.84-1.91 (m, 2H), 1.50-1.58 (m, 2H).
EXAMPLE 26
[0535] .sup.1H NMR (400 MHz, DMSO) : 10.05 (s, 1H), 7.88 (s, 1H), 7.76-7.81 (m, 2H), 7.40 (s, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.79-4.84 (m, 2H), 4.64 (t, J=8.7 Hz, 2H), 4.43-4.48 (m, 2H), 3.27 (t, J=8.7 Hz, 2H), 2.02-2.09 (m, 2H), 1.69-1.77 (m, 2H), 1.39-1.47 (m, 2H).
EXAMPLE 30
[0536] .sup.1H NMR (400 MHz, DMSO) : 10.01 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=8.4 Hz, 1 H), 7.76 (d, J=1.2 Hz), 7.34-7.43 (m, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.65 (t, J=8.7 Hz, 2H), 3.98 (s, 4H), 3.53-3.60 (m, 2H), 3.27 (t, J=8.7 Hz, 2H), 1.76-1.84 (m, 4H).
EXAMPLE 34
[0537] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.82 (s, 1H), 7.80 (s, 1H), 7.68 (dd, J.sub.1=1.4 Hz, J.sub.2 =8.3 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.43 dd, J.sub.1=2.0 Hz, J.sub.2=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H), 4.21 (d, J=8.7 Hz, 2H), 4.11 (d, J=8.7 Hz, 2H), 3.69-3.73 (m, 2H), 3.29 (t, J=8.7 Hz, 2H), 1.86-1.92 (m, 2H), 1.68-1.75 (m, 2H), 1.57-1.64 (m, 2H).
EXAMPLE 39
[0538] .sup.1H NMR (400 MHz, DMSO) : 10.06 (s, 1H), 7.77 (s, 1H), 7.47-7.53 (m, 2H), 7.40 (s, 2H), 6.98 (d, J=8.3 Hz, 1H), 4.26-4.35 (m, 4H), 4.03-4.11 (m, 4H), 3.30-3.37 (m, 4H).
EXAMPLE 41: .SUP.1.H NMR (400 MHz, DMSO) : 9.99 (s, 1H), 7.77 (s, 1H), 7.39 (s, 2H), 7.23-7.29
[0539] (m, 2H), 6.77 (d, J=8.8 Hz, 1H), 4.26-4.33 (m, 2H), 4.03-4.11 (m, 4H), 3.30-3.37 (m, 4H), 3.24-3.30 (m, 2H), 2.90 (s, 3H).
EXAMPLE 37
1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylic acid tert-butyl ester
[0540] To a solution of 2,3-dihydrobenzofuran-5-carboxylic acid (10 mg, 63 mol) and HBTU (24 mg, 63 mol) in DMF (1 mL) DIPEA (33 L, 190 mol) was added. The mixtures were stirred at rt for 30 min before by tert-butyl 1-(5-aminobenzo[d]oxazol-2-yl)azetidine-3-carboxylate (18 mg, 63 mol) was added. Stirring was continued at 55 C. for 16 h. The mixture was separated by prep. HPLC to give 1-{5-[(2,3-dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylic acid tert-butyl ester (4 mg) as a colourless resin; LC-MS: t.sub.R=0.88 min; [M+H].sup.+=436.11.
EXAMPLE 42
(R)N-(2-(3-hydroxypiperidin-1-yl)benzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide
[0541] To a mixture of N-(2-mercaptobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide (Intermediate B1) (20 mg, 64 mol) in DCM (1 mL) and SOCl.sub.2 (0.1 mL) DMF (20 L) was added. The suspension was stirred at rt for 1 h before the solvent was removed in vacuo to give crude N-(2-chlorobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamid; LC-MS: t.sub.R=0.85 min; [M+H].sup.+=314.96. To this material a solution of (R)-piperidin-3-ol (7.8 mg, 77 mol) in DMF (0.8 mL) and K.sub.2CO.sub.3 (27 mg, 192 mol) was added. The mixture was stirred at 70 C. for 16 h before it was cooled to rt and separated by prep. HPLC to give the title compound (7 mg) as a colourless resin; LC-MS: t.sub.R=0.68 min; [M+H].sup.+=380.15; .sup.1H NMR (400 MHz, DMSO) : 9.99 (s, 1H), 7.86 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.30-7.36 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 5.06 (d, J=4.0 Hz, 1H), 4.63 (t, J=8.6 Hz, 2H), 3.88 (dd, J.sub.1=3.4 Hz, J.sub.2=13.0 Hz, 1H), 3.73-3.79 (m, 1H), 3.59-3.65 (m, 1H), 3.29-.3.36 (m, 1H), 3.25 (t, J=8.8 Hz, 2H), 3.14 (dd, J.sub.1=8.1 Hz, J.sub.2=12.5 Hz, 1H), 1.79-1.90 (m, 2H), 1.37-1.54 (m, 2H).
EXAMPLES 43 TO 74
[0542] The following Example compounds were prepared in analogy to Example 42 starting from Intermediate B1 and the appropriate amines.
TABLE-US-00006 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 43 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-l-yl)-benzooxazol-5-yl]-amide 0.74 380.08 44 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-isopropoxy-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.94 394.05 45 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.63 366.20 46 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-pyrrolidin-l-yl)-benzooxazol-5-yl]-amide 0.71 365.76 47 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.70 352.03 48 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.73 380.02 49 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 1.02 411.94 50 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.81 405.99 51 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-ethoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 1.02 408.02 52 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(3-fluoro-oxetan-3-ylmethyl)-methyl-amino]-benzooxazol-5-yl}- 0.82 397.73 amide 53 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-oxetan-3-yl-piperazin-1-yl)-benzooxazol-5-yl]-amide 0.59 421.18 54 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzooxazol-5-yl}- 0.74 448.93 amide 55 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 0.78 405.94 56 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-ylmethyl-amino)-benzooxazol-5-yl]-amide 0.77 379.94 57 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide 0.77 365.71 58 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin-1-yl)benzooxazol-5-yl]-amide 0.95 393.95 59 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.87 393.98 60 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.86 407.04 61 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 0.66 407.24 62 rac-2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.96 412.01 63 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide 0.82 391.99 64 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.78 405.02 65 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-benzooxazol-5-yl}- 0.76 393.80 amide 66 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.76 392.93 67 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-1,7-diaza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 0.62 419.15 68 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-2,7-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 0.77 419.03 69 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.78 379.01 70 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2,2-dioxo-2l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]- 0.76 425.87 amide 71 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 0.80 391.99 72 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]- 0.75 425.90 amide 73 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.81 393.02 74 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide 0.77 391.95
EXAMPLE 44
[0543] .sup.1H NMR (400 MHz, DMSO) : 10.02 (s, 1H), 7.86 (s, 1H), 7.77 (dd, J.sub.1=1.2 Hz, J.sub.2=8.3 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 7.38 dd, J.sub.1=1.7 Hz, J.sub.2=8.8 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 4.52-4.58 (m, 1H), 4.38-4.44 (m, 2H), 3.99 (dd, J,=4.6 Hz, J.sub.2=9.0 Hz, 2H), 3.65 (hept, J=6.6 Hz, 1H), 3.25 (t, J=8.6 Hz, 2H), 1.11 (d, J=6.1 Hz, 6H).
EXAMPLE 47
[0544] .sup.1H NMR (400 MHz, DMSO) : 10.01 (s, 1H), 7.86 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.73 (d, J=0.7 Hz, 1H), 7.32-7.40 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 5.93 (d, J=6.8 Hz, 1H), 4.59-4.66 (m, 3H), 4.38 (t, J=7.8 Hz, 2H), 3.95 (dd, J.sub.1=4.6 Hz, J.sub.2=8.6 Hz, 2H), 3.25 (t, J=8.6 Hz, 2H).
EXAMPLE 50
[0545] .sup.1H NMR (400 MHz, DMSO) : 10.00 (s, 1H), 7.86 (s, 1H), 7.77 (dd, J.sub.1=0.7 Hz, J.sub.2=8.3 Hz, 1H), 7.70 (s, 1H), 7.30-7.37 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 4.62 (t, J=8.8 Hz, 2H), 4.36 (s, 4H), 3.52-3.57 (m, 2H), 3.25 (t, J=8.8 Hz, 2H), 1.85-1.91 (m, 4H).
EXAMPLE 57
[0546] .sup.1H NMR (400 MHz, DMSO) : 10.02 (s,1H), 7.86 (s,1H), 7.77 (d, J=8.6 Hz, 1H), 7.73 (s, 1H), 7.30-7.40 (m, 2H), 6.87 (d, J=8.3 Hz,1H), 5.25 (quint, J=6.8 Hz, 1H), 4.76-4.83 (m, 4H), 4.62 (t, J=8.6 Hz, 2H), 3.25 (t, J=8.6 Hz, 2H), 3.23 (s, 3H).
EXAMPLE 70
[0547] .sup.1H NMR (400 MHz, DMSO) : 10.03 (s, 1H), 7.87 (s, 1H), 7.76-7.80 (m, 2H), 7.36-7.44 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 4.63 (t, J=8.6 Hz,2H), 4.54 (s, 4H), 4.45 (s, 4H), 3.25 (t, J=8.8 Hz, 2H).
EXAMPLE 71
[0548] .sup.1H NMR (400 MHz, DMSO) : 10.01 (s, 1H), 7.87 (s, 1H), 7.78 (dd, J.sub.1=1.0 Hz, J.sub.2=8.3 Hz, 1H), 7.74 (s, 1H), 7.33-7.41 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 3.98-4.12 (m, 4H), 3.77-3.88 (m, 2H), 3.26 (t, J=9.0 Hz, 2H), 2.54-2.64 (m, 2H), 2.09-2.20 (m, 2H).
EXAMPLE 72
[0549] .sup.1H NMR (400 MHz, DMSO) : 10.06 (s, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=8.3 Hz), 7.38-7.46 (m, 2H), 6.88 (d, J=8.4 Hz, 1H), 5.03-5.11 (m, 2H), 4.63 (t, J=8.6 Hz, 2H), 4.44-4.52 (m, 2H), 4.13-4.19 (m, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H).
EXAMPLE 75
2-(4-Methyl-piperazin-1-yl)-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide
[0550] To a solution of 2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylic acid (45 mg, 172 mol) and 5-amino-2,3-dihydrobenzofuran (47 mg, 344 mol) in DCM (2 mL) and pyridine (0.14 mL) POCl.sub.3 (17 L, 189 mol) was added. The mixture was stirred at rt for 30 min gefore it was concentrated. The residue was dissolved in acetonitrile (1 mL) and separated by prep. HPLC to give the title compound (35 mg) as a beige solid; LC-MS: t.sub.R=0.57 min; [M+H].sup.+=379.19; .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.81 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.16 (dd, J.sub.1=0.7 Hz, J.sub.2=8.2 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.76-3.85 (m, 4H), 3.25 (t, J=8.7 Hz, 2H), 2.56-2.66 (m, 4H), 2.41 (s, 3H).
EXAMPLES 76 TO 80
[0551] The following Example compoundss were prepared in analogy to Example 75 starting from Intermediates C2 to C6 and 5-amino-2,3-dihydrobenzofuran.
TABLE-US-00007 LC-MS Exam- t.sub.R ple Name [min] [M + H].sup.+ 76 2-Piperidin-1-yl-benzooxazole-5-carboxylic acid 0.84 364.01 (2,3-dihydro-benzofuran-5-yl)-amide 77 2-Morpholin-4-yl-benzooxazole-5-carboxylic 0.76 366.14 acid (2,3-dihydro-benzofuran-5-yl)-amide 78 2-Diethylamino-benzooxazole-5-carboxylic acid 0.81 352.05 (2,3-dihydro-benzofuran-5-yl)-amide 79 2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic 0.76 350.02 acid (2,3-dihydro-benzofuran-5-yl)-amide 80 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.75 377.98 benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide
EXAMPLE 76
[0552] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.81 (s, 2H), 7.67 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd, J.sub.1=1.5 Hz, J.sub.2=8.3 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.69-3.77 (m, 4H), 3.26 (t, J=8.7 Hz, 2H), 1.70-1.78 (m, 6H).
EXAMPLE 77
[0553] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.84 (s, 1H), 7.75 (s, 1H), 7.63-7.69 (m, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.16 (dd, J.sub.1=1.1 Hz, J.sub.2=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.84-3.89 (m, 4H), 3.73-3.79 (m, 4H), 3.26 (t, J=8.7 Hz, 2H).
EXAMPLE 78
[0554] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.80 (d, J=0.8 Hz, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.60 (dd, J.sub.1=1.2 Hz, J.sub.2=8.3 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.16 (dd, J.sub.1=1.5 Hz, J.sub.2=8.3 Hz), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.64 (q, J=7.1 Hz, 4H), 3.26 (t, J=8.6 Hz, 2H), 1.33 (t, J=7.1 Hz, 6H).
EXAMPLE 79
[0555] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.82 (d, J=0.7 Hz, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.61 (dd, J.sub.1=1.4 Hz, J.sub.2=8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.17 (dd, J.sub.1=1.5 Hz, J.sub.2=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.67-3.74 (m, 4H), 3.26 (t, J=8.6 Hz, 2H), 2.03-2.13 (m, 4H).
EXAMPLE 80
[0556] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.90 (s, 1H), 7.79 (s br, 1H), 7.66-7.71 (m, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 5.43 (d, J=7.5 Hz, 2H), 4.79 (d, J=7.5 Hz, 2H), 4.61 (t, J=8.7 Hz, 2H), 4.15 (t, J=7.3 Hz, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H).
EXAMPLE 81
2,3-Dihydro-benzofuran-5-carboxylic acid (2-piperidin-1-yl-benzothiazol-5-yl)-amide
[0557] To a solution of 2-(piperidin-1-yl)benzo[d]thiazol-5-amine (53 mg, 226 mol) and 2,3-dihydrobenzo[b]furan-5-carboxylic acid (37 mg, 226 mol) in MeCN (2 mL) pyridine (0.18 mL) followed by POCl.sub.3 (0.23 mL, 248 mol) was added. The mixture was stirred at rt for 15 in before it was diluted with water (0.25 mL) and then concentrated. The residue was dissolved in DMF (1.5 mL) and formic acid (0.1 mL) and separated by prep. HPLC to give the title compound (31 mg) as a solid; LC-MS: t.sub.R=0.76 min; [M+H].sup.+=380.25; .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.80 (s, 2H), 7.66-7.71 (m, 2H), 7.56 (s, 2H), 6.86 (d, J=8.3 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H), 3.60-3.67 (m, 4H), 3.29 (t, J=8.7 Hz, 2H), 1.68-1.78 (m, 6H).
EXAMPLES 82 TO 97
[0558] The following Example compounds were prepared in analogy to Example 81 starting from Intermediates D2 to D17 and 2,3-dihydrobenzo[b]furan-5-carboxylic acid.
TABLE-US-00008 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 82 2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzothiazol-5-yl)-amide 0.76 382.23 83 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzothiazol-5-yl]-amide 0.62 395.22 84 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzothiazol-5-yl)-amide 0.69 366.17 85 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzothiazol-5-yl)-amide 0.73 367.98 86 2,3-Dihydro-benzofuran-5-carboxylic acid (2-dimethylamino-benzothiazol-5-yl)-amide 0.66 344.01 87 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzothiazol-5-yl]-amide 0.85 388.11 88 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 0.84 401.96 89 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzothiazol-5-yl]-amide 0.89 416.07 90 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazol-5-yl]-amide 0.75 394.12 91 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-yl]-amide 0.69 394.12 92 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzothiazol-5-yl]-amide 0.78 430.01 93 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-5-yl}- 0.64 397.16 amide 94 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 0.70 396.14 95 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide 0.77 410.12 96 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzothiazol-5-yl]-amide 0.67 382.14 97 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-dimethylamino-piperidin-1-yl)-benzothiazol-5-yl]-amide 0.62 423.13
EXAMPLE 82
[0559] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.80 (s, 2H), 7.76 (d, J=1.7 Hz, 1H), 7.69 (dd, J.sub.1=1.8 Hz, J.sub.2=8.3 Hz, 1H), 7.58 (m, 2H), 6.86 (d, J=8.3 Hz, 1H), 4.69 (t, J=8.8 Hz, 2H), 3.86 (m, 4H), 3.66 (m, 4H), 3.30 (t, J=8.8 Hz, 2H).
EXAMPLE 83
[0560] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.06 (s, 1H), 7.98 (d, J=1.9 Hz, 1H), 7.89 (s, 1H), 7.80 (dd, J.sub.1=1.8 Hz, J.sub.2=8.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.48 (dd, J.sub.1=2.0 Hz, J.sub.2=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.56-3.61 (m, 4H), 3.27 (t, J=8.7 Hz, 2H), 2.49-2.53 (m, 4H), 2.30 (s, 3H).
EXAMPLE 87
[0561] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.84 (s, 1H), 7.81 (s, 2H), 7.69 (dd, J,=1.8 Hz, J.sub.2=8.8 Hz), 7.59-7.65 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 4.70 (t, J=8.8 Hz, 2H), 4.59 (t, J=11.7 Hz, 4H), 3.30 (t, J=8.7 Hz, 2H).
EXAMPLE 90
[0562] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.09 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 5.34 (d, J=7.2 Hz, 2H), 4.59-4.74 (m, 4H), 3.90-4.02 (m, 2H), 3.29 (t, J=8.7 Hz, 2H), 2.68-2.79 (m, 2H).
EXAMPLE 92
[0563] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.08 (s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.89 (s, 1H), 7.80 (dd, J.sub.1=1.6 Hz, J.sub.2=8.4 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.51 (dd, J.sub.1=1.9 Hz, J.sub.2=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H), 4.04-4.09 (m, 4H), 3.31-3.34 (m, 4H), 3.27 (t, J=8.8 Hz, 2H).
EXAMPLE 96
[0564] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.05 (s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J.sub.1=1.4 Hz, J.sub.2=8.4 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.48 (dd,J.sub.1=1.9 Hz, J.sub.2=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 5.85 (s br, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.95-4.04 (m, 4H), 3.27 (t, J=8.7 Hz, 2H), 1.47 (s, 3H).
EXAMPLE 98
(S)N-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide
[0565] To a solution of (S)-pyrrolidin-3-ol (8 mg, 91 mol) and Et.sub.3N (51 L, 362 mol) in THF (0.6 mL) N-(2-chlorobenzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide (30 mg, 72.5 mol) was added and the mixture was stirred at 65 C. for 16 h. The mixture was concentrated, dissolved in DMSO (0.6 mL) and separated by prep. HPLC to give the title compound (17 mg) as a white solid; LC-MS: t.sub.R=0.80 min; [M+H].sup.+=382.00; .sup.1H NMR (400 MHz, DMSO) : 10.06 (s, 1H), 7.89 (s, 1H), 7.85 (s, H), 7.76 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.28 (d, J=3.2 Hz, 1H), 4.61 (t, J=8.6 Hz, 2H), 4.40-4.46 (m, 1H), 3.66-3.82 (m, 4H), 3.24 (t, J=8.6 Hz, 2H), 2.04-2.17 (m, 1H), 1.89-2.00 (m, 1H).
EXAMPLES 99 TO 117
[0566] The following Example compounds were prepared in analogy to Example 98 starting from Intermediate E1 and the appropriate amines.
TABLE-US-00009 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 99 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzothiazol-5-yl]-amide 0.91 421.68 100 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzothiazol-5-yl}- 0.87 465.05 amide 101 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzothiazol-5-yl]-amide 0.93 421.70 102 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-oxetan-3-yl-piperazin-1-yl)-benzothiazol-5-yl]-amide 0.84 437.02 103 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)-benzothiazol-5-yl]-amide 0.87 382.01 104 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-yl]-amide 0.88 394.01 105 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 0.96 422.95 106 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-isopropoxy-azetidin-1-yl)-benzothiazol-5-yl]-amide 1.01 410.05 107 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-ethoxymethyl-pyrrolidin-1-yl)benzothiazol-5-yl]-amide 1.07 424.05 108 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-l-yl)-benzothiazol-5-yl]-amide 0.98 410.02 109 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzothiazol-5-yl]-amide 0.79 367.97 110 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-l-yl)-benzothiazol-5-yl]-amide 0.83 395.99 111 rac-2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)-benzothiazol-5-yl]-amide 1.10 428.00 112 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)benzothiazol-5-yl]-amide 0.81 381.98 113 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 1.00 410.01 114 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((5)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide 0.85 396.00 115 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzothiazol-5-yl]-amide 0.87 408.02 116 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide 0.85 395.99 117 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 1.05 422.94
EXAMPLE 101
[0567] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.08 (s, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.42 (dd, J.sub.1=1.1 Hz, J.sub.2=8.5 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 4.31 (s br, 4H), 3.79-3.82 (m, 2H), 3.42-3.48 (m, 2H), 3.24 (t, J=8.7 Hz, 2H), 1.84-1.90 (m, 2H), 1.52-1.60 (m, 2H).
EXAMPLE 102
[0568] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.09 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 4.53-4.58 (m, 2H), 4.44-4.49 (m, 2H), 3.62-3.70 (m, 2H), 3.54-3.60 (m, 2H), 3.43-3.49 (m, 1H), 3.24 (t, J=8.8 Hz, 2H), 2.36-2.42 (m, 4H).
EXAMPLE 103
[0569] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.09 (s, 1H), 7.93 (d, J=1.4 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.41 (dd, J.sub.1=1.5 Hz, J.sub.2=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.25 (quint, J=6.8 Hz, 1H), 4.75-4.85 (m, 4H), 4.61 (t, J=8.6 Hz, 2H), 3.22-3.27 (t, J=8.6 Hz, 2H), 3.21 (s, 3H).
EXAMPLE 109
[0570] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.09 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.09 (d, J=6.5 Hz, 1H), 4.64-4.70 (m, 1H), 4.61 (t, J=8.6 Hz, 2H), 4.28-4.34 (m, 2H), 3.87 (dd, J.sub.1=4.4 Hz, J.sub.2=8.6 Hz, 2H), 3.24 (t, J=8.7 Hz, 2H).
EXAMPLE 116
[0571] .sup.1H NMR (400 MHz, D.sub.6-DMSO) : 10.07 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.38 (dd, J.sub.1=1.0 Hz, J.sub.2=8.6 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.25 (d, J=3.9 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.57-3.76 (m, 2H), 3.19-3.30 (m, 3H), 3.08 (dd, J,=8.6 Hz, J.sub.2=12.7 Hz, 1H), 1.75-1.91 (m, 2H), 1.40-1.54 (m, 2H).
EXAMPLE 118
[0572] 2,3-Dihydro-benzofuran-5-carboxylic acid (2-azetidin-1-yl-benzooxazol-5-yl)-amide
[0573] A solution of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (30.3 mg, 0.185 mmol), HBTU (70.1 mg, 0.185 mmol) and DIPEA (95 L, 0.554 mmol) in DMF (1 mL) was stirred at rt for 30 min before 2-azetidin-1-yl-benzooxazol-5-ylamine (35 mg, 0.185 mmol, Intermediate A40) was added. The mixture was stirred at 50 C. for 16 h before it was separated by prep. HPLC to give the title compound (59 mg) as a colourless resin; LC-MS: t.sub.R=0.72 min; [M+H].sup.+=336.09; .sup.1H NMR (400 MHz, CDCl.sub.3): 7.81 (s, 1H), 7.77 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.69 (t, J=8.8 Hz, 2H), 4.33 (t, J=7.6 Hz, 4H), 3.30 (t, J=8.7 Hz, 2H), 2.54 (quint, J=7.5 Hz).
EXAMPLES 119 TO 195
[0574] The following Example compounds were prepared in analogy to Example 118 starting from Intermediates A2 to A6, A8, Al2, A16, A17, A25, A36, A37, and A40 to A48 and the appropriate benzoic acid derivatives.
TABLE-US-00010 LC-MS Exam- t.sub.R ple Name [min] [M + H].sup.+ 119 2,3-Dihydro-benzofuran-5-carboxylic acid (2-ethylamino-benzooxazol-5-yl)-amide 0.67 324.09 120 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyridin-2-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.66 413.26 121 Benzo[1,3]dioxole-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.89 374.02 122 Benzo[1,3]dioxole-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.72 353.89 123 Benzo[1,3]dioxole-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 1.01 378.07 124 Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 0.79 380.05 125 Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 0.83 394.06 126 Benzo[1,3]dioxole-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 0.85 408.10 127 Benzo[1,3]dioxole-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide 0.89 352.04 128 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 0.76 394.26 129 Benzo[1,3]dioxole-5-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide 0.97 266.04 130 Benzo[1,3]dioxole-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.94 401.83 131 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.88 396.08 132 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.83 408.10 133 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 0.84 408.10 134 Benzo[1,3]dioxole-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.95 401.84 135 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.75 382.08 136 Benzo[1,3]dioxole-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide 0.81 368.03 137 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide 0.79 381.10 138 Benzo[1,3]dioxole-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide 0.84 394.07 139 Benzo[1,3]dioxole-5-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide 0.95 353.90 140 Chroman-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.78 366.05 141 Chroman-6-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.95 385.84 142 Chroman-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 1.06 390.10 143 Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 0.85 392.09 144 Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 0.89 406.09 145 Chroman-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 0.91 420.13 146 Chroman-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide 0.94 364.06 147 Chroman-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 0.80 406.28 148 Chroman-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide 1.03 378.09 149 Chroman-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 1.01 414.11 150 Chroman-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide 1.00 141.09 151 Chroman-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.81 394.10 152 Chroman-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.94 408.13 153 Chroman-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.89 420.15 154 Chroman-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 0.90 420.14 155 Chroman-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide 0.87 380.09 156 Chroman-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide 0.85 393.11 157 Chroman-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide 1.00 366.12 158 Chroman-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide 0.90 406.12 159 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide 0.72 368.04 160 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 0.79 394.07 161 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 1.01 392.08 162 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 0.83 408.11 163 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 0.86 422.12 164 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide 0.89 366.05 165 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 0.76 408.27 166 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide 0.98 380.09 167 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide 0.75 396.09 168 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)benzooxazol-5-yl]-amide 0.94 416.09 169 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)benzooxazol-5-yl]-amide 0.88 410.11 170 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)benzooxazol-5-yl]-amide 0.95 416.09 171 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 0.85 422.12 172 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 0.83 422.12 173 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide 0.81 382.09 174 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide 0.79 395.11 175 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide 0.95 368.07 176 2,3-Dihydro-benzo[1,4]diozine-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide 0.85 408.10 177 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]- 0.72 381.08 amide 178 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]- 0.92 401.03 amide 179 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]- 0.96 405.12 amide 180 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol- 0.81 407.10 5-yl]-amide 181 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol- 0.82 421.11 5-yl]-amide 182 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol- 0.83 435.13 5-yl]-amide 183 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide 0.79 379.13 184 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol- 0.78 421.26 5-yl]-amide 185 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide 0.90 393.12 186 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]- 0.74 409.13 amide 187 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5- 0.97 429.12 yl]-amide 188 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5- 0.97 429.14 yl]-amide 189 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol- 0.84 435.14 5-yl]-amide 190 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol- 0.82 435.13 5-yl]-amide 191 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]- 0.86 423.15 amide 192 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide 0.82 395.09 193 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]- 0.67 408.15 amide 194 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide 0.86 381.12 195 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol- 0.85 421.13 5-yl]-amide
EXAMPLE 124
[0575] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.07 (s, 1H), 7.80 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H), 7.40-7.47 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.15 (s, 2H), 5.23 (d, J=7.4 Hz, 2H), 4.67 (d, J=7.4 Hz, 2H), 4.02 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.1 Hz, 2H).
EXAMPLE 133
[0576] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.04 (s, 1H), 7.73 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.37 (s, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.15 (s, 2H), 4.32 (s, 4H), 3.84 (s, 2H), 3.54 (t, J=5.1 Hz, 2H), 1.86-1.92 (m, 2H), 1.54-1.62 (m, 2H).
EXAMPLE 144
[0577] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.00 (s, 1H), 7.70-7.78 (m, 3H), 7.34-7.41 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 4.22 (t, J=4.8 Hz, 2H), 4.00-4.13 (m, 4H), 3.79-3.90 (m, 2H), 2.83 (t, J=6.1 Hz, 2H), 2.54-2.65 (m, 3H), 2.11-2.20 (m, 1H), 1.93-2.01 (m, 2H).
EXAMPLE 159
[0578] .sup.1H NMR (400 MHz, DMSO): 10.03 (s, 1H), 7.76 (s, 1H), 7.49-7.55 (m, 2H), 7.34-7.43 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 5.91 (d, J=6.7 Hz, 1H), 4.62-4.70 (m, 1H), 4.36-4.43 (m, 2H), 4.29-4.36 (m, 4H), 3.94-4.00 (m, 2H).
EXAMPLE 176
[0579] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.04 (s, 1H), 7.77 (s, 1H), 7.48-7.55 (m, 2H), 7.38-7.44 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 4.89-5.00 (m, 3H), 4.75 (t, J=6.2 Hz, 2H), 4.29-4.37 (m, 4H), 2.93-3.01 (m, 1H), 0.88-0.96 (m, 2H), 0.76-0.82 (m, 2H).
EXAMPLE 186
[0580] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 9.94 (s, 1H), 7.72 (s, 1H), 7.34 (s, 2H), 7.27 (m, 2H), 6.77-6.81 (m, 1H), 4.87 (d, J=4.0 Hz, 1H), 4.29-4.33 (m, 2H), 3.88-3.96 (m, 2H), 3.73-3.80 (m, 2H), 3.27-3.31 (m, 2H), 3.19 (d, J=5.2 Hz, 1H), 2.93 (s, 3H), 1.82-1.90 (m, 2H), 1.42-1.52 (m, 2H).
EXAMPLE 196
2-Piperidin-1-yl-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide
[0581] To a solution of 2-chloro-N-(2,3-dihydrobenzofuran-5-yl)benzo[d]thiazole-5-carboxamide (62 mg, 0.174 mmol, Intermediate E2) and piperidine (17.2 L, 0.174 mmol) in THF (1 mL), DIPEA (35 L, 0.198 mmol) was added. The brown suspension was stirred at 70 C. for 6 h before another portion of piperidine (28 L, 0.282 mmol) was added. Stirring was continued at 70 C. for 16 h. The mixture was concentrated and the residue was dissolved in DMF (2 mL) and purified by prep. HPLC to give the title compound (33 mg) as a pale yellow resin; LC-MS: t.sub.R=0.84 min; [M+H].sup.+=380.22; .sup.1H NMR (500 MHz, CDCl.sub.3): 7.96 (d, J=1.5 Hz, 1H), 7.80 (s, 1H), 7.67-7.72 (m, 2H), 7.64 dd, J.sub.1=1.7 Hz, J.sub.2=8.2 Hz, 1H), 7.16 (dd, J.sub.1=2.2 Hz, J.sub.2=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.63-3.70 (m, 4H), 3.26 (t, J=8.7 Hz, 2H), 1.72-1.81 (m, 6H).
EXAMPLES 197 TO 212
[0582] The following Example compounds were prepared in analogy to Example 196 starting from Intermediates E2 to E4 and the appropriate aniline derivatives.
TABLE-US-00011 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 197 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.78 394.08 198 2-(4,4-Difluoro-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.89 416.09 199 2-(1,1-Dioxo-thiomorpholin-4-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.76 430.06 200 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.82 410.11 201 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.60 395.10 202 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-yl)-amide 0.76 408.07 203 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.79 410.04 204 2-(4,4-Difluoro-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.89 432.07 205 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.83 426.08 206 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.60 411.00 207 2-Piperidin-1-yl-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.85 396.06 208 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 0.77 424.09 209 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxol-5-ylamide 0.79 396.00 210 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxol-5-ylamide 0.83 411.96 211 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxol-5-ylamide 0.60 397.06
EXAMPLE 197
[0583] .sup.1H NMR (500 MHz, D.sub.6-DMSO): 10.08 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.71-7.73 (m, 1H), 7.70 (dd, J.sub.1=1.7 Hz, J.sub.2=8.2 Hz, 1H), 7.46 (dd, J.sub.1=2.2 Hz, J.sub.2=8.5 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 5.35 (d, J=7.8 Hz, 2H), 4.68 (d, J=7.9 Hz, 2H), 4.53 (t, J=8.7 Hz, 2H), 3.97 (t, J=7.1 Hz, 2H), 3.20 (m, J=8.7 Hz, 2H), 2.74 (t, J=7.2 Hz, 2H), 1.23-1.30 (m, 2H).
EXAMPLE 198
[0584] .sup.1H NMR (500 MHz, DMSO): 10.07 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.69-7.71 (m, 1H), 7.69 (d, J.sub.1=1.7 Hz, J.sub.2=8.4 Hz, 1H), 7.44 (dd, J.sub.1=2.2 Hz, J.sub.2=8.5 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 3.74-3.79 (m, 4H), 3.20 (t, J=8.7 Hz, 2H), 2.12-2.21 (m, 4H).
EXAMPLE 207
[0585] .sup.1H NMR (400 MHz, D.sub.6-DMSO): 10.05 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.62 (dd, J.sub.1=1.6 Hz, J.sub.2=8.2 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.25 (dd, J.sub.1=2.4 Hz, J.sub.2=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.15-4.32 (m, 4H), 3.56-3.65 (m, 4H), 1.57-1.73 (m, 6H).
EXAMPLE 211
[0586] .sup.1H NMR (500 MHz, D.sub.6-DMSO): 10.13 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.65 (dd, J.sub.1=1.7 Hz, J.sub.2=8.2 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.24 (dd, J.sub.1=2.1 Hz, J.sub.2=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.01 (s, 2H), 3.60 (m, 4H), 2.44-2.48 (m, 4H), 2.25 (s, 3H).
[0587] Biological Assays
[0588] The nucleotide sequence and the amino acid sequence for the human NOX4 (Entrez Gene ID 50507) is known in the art and are published. The potency and efficacy of the compounds of Formula (I) are assessed for their potential to inhibit the formation of ROS in a cellular assay.
[0589] Plasmid Production
[0590] The full-length human NOX4 (NM_016931.3) transcript was cloned into the pDONR221 vector (Life Technologies) in order to generate, by site-specific integration according to the recommendation of the manufacturer (Life Technologies), a recombinant pJTI R4 DEST CMV-TO vector containing the NOX4 coding information controlled by tetracycline (tet) responsive tet-on cytomegalovirus promoter (hNOX4 pDEST).
[0591] Cell Culture and Transfection
[0592] Modified human embryonic kidney cells overexpressing a tet receptor (Jump-In T-REx HEK293; Life Technologies) were transfected with the NOX4-containing tet-on vector (hNOX4 pDEST) to generate a stable recombinant cell pool (hNOX4 T-REx-293). hNOX4 T-REx-293 cells were cultured in DMEM containing 4.5 g/L glucose supplemented with 10% fetal calf serum, penicillin (100 U/mL), streptomycin (100 g/mL), geneticin (1 mg/mL), and blasticidin (5 g/mL) at 37 C. in air with 5% CO2. Human Nox4 expression was induced with tet (1 g/mL) for 24 h and extracellular H.sub.2O.sub.2 was quantified using the Amplex Red reagent (Life Technologies).
[0593] Amplex Red Activity Assay
[0594] Inhibitory activities on NOX4 have been measured for each example compound using the following procedure:
[0595] Compounds were prepared as 10 mM stock solution in DMSO vehicle, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into the assay plate. As a control, diphenylene iodonium was included at a final concentration of 10 M. Compounds were tested at 10 concentrations in the range from 50 M highest to 100 nM lowest.
[0596] Cellular H.sub.2O.sub.2 formation was measured using the Amplex Red reagent. Cells were washed with 1 PBS, trypsinized with 1 Trypsin-EDTA, collected by centrifugation and resuspended in 1 PBS. Cells were seeded into 384-well clear bottom plates at a density of 20 000 cells per well in presence or absence of compounds. The assay was started by the addition of Amplex Red and horseradish peroxidase at final concentrations of 25 M and 0.1 U/mL, respectively. All wells contained 1.25% of DMSO. The plates were kept at 25 C. for 60 min. The amount of produced resorufin was detected with the Synergy Mx microplate reader (BioTek) with excitation and emission wavelengths set to 550 nm and 600 nm, respectively. Fluorescence was measured for each well and the fluorescence at 600 nm wavelength was compared to the fluorescence of the vehicle in place of compound. Inhibitory activities of example compounds were determined by calculating the IC.sub.50 value (the concentration of compound needed to inhibit 50% of the enzyme activity). The calculated IC.sub.50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC.sub.50 values have been determined several times for the same compound, the geometric mean is given. IC.sub.50 values of exemplified compounds are displayed in the Table below.
[0597] Amplex Red Counter Screen Assay
[0598] In order to identify compounds that interfere with the activity assay either by inhibiting the activity of horseradish peroxidase or by directly interacting with the formed H.sub.2O.sub.2 a counter screen assay was established. This control assay is almost identical to the described Amplex Red activity assay with the only difference that the H.sub.2O.sub.2 generating cells are replaced by 1562.5 nM H.sub.2O.sub.2 in 1 PBS.
TABLE-US-00012 TABLE 1 IC.sub.50 IC.sub.50 Compound Amplex Control of Example [nM] [M] 1 344 >50 2 639 >50 3 899 >50 4 967 >50 5 627 >50 6 559 >50 7 358 >50 8 1890 >50 9 573 >50 10 711 >50 11 358 >50 12 688 >50 13 5360 >50 14 1700 >50 15 405 >50 16 389 >50 17 2300 >50 18 568 >50 19 2890 >50 20 1400 >50 21 1610 >50 22 505 >50 23 1470 >50 24 352 >50 25 804 >50 26 1490 >50 27 729 >50 28 695 >50 29 541 >50 30 1230 >50 31 2170 >50 32 2410 >50 33 2140 >50 34 1220 >50 35 379 >50 36 404 >50 37 841 >50 38 1750 >50 39 444 >50 40 812 >50 41 2520 >50 42 566 >50 43 541 >50 44 1140 >50 45 573 >50 46 570 >50 47 657 >50 48 448 >50 49 1230 >50 50 451 >50 51 4570 >50 52 899 >50 53 913 >50 54 2910 >50 55 400 >50 56 906 >50 57 681 >50 58 1330 >50 59 731 >50 60 1670 >50 61 5240 >50 62 702 >50 63 359 >50 64 2130 >50 65 851 >50 66 4170 >50 67 3080 >50 68 1790 >50 69 1930 >50 70 889 >50 71 336 >50 72 524 >50 73 4100 >50 74 1080 >50 75 421 >50 76 414 >50 77 548 >50 78 417 >50 79 585 >50 80 312 >50 81 2450 >50 82 2350 >50 83 3540 >50 84 1320 >50 85 1650 >50 86 2680 >50 87 4100 >50 88 3660 >50 89 1920 >50 90 361 >50 91 4331 >50 92 2460 >50 93 10300 >50 94 3290 >50 95 2140 >50 96 2670 >50 97 6303 >50 98 2530 >50 99 3080 >50 100 3390 >50 101 2370 >50 102 9170 >50 103 3210 >50 104 6870 >50 105 14800 >50 106 9390 >50 107 9510 >50 108 2540 >50 109 1780 >50 110 2030 >50 111 1090 >50 112 2270 >50 113 3250 >50 114 2940 >50 115 3410 >50 116 2170 >50 117 3760 >50 118 504 >50 119 990 >50 120 2340 >50 121 9530 >50 122 2110 >50 123 434 >50 124 414 >50 125 772 >50 126 757 >50 127 1250 >50 128 1740 >50 129 857 >50 130 991 >50 131 1050 >50 132 1080 >50 133 614 >50 134 870 >50 135 1090 >50 136 1280 >50 137 1640 >50 138 1480 >50 139 1090 >50 140 2520 >50 141 10600 >50 142 891 >50 143 681 >50 144 1540 >50 145 1400 >50 146 3180 >50 147 379 >50 148 1880 >50 149 1430 >50 150 2200 >50 151 1410 >50 152 1350 >50 153 1300 >50 154 1130 >50 155 756 >50 156 1790 >50 157 2030 >50 158 2860 >50 159 1480 >50 160 541 >50 161 665 >50 162 954 >50 163 1140 >50 164 1280 >50 165 764 >50 166 1500 >50 167 1220 >50 168 1140 >50 169 793 >50 170 899 >50 171 792 >50 172 8850 >50 173 1420 >50 174 1390 >50 175 1350 >50 176 2970 >50 177 6870 >50 178 21800 >50 179 1740 >50 180 1770 >50 181 2440 >50 182 3390 >50 183 8700 >50 184 1890 >50 185 3860 >50 186 3450 >50 187 3390 >50 188 3640 >50 189 2190 >50 190 3580 >50 191 4380 >50 192 4320 >50 193 4040 >50 194 3580 >50 195 4440 >50 196 2560 >50 197 728 >50 198 45200 >50 199 23900 >50 200 2750 >50 201 2870 >50 202 729 >50 203 1840 >50 204 25500 >50 205 26800 >50 206 21200 >50 207 12800 >50 208 2710 >50 209 1500 >50 210 6900 >50 211 8900 >50