NADPH OXIDASE 4 INHIBITORS

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 benzothiazole moiety; X represents 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 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 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 CH.sub.2, 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; 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; 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 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## ##STR00042## 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): ##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-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 [2-((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-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]dioxol-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, a pharmaceutically effective amount of a 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.

18. The method according to claim 16, wherein said fibrotic disease is pulmonary fibrosis; scleroderma; pancreatic fibrosis; liver fibrosis; chronic kidney disease; or cardiomyopathy.

19. 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, a pharmaceutically effective amount of a compound of the Formula (I), ##STR00044## 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 moiety; X represents O; 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 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; in free or pharmaceutically acceptable salt form.

20. The method according to claim 19, wherein said fibrotic disease is pulmonary fibrosis; scleroderma; pancreatic fibrosis; liver fibrosis; chronic kidney disease; or cardiomyopathy.

21. The method according to claim 19, wherein in said compound of the Formula (I) the fragment ##STR00045## represents a group selected from: ##STR00046## wherein R.sup.a represents hydrogen, or C.sub.1-3-alkyl; or a pharmaceutically acceptable salt thereof.

22. The method according to claim 19, wherein in said compound of the Formula (I) the fragment ##STR00047## represents ##STR00048## or a pharmaceutically acceptable salt thereof.

23. The method according to claim 19, wherein in said compound of the Formula (I) L represents CONH*, wherein the asterisk (*) indicates the bond that is linked to the benzoxazole moiety; or a pharmaceutically acceptable salt thereof.

24. The method according to claim 19, wherein in said compound of the Formula (I) 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 ##STR00049## 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 CH.sub.2, 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 attached to a ring nitrogen atom having a free valency; or a pharmaceutically acceptable salt thereof.

25. The method according to claim 19, wherein in said compound of the Formula (I) 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; 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; 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 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.

26. The method according to claim 19, wherein in said compound of the Formula (I) Y represents a group independently selected from the following groups A), B), C), or D): ##STR00050## ##STR00051## or a pharmaceutically acceptable salt thereof.

27. The method according to claim 19, wherein in said compound of the Formula (I) Y represents a group independently selected from the following groups A), B), C), or D): ##STR00052## or a pharmaceutically acceptable salt thereof.

28. The method according to claim 19, wherein said compound of the Formula (I) is selected from the group consisting of: 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-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-1l6-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-l-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-2l6-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-1l6-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-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; or a pharmaceutically acceptable salt thereof.

Description

EXAMPLE 1

2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide

[0519] 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

[0520] 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- 0.78 364.26 yl)-amide 3 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5- 0.71 350.29 yl)-amide 4 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)- 0.59 379.23 benzooxazol-5-yl]-amide 5 2,3-Dihydro-benzofuran-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5- 0.76 366.25 yl)-amide 6 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzooxazol-5- 0.75 352.29 yl)-amide 7 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)- 0.86 400.20 benzooxazol-5-yl]-amide 8 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)- 0.82 372.10 benzooxazol-5-yl]-amide 9 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)- 0.93 386.04 benzooxazol-5-yl]-amide 10 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)- 0.84 380.04 benzooxazol-5-yl]-amide 11 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)- 0.89 394.09 benzooxazol-5-yl]-amide 12 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin- 0.78 366.04 1-yl)-benzooxazol-5-yl]-amide 13 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(2-dimethylamino-ethyl)- 0.60 381.08 methyl-amino]-benzooxazol-5-yl}-amide; compound with formic acid 14 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-dimethylamino-piperidin-1- 0.78 406.95 yl)-benzooxazol-5-yl]-amide; compound with formic acid 15 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1- 0.75 378.23 yl)-benzooxazol-5-yl]-amide 16 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pipeiidin-1-yl)- 0.85 400.21 benzooxazol-5-yl]-amide 17 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-morpholin-4-yl-azetidin-1- 0.59 421.02 yl)-benzooxazol-5-yl]-amide 18 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(3-methyl-oxetan-3- 0.78 380.20 yl)-amino]-benzooxazol-5-yl}-amide 19 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1,1-dioxo-1l6- 0.70 469.10 thiomoipholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide 20 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl- 0.61 421.20 [1,3]biazetidinyl-1-yl)-benzooxazol-5-yl]-amide 21 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.3]hept-6- 0.74 378.20 yl)-benzooxazol-5-yl]-amide 22 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6- 0.70 392.20 yl)-benzooxazol-5-yl]-amide 23 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.5]non-2- 0.77 406.11 yl)-benzooxazol-5-yl]-amide 24 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5- 0.76 392.11 yl)-benzooxazol-5-yl]-amide 25 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.5]non-6- 0.75 406.11 yl)-benzooxazol-5-yl]-amide 26 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.5]non-5- 0.84 406.12 yl)-benzooxazol-5-yl]-amide 27 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5]non-7- 0.76 406.09 yl)-benzooxazol-5-yl]-amide 28 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-7-aza-spiro[3.5]non-7- 0.73 420.13 yl)-benzooxazol-5-yl]-amide 29 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-8-aza-spiro[4.5]dec-8- 0.80 420.12 yl)-benzooxazol-5-yl]-amide 30 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-2-aza-spiro[3.5]non-2- 0.76 406.11 yl)-benzooxazol-5-yl]-amide 31 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro[3.4]oct-2- 0.78 392.11 yl)-benzooxazol-5-yl]-amide 32 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(4-hydroxy-piperidin-1-yl)- 0.58 435.15 azetidin-1-yl]-benzooxazol-5-yl}-amide 33 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-methyl-2,6-diaza- 0.61 419.14 spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 34 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(5-oxa-2-aza-spiro[3.5]non-2- 0.82 406.12 yl)-benzooxazol-5-yl]-amide 35 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)- 0.83 376.10 benzooxazol-5-yl]-amide 36 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1- 0.75 406.11 yl)-benzooxazol-5-yl]-amide 37 1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}- 0.88 436.11 azetidine-3-carboxylic acid tert-butyl ester 38 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxo-pyrrolidin-1-yl)- 0.66 364.15 benzooxazol-5-yl]-amide 39 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(1,1-dioxo- 0.73 429.90 thiomorpholin-4-yl)-benzooxazol-5-yl]-amide 40 Chroman-6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol- 0.77 427.97 5-yl]-amide 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

[0521] Example 3: .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).

[0522] Example 5: .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).

[0523] Example 6: .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).

[0524] Example 15: .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).

[0525] Example 23: .sup.1H NMR (400 MHz, DMSO) 5:10.02 (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).

[0526] Example 26: .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).

[0527] Example 30: .sup.1H NMR (400 MHz, DMSO) : 10.01 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 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).

[0528] Example 34: .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).

[0529] Example 39: .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).

[0530] Example 41: .sup.1H NMR (400 MHz, DMSO) : 9.99 (s, 1H), 7.77 (s, 1H), 7.39 (s, 2H), 7.23-7.29 (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

[0531] 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

[0532] 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

[0533] 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-1-yl)- 0.74 380.08 benzooxazol-5-yl]-amide 44 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-isopropoxy-azetidin-1-yl)- 0.94 394.05 benzooxazol-5-yl]-amide 45 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)- 0.63 366.20 benzooxazol-5-yl]-amide 46 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-pyirolidin-1-yl)- 0.71 365.76 benzooxazol-5-yl]-amide 47 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)- 0.70 352.03 benzooxazol-5-yl]-amide 48 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)- 0.73 380.02 benzooxazol-5-yl]-amide 49 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-phenyl-azetidin-1-yl)- 1.02 411.94 benzooxazol-5-yl]-amide 50 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)- 0.81 405.99 benzooxazol-5-yl]-amide 51 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-ethoxymethyl-pyrrolidin-1-yl)- 1.02 408.02 benzooxazol-5-yl]-amide 52 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(3-fluoro-oxetan-3-ylmethyl)- 0.82 397.73 methyl-amino]-benzooxazol-5-yl}-amide 53 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-oxetan-3-yl-piperazin-1-yl)- 0.59 421.18 benzooxazol-5-yl]-amide 54 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl-piperidin- 0.74 448.93 4-yl)-amino]-benzooxazol-5-yl}-amide 55 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)- 0.78 405.94 benzooxazol-5-yl]-amide 56 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-ylmethyl- 0.77 379.94 amino)-benzooxazol-5-yl]-amide 57 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)- 0.77 365.71 benzooxazol-5-yl]-amide 58 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyirolidin-1- 0.95 393.95 yl)-benzooxazol-5-yl]-amide 59 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)- 0.87 393.98 benzooxazol-5-yl]-amide 60 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl- 0.86 407.04 pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 61 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl- 0.66 407.24 pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 62 rac-2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)- 0.96 412.01 benzooxazol-5-yl]-amide 63 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)- 0.82 391.99 benzooxazol-5-yl]-amide 64 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyrrolidin-1-yl-azetidin-1-yl)- 0.78 405.02 benzooxazol-5-yl]-amide 65 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[3-(1-hydroxy-1-methyl-ethyl)- 0.76 393.80 azetidin-1-yl]-benzooxazol-5-yl}-amide 66 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl- 0.76 392.93 azetidin-1-yl)-benzooxazol-5-yl]-amide 67 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-1,7-diaza- 0.62 419.15 spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 68 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(7-methyl-2,7-diaza- 0.77 419.03 spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide 69 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-azetidin-1-yl)- 0.78 379.01 benzooxazol-5-yl]-amide 70 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2,2-dioxo-2l6-thia-6-aza- 0.76 425.87 spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 71 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)- 0.80 391.99 benzooxazol-5-yl]-amide 72 2,3-Dihydro-benzofuran-5-carboxylic acid [2(1,1-dioxo-1l6-thia-6-aza- 0.75 425.90 spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 73 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylamino-3-methyl- 0.81 393.02 azetidin-1-yl)-benzooxazol-5-yl]-amide 74 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)- 0.77 391.95 benzooxazol-5-yl]-amide

[0534] Example 44: .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.sub.1=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).

[0535] Example 47: .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).

[0536] Example 50: .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).

[0537] Example 57: .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).

[0538] Example 70: .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).

[0539] Example 71: .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).

[0540] Example 72: .sup.1H NMR (400 MHz, DMSO) 5:10.06 (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

[0541] 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 before 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

[0542] The following Example compounds were prepared in analogy to Example 75 starting from Intermediates C2 to C6 and 5-amino-2,3-dihydrobenzofuran.

TABLE-US-00007 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 76 2-Piperidin-1-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5- 0.84 364.01 yl)-amide 77 2-Morpholin-4-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran- 0.76 366.14 5-yl)-amide 78 2-Diethylamino-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran-5- 0.81 352.05 yl)-amide 79 2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic acid (2,3-dihydro-benzofuran- 0.76 350.02 5-yl)-amide 80 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazole-5-carboxylic acid (2,3- 0.75 377.98 dihydro-benzofuran-5-yl)-amide

[0543] Example 76: .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).

[0544] Example 77: .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).

[0545] Example 78: .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).

[0546] Example 79: .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).

[0547] Example 80: .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

[0548] 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

[0549] 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- 0.76 382.23 yl)-amide 83 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)- 0.62 395.22 benzothiazol-5-yl]-amide 84 2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin-1-yl-benzothiazol-5- 0.69 366.17 yl)-amide 85 2,3-Dihydro-benzofuran-5-carboxylic acid (2-diethylamino-benzothiazol-5- 0.73 367.98 yl)-amide 86 2,3-Dihydro-benzofuran-5-carboxylic acid (2-dimethylamino-benzothiazol- 0.66 344.01 5-yl)-amide 87 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)- 0.85 388.11 benzothiazol-5-yl]-amide 88 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-pyrrolidin-1-yl)- 0.84 401.96 benzothiazol-5-yl]-amide 89 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)- 0.89 416.07 benzothiazol-5-yl]-amide 90 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1- 0.75 394.12 yl)-benzothiazol-5-yl]-amide 91 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.3]hept-6- 0.69 394.12 yl)-benzothiazol-5-yl]-amide 92 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1,1-dioxo-1l6-thiomorpholin- 0.78 430.01 4-yl)-benzothiazol-5-yl]-amide 93 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[(2-dimethylamino-ethyl)- 0.64 397.16 methyl-amino]-benzothiazol-5-yl}-amide 94 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-pyrrolidin-1-yl)- 0.70 396.14 benzothiazol-5-yl]-amide 95 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)- 0.77 410.12 benzothiazol-5-yl]-amide 96 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-3-methyl-azetidin- 0.67 382.14 1-yl)-benzothiazol-5-yl]-amide 97 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-dimethylamino-piperidin-1- 0.62 423.13 yl)-benzothiazol-5-yl]-amide

[0550] Example 82: .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).

[0551] Example 83: .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).

[0552] Example 87: .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.84 (s, 1H), 7.81 (s, 2H), 7.69 (dd, J.sub.1=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).

[0553] Example 90: .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).

[0554] Example 92: .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).

[0555] Example 96: .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

[0556] 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

[0557] 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- 0.91 421.68 7-yl)-benzothiazol-5-yl]-amide 100 2,3-Dihydro-benzofuran-5-carboxylic acid {2-[methyl-(1-oxetan-3-yl- 0.87 465.05 piperidin-4-yl)-amino]-benzothiazol-5-yl}-amide 101 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non- 0.93 421.70 6-yl)-benzothiazol-5-yl]-amide 102 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-oxetan-3-yl-piperazin-1- 0.84 437.02 yl)-benzothiazol-5-yl]-amide 103 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(methyl-oxetan-3-yl-amino)- 0.87 382.01 benzothiazol-5-yl]-amide 104 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-oxa-6-aza-spiro[3.3]hept- 0.88 394.01 6-yl)-benzothiazol-5-yl]-amide 105 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-dimethylaminomethyl- 0.96 422.95 pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 106 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-isopropoxy-azetidin-1-yl)- 1.01 410.05 benzothiazol-5-yl]-amide 107 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-ethoxymethyl-pyrrolidin-1- 1.07 424.05 yl)-benzothiazol-5-yl]-amide 108 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-methoxy-piperidin-1-yl)- 0.98 410.02 benzothiazol-5-yl]-amide 109 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)- 0.79 367.97 benzothiazol-5-yl]-amide 110 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)- 0.83 395.99 benzothiazol-5-yl]-amide 111 rac-2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-phenyl-azetidin-1-yl)- 1.10 428.00 benzothiazol-5-yl]-amide 112 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1- 0.81 381.98 yl)-benzothiazol-5-yl]-amide 113 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-methoxymethyl-pyrrolidin- 1.00 410.01 1-yl)-benzothiazol-5-yl]-amide 114 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((S)-3-hydroxy-piperidin-1- 0.85 396.00 yl)-benzothiazol-5-yl]-amide 115 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.4]oct-6- 0.87 408.02 yl)-benzothiazol-5-yl]-amide 116 2,3-Dihydro-benzofuran-5-carboxylic acid [2-((R)-3-hydroxy-piperidin-1- 0.85 395.99 yl)-benzothiazol-5-yl]-amide 117 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(2-dimethylaminomethyl- 1.05 422.94 pyrrolidin-1-yl)-benzothiazol-5-yl]-amide

[0558] Example 101: .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).

[0559] Example 102: .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).

[0560] Example 103: .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).

[0561] Example 109: .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).

[0562] Example 116: .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.sub.1=8.6 Hz, J.sub.2=12.7 Hz, 1H), 1.75-1.91 (m, 2H), 1.40-1.54 (m, 2H).

EXAMPLE 118

2,3-Dihydro-benzofuran-5-carboxylic acid (2-azetidin-1-yl-benzooxazol-5-yl)-amide

[0563] 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

[0564] The following Example compounds were prepared in analogy to Example 118 starting from Intermediates A2 to A6, A8, A12, A16, A17, A25, A36, A37, and A40 to A48 and the appropriate benzoic acid derivatives.

TABLE-US-00010 LC-MS Example Name t.sub.R [min] [M + H].sup.+ 119 2,3-Dihydro-benzofuran-5-carboxylic acid (2-ethylamino-benzooxazol-5-yl)- 0.67 324.09 amide 120 2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyridin-2-yl-azetidin-1-yl)- 0.66 413.26 benzooxazol-5-yl]-amide 121 Benzo[1,3]dioxole-5-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)- 0.89 374.02 benzooxazol-5-yl]-amide 122 Benzo[1,3]dioxole-5-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)- 0.72 353.89 benzooxazol-5-yl]-amide 123 Benzo[1,3]dioxole-5-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)- 1.01 378.07 benzooxazol-5-yl]-amide 124 Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)- 0.79 380.05 benzooxazol-5-yl]-amide 125 Benzo[1,3]dioxole-5-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)- 0.83 394.06 benzooxazol-5-yl]-amide 126 Benzo[1,3]dioxole-5-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)- 0.85 408.10 benzooxazol-5-yl]-amide 127 Benzo[1,3]dioxole-5-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)- 0.89 352.04 amide 128 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)- 0.76 394.26 benzooxazol-5-yl]-amide 129 Benzo[1,3]dioxole-5-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)- 0.97 266.04 amide 130 Benzo[1,3]dioxole-5-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)- 0.94 401.83 benzooxazol-5-yl]-amide 131 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methoxy-piperidin-1-yl)- 0.88 396.08 benzooxazol-5-yl]-amide 132 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)- 0.83 408.10 benzooxazol-5-yl]-amide 133 Benzo[1,3]dioxole-5-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)- 0.84 408.10 benzooxazol-5-yl]-amide 134 Benzo[1,3]dioxole-5-carboxylic acid [2-(4,4-difluoro-piperidin-1-yl)- 0.95 401.84 benzooxazol-5-yl]-amide 135 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-hydroxy-piperidin-1-yl]- 0.75 382.08 benzooxazol-5-yl]-amide 136 Benzo[1,3]dioxole-5-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)- 0.81 368.03 amide 137 Benzo[1,3]dioxole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)- 0.79 381.10 benzooxazol-5-yl]-amide 138 Benzo[1,3]dioxole-5-carboxylic acid [2-(cyclopropyl-oxetan-3-yl-amino)- 0.84 394.07 benzooxazol-5-yl]-amide 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]- 0.78 366.05 amide 141 Chroman-6-carboxylic acid [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]- 0.95 385.84 amide 142 Chroman-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]- 1.06 390.10 amide 143 Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol- 0.85 392.09 5-yl]-amide 144 Chroman-6-carboxylic acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol- 0.89 406.09 5-yl]-amide 145 Chroman-6-carboxylic acid [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol- 0.91 420.13 5-yl]-amide 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- 0.80 406.28 5-yl]-amide 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]- 1.01 414.11 amide 150 Chroman-6-carboxylic acid [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]- 1.00 141.09 amide 151 Chroman-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]- 0.81 394.10 amide 152 Chroman-6-carboxylic acid [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]- 0.94 408.13 amide 153 Chroman-6-carboxylic acid [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol- 0.89 420.15 5-yl]-amide 154 Chroman-6-carboxylic acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol- 0.90 420.14 5-yl]-amide 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]- 0.85 393.11 amide 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- 0.90 406.12 5-yl]-amide 159 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(3-hydroxy-azetidin-1-yl)- 0.72 368.04 benzooxazol-5-yl]-amide 160 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-oxa-1-aza- 0.79 394.07 spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 161 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(1-aza-spiro[3.3]hept-1- 1.01 392.08 yl)-benzooxazol-5-yl]-amide 162 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(6-oxa-1-aza- 0.83 408.11 spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 163 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(7-oxa-1-aza- 0.86 422.12 spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 164 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-pyrrolidin-1-yl- 0.89 366.05 benzooxazol-5-yl)-amide 165 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(2-oxa-5-aza- 0.76 408.27 spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 166 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-piperidin-1-yl- 0.98 380.09 benzooxazol-5-yl)-amide 167 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-hydroxy-piperidin-1-yl)- 0.75 396.09 benzooxazol-5-yl]-amide 168 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(3,3-difluoro-piperidin-1- 0.94 416.09 yl)-benzooxazol-5-yl]-amide 169 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-methoxy-piperidin-1- 0.88 410.11 yl)-benzooxazol-5-yl]-amide 170 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4,4-difluoro-piperidin-1- 0.95 416.09 yl)-benzooxazol-5-yl]-amide 171 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(2-oxa-6-aza- 0.85 422.12 spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 172 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(2-oxa-7-aza- 0.83 422.12 spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 173 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-morpholin-4-yl- 0.81 382.09 benzooxazol-5-yl)-amide 174 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(4-methyl-piperazin-1-yl)- 0.79 395.11 benzooxazol-5-yl]-amide 175 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid (2-diethylamino- 0.95 368.07 benzooxazol-5-yl)-amide 176 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid [2-(cyclopropyl-oxetan-3-yl- 0.85 408.10 amino)-benzooxazol-5-yl]-amide 177 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3-hydroxy- 0.72 381.08 azetidin-1-yl)-benzooxazol-5-yl]-amide 178 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3,3-difluoro- 0.92 401.03 azetidin-1-yl)-benzooxazol-5-yl]-amide 179 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(1-aza- 0.96 405.12 spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 180 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1- 0.81 407.10 aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 181 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(6-oxa-1- 0.82 421.11 aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 182 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(7-oxa-1- 0.83 435.13 aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 183 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-pyrrolidin-1- 0.79 379.13 yl-benzooxazol-5-yl)-amide 184 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-5- 0.78 421.26 aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 185 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-piperidin-1- 0.90 393.12 yl-benzooxazol-5-yl)-amide 186 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-hydroxy- 0.74 409.13 piperidin-1-yl)-benzooxazol-5-yl]-amide 187 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4,4-difluoro- 0.97 429.12 piperidin-1-yl)-benzooxazol-5-yl]-amide 188 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(3,3-difluoro- 0.97 429.14 piperidin-1-yl)-benzooxazol-5-yl]-amide 189 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-6- 0.84 435.14 aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide 190 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(2-oxa-7- 0.82 435.13 aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide 191 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methoxy- 0.86 423.15 piperidin-1-yl)-benzooxazol-5-yl]-amide 192 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2-morpholin-4- 0.82 395.09 yl-benzooxazol-5-yl)-amide 193 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(4-methyl- 0.67 408.15 piperazin-1-yl)-benzooxazol-5-yl]-amide 194 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (2- 0.86 381.12 diethylamino-benzooxazol-5-yl)-amide 195 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [2-(cyclopropyl- 0.85 421.13 oxetan-3-yl-amino)-benzooxazol-5-yl]-amide

[0565] Example 124: .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).

[0566] Example 133: .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).

[0567] Example 144: .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).

[0568] Example 159: .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).

[0569] Example 176: .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).

[0570] Example 186: .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

[0571] 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

[0572] 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- 0.78 394.08 dihydro-benzofuran-5-yl)-amide 198 2-(4,4-Difluoro-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.89 416.09 benzofuran-5-yl)-amide 199 2-(1,1-Dioxo-thiomorpholin-4-yl)-benzothiazole-5-carboxylic acid (2,3- 0.76 430.06 dihydro-benzofuran-5-yl)-amide 200 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.82 410.11 benzofuran-5-yl)-amide 201 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.60 395.10 benzofuran-5-yl)-amide 202 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3- 0.76 408.07 dihydro-benzofuran-5-yl)-amide 203 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid (2,3- 0.79 410.04 dihydro-benzo[1,4]dioxin-6-yl)-amide 204 2-(4,4-Difluoro-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.89 432.07 benzo[1,4]dioxin-6-yl)-amide 205 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.83 426.08 benzo[1,4]dioxin-6-yl)-amide 206 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.60 411.00 benzo[1,4]dioxin-6-yl)-amide 207 2-Piperidin-1-yl-benzothiazole-5-carboxylic acid (2,3-dihydro- 0.85 396.06 benzo[1,4]dioxin-6-yl)-amide 208 2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid (2,3- 0.77 424.09 dihydro-benzo[1,4]dioxin-6-yl)-amide 209 2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid 0.79 396.00 benzo[1,3]dioxol-5-ylamide 210 2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid 0.83 411.96 benzo[1,3]dioxol-5-ylamide 211 2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid benzo[1,3]dioxol- 0.60 397.06 5-ylamide

[0573] Example 197. .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).

[0574] Example 198. .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, =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).

[0575] Example 207. .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).

[0576] Example 211. .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).

[0577] Biological Assays

[0578] 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.

[0579] Plasmid Production

[0580] 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).

[0581] Cell Culture and Transfection

[0582] 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).

[0583] Amplex Red Activity Assay

[0584] Inhibitory activities on NOX4 have been measured for each example compound using the following procedure:

[0585] 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.

[0586] Cellular H.sub.2O.sub.2 formation was measured using the Amplex Red reagent. Cells were washed with 1PBS, trypsinized with 1Trypsin-EDTA, collected by centrifugation and resuspended in 1PBS. 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.

[0587] Amplex Red Counter Screen Assay

[0588] 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 1PBS.

TABLE-US-00012 TABLE 1 IC.sub.50 IC.sub.50 Compound of Amplex Control 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