# US 9,040,690 B2 · 2,3,5-trisubstituted thiophene compounds and uses thereof

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- Number: US 9,040,690 B2
- Document ID: US9040690B2
- Status: Granted
- Kind: B2
- Application number: 13/810,277
- Filed: 2011-07-21
- Published: 2013-05-16
- Granted: 2015-05-26
- Earliest claimed: 2010-07-22
- Assignees: Novartis AG
- Applicants: David Barnes; Scott Louis Cohen; Jiping Fu; Lei Shu; Rui Zheng
- Inventors: David Barnes; Scott Louis Cohen; Jiping Fu; Lei Shu; Rui Zheng
- Web page: https://patentgrep.com/patent/US9040690B2

## CPC

- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/381: having five-membered rings
- A61K 31/4025: not condensed and containing further heterocyclic rings, e.g. cromakalim
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4535: containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a compound of formula I: a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

## Claims

### Claim 1

A compound of formula (I):
or a salt thereof, wherein
m is 0, 1 or 2;
n is 0 or 1, wherein m+n is 1, 2 or 3;
R1 is C3-C10alkynyl or phenyl, which phenyl is substituted with 0, 1, 2, or 3 substituents which are independently selected from the group consisting of halogen, hydroxy, cyano, C1-C4alkyl, haloC1-C4alkyl and C1-C4alkoxy, and which alkynyl is optionally substituted with a C3-C7cycloalkyl substituent, which cycloalkyl is optionally substituted with 1 or 2 independently selected C1-C4alkyl groups;
R2 is CO2H or C(O)N(H)S(O)2CH3;
R3 is C3-C7cycloalkyl which is substituted with 0, 1, 2 or 3 halogen atoms;
R3a represents 0, 1, 2, 3 or 4 residues independently selected at each occurrence from the group consisting of hydroxy, amino, cyano, halogen, C1-C6alkyl, and C1-C6alkoxy, wherein each alkyl or alkoxy substituent is substituted with 0, 1 or 2 substituents independently selected from hydroxy, cyano, C1-C4alkoxy, C1-C4alkylsulfone, N(R3b)2, C(O)N(R3b), heterocycle having 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, O and S and 5 or 6 member heteroaryl; or two geminal R3a substituents, taken in combination form a spirocyclic 3 to 6 member cycloalkyl or heterocycle;
R3b is independently selected at each occurrence from hydrogen, C1-C4alkyl, C1-C4alkoxyC1-C4alkyl and C1-C4alkanoyl; or N(R3b)2, taken in combination, form a 4 to 6 member heterocycle having 0 or 1 additional ring heteroatoms selected from N, O and S;
X is O, N-L-R4 or CR5R6;
L is a bond, S(O)2 or C(O);
R4 is C1-C6alkyl or C3-C7cycloalkyl each of which is substituted with 0, 1, or 2 hydroxy and 0 or 1 substituents selected from cyano, S(O)2—C1-C4alkyl, CO2H or NR4aR4b or phenyl;
R4 is naphthyl or phenyl, which phenyl is substituted with 0, 1, 2, or 3 substituents independently selected form the group consisting of halogen, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, amino, hydroxy, mono- and di-C1-C6alkylamino, hydroxyC1-C4alkyl, aminoC1-C4alkyl, C1-C6alkyl-OC(O)NH—, C1-C4alkyl-C(O)NH—, —C(O)NR4aR4b, phenyl, phenoxy, heteroaryl having one or two ring nitrogen atoms and having 0, 1, or 2 C1-C4alkyl substituents, or two substituents combine to form a fused heterocyclic ring, which heterocycle has 5, 6 or 7 ring atoms, 1 or 2 ring heteroatoms selected from N, O and S and which heterocycle is substituted with 0, 1 or 2 substituents independently selected from C1-C6alkyl; or
R4 is a 5 or 6 member heteroaryl having 1 to 3 heteroatoms selected from N, O and S, which heteroaryl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, cyano, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, hydroxy, NR4aR4b, hydroxyC1-C4alkyl, aminoC1-C4alkyl, C1-C6alkyl-OC(O)NH—, C3-C7cycloalkyl, C5-C7cycloalkenyl, phenyl, 5 or 6 membered heteroaryl having 1 or 2 ring heteroatoms selected from N, O and S, and saturated or partially unsaturated monocyclic or bicyclic heterocycle which heterocycle has 1 or 2 ring N, O or S atoms, 5 to 7 ring atoms in each ring and is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkanoyl, C1-C6alkoxyC(O)N(H)CH2, aminoC1-C4alkyl, C1-C4alkoxyC1-C4alkyl and NR4aR4b, and wherein the phenyl or heteroaryl substituent is unsubstituted or substituted with 1 or 2 independently selected substituents selected from halogen, CO2H, cyano, C1-C4alkyl, C1-C4alkoxy, CH2NR4aR4b and C(O)NR4aR4b; or
R4 is a saturated heterocycle having 1 ring nitrogen and 0 or 1 additional ring heteroatom selected from N, O and S, which heterocyclic ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C1-C6alkyl, CO2C1-C6alkyl and CO2-benzyl;
R4a is independently selected at each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein the alkyl substituent is unsubstituted or substituted with hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino;
R4b is independently selected at each occurrence from the group consisting of hydrogen, C1-C6alkyl and C1-C4alkanoyl, wherein the alkyl substituent is unsubstituted or substituted with hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino; or
NR4aR4b, taken in combination, form a heterocyclic ring having one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from N, O and S, which heterocyclic ring is substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, aminoC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, and mono- and di-C1-C4alkylamino;
R5 is absent or is selected from the group consisting of hydrogen and C1-C6alkyl;
R6 is oxo, hydrogen, hydroxy, amino, N(H)-J-R7;
J is absent, C(O) or S(O)2; and
R7 is C1-C6alkyl, phenyl or benzyl, each of is optionally substituted with C1-C6alkyl, C1-C6alkoxy, halogen, phenyl or phenoxy.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula II, or a salt thereof:
wherein
Z is CH or N;
R8 is selected from hydrogen, CO2H, C1-C4alkyl, C-C4alkoxy, cyano and halogen;
R9 is selected from C1-C6alkyl, C1-C6alkoxy, phenyl, NR9aR9b, N(H)—C(O)—O—C1-C4alkyl, and heterocycle, wherein the heterocycle has one or two rings, each ring having 5, 6, or 7 ring atoms, one ring nitrogen atom and 0 or 1 additional ring heteroatom selected from N, O and S, and wherein the heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, aminoC1-C4alkyl, C1-C4alkoxy, C1-C4alkoxyC1-C4alkyl, and mono- and di-C1-C4alkylamino;
R9a is selected from the group consisting of hydrogen and C1-C6alkyl, wherein the alkyl substituent is unsubstituted or substituted with hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino; and
R9b is selected from the group consisting of hydrogen, C1-C6alkyl and C1-C4alkanoyl, wherein the alkyl substituent is unsubstituted or substituted with hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula III, or a salt thereof:
wherein
R6 is hydrogen, hydroxy, amino or N(H)-J-R7;
J is C(O) or S(O)2;
R7 is (a) C1-C4alkyl optionally substituted with phenyl or phenoxy, or (b) phenyl optionally substituted with C1-C4alkyl, halogen or C1-C4alkoxy;
R10 is selected from hydrogen and C1-C6alkyl which alkyl is substituted with 0, 1, or 2 hydroxy and 0 or 1 substituents selected from cyano, SO2CH3, methoxy, ethoxy, N(R10a)2 and C(O)(NR10a)2;
R10a is selected at each occurrence from the group consisting of hydrogen and C1-C4alkyl which is substituted with 0 or 1 substituents selected from hydroxy, methoxy and ethoxy;
R11 is selected from the group consisting of hydrogen, fluoro, cyano, hydroxy and C1-C4alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula IV, or a salt thereof:
wherein
R10 and R11 are independently selected from hydrogen and C1-C6alkyl which alkyl is substituted with 0, 1, or 2 hydroxy and 0 or 1 substituents selected from SO2CH3, cyano, methoxy, ethoxy, N(R10a)2 and C(O)N(R10a)2;
R10a is selected at each occurrence from the group consisting of hydrogen and C1-C4alkyl which is substituted with 0 or 1 substituents selected from hydroxy, methoxy and ethoxy, or N(R10a)2, taken in combination forms a 4 to 6 member heterocyclic ring;
R12 is selected from the group consisting of hydrogen and C1-C4alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is tert-butylethynyl, phenyl, or phenyl para-substituted with F, Cl, or Me.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1 is tert-butylethynyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R2 is CO2H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 is cyclohexyl.

### Claim 9 (depends on 3)

The compound of claim 3, wherein R6 is hydrogen;
R10 is hydrogen or hydroxyC1-C6alkyl; and
R11 is hydrogen, methyl, hydroxy or fluoro.

### Claim 10 (depends on 4)

The compound of claim 4, wherein R10 is hydroxyC1-C6alkyl;
R11 is hydrogen or methyl; and
R12 is hydrogen or methyl.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3-((S)-2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid;
3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid;
3-(3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-phenyl-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid;
3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic acid;
5-(4-Chloro-phenyl)-3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylic acid;
3-[2-Cyclohexyl-4-(6-dipropylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-{(R)-2-Cyclohexyl-4-[6-((R)-2-methyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-{(R)-2-Cyclohexyl-4-[6-((2S,5R)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic acid;
3-[2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-{(R)-2-Cyclohexyl-4-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic acid;
3-[2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-4-(6-diethylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-6-oxo-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-4-(4-methoxy-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-4-(6-methoxy-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-2-Cyclohexyl-4-(1-methyl-1H-pyrazole-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-{(R)-2-Cyclohexyl-4-[6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-p-tolyl-thiophene-2-carboxylic acid;
3-(2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((4S,5R)-5-Cyclohexyl-3,4-dimethyl-2-oxo-imidazolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
5-(4-Chloro-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-thiophene-2-carboxylic acid;
3-[(R)-5-Cyclohexyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(R)-5-Cyclohexyl-2-(3-methanesulfonyl-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-{(R)-5-Cyclohexyl-2-[(2-methoxy-ethylamino)-methyl]-3-oxo-morpholin-4-yl}-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-(4-Cyclohexyl-2-oxo-[1,3]oxazinan-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((R)-5-Cyclohexyl-2-morpholin-4-ylmethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((2S,5R)-2-Cyanomethyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((R)-5-Cyclohexyl-2,2-dimethyl-3-oxo-morpholin-4-yl)-5-p-tolyl-thiophene-2-carboxylic acid;
3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-(6-Cyclohexyl-3-hydroxy-3-methyl-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic acid;
3-((R)-3-Cyclohexyl-5-oxo-1,9-dioxa-4-aza-spiro[5.5]undec-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((R)-5-Cyclohexyl-2-hydroxymethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[6-Cyclohexyl-3-hydroxy-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-[(S)-6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid;
3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid; and
3-[(S)-6-Cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid.

### Claim 12 (depends on 1)

A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound according to claim 1 and
one or more pharmaceutically acceptable carriers.

### Claim 13 (depends on 1)

A pharmaceutical combination, comprising:
a therapeutically effective amount of the compound according to claim 1 and
one or more therapeutically active agents.