Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation

Abstract

Provided are cycloalkyl- and cycloalkenyl-substituted benzaldehydes and heteroaldehydes of formula (I) that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions containing the modulators, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation. ##STR00001##

Claims

1. A compound of Formula (I): ##STR00597## a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is cycloalkyl or cycloalkenyl, each of which is substituted with one to three R.sup.a; Y is CR.sup.1aR.sup.1b, wherein R.sup.1a is H or halo, and R.sup.1b is H or halo; X is 0; T.sup.1, T.sup.2, T.sup.3, and T.sup.4 are independently C or N provided that at least one of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is C; wherein when T.sup.1, T.sup.2, T.sup.3, or T.sup.4 are N, then R.sup.2, R.sup.3, R.sup.4, or R.sup.5, respectively, are absent; R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, halo, R.sup.b, OR.sup.d, or NR.sup.dNR.sup.d; R.sup.5 is selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.zOR.sup.d, O(CH.sub.2).sub.zNR.sup.dR.sup.d, OC(O)R.sup.e, SR.sup.d, CN, NO.sub.2, CO.sub.2R.sup.d, CONR.sup.dR.sup.d, C(O)R.sup.d, OC(O)NR.sup.dR.sup.d, NR.sup.dR.sup.d, NR.sup.dC(O)R.sup.e, NR.sup.dC(O).sub.2R.sup.e, NR.sup.dC(O)NR.sup.dR.sup.d, S(O)R.sup.e, S(O).sub.2R.sup.e, NR.sup.dS(O).sub.2R.sup.e, S(O).sub.2NR.sup.dR.sup.d, and N.sub.3; wherein z is 0, 1, 2, 3, 4, 5, or 6; or R.sup.5 is (CH.sub.2).sub.pR.sup.5a, wherein p is 0 or 1 and R.sup.5a is OH; R.sup.6 and R.sup.7 together form oxo or an aldehyde protecting group, or R.sup.6 together with R.sup.1b or R.sup.5 forms a cyclic ether, wherein one of R.sup.1b or R.sup.5a is O, R.sup.6 is a bond, and R.sup.7 is selected from the group consisting of OH, C.sub.1-8alkoxy, and haloC.sub.1-8alkoxy; each R.sup.a is independently selected from the group consisting of halo, R.sup.b, OR.sup.d, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)OH, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.kCONR.sup.dR.sup.d, (CH.sub.2).sub.kC(O)R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, and (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c ; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R.sup.a is selected from the group consisting of OR.sup.d, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)OH, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.kCONR.sup.dR.sup.d, (CH.sub.2).sub.kC(O)R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl; wherein the substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl are each substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d; each R.sup.b is independently selected from the group consisting of C.sub.1-8alkyl, C.sub.2-8alkenyl, and C.sub.2-8 alkynyl, each optionally independently substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d; each R.sup.c is independently selected from the group consisting of halo, C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.2-8alkenyl, haloC.sub.2-8 alkenyl, C.sub.2-8alkynyl, haloC.sub.2-8alkynyl, (CH.sub.2).sub.mOR.sup.f, heteroaryl, cycloalkyl, and heterocycloalkyl; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; each R.sup.d is independently selected from the group consisting of hydrogen, C.sub.1-8 alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8 alkynyl, haloC.sub.2-8alkynyl, (CH.sub.2).sub.kheterocycloalkyl, and (CH.sub.2).sub.uO(CH.sub.2).sub.uH; wherein k is 0, 1, 2, 3, 4, 5, or 6 and each u is independently 1, 2, 3, 4, 5, or 6; each R.sup.f is independently selected from the group consisting of hydrogen, C.sub.1-8 alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8 alkynyl, and haloC.sub.2-8alkynyl; and R.sup.e is C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8alkynyl, or haloC.sub.2-8alkynyl; provided that: at least one of R.sup.4 and R.sup.5 is other than hydrogen or T.sup.1 and T.sup.3 are C; T.sup.2 is N and T.sup.4 is C, or T.sup.2 is C and T.sup.4 is N.

2. The compound according to claim 1, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: T.sup.1, T.sup.2, T.sup.3, and T.sup.4 are C.

3. The compound according to claim 2, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently hydrogen, halo, R.sup.b, or OR.sup.d.

4. The compound according to claim 3, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Y is CH.sub.2.

5. The compound according to claim 1, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.5 is OH; and R.sup.2, R.sup.3 and R.sup.4 are hydrogen.

6. The compound according to claim 5, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is cyclopentyl or cyclohexyl.

7. The compound according to claim 6, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each R.sup.a is independently selected from the group consisting of R.sup.b, OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2)kheteroaryl optionally substituted with one to three R.sup.c, and (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R.sup.a is selected from the group consisting of OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2)karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl, wherein the substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl are each substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d.

8. The compound according to claim 6, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is substituted with one R.sup.a which is heteroaryl optionally substituted with one to three R.sup.c.

9. The compound according to claim 8, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of pyridinyl, pyrazolyl, and imidazolyl, and wherein each R.sup.c is independently selected from the group consisting of halo, OR.sup.f, C.sub.1-8alkyl, haloC.sub.1-8alkyl, cycloalkyl, and heterocycloalkyl.

10. A compound according to claim 8, a tautomer, a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of 2-chloropyridin-3-yl, 2-methoxypyridin-3-yl, 2-cyclobutylpyrazol-3-yl, 2-cyclopentylpyrazol-3-yl, 2-cyclopropylpyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, 2-(2,2,2-trifluoroethyl)pyrazol-3-yl, 2-(2,2-difluoroethyl)pyrazol-3-yl, 2-(3,3,3-trifluoropropyl)pyrazol-3-yl, 2-(oxetan-3-yl)pyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, and 3-propan-2-ylimidazol-4yl.

11. The compound according to claim 5, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is cyclopentenyl or cyclohexenyl.

12. The compound according to claim 11, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each R.sup.a is independently selected from the group consisting of R.sup.b, OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, and (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R.sup.a is selected from the group consisting of OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl; wherein the substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl are each substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d.

13. The compound according to claim 12, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is substituted with one R.sup.a which is heteroaryl optionally substituted with one to three R.sup.c.

14. The compound according to claim 13, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of pyridinyl, pyrazolyl, and imidazolyl, and wherein each R.sup.c is independently selected from the group consisting of halo, OR.sup.f, C.sub.1-8alkyl, haloC.sub.1-8alkyl, cycloalkyl, and heterocycloalkyl.

15. The compound according to claim 14, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of 2-chloropyridin-3-yl, 2-methoxypyridin-3-yl, 2-cyclobutylpyrazol-3-yl, 2-cyclopentylpyrazol-3-yl, 2-cyclopropylpyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, 2-(2,2,2-trifluoroethyl)pyrazol-3-yl, 2-(2,2-difluoroethyl)pyrazol-3-yl, 2-(3,3,3-trifluoropropyl)pyrazol-3-yl, 2-(oxetan-3-yl)pyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, and 3-propan-2-ylimidazol-4 -yl.

16. The compound according to claim 1, a tautomer, a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, wherein at least one of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is N.

17. The compound according to claim 16, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: T.sup.1 and T.sup.3 are C; T.sup.2 is N and T.sup.4 is C, or T.sup.2 is C and T.sup.4 is N; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently hydrogen, halo, R.sup.b, or OR.sup.d.

18. The compound according to claim 17, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: T.sup.2 is N and T.sup.4 is C; R.sup.2, R.sup.3, and R.sup.4 are hydrogen; and R.sup.5 is OR.sup.d wherein R.sup.d is hydrogen.

19. The compound according to claim 17, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is cyclopentyl or cyclohexyl.

20. The compound according to claim 19, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each R.sup.c is independently selected from the group consisting of R.sup.b, OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, and (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R.sup.a is selected from the group consisting of OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl; wherein the substituted C.sub.1-8alkyl, substituted C.sub.2-8alkenyl, and substituted C.sub.2-8 alkynyl are each substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d.

21. The compound according to claim 20, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is substituted with one R.sup.a which is heteroaryl optionally substituted with one to three R.sup.c.

22. The compound according to claim 21, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of pyridinyl, pyrazolyl, and imidazolyl, and wherein each R.sup.c is independently selected from the group consisting of halo, OR.sup.f, C.sub.1-8alkyl, haloC.sub.1-8alkyl, cycloalkyl, and heterocycloalkyl.

23. The compound according to claim 21, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R.sup.a is selected from the group consisting of 2-chloropyridin-3-yl, 2-methoxypyridin-3-yl, 2-cyclobutylpyrazol-3-yl, 2-cyclopentylpyrazol-3-yl, 2-cyclopropylpyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, 2-(2,2,2-trifluoroethyl)pyrazol-3-yl, 2-(2,2-difluoroethyl)pyrazol-3-yl, 2-(3,3,3-trifluoropropyl)pyrazol-3-yl, 2-(oxetan-3-yl)pyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, and 3-propan-2-ylimidazol-4 -yl.

24. A compound selected from the group consisting of cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; cis-4((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; (1R,3S)-3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; trans-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; trans-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; methyl3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; trans-methyl4-((2-formyl-3-methoxyphenoxy)methyl)cyclohexanecarboxylate; 2-hydroxy-6-((3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methoxy)benzaldehyde; 2-hydroxy-6-((2-phenylcyclohexyl)methoxy)benzaldehyde; 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohex-1-en-1-yl)methoxy)benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy--[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde; 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-3-methylbenzaldehyde; 6-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-3-methyl-64[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 6-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 6-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-3-methyl-6-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]-3-methylbenzaldehyde; 6-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-6-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxyThenzaldehyde; 2-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde; 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-fluorophenyl)cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]benzaldehyde; 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-hydroxybenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-3-methylbenzaldehyde; 6-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-3-methyl-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 6-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]-3-methylbenzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 6-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 2-hydroxy-3-methyl-6-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[(2-phenylcyclohexen-1-yl)methoxy]benzaldehyde; 2-hydroxy-3-methyl-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]-3-methylbenzaldehyde; 6-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 6-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxy-3-methylbenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-6-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[(2-phenylcyclohexen-1-yl)methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-6-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-6-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxybenzaldehyde; 3-chloro-2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-chloro-2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[(2-phenylcyclohexen-1-yl)methoxy]benzaldehyde; 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 2-fluoro-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]benzaldehyde; 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-fluorobenzaldehyde; 2-fluoro-6-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]benzaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[(2-phenylcyclohexyl)methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[242-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 6-methyl-3-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde; 6-methyl-3-[(2-phenylcyclohexyl)methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-2-carbaldehyde; 3-chloro-5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-methyl-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]- 5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 5-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-54[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[(2-phenylcyclohexyl)methoxy]pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-methoxypyridin-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-methoxyphenyl)cyclohexyl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexyl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-2-carbaldehyde; 3-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 6-methyl-3-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 6-methyl-3-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-2-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]-6-methylpyridine-2-carbaldehyde; 6-methyl-3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde; 3-chloro-5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-chloro-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-methyl-5-[[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(3-propan-2-yhmidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-5-methylpyridine-4-carbaldehyde; 3-methyl-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(3-propan-2-yhmidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-hydroxy-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-hydroxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 3-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-5-methoxypyridine-4-carbaldehyde; 3-methoxy-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-hydroxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-methoxy-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-methoxyethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[(2-phenylcyclohexen-1-yl)methoxy]pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 5-[[2-(2-methoxyphenyl)cyclohexen-1-yl]methoxy]-2-(2-morpholin-4-ylethoxy)pyridine-4-carbaldehyde; 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(oxetan-3-yl)pyrazol-3-yl]cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde; and 2-(2-morpholin-4-ylethoxy)-5-[[2-(3-propan-2-ylimidazol-4-yl)cyclohexen-1-yl]methoxy]pyridine-4-carbaldehyde, or a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 24, selected from the group consisting of cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; cis-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; (1R,3S)-3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; trans-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; trans-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; methyl3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; trans-methyl4-((2-formyl-3-methoxyphenoxy)methyl)cyclohexanecarboxylate; 2-hydroxy-6-((3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methoxy)benzaldehyde; 2-hydroxy-6-((2-phenylcyclohexyl)methoxy)benzaldehyde; and 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohex-1-en-1-yl)methoxy)benzaldehyde, or a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound of claim 1, a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) I. Definitions

(2) As used herein, the below terms have the following meanings unless specified otherwise.

(3) The abbreviations used herein are conventional, unless otherwise defined: aq=aqueous; Boc=t-butylcarboxy, (Boc).sub.2O=di-tert-butyl dicarbonate, C.=degrees celcius, mCPBA=m-chloroperoxybenzoic acid, DIAD=diisopropylazodicarboxylate, DCM=dichloromethane (CH.sub.2Cl.sub.2), DIBAL=diisobutylaluminum hydride, DMF=dimethyl formamide, EtOAc=ethyl acetate, g=gram, H.sub.2=hydrogen; H.sub.2O=water; HBr=hydrogen bromide; HCl=hydrogen chloride, HPLC=high pressure liquid chromatography, h=hour, LAH=lithium aluminum hydride (LiAlH.sub.4); MeCN=acetonitrile; MS=Mass Spectrum, m/z=mass to charge ratio, MHz=Mega Hertz, MeOH=methanol, M=micromolar, L=microliter, mg=milligram, mM=millimolar, mmol=millimole, mL=milliliter, min=minute, M=molar, Na.sub.2CO.sub.3=sodium carbonate, ng=nanogram, N=Normal, NMR=nuclear magnetic resonance, Pd/C=palladium on carbon, rp=reverse phase, sat=saturated, rt=room temperature, TEA=triethylamine, THF=tetrahydrofuran, TFA=trifluoroacetic acid, TLC=thin layer chromatography, and TMS=trimethylsilyl.

(4) It is noted here that as used in this specification and the appended claims, the singular forms a, an, and the include plural reference unless the context clearly dictates otherwise.

(5) Alkoxy refers to O(alkyl) where alkyl as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, and the like.

(6) Alkyl, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, C.sub.1-8alkyl refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like. Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

(7) Alkenyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond, but no more than three double bonds. For example, C.sub.2-8alkenyl is meant to include, ethenyl, propenyl, 1,3-butadienyl and the like.

(8) Alkynyl means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. The term alkynyl is also meant to include those alkyl groups having one triple bond and one double bond. For example, C.sub.2-8alkynyl is meant to include ethynyl, propynyl and the like.

(9) The term allosteric modulators refers to compounds that bind to hemoglobin to modulate its affinity for oxygen. In one group of embodiments, the allosteric modulators act to stabilize or destabilize a particular hemoglobin conformation. In one group of embodiments, the modulators stabilize the relaxed R state. In other embodiments, the modulators destabilize the tense T state. In one group of embodiments, the allosteric modulators can destabilize one conformation while stabilizing another. In some such embodiments, the modulators stabilize a relaxed R state and destabilize the tense T state. The modulators, in addition to modulating the affinity of hemoglobin for oxygen, may also confer additional properties to hemoglobin such as increasing its solubility. The present disclosure is not intended to be limited to the mechanism by which the allosteric modulators interact with and regulate hemoglobin. In one group of embodiments, the allosteric modulators inhibit the polymerization of HbS and the sickling of red blood cells. In one group of embodiments, the binding of the allosteric modulators provided herein to hemoglobin can occur through covalent or non-covalent interactions. In one embodiment, the allosteric modulators react through its aldehyde substituent with an amine group on a hemoglobin amino acid side chain to form a Schiff base.

(10) Amino refers to a monovalent radical NH.sub.2.

(11) Aryl by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl and 4-biphenyl.

(12) Bond when used as an element in a Markush group means that the corresponding group does not exist, and the groups of both sides are directly linked.

(13) Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and Spiro ring systems. The term cycloalkyl includes cycloalkenyl groups, i.e., partially saturated cycloalkyl rings having at least one site of >CC< ring unsaturation. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl. C.sub.u-vcycloalkyl refers to cycloalkyl groups having u to v carbon atoms as ring members. C.sub.u-vcycloalkenyl refers to cycloalkenyl groups having u to v carbon atoms as ring members. Cycloalkyl and cycloalkenyl groups can have, for example, 5-8 carbon atoms as ring members, or 5-6 carbon atoms as ring members.

(14) The term hemoglobin as used herein refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).

(15) Heteroaryl refers to a cyclic or polycyclic radical having at least one aromatic ring and from one to five ring heteroatom selected from N, O, and S, and optionally one or more oxo (O) substituents attached to one or more carbon ring atoms, and wherein the nitrogen and sulfur ring atoms are optionally oxidized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms. Heteroaryl groups include polycyclic aromatic ring(s) fused to non-aromatic cycloalkyl or heterocycloalkyl groups, and where the point of attachment to the remainder of the molecule can be through any suitable ring atom of any ring. In a polycyclic heteroaryl group, the ring heteroatom(s) can be in either an aromatic or non-aromatic ring or both. The term aromatic ring include any ring having at least one planar resonance structure where 2n+2 pi electrons are delocalized about the ring. Examples of heteroaryl groups include, but are not limited to, imidazopyridinyl groups, pyrrolopyridinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrazolopyrazinyl groups, pyridinyl groups, pyrazinyl groups, oxazolyl groups, imidazolyl groups, triazolyl groups, tetrazolyl groups, pyrazolyl groups, quinolinyl groups, isoquinolinyl groups, indazolyl groups, benzooxazolyl groups, naphthyridinyl groups, and quinoxalinyl groups. Other non-limiting examples of heteroaryl groups include xanthine, hypoxanthine, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, azaindole, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. Bicyclic heteroaryl refers to a heteroaryl radical that contains two rings.

(16) The term heterocycloalkyl refers to a cycloalkyl group containing at least one ring heteroatom and optionally one or more oxo substituents. As used herein, the term heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S), wherein the heteroatoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together. Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1-oxide, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrrolidine, and the like.

(17) Halo or halogen by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as haloalkyl, are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m+1), where m is the total number of carbon atoms in the alkyl group. For example, the term haloC1-8alkyl is meant to include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term haloalkenyl, and haloalkynyl refers to alkenyl and alkynyl radicals having one or more halogen atoms. Additionally, term haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms. In one group of embodiments, the haloalkyl, haloalkenyl, haloalkynyl, and haloalkoxy groups have from one to 5 or from one to 3 halo atoms. Examples of haloalkoxy groups include difluoromethoxy and trifluoromethoxy. In one group of embodiments, the halo atoms of the haloalkenyl and haloalkynyl groups are attached to the aliphatic portions of these groups.

(18) The terms optional or optionally as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, heteroaryl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heteroaryl group is substituted with an alkyl group and situations where the heteroaryl group is not substituted with the alkyl group.

(19) Oxo refers to the divalent atom O.

(20) In each of the above embodiments designating a number of atoms e.g. C.sub.1-8 is meant to include all possible embodiments that have one fewer atom. Non-limiting examples include C.sub.1-4, C.sub.1-5, C.sub.1-6, C.sub.1-7, C.sub.2-8, C.sub.2-7, C.sub.3-8, C.sub.3-7 and the like.

(21) The term pharmaceutically acceptable salts is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19, 1977). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

(22) The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

(23) The term pharmaceutically acceptable carrier or excipient means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. A pharmaceutically acceptable carrier or excipient as used in the specification and claims includes both one and more than one such carrier or excipient.

(24) The terms pharmaceutically effective amount, therapeutically effective amount or therapeutically effective dose refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.

(25) Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3.sup.rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (TES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.

(26) The term aldehyde protecting group refers to any known protecting group used to mask the aldehyde functionality. Aldehyde protecting groups include acetals and hemiacetals. The acetals and hemiacetals can be prepared from C.sub.1-8 alcohols or C.sub.2-8 diols. In one group of embodiments, the aldehyde protecting group is a five or six membered cyclic acetal formed from condensation of the aldehyde with ethylene or propylene glycol. In another group of embodiments the aldehyde protecting group is an imine or hydroxyimine. The aldehyde protecting groups of the present disclosure also include prodrug groups that convert the aldehyde to a prodrug, where the aldehyde is formed in vivo as the active agent under physiological conditions upon administration of the prodrug. The prodrug group can also serve to increase the bioavailability of the aldehyde. In one group of embodiments, the prodrug group is hydrolyzed in vivo to the aldehyde. In one group of embodiments, the aldehyde protecting group is a thiazolidine or N-acetylthiazolidine prodrug group. In one group of embodiments, the aldehyde protecting group is a thiazolidine prodrug group disclosed in U.S. Pat. No. 6,355,661. In one group of embodiments the modulators provided herein are condensed with L-cysteine or a L-cysteine derivative to form the corresponding thiazolidine protected aldehyde prodrug. In one group of embodiments, the thiazolidine has the formula

(27) ##STR00002##
wherein R.sup.11 is selected from OH, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, N(R.sup.13).sub.2 where R.sup.13 is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R.sup.12 is H or -L-R.sup.14, where L is carbonyl or sulfonyl; R.sup.14 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the wavy line signifies the point of attachment to the phenyl ring of the allosteric modulators disclosed herein; and the term substituted refers to substitution by one or more substituents selected from COOH, CHO, oxyacyl, acyloxy, cycloacyloxy, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, alkoxy, cycloalkoxy, F, Cl, Br, NO.sub.2, cyano, sulfuryl, and the like. In one group of embodiments, provided are modulators having a thiazolidine protecting group where R.sup.11 is alkoxy and R.sup.12 is H, or where R.sup.11 is OH and R.sup.12 is C(O)alkyl, or where R.sup.11 is NH(heteroaryl) and R.sup.12 is C(O)alkyl.

(28) The term sickle cell disease refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb). Sickle cell diseases includes sickle cell anemia, sickle-hemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/.sup.+) and sickle beta-zero-thalassaemia)(HbS/.sup.0).

(29) The subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.

(30) Tautomer refers to alternate forms of a molecule that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a NC(H)NH ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

(31) The terms treat, treating, treatment and grammatical variations thereof as used herein, includes partially or completely delaying, alleviating, mitigating or reducing the intensity, progression, or worsening of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.

(32) The symbol > when used in connection with a substituent signifies that the substituent is a divalent substituent attached to two different atoms through a single atom on the substituent.

(33) The term wavy line signifies the point of attachment of the substituent to the remainder of the molecule. When the wavy line is not depicted as being specifically appended to a specific ring atom, the point of attachment can be to any suitable atom of the substituent. For example, the wavy line in the following structure:

(34) ##STR00003##
is intended to include, as the point of attachment, any of the six substitutable carbon atoms.

(35) Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed isomers. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomer and stereoisomers refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed diastereomers and those that are non-superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ()-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a racemic mixture. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) differ in the chirality of one or more stereocenters.

(36) The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with isotopes, such as for example deuterium (.sup.2H), tritium (.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

(37) Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent alkoxyalkyl refers to an alkyl group that is substituted with alkoxy and hydoxyalkyl refers to an alkyl group that is substituted with hydroxy. For both of these substituents, the point of attachment is at the alkyl group.

(38) It is understood that the definitions and formulas provided herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

(39) II. Hemoglobin Modulators

(40) Some groups of embodiments provide a compound of Formula (I):

(41) ##STR00004## or a tautomer or pharmaceutically acceptable salt thereof, wherein: Q is cycloalkyl or cycloalkenyl optionally substituted with one to three R.sup.a; Y is O, S(O).sub.q or CR.sup.1aR.sup.1b, where R.sup.1a is H or halo, and R.sup.1b is selected from the group consisting of H, C.sub.1-C.sub.8alkyl, halo, and OH; X is selected from the group consisting of O, S(O).sub.q, CH(CH.sub.2).sub.nR.sup.8, and C(R.sup.9).sub.2, where q is 0, 1 or 2, n is 0 or 1, R.sup.8 is OH, and R.sup.9 is independently H or halo; or YX taken together is NHC(O) or C(O)NH; T.sup.1, T.sup.2, T.sup.3, and T.sup.4 are independently C or N provided that at least one of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is C; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently absent or selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.zOR.sup.d, O(CH.sub.2).sub.zNR.sup.dR.sup.d, OC(O)R.sup.e, SR.sup.d, CN, NO.sub.2, CO.sub.2R.sup.d, CONR.sup.dR.sup.d, C(O)R.sup.d, OC(O)NR.sup.dR.sup.d, NR.sup.dR.sup.d, NR.sup.dC(O)R.sup.e, NR.sup.dC(O).sub.2R.sup.e, NR.sup.dC(O)NR.sup.dR.sup.d, S(O)R.sup.e, S(O).sub.2R.sup.e, NR.sup.dS(O).sub.2R.sup.e, S(O).sub.2NR.sup.dR.sup.d, and N.sub.3, where z is 0, 1, 2, 3, 4, 5, or 6; or R.sup.5 is (CH.sub.2).sub.pR.sup.5a, where p is 0 or 1 and R.sup.5a is OH; R.sup.6 and R.sup.7 together form oxo or an aldehyde protecting group, or R.sup.6 together with R.sup.1b, R.sup.8, or R.sup.5 forms a cyclic ether, where one of R.sup.1b, R.sup.8, or R.sup.5a is O, R.sup.6 is a bond, and R.sup.7 is selected from the group consisting of OH, C.sub.1-8alkoxy, and haloC.sub.1-8alkoxy; each R.sup.a is independently selected from the group consisting of of halo, CN, R.sup.b, OR.sup.d, O(CH.sub.2).sub.uOR.sup.d, O(CH.sub.2).sub.uNR.sup.dR.sup.d, O(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, O(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, O(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, NH.sub.2, (CH.sub.2).sub.kOC(O)R.sup.e, (CH.sub.2).sub.kSR.sup.d, NO.sub.2, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)OH, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)(heteroaryl)C(O)(C.sub.1-8alkyl), (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.kCONR.sup.dR.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.e, (CH.sub.2).sub.k C(O)R.sup.d, (CH.sub.2).sub.kOC(O)NR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uOR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)NR.sup.dR.sup.d, (CH.sub.2).sub.kS(O)R.sup.e, (CH.sub.2).sub.kS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kS(O).sub.2NR.sup.dR.sup.d, N.sub.3, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, and NR.sup.d(CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; each R.sup.b is independently selected from the group consisting of C.sub.1-8alkyl, C.sub.2-8alkenyl, and C.sub.2-8 alkynyl, each optionally independently substituted with one to three halo, OR.sup.d, or NR.sup.dR.sup.d; each R.sup.c is independently selected from the group consisting of halo, C.sub.1-8alkyl, haloC.sub.1-8alkyl, C.sub.2-8alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8alkynyl, haloC.sub.2-8alkynyl, (CH.sub.2).sub.mOR.sup.f, OC(O)R.sup.g, SR.sup.f, CN, NO.sub.2, CO.sub.2R.sup.f, CONR.sup.fR.sup.f, C(O)R.sup.f, OC(O)NR.sup.fR.sup.f, (CH.sub.2).sub.mNR.sup.fR.sup.f, NR.sup.fC(O)R.sup.g, NR.sup.fC(O).sub.2R.sup.g, NR.sup.fC(O)NR.sup.fR.sup.f, S(O)R.sup.g, S(O).sub.2R.sup.g, NR.sup.fS(O).sub.2R.sup.g, S(O).sub.2NR.sup.fR.sup.f, N.sub.3, heteroaryl optionally substituted with one to three R.sup.h, cycloalkyl optionally substituted with one to three R.sup.h, and heterocycloalkyl optionally substituted with one to three R.sup.h where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; each R.sup.h is independently selected from the group consisting of halo, C.sub.1-8alkyl, haloC.sub.1-8alkyl, OR.sup.j, OC(O)R, SR.sup.j, NO.sub.2, CO.sub.2R.sup.j, CONR.sup.jR.sup.j, C(O)R.sup.j, OC(O)NR.sup.jR.sup.j, NR.sup.jR.sup.j, NR.sup.jC(O)R.sup.t, NR.sup.jC(O).sub.2R.sup.t, NR.sup.jC(O)NR.sup.jR.sup.j, S(O)R.sup.t, S(O).sub.2R.sup.t, NR.sup.jS(O).sub.2R.sup.t, and S(O).sub.2NR.sup.jR.sup.j; each R.sup.d is independently selected from the group consisting of hydrogen, C.sub.1-8 alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8 alkynyl, haloC.sub.2-8alkynyl, (CH.sub.2).sub.kheterocycloalkyl, and (CH.sub.2).sub.uO(CH.sub.2).sub.uH where k is 0, 1, 2, 3, 4, 5, or 6 and each u is independently 1, 2, 3, 4, 5, or 6; R.sup.f and R.sup.j are each independently selected from the group consisting of hydrogen, C.sub.1-8 alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8 alkynyl, and haloC.sub.2-8alkynyl; and R.sup.e, R.sup.g, and R.sup.t are each independently selected from the group consisting of C.sub.1-8 alkyl, haloC.sub.1-8alkyl, C.sub.2-8 alkenyl, haloC.sub.2-8alkenyl, C.sub.2-8 alkynyl, and haloC.sub.2-8alkynyl; provided that X and Y are not both O; provided that when X is O, R.sup.1b is not OH; and provided that when Y is O, and n is 0, R.sup.8 is not OH.

(42) In some groups of embodiments, T.sup.1, T.sup.2, T.sup.3, and T.sup.4 are C; and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.zOR.sup.d, O(CH.sub.2).sub.zNR.sup.dR.sup.d, OC(O)R.sup.e, SR.sup.d, CN, NO.sub.2, CO.sub.2R.sup.d, CONR.sup.dR.sup.d, C(O)R.sup.d, OC(O)NR.sup.dR.sup.d, NR.sup.dR.sup.d, NR.sup.dC(O)R.sup.e, NR.sup.dC(O).sub.2R.sup.e, NR.sup.dC(O)NR.sup.dR.sup.d, S(O)R.sup.e, S(O).sub.2R.sup.e, NR.sup.dS(O).sub.2R.sup.e, S(O).sub.2NR.sup.dR.sup.d, and N.sub.3, where z is 0, 1, 2, 3, 4, 5, or 6; or R.sup.5 is (CH.sub.2).sub.pR.sup.5a where p is 0 or 1 and R.sup.5a is OH.

(43) In some groups of embodiments, Q is substituted with one to three R.sup.a; R.sup.2, and R.sup.3 are independently selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.zOR.sup.d, O(CH.sub.2).sub.zNR.sup.dR.sup.d, OC(O)R.sup.e, SR.sup.d, CN, NO.sub.2, CO.sub.2R.sup.d, CONR.sup.dR.sup.d, C(O)R.sup.d, OC(O)NR.sup.dR.sup.d, NR.sup.dR.sup.d, NR.sup.dC(O)R.sup.e, NR.sup.dC(O).sub.2R.sup.e, NR.sup.dC(O)NR.sup.dR.sup.d, S(O)R.sup.e, S(O).sub.2R.sup.e, NR.sup.dS(O).sub.2R.sup.e, S(O).sub.2NR.sup.dR.sup.d, and N.sub.3, where z is 0, 1, 2, 3, 4, 5, or 6; R.sup.4 and R.sup.5 are selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, and (CH.sub.2).sub.pR.sup.5a, where p is 0 or 1 and R.sup.5a is OH; and each R.sup.a is independently selected from the group consisting of halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.uOR.sup.d, O(CH.sub.2).sub.uNR.sup.dR.sup.d, O(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, O(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, O(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, NH.sub.2, (CH.sub.2)kOC(O)R.sup.e, (CH.sub.2).sub.kSR.sup.d, NO.sub.2, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)OH, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)(heteroaryl)C(O(C.sub.1-8alkyl), (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.kCONR.sup.dR.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.e, (CH.sub.2).sub.kC(O)R.sup.d, (CH.sub.2).sub.kOC(O)NR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uOR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)NR.sup.dR.sup.d, (CH.sub.2).sub.kS(O)R.sup.e, (CH.sub.2).sub.kS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kS(O).sub.2NR.sup.dR.sup.d, N.sub.3, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2)karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three Rc, and NR.sup.d(CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; provided that at least one of R.sup.4 and R.sup.5 is other than hydrogen.

(44) In some groups of embodiments, Y is O or CH.sub.2; X is O or CH.sub.2; R.sup.4 is selected from the group consisting of hydrogen, halo, R.sup.b, and OR.sup.d; R.sup.5 is selected from the group consisting of halo and OR.sup.d; and R.sup.6 and R.sup.7 together form oxo or an aldehyde protecting group.

(45) In some groups of embodiments, Y is CH.sub.2 and X is O.

(46) In some groups of embodiments, R.sup.2 and R.sup.3 are hydrogen.

(47) In some groups of embodiments, R.sup.5 is OH and R.sup.4 is hydrogen.

(48) In some groups of embodiments, R.sup.5 is OH and R.sup.4 is R.sup.b.

(49) In some groups of embodiments, R.sup.4 is methyl.

(50) In some groups of embodiments, R.sup.5 is OH and R.sup.4 is halogen.

(51) In some groups of embodiments, R.sup.5 is Cl.

(52) In some groups of embodiments, at least one of T.sup.1, T.sup.2, T.sup.3, and T.sup.4 is N.

(53) In some groups of embodiments, Q is substituted with one to three R.sup.a; T.sup.1 and T.sup.3 are C; T.sup.2 is N and T.sup.4 is C, or T.sup.2 is C and T.sup.4 is N; R.sup.2, and R.sup.3 are independently selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.zOR.sup.d, O(CH.sub.2).sub.zNR.sup.dR.sup.d, OC(O)R.sup.e, SR.sup.d, CN, NO.sub.2, CO.sub.2R.sup.d, CONR.sup.dR.sup.d, C(O)R.sup.d, OC(O)NR.sup.dR.sup.d, NR.sup.dR.sup.d, NR.sup.dC(O)R.sup.e, NR.sup.dC(O).sub.2R.sup.e, NR.sup.dC(O)NR.sup.dR.sup.d, S(O)R.sup.e, S(O).sub.2R.sup.e, NR.sup.dS(O).sub.2R.sup.e, S(O).sub.2NR.sup.dR.sup.d, and N.sub.3, where z is 0, 1, 2, 3, 4, 5, or 6; R.sup.4 and R.sup.5 are absent or are independently selected from the group consisting of hydrogen, halo, R.sup.b, OR.sup.d, and (CH.sub.2).sub.pR.sup.5a, where p is 0 or 1 and R.sup.5a is OH; and each R.sup.a is independently selected from the group consisting of halo, R.sup.b, OR.sup.d, O(CH.sub.2).sub.uOR.sup.d, O(CH.sub.2).sub.uNR.sup.dR.sup.d, O(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, O(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, O(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, NH.sub.2, (CH.sub.2)kOC(O)R.sup.e, (CH.sub.2).sub.kSR.sup.d, NO.sub.2, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)OH, (CH.sub.2).sub.kCO.sub.2(C.sub.1-8alkyl)(heteroaryl)C(O(C.sub.1-8alkyl), (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.kCONR.sup.dR.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.e, (CH.sub.2).sub.kC(O)R.sup.d, (CH.sub.2).sub.kOC(O)NR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uOR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dR.sup.d, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O)R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dC(O).sub.2R.sup.e, NR.sup.d(CH.sub.2).sub.uNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O)R.sup.e, (CH.sub.2).sub.kNR.sup.dC(O).sub.2R.sup.d, (CH.sub.2).sub.kNR.sup.dC(O)NR.sup.dR.sup.d, (CH.sub.2).sub.kS(O)R.sup.e, (CH.sub.2).sub.kS(O).sub.2R.sup.e, (CH.sub.2).sub.kNR.sup.dS(O).sub.2R.sup.e, (CH.sub.2).sub.kS(O).sub.2NR.sup.dR.sup.d, N.sub.3, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2)karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, NR.sup.d(CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three Rc, and NR.sup.d(CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6.

(54) In some groups of embodiments, T.sup.2 is C and T.sup.4 is N; and R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are hydrogen.

(55) In some groups of embodiments, T.sup.2 is C and T.sup.4 is N; R.sup.2, R.sup.3, and R.sup.5 are hydrogen; and R.sup.4 is R.sup.b.

(56) In some groups of embodiments, T.sup.2 is N and T.sup.4 is C; R.sup.2, R.sup.3, R.sup.4, are hydrogen; and R.sup.5 is halo.

(57) In some groups of embodiments, T.sup.2 is N and T.sup.4 is C; R.sup.2, R.sup.3, R.sup.4, are hydrogen; and R.sup.5 is R.sup.b.

(58) In some groups of embodiments, T.sup.2 is N and T.sup.4 is C; R.sup.2, R.sup.3, R.sup.4, are hydrogen; and R.sup.5 is OR.sup.d.

(59) In some groups of embodiments, T.sup.2 is N and T.sup.4 is C; R.sup.2, R.sup.3, R.sup.5, are hydrogen; and R.sup.4 is OR.sup.d.

(60) In some groups of embodiments, R.sup.d is hydrogen.

(61) In some groups of embodiments, R.sup.d is C.sub.1-8 alkyl.

(62) In some groups of embodiments, R.sup.d is (CH.sub.2).sub.kheterocycloalkyl, and where k is 1, 2, or 3.

(63) In some groups of embodiments, R.sup.d is (CH.sub.2).sub.uO(CH.sub.2).sub.uH, and where each u is independently 1, 2, or 3.

(64) In some groups of embodiments, Q is C.sub.3-C.sub.8 cycloalkyl.

(65) In some groups of embodiments, Q is C.sub.3-C.sub.6 cycloalkyl.

(66) In some groups of embodiments, Q is C.sub.3-C.sub.8 cycloalkenyl.

(67) In some groups of embodiments, Q is C.sub.3-C.sub.6 cycloalkenyl.

(68) In some groups of embodiments, Q is cyclopentyl.

(69) In some groups of embodiments, Q is cyclohexyl.

(70) In some groups of embodiments, Q is cyclopentenyl.

(71) In some groups of embodiments, Q is cyclohexenyl.

(72) In some groups of embodiments, each R.sup.a is independently selected from the group consisting of R.sup.b, OR.sup.d, (CH.sub.2).sub.kCO.sub.2R.sup.d, (CH.sub.2).sub.karyl optionally substituted with one to three R.sup.c, (CH.sub.2).sub.kheteroaryl optionally substituted with one to three R.sup.c, and (CH.sub.2).sub.kheterocycloalkyl optionally substituted with one to three R.sup.c, where k is 0, 1, 2, 3, 4, 5, or 6.

(73) In some groups of embodiments, Q is substituted with one R.sup.a which is (CH.sub.2).sub.kCO.sub.2R.sup.d k is 0, 1, 2, 3, 4, 5, or 6.

(74) In some groups of embodiments, Q is substituted with one R.sup.a which is R.sup.b.

(75) In some groups of embodiments, R.sup.b is C.sub.1-8alkyl optionally substituted with one to three OR.sup.d.

(76) In some groups of embodiments, R.sup.b is selected from the group consisting of 2-hydroxybutan-2-yl, 2-hydroxypentan-2-yl, and 2-hydroxypropan-2-yl.

(77) In some groups of embodiments, Q is substituted with one R.sup.a which is aryl optionally substituted with one to three R.sup.c.

(78) In some groups of embodiments, R.sup.a is phenyl optionally substituted with one to three R.sup.c, and wherein each R.sup.c is independently selected from the group consisting of halo and OR.sup.f.

(79) In some groups of embodiments, R.sup.a is selected from the group consisting of phenyl, 2-chlorophenyl, 2-fluorophenyl, and 2-methoxyphenyl.

(80) In some groups of embodiments, Q is substituted with one R.sup.a which is heteroaryl optionally substituted with one to three R.sup.c.

(81) In some groups of embodiments, R.sup.a is selected from the group consisting of pyridinyl, pyrazolyl, and imadazolyl, and wherein each R.sup.c is independently selected from the group consisting of halo, OR.sup.f, C.sub.1-8alkyl, haloC.sub.1-8alkyl, cycloalkyl, and heterocycloalkyl.

(82) In some groups of embodiments, R.sup.a is selected from the group consisting of 2-chloropyridin-3-yl, 2-methoxypyridin-3-yl, 2-cyclobutylpyrazol-3-yl, 2-cyclopentylpyrazol-3-yl, 2-cyclopropylpyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, 2-(2,2,2-trifluoroethyl)pyrazol-3-yl, 2-(2,2-difluoroethyl)pyrazol-3-yl, 2-(3,3,3-trifluoropropyl)pyrazol-3-yl, 2-(oxetan-3-yl)pyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, and (3-propan-2-ylimidazol-4-yl).

(83) In some groups of embodiments, Q is cyclohexyl substituted with one R.sup.c; Y is CH.sub.2 and X is O; R.sup.2, R.sup.3, and R.sup.4 are hydrogen; R.sup.5 is OH; and R.sup.6 and R.sup.7 together form oxo.

(84) In some groups of embodiments, Q is cyclohexyl substituted with one R.sup.c. In some groups of embodiments Y is CH.sub.2 and X is O; R.sup.6 and R.sup.7 together form oxo.

(85) In some groups of embodiments, R.sup.a is pyrazolyl substituted with one R.sup.c; Y is CH.sub.2 and X is O; R.sup.2, R.sup.3, and R.sup.4 are hydrogen; R.sup.5 is OH; and R.sup.6 and R.sup.7 together form oxo.

(86) In some groups of embodiments, R.sup.a is pyrazolyl substituted with one R.sup.c; Y is CH.sub.2 and X is O; and R.sup.6 and R.sup.7 together form oxo.

(87) In some groups of embodiments, R.sup.a is pyrazol-3-yl substituted with one R.sup.c.

(88) In some groups of embodiments, the compound is selected from those listed in Table 1, or tautomers or pharmaceutically acceptable salts thereof.

(89) TABLE-US-00001 TABLE 1 Compound Structure Name 1 cis-methyl 4-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylate 2 cis-4-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylic acid 3 cis-3-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylic acid 4 trans-methyl 4-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylate 5 cis-3-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylic acid 6 0 trans-4-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylic acid 7 methyl 3-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylate 8 trans-methyl 4-((2-formyl-3- methoxyphenoxy)methyl)cyclohexanecarboxylate 9 methyl 3-((2-formyl-3- hydroxyphenoxy)methyl)cyclohexanecarboxylate 10 2-hydroxy-6-((3,4,5,6-tetrahydro-[1,1-biphenyl]- 2-yl)methoxy)benzaldehyde 11 2-hydroxy-6-((2- phenylcyclohexyl)methoxy)benzaldehyde 12 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5- yl)cyclohex-1-en-1-yl)methoxy)benzaldehyde 13 2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]benzaldehyde 14 2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]benzaldehyde 15 2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]benzaldehyde 16 0 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol- 3-yl]cyclohexyl]methoxy]benzaldehyde 17 2-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-6- hydroxybenzaldehyde 18 2-hydroxy-6-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]benzaldehyde 19 2-hydroxy-6-[(2- phenylcyclohexyl)methoxy]benzaldehyde 20 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-6-hydroxybenzaldehyde 21 2-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-6- hydroxybenzaldehyde 22 2-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde 23 2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]benzaldehyde 24 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 25 2-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde 26 0 2-hydroxy-6-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 27 2-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]- 6-hydroxybenzaldehyde 28 2-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-6-hydroxybenzaldehyde 29 2-hydroxy-6-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]benzaldehyde 30 2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 31 2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 32 2-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-6- hydroxybenzaldehyde 33 2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-3-methylbenzaldehyde 34 2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-3-methylbenzaldehyde 35 2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-3-methylbenzaldehyde 36 0 6-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxy-3- methylbenzaldehyde 37 2-hydroxy-3-methyl-6-[[2-(2-propan-2-ylpyrazol- 3-yl)cyclohexyl]methoxy]benzaldehyde 38 6-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]- 2-hydroxy-3-methylbenzaldehyde 39 6-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-hydroxy-3- methylbenzaldehyde 40 6-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2- hydroxy-3-methylbenzaldehyde 41 6-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxy-3- methylbenzaldehyde 42 2-hydroxy-6-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]-3- methylbenzaldehyde 43 2-hydroxy-3-methyl-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 44 2-hydroxy-3-methyl-6-[[2-[2-(oxetan-3-yl)pyrazol- 3-yl]cyclohexyl]methoxy]benzaldehyde 45 6-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-2- hydroxy-3-methylbenzaldehyde 46 0 2-hydroxy-3-methyl-6-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 47 2-hydroxy-3-methyl-6-[[2-(3-propan-2-ylimidazol- 4-yl)cyclohexyl]methoxy]benzaldehyde 48 2-hydroxy-3-methyl-6-[(2- phenylcyclohexyl)methoxy]benzaldehyde 49 2-hydroxy-3-methyl-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 50 2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]-3-methylbenzaldehyde 51 6-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-2 hydroxy-3-methylbenzaldehyde 52 6-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxy-3- methylbenzaldehyde 53 3-chloro-2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]benzaldehyde 54 3-chloro-2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]benzaldehyde 55 3-chloro-2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]benzaldehyde 56 0 3-chloro-6-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-hydroxybenzaldehyde 57 3-chloro-2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol- 3-yl]cyclohexyl]methoxy]benzaldehyde 58 3-chloro-2-hydroxy-6-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 59 3-chloro-6-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde 60 3-chloro-2-hydroxy-6-[[2-(3-propan-2-ylimidazol- 4-yl)cyclohexyl]methoxy]benzaldehyde 61 3-chloro-2-hydroxy-6-[(2- phenylcyclohexyl)methoxy]benzaldehyde 62 3-chloro-2-hydroxy-6-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]benzaldehyde 63 3-chloro-2-hydroxy-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 64 3-chloro-6-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde 65 3-chloro-6-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde 66 0 3-chloro-6-[[2-(2- chlorophenyl)cyclohexyl]methoxy]-2- hydroxybenzaldehyde 67 3-chloro-2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 68 3-chloro-6-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde 69 3-chloro-6-[[2-(2- fluorophenyl)cyclohexyl]methoxy]-2- hydroxybenzaldehyde 70 3-chloro-6-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxybenzaldehyde 71 3-chloro-2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]benzaldehyde 72 3-chloro-2-hydroxy-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 73 2-fluoro-6-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]benzaldehyde 74 2-fluoro-6-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]benzaldehyde 75 2-fluoro-6-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]benzaldehyde 76 0 2-fluoro-6-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 77 2-[[2-(2-chloropyridin-3-yl)cyclohexyl]methoxy]- 6-fluorobenzaldehyde 78 2-fluoro-6-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]benzaldehyde 79 2-fluoro-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 80 2-fluoro-6-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 81 2-[[2-(2-ethylpyrazol-3-yl)cyclohexyl]methoxy]-6- fluorobenzaldehyde 82 2-[[2-(2-chlorophenyl)cyclohexyl]methoxy]-6- fluorobenzaldehyde 83 2-fluoro-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]benzaldehyde 84 2-fluoro-6-[(2- phenylcyclohexyl)methoxy]benzaldehyde 85 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-6-fluorobenzaldehyde 86 0 2-fluoro-6-[[2-(2- fluorophenyl)cyclohexyl]methoxy]benzaldehyde 87 2-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde 88 2-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde 89 2-fluoro-6-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]benzaldehyde 90 2-fluoro-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]benzaldehyde 91 2-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-6-fluorobenzaldehyde 92 2-fluoro-6-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]benzaldehyde 93 2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 94 2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 95 2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 96 00 2-hydroxy-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol- 3-yl]cyclohexen-1-yl]methoxy]benzaldehyde 97 01 2-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]- 6-hydroxybenzaldehyde 98 02 2-hydroxy-6-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]benzaldehyde 99 03 2-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]- 6-hydroxybenzaldehyde 100 04 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-l- yl]methoxy]-6-hydroxybenzaldehyde 101 05 2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 102 06 2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 103 07 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-hydroxybenzaldehyde 104 08 2-hydroxy-6-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 105 09 2-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-6-hydroxybenzaldehyde 106 0 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-hydroxybenzaldehyde 107 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]benzaldehyde 108 2-hydroxy-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]benzaldehyde 109 2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]benzaldehyde 110 2-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-hydroxybenzaldehyde 111 2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]-3- methylbenzaldehyde 112 2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]-3- methylbenzaldehyde 113 2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]-3- methylbenzaldehyde 114 6-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxy-3-methylbenzaldehyde 115 2-hydroxy-3-methyl-6-[[2-(2-propan-2-ylpyrazol- 3-yl)cyclohexen-1-yl]methoxy]benzaldehyde 116 0 6-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxy-3-methylbenzaldehyde 117 6-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2-hydroxy-3- methylbenzaldehyde 118 6-[[2-(2-fluorophenyl)cyclohexen-1-yl]methoxy]- 2-hydroxy-3-methylbenzaldehyde 119 6-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxy-3-methylbenzaldehyde 120 2-hydroxy-6-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]-3-methylbenzaldehyde 121 2-hydroxy-3-methyl-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]benzaldehyde 122 2-hydroxy-3-methyl-6-[[2-[2-(oxetan-3-yl)pyrazol- 3-yl]cyclohexen-1-yl]methoxy]benzaldehyde 123 6-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]- 2-hydroxy-3-methylbenzaldehyde 124 2-hydroxy-3-methyl-6-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 125 2-hydroxy-3-methyl-6-[[2-(3-propan-2-ylimidazol- 4-yl)cyclohexen-1-yl]methoxy]benzaldehyde 126 0 2-hydroxy-3-methyl-6-[(2-phenylcyclohexen-1- yl)methoxy]benzaldehyde 127 2-hydroxy-3-methyl-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]benzaldehyde 128 2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]-3- methylbenzaldehyde 129 6-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxy-3-methylbenzaldehyde 130 6-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxy-3-methylbenzaldehyde 131 3-chloro-2-hydroxy-6-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 132 3-chloro-2-hydroxy-6-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 133 3-chloro-2-hydroxy-6-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]benzaldehyde 134 3-chloro-6-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2- hydroxybenzaldehyde 135 3-chloro-2-hydroxy-6-[[2-[2-(oxetan-3-yl)pyrazol- 3-yl]cyclohexen-1-yl]methoxy]benzaldehyde 136 0 3-chloro-2-hydroxy-6-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 137 3-chloro-6-[[2-(2-chloropyridin-3-yl)cyclohexen- 1-yl]methoxy]-2-hydroxybenzaldehyde 138 3-chloro-2-hydroxy-6-[[2-(3-propan-2-ylimidazol- 4-yl)cyclohexen-1-yl]methoxy]benzaldehyde 139 3-chloro-2-hydroxy-6-[(2-phenylcyclohexen-1- yl)methoxy]benzaldehyde 140 3-chloro-2-hydroxy-6-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]benzaldehyde 141 3-chloro-2-hydroxy-6-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]benzaldehyde 142 3-chloro-6-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexen-1-yl]methoxy]-2- hydroxybenzaldehyde 143 3-chloro-6-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxybenzaldehyde 144 3-chloro-6-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-2-hydroxybenzaldehyde 145 3-chloro-2-hydroxy-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 146 0 3-chloro-6-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexen-1-yl]methoxy]-2- hydroxybenzaldehyde 147 3-chloro-6-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-2-hydroxybenzaldehyde 148 3-chloro-6-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexen-1-yl]methoxy]-2- hydroxybenzaldehyde 149 3-chloro-2-hydroxy-6-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 150 3-chloro-2-hydroxy-6-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]benzaldehyde 151 2-fluoro-6-[[2-(2-hydroxypropan-2-yl)cyclohexen- 1-yl]methoxy]benzaldehyde 152 2-fluoro-6-[[2-(2-hydroxypentan-2-yl)cyclohexen- 1-yl]methoxy]benzaldehyde 153 2-fluoro-6-[[2-(2-hydroxybutan-2-yl)cyclohexen- 1-yl]methoxy]benzaldehyde 154 2-fluoro-6-[[2-(2-propylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]benzaldehyde 155 2-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-6-fluorobenzaldehyde 156 0 2-fluoro-6-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]benzaldehyde 157 2-fluoro-6-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]benzaldehyde 158 2-fluoro-6-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]benzaldehyde 159 2-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-fluorobenzaldehyde 160 2-[[2-(2-chlorophenyl)cyclohexen-1-yl]methoxy]- 6-fluorobenzaldehyde 161 2-fluoro-6-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 162 2-fluoro-6-[(2-phenylcyclohexen-1- yl)methoxy]benzaldehyde 163 2-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-6- fluorobenzaldehyde 164 2-fluoro-6-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]benzaldehyde 165 2-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-fluorobenzaldehyde 166 0 2-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-fluorobenzaldehyde 167 2-fluoro-6-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]benzaldehyde 168 2-fluoro-6-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]benzaldehyde 169 2-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-fluorobenzaldehyde 170 2-fluoro-6-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]benzaldehyde 171 3-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 172 3-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 173 3-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 174 3-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 175 3-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 176 0 3-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 2-carbaldehyde 177 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 178 3-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 179 3-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 180 3-[[2-(2- chlorophenyl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 181 3-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 182 3-[(2-phenylcyclohexyl)methoxy]pyridine-2- carbaldehyde 183 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 184 3-[[2-(2- fluorophenyl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 185 3-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 186 0 3-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 187 3-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 188 3-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 189 3-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 190 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 191 3-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 192 3-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 193 3-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 194 3-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 195 3-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 196 00 6-methyl-3-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 197 01 3-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 198 02 6-methyl-3-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 199 03 3-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]-6- methylpyridine-2-carbaldehyde 200 04 6-methyl-3-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 201 05 6-methyl-3-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 202 06 3-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 203 07 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 6-methylpyridine-2-carbaldehyde 204 08 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-2- carbaldehyde 205 09 6-methyl-3-[(2- phenylcyclohexyl)methoxy]pyridine-2- carbaldehyde 206 0 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 207 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-6- methylpyridine-2-carbaldehyde 208 3-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 209 3-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]-6-methylpyridine-2- carbaldehyde 210 6-methyl-3-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-2- carbaldehyde 211 3-chloro-5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 212 3-chloro-5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 213 3-chloro-5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 214 3-chloro-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 215 3-chloro-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 216 0 3-chloro-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 217 3-chloro-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 218 3-chloro-5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 219 3-chloro-5-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 220 3-chloro-5-[[2-(2- chlorophenyl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 221 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 222 3-chloro-5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 223 3-chloro-5-[[2-[2-(2,2-difluoroethyl)pyrazol- 3-yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 224 3-chloro-5-[[2-(2- fluorophenyl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 225 3-chloro-5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 226 0 3-chloro-5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 227 3-chloro-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 228 3-chloro-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 229 3-chloro-5-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 230 3-chloro-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 231 3-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 232 3-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 233 3-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 234 3-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]-5- methylpyridine-4-carbaldehyde 235 3-methyl-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 236 0 3-methyl-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 237 3-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 238 3-methyl-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 239 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 240 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-5- methylpyridine-4-carbaldehyde 241 3-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 242 3-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 243 3-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 244 3-methyl-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 245 3-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 246 0 3-methyl-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 247 3-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-5-methylpyridine-4- carbaldehyde 248 3-methyl-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 249 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 5-methylpyridine-4-carbaldehyde 250 3-methyl-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 251 3-hydroxy-5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 252 3-hydroxy-5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 253 3-hydroxy-5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 254 3-hydroxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 255 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 256 0 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-5- hydroxypyridine-4-carbaldehyde 257 3-hydroxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 258 3-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 259 3-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 260 3-hydroxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 261 3-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 262 3-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 263 3-hydroxy-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 264 3-hydroxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 265 3-hydroxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 266 0 3-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 267 3-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 268 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 5-hydroxypyridine-4-carbaldehyde 269 3-hydroxy-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 270 3-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-5-hydroxypyridine-4- carbaldehyde 271 3-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 272 3-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 273 3-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 274 3-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-5- methoxypyridine-4-carbaldehyde 275 3-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 276 0 3-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 277 3-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 278 3-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 5-methoxypyridine-4-carbaldehyde 279 3-methoxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 280 3-methoxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 281 3-methoxy-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 282 3-methoxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 283 3-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 284 3-methoxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 285 3-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 286 0 3-methoxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 287 3-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 288 3-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 289 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-5-methoxypyridine- 4-carbaldehyde 290 3-methoxy-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 291 2-hydroxy-5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 292 2-hydroxy-5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 293 2-hydroxy-5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 294 5-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 295 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 2-hydroxypyridine-4-carbaldehyde 296 00 2-hydroxy-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 297 01 5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 298 02 5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 299 03 2-hydroxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 300 04 2-hydroxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 301 05 5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 302 06 2-hydroxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 303 07 5-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 304 08 2-hydroxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 305 09 2-hydroxy-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 306 0 2-hydroxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 307 2-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 308 2-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 309 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-hydroxypyridine-4- carbaldehyde 310 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2- hydroxypyridine-4-carbaldehyde 311 5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 312 5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 313 5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 314 2-methoxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 315 5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 316 0 2-methoxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 317 5-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 318 5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 319 2-methoxy-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 320 2-methoxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 321 2-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 322 2-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 323 5-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 324 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 2-methoxypyridine-4-carbaldehyde 325 2-methoxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 326 0 2-methoxy-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 327 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 328 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2- methoxypyridine-4-carbaldehyde 329 5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-methoxypyridine- 4-carbaldehyde 330 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 331 5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 332 5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 333 5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 334 2-(2-methoxyethoxy)-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 335 5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 336 0 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 2-(2-methoxyethoxy)pyridine-4-carbaldehyde 337 2-(2-methoxyethoxy)-5-[[2-(2-propan-2- ylpyrazol-3-yl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 338 5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 339 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 340 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2- (2-methoxyethoxy)pyridine-4-carbaldehyde 341 5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 342 2-(2-methoxyethoxy)-5-[[2-(2- methoxypyridin-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 343 2-(2-methoxyethoxy)-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 344 2-(2-methoxyethoxy)-5-[[2-[2-(oxetan-3- yl)pyrazol-3-yl]cyclohexyl]methoxy]pyridine- 4-carbaldehyde 345 2-(2-methoxyethoxy)-5-[[2-(2-propylpyrazol- 3-yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 346 0 5-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 347 2-(2-methoxyethoxy)-5-[[2-(3-propan-2- ylimidazol-4-yl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 348 2-(2-methoxyethoxy)-5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]pyridine- 4-carbaldehyde 349 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 350 5-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 351 5-[[2-(2-hydroxybutan-2- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 352 5-[[2-(2-hydroxypropan-2- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 353 5-[[2-(2-hydroxypentan-2- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 354 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 355 5-[[2-(2-chlorophenyl)cyclohexyl]methoxy]- 2-(2-morpholin-4-ylethoxy)pyridine-4- carbaldehyde 356 0 2-(2-morpholin-4-ylethoxy)-5-[[2-(2- propylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 357 2-(2-morpholin-4-ylethoxy)-5-[(2- phenylcyclohexyl)methoxy]pyridine-4- carbaldehyde 358 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 359 5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 360 5-[[2-(2-methoxypyridin-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 361 5-[[2-(2-ethylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 362 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan- 2-ylpyrazol-3- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 363 5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 364 5-[[2-(2-chloropyridin-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 365 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 366 0 5-[[2-(2-fluorophenyl)cyclohexyl]methoxy]-2- (2-morpholin-4-ylethoxy)pyridine-4- carbaldehyde 367 5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexyl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 368 5-[[2-(2- methoxyphenyl)cyclohexyl]methoxy]-2-(2- morpholin-4-ylethoxy)pyridine-4- carbaldehyde 369 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(oxetan- 3-yl)pyrazol-3- yl]cyclohexyl]methoxy]pyridine-4- carbaldehyde 370 2-(2-morpholin-4-ylethoxy)-5-[[2-(3-propan- 2-ylimidazol-4- yl)cyclohexyl]methoxy]pyridine-4- carbaldehyde 371 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 372 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 373 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 374 3-[[2-(2-propylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 375 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 376 0 3-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 377 3-[[2-[2-(3,3,3-trifluoropropyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 378 3-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 379 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 380 3-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 381 3-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 382 3-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-2-carbaldehyde 383 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 384 3-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 385 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 386 0 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 387 3-[[2-(2-propan-2-ylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]pyridine-2-carbaldehyde 388 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]pyridine-2-carbaldehyde 389 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]pyridine-2-carbaldehyde 390 3-[[2-[2-(2,2,2-trifluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 391 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 392 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 393 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 394 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 395 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-6-methylpyridine-2- carbaldehyde 396 00 6-methyl-3-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 397 01 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 398 02 6-methyl-3-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 399 03 3-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 400 04 6-methyl-3-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 401 05 6-methyl-3-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 402 06 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 403 07 3-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 404 08 6-methyl-3-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-2- carbaldehyde 405 09 6-methyl-3-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-2-carbaldehyde 406 0 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-6- methylpyridine-2-carbaldehyde 407 3-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 408 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-6-methylpyridine-2- carbaldehyde 409 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1- yl]methoxy]-6-methylpyridine-2-carbaldehyde 410 6-methyl-3-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-2-carbaldehyde 411 3-chloro-5-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 412 3-chloro-5-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 413 3-chloro-5-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 414 3-chloro-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 415 3-chloro-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 416 0 3-chloro-5-[[2-(2-methoxyphenyl)cyclohexen- 1-yl]methoxy]pyridine-4-carbaldehyde 417 3-chloro-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 418 3-chloro-5-[[2-(2-cyclobutylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 419 3-chloro-5-[[2-(2-ethylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 420 3-chloro-5-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 421 3-chloro-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 422 3-chloro-5-[[2-(2-cyclopentylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 423 3-chloro-5-[[2-[2-(2,2-difluoroethyl)pyrazol- 3-yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 424 3-chloro-5-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 425 3-chloro-5-[[2-(2-cyclopropylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 426 0 3-chloro-5-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 427 3-chloro-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 428 3-chloro-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 429 3-chloro-5-[[2-(2-chloropyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 430 3-chloro-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 431 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 432 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 433 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 434 3-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 435 3-methyl-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 436 0 3-methyl-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 437 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 438 3-methyl-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 439 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-5- methylpyridine-4-carbaldehyde 440 3-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 441 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-methylpyridine-4- carbaldehyde 442 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 443 3-[[2-(2-methoxypyridin-3-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 444 3-methyl-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 445 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-methylpyridine-4- carbaldehyde 446 0 3-methyl-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 447 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 448 3-methyl-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 449 3-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-5-methylpyridine-4-carbaldehyde 450 3-methyl-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 451 3-hydroxy-5-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 452 3-hydroxy-5-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 453 3-hydroxy-5-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 454 3-hydroxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 455 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-5- hydroxypyridine-4-carbaldehyde 456 0 3-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 457 3-hydroxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 458 3-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 459 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 460 3-hydroxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 461 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 462 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 463 3-hydroxy-5-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 464 3-hydroxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 465 3-hydroxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 466 0 3-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 467 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 468 3-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 469 3-hydroxy-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 470 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-hydroxypyridine-4- carbaldehyde 471 3-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 472 3-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 473 3-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 474 3-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 475 3-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-methoxypyridine-4- carbaldehyde 476 0 3-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 477 3-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 478 3-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 479 3-methoxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 480 3-methoxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 481 3-methoxy-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 482 3-methoxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 483 3-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 484 3-methoxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 485 3-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 486 0 3-methoxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 487 3-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-5-methoxypyridine-4- carbaldehyde 488 3-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-5-methoxypyridine-4- carbaldehyde 489 3-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-5- methoxypyridine-4-carbaldehyde 490 3-methoxy-5-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 491 2-hydroxy-5-[[2-(2-hydroxybutan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 492 2-hydroxy-5-[[2-(2-hydroxypropan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 493 2-hydroxy-5-[[2-(2-hydroxypentan-2- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 494 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 495 5-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 496 00 2-hydroxy-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 497 01 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 498 02 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 499 03 2-hydroxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 500 04 2-hydroxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 501 05 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 502 06 2-hydroxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 503 07 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 504 08 2-hydroxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 505 09 2-hydroxy-5-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 506 0 2-hydroxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 507 2-hydroxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 508 2-hydroxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 509 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2- hydroxypyridine-4-carbaldehyde 510 5-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-2-hydroxypyridine-4- carbaldehyde 511 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 512 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 513 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 514 2-methoxy-5-[[2-(2-methoxypyridin-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 515 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-methoxypyridine-4- carbaldehyde 516 0 2-methoxy-5-[[2-(2-propylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 517 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 518 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-methoxypyridine-4- carbaldehyde 519 2-methoxy-5-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 520 2-methoxy-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 521 2-methoxy-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 522 2-methoxy-5-[[2-[2-(oxetan-3-yl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 523 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 524 5-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 525 2-methoxy-5-[[2-(3-propan-2-ylimidazol-4- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 526 0 2-methoxy-5-[(2-phenylcyclohexen-1- yl)methoxy]pyridine-4-carbaldehyde 527 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2- methoxypyridine-4-carbaldehyde 528 5-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 529 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-methoxypyridine-4- carbaldehyde 530 2-methoxy-5-[[2-(2-propan-2-ylpyrazol-3- yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 531 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 532 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 533 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 534 2-(2-methoxyethoxy)-5-[(2- phenylcyclohexen-1-yl)methoxy]pyridine-4- carbaldehyde 535 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 536 0 5-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 537 2-(2-methoxyethoxy)-5-[[2-(2-propan-2- ylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 538 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-(2-methoxyethoxy)pyridine- 4-carbaldehyde 539 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2-(2- methoxyethoxy)pyridine-4-carbaldehyde 540 5-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 541 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-(2-methoxyethoxy)pyridine- 4-carbaldehyde 542 2-(2-methoxyethoxy)-5-[[2-(2- methoxypyridin-3-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 543 2-(2-methoxyethoxy)-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 544 2-(2-methoxyethoxy)-5-[[2-[2-(oxetan-3- yl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 545 2-(2-methoxyethoxy)-5-[[2-(2-propylpyrazol- 3-yl)cyclohexen-1-yl]methoxy]pyridine-4- carbaldehyde 546 0 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 547 2-(2-methoxyethoxy)-5-[[2-(3-propan-2- ylimidazol-4-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 548 2-(2-methoxyethoxy)-5-[[2-(2- methoxyphenyl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 549 2-(2-methoxyethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 550 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-(2-methoxyethoxy)pyridine-4- carbaldehyde 551 5-[[2-(2-hydroxybutan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 552 5-[[2-(2-hydroxypropan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 553 5-[[2-(2-hydroxypentan-2-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 554 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(3,3,3- trifluoropropyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 555 5-[[2-(2-chlorophenyl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 556 0 2-(2-morpholin-4-ylethoxy)-5-[[2-(2- propylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 557 2-(2-morpholin-4-ylethoxy)-5-[(2- phenylcyclohexen-1-yl)methoxy]pyridine-4- carbaldehyde 558 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(2,2,2- trifluoroethyl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 559 5-[[2-(2-cyclobutylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 560 5-[[2-(2-methoxypyridin-3-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 561 5-[[2-(2-ethylpyrazol-3-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 562 2-(2-morpholin-4-ylethoxy)-5-[[2-(2-propan- 2-ylpyrazol-3-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 563 5-[[2-(2-cyclopentylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 564 5-[[2-(2-chloropyridin-3-yl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 565 5-[[2-[2-(2,2-difluoroethyl)pyrazol-3- yl]cyclohexen-1-yl]methoxy]-2-(2-morpholin- 4-ylethoxy)pyridine-4-carbaldehyde 566 0 5-[[2-(2-fluorophenyl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 567 5-[[2-(2-cyclopropylpyrazol-3-yl)cyclohexen- 1-yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 568 5-[[2-(2-methoxyphenyl)cyclohexen-1- yl]methoxy]-2-(2-morpholin-4- ylethoxy)pyridine-4-carbaldehyde 569 2-(2-morpholin-4-ylethoxy)-5-[[2-[2-(oxetan- 3-yl)pyrazol-3-yl]cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde 570 2-(2-morpholin-4-ylethoxy)-5-[[2-(3-propan- 2-ylimidazol-4-yl)cyclohexen-1- yl]methoxy]pyridine-4-carbaldehyde

(90) In some groups of embodiments, the invention provides a compound, or a tautomer or pharmaceutically acceptable salt thereof, selected from: cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; cis-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; cis-3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; trans-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; cis-3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; trans-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid; methyl3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; trans-methyl4-((2-formyl-3-methoxyphenoxy)methyl)cyclohexanecarboxylate; methyl3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate; 2-hydroxy-6-((3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methoxy)benzaldehyde; 2-hydroxy-6-((2-phenylcyclohexyl)methoxy)benzaldehyde; and 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohex-1-en-1-yl)methoxy)benzaldehyde.

(91) In some groups of embodiments, the invention provides a compound, or a tautomer or pharmaceutically acceptable salt thereof, selected from: 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)methoxy)benzaldehyde; 2,6-dihydroxy-3-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)methyl)benzaldehyde; 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl)-methoxy)benzaldehyde; 2-hydroxy-6-((2-(2-methoxypyridin-3-yl)cyclopent-1-en-1-yl)methoxy)benzaldehyde; 2-hydroxy-6-((2-(2-methoxypyridin-3-yl)cyclopentyl)methoxy)-benzaldehyde; 2-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)-methoxy)-6-hydroxybenzaldehyde; and 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohept-1-en-1-yl)methoxy)-benzaldehyde.

(92) In some groups of embodiments, the invention provides cis-cycloalkyl substituted aldehydes having a cycloalkyl moiety containing two substituents on the same face of the cycloalkyl moiety. In some groups of embodiments, the invention provides trans-cycloalkyl substituted aldehydes having a cycloalkyl moiety containing two substituents on different faces of the cycloalkyl moiety. In some groups of embodiments, the cis and trans isomers of any cycloalkyl substituted aldehyde described herein are provided. As one non-limiting example, 2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde (Compound 13) can be provided as cis-2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde or trans-2-hydroxy-6-[[2-(2-hydroxypropan-2-yl)cyclohexyl]methoxy]benzaldehyde. As another non-limiting example, 3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde (Compound 174) can be provided as cis-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde or trans-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde. In some groups of embodiments, the invention provides the cis isomer of any cyclohexyl-substituted aldehyde listed in Table 1. In some groups of embodiments, the invention provides the trans isomer of any cyclohexyl-substituted aldehyde listed in Table 1.

(93) In one group of embodiments, provided is a compound in any of the Examples or Tables. In another group of embodiments, provided are any combinations of subembodiments as disclosed herein including any combination of elements disclosed herein including the a selection of any single elements.

(94) In one group of embodiments, the invention provides a pharmaceutical composition containing a compound of any of the preceding claims or a tautomer or pharmaceutically acceptable salt thereof.

(95) The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.

(96) In one group of embodiments, provided is an intermediate compound used in the preparation of the compounds disclosed herein.

(97) In one group of embodiments, provided are methods for preparing the compounds disclosed herein.

(98) For example, Scheme I shows a synthetic route for the synthesis of the compounds of Formula (I) where X is O and Y is CH.sub.2. Phenol 1.1 is contacted with intermediate 1.2 in the presence of base under ether forming conditions to give ether 1.3, where Lg represents a leaving group such as a halogen leaving group or an oxophosphonium leaving group or sulfonate leaving group. Conversely, when X is O and Y is CH.sub.2, the compounds of Formula (I) can be prepared using the appropriate starting materials where the OH moiety of intermediate 1.1 is replaced with a leaving group and the Lg group of intermediate 1.2 is replaced with an OH group.

(99) ##STR00575##

(100) Scheme II shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where X and Y are CH.sub.2. Alkene 2.1 is contacted with alkene 2.2 under metathesis forming conditions in the presence of an appropriate transition metal catalyst. Suitable catalysts include ruthenium catalysts such as Grubbs' catalyst. Product 2.3 is then hydrogenated to give compound 2.4.

(101) ##STR00576##

(102) Scheme III shows an example of a synthetic route for the synthesis of the compounds of Formula (I) where R.sup.6 together with R.sup.1b form a cyclic ether. Compound 3.1, is reacted with diethylphosphite and a base such as sodium methoxide to give intermediate 3.2, that is then condensed with aldehyde 3.3 to give alkene 3.4. Treatment of the alkene with H.sub.2 under hydrogenation conditions gives lactone 3.4, which is then reduced with a suitable reducing agent such as LiBHEt.sub.3 to give cyclic hemiacetal 3.5.

(103) ##STR00577##

(104) In some embodiments, cyclohexane- and cyclohexene-substituted aldehydes can be synthesized according to Schemes IV and V. Scheme IV shows a general scheme for the synthesis of a cyclohexane-substituted benzaldehyde 4.4 from hydroxy-aldehyde 4.3 via a Mitsunobu reaction with cyclohexylmethanol 4.1, or via alkylation of cyclohexylmethane 4.2. The cyclohexylmethane 4.2 is substituted with a leaving group X, such as a halogen or a sulfonic ester.

(105) ##STR00578##

(106) Scheme V shows the synthesis of cyclohexylmethanol 5.7a, cyclohexenylmethanol 5.5a, cyclohexylmethane 5.7b, and cyclohexenylmethane 5.5b. Ketoester 5.1 can be converted to aryl triflate 5.2, which can be elaborated via Suzuki coupling to provide cyclohexenylester 5.4. Cyclohexenylester 5.4 can then be used to access the cyclohexenylmethanol 5.5a and cyclohexenylmethane 5.5b. Cyclohexenylester 5.4 can also be hydrogenated in order to access cyclohexylmethanol 5.7a and cyclohexylmethane 5.7b. One skilled in the art will appreciate that this approach can be used to synthesize cis and trans isomers of cycloalkane-substituted methane and methanol compounds. The substituted methanol and methane compounds can be used for synthesis of substituted benzaldehydes 5.9 as described above. Scheme VI shows that cylopentane- and cyclopentene-substituted aldehydes 6.10 can be synthesized using an analogous approach.

(107) ##STR00579##

(108) ##STR00580##

(109) One skilled in the art will recognize that in certain embodiments it may be advantageous to use a protecting group strategy. The protecting group can be removed using methods known to those skilled in the art.

(110) In one group of embodiments, certain of the compounds disclosed herein may generally be utilized as the free base. Alternatively, certain of the compounds may be used in the form of acid addition salts.

(111) It is understood that in another group of embodiments, any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention. Similarly, it is understood that in other embodiments, listing of groups includes embodiments wherein one or more of the elements of those groups is not included.

(112) III. Compositions and Methods of Administration

(113) Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, preferably in unit dosage form suitable for single administration of a precise dosage. In addition to an effective amount of the active compound(s), the compositions may contain suitable pharmaceutically-acceptable excipients, including adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Pharmaceutically acceptable excipient refers to an excipient or mixture of excipients which does not interfere with the effectiveness of the biological activity of the active compound(s) and which is not toxic or otherwise undesirable to the subject to which it is administered.

(114) For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmacologically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in water or an aqueous excipient, such as, for example, water, saline, aqueous dextrose, and the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary excipients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.

(115) For oral administration, the composition will generally take the form of a tablet or capsule, or it may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used excipients such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending excipients. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional excipients for incorporation into an oral formulation include preservatives, suspending agents, thickening agents, and the like.

(116) Injectable formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions or liposomal formulations. The sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.

(117) The pharmaceutical compositions of this invention may also be formulated in lyophilized form for parenteral administration. Lyophilized formulations may be reconstituted by addition of water or other aqueous medium and then further diluted with a suitable diluent prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are isotonic saline solution, 5% dextrose in water, and buffered sodium or ammonium acetate solution. Pharmaceutically acceptable solid or liquid excipients may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.

(118) Typically, a pharmaceutical composition of the present invention is packaged in a container with a label, or instructions, or both, indicating use of the pharmaceutical composition in the treatment of the indicated disease.

(119) The pharmaceutical composition may additionally contain one or more other pharmacologically active agents in addition to a compound of this invention.

(120) Dosage forms containing effective amounts of the modulators are within the bounds of routine experimentation and within the scope of the invention. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD.sub.50 and ED.sub.50. The LD.sub.50 is the dose lethal to 50% of the population and the ED.sub.50 is the dose therapeutically effective in 50% of the population. The LD.sub.50 and ED.sub.50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated. The amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.

(121) IV. Methods

(122) In one group of embodiments, the invention provides a method for increasing tissue oxygenation, the method including administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the preceding claims, or a tautomer or pharmaceutically acceptable salt thereof.

(123) In one group of embodiments, the invention provides a method for treating a condition associated with oxygen deficiency, the method including administering to a subject in need thereof a therapeutically effective amount of a compound according to any of the preceding claims, or a tautomer or pharmaceutically acceptable salt thereof.

(124) In one group of embodiments, the invention provides a method for treating a condition associated with oxygen deficiency as described above, wherein the condition is selected from sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound

(125) V. Examples

(126) The following examples are offered to illustrate, but not to limit, the claimed invention.

PREPARATIVE EXAMPLES

(127) The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.

(128) The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

(129) Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about 78 C. to about 150 C., more preferably from about 0 C. to about 125 C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 C. to about 75 C.

(130) Referring to the examples that follow, compounds of the present invention were synthesized using the methods described herein, or other methods known in the art.

Example 1

Preparation of cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate (Compound 1)

(131) Step 1.

(132) ##STR00581##

(133) To a mixture of 2,6-dihydroxybenzaldehyde (100 mg, 0.73 mmol, 1 eq.) and CH(OEt).sub.3 in EtOH (10.0 mL) were added ethane-1,2-diol (225 mg, 3.62 mmol, 5.0 eq.) and tetrabutylammonium tribromide (TBATB, 3.5 mg, 0.007 mmol, 0.01 eq.). The mixture was stirred at rt for 2 h, diluted with EtOAc (20 mL), washed with water and brine, dried over Na.sub.2SO.sub.4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(1,3-dioxolan-2-yl)benzene-1,3-diol (40 mg, 30%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96 (s, 2H), 7.07 (t, J=8.2 Hz, 2H), 6.41 (d, J=8.2 Hz, 2H), 6.01 (s, 2H), 3.76-3.66 (m, 4H).

(134) Step 2.

(135) ##STR00582##

(136) To a mixture of 2-(1,3-dioxolan-2-yl)benzene-1,3-diol (40 mg, 0.22 mmol, 1 eq.), cis-methyl4-(hydroxymethyl)cyclohexanecarboxylate (45 mg, 0.26 mmol, 1.2 eq.), and PPh.sub.3 (86 mg, 0.33 mmol, 1.5 eq.) in THF (0.5 mL) was added DIAD (67 mg, 0.33, 1.5 eq.). The mixture was stirred at rt for 1 h and filtered. The filtrate was purified by RP-HPLC (Gemini 21.2150 mm) using a mixture of CH.sub.3CN and water as eluent to give cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate (16 mg, 25%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 11.96 (s, 1H), 10.38 (s, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.37 (d, J=8.3 Hz, 1H), 3.91 (d, J=6.7 Hz, 2H), 3.72 (s, 3H), 2.66 (quin, J=4.8 Hz, 1H), 2.14-2.05 (m, 2H), 2.04-1.91 (m, 1H), 1.84-1.70 (m, 2H), 1.70-1.57 (m, 2H), 1.52-1.38 (m, 2H). LRMS (MH.sup.+) m/z 291.2.

Example 2

Preparation of cis-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid (Compound 2)

(137) ##STR00583##

(138) To cis-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylate (13 mg, 0.045 mmol, 1 eq.) in MeOH (3.0 mL) was added NaOH (3 N, 1 mL, 4.6 mmol). The mixture was stirred at rt for 2 h, acidified to pH 3, and filtered. The filtrate was purified by RP-HPLC (Gemini 21.2150 mm) using a mixture of CH.sub.3CN and water as eluent to give cis-4-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid (6.0 mg, 49%) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 12.14 (s, 1H), 10.57 (s, 1H), 7.59 (t, J=8.4 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 4.10 (d, J=6.6 Hz, 2H), 2.92 (quin, J=4.5 Hz, 1H), 2.37-2.27 (m, 2H), 2.24-2.14 (m, 1H), 2.03-1.92 (m, 2H), 1.92-1.80 (m, 2H), 1.74-1.60 (m, 2H). LRMS (MH.sup.+) m/z 277.1.

(139) The compounds in Examples 3-7 were prepared according to the procedure described in Examples 1 and 2.

Example 3

Preparation of (1R,3S)-3-((2-formyl-3-hydroxyphenoxy)methyl)cyclohexanecarboxylic acid (Compound 3)

(140) .sup.1H NMR (400 MHz, CDCl.sub.3) 11.95 (s, 1H), 10.39 (s, 1H), 7.40 (t, J=8.4 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 3.95-3.83 (m, 2H), 3.70 (s, 3H), 2.49-2.32 (m, 1H), 2.16 (d, J=12.9 Hz, 1H), 2.10-2.01 (m, 1H), 2.01-1.82 (m, 3H), 1.48-1.22 (m, 3H), 1.22-0.99 (m, 1H).

Example 4

Preparation of trans-methyl4-((2-formyl-3-hydroxyphenoxy)methyl)-cyclohexanecarboxylate (Compound 4)

(141) .sup.1H NMR (400 MHz, CDCl.sub.3) 11.95 (s, 1H), 10.40 (s, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 3.88 (d, J=6.2 Hz, 2H), 2.32 (tt, J=12.3, 3.5 Hz, 1H), 2.10 (dd, J=13.6, 2.7 Hz, 2H), 1.99 (dd, J=13.3, 2.6 Hz, 2H), 1.95-1.77 (m, 1H), 1.53 (ddd, J=25.8, 13.1, 3.3 Hz, 2H), 1.18 (ddd, J=25.4, 13.1, 3.4 Hz, 2H).

Example 5

Preparation of (1R,3S)-3-((2-formyl-3-hydroxyphenoxy)methyl)-cyclohexanecarboxylic acid (Compound 5)

(142) ##STR00584##
Step 1

(143) Into a 150-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of cyclohexane-1,3-dicarboxylic acid (25 g, 145.20 mmol, 1.00 equiv) in dichloromethane (1000 mL). This was followed by the addition of a solution of DCC (29.8 g, 144.43 mmol, 1.00 equiv) in dichloromethane (100 mL) dropwise with stirring in 30 min. The resulting solution was stirred for 4 h at 25 C. The solids were collected by filtration, then dried in an oven under reduced pressure. The crude product was purified by re-crystallization from MTBE. This resulted in 7.2 g (32%) of 3-oxabicyclo[3.3.1]nonane-2,4-dione as a white solid.

(144) Step 2

(145) Into a 150-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-oxabicyclo[3.3.1]nonane-2,4-dione (5.5 g, 35.68 mmol, 1.00 equiv) in ether (100 ml). Methanol (11.4 g, 355.78 mmol, 10.00 equiv) was added to the reaction. The resulting solution was stirred for 24 h at 25 C., and then it was concentrated under vacuum. This resulted in 5.6 g (84%) of cis-3-(methoxycarbonyl)cyclohexane-1-carboxylic acid as a white solid.

(146) Step 3

(147) Into a 150-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of cis-3 (methoxycarbonyl)cyclohexane-1-carboxylic acid (5.5 g, 29.54 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). This was followed by the addition of BH.sub.3Me.sub.2S(2M) (16.5 mL, 1.10 equiv) dropwise with stirring at 78 C. in 30 min. The resulting solution was stirred for 18 h at room temperature, and then it was quenched by the addition of 20 mL of NH.sub.4Cl (sat. aq). The resulting solution was extracted with 3200 mL of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with PE:EA (2:1) as eluent. This resulted in 3.5 g (69%) of methyl cis-3-(hydroxymethyl)cyclohexane-1-carboxylate as a colorless oil.

(148) Step 4

(149) Into a 70-mL round-bottom flask, was placed a solution of methyl cis-3-(hydroxymethyl)cyclohexane-1-carboxylate (598 mg, 3.47 mmol, 1.20 equiv) in tetrahydrofuran (40 mL). 2,6-Dihydroxybenzaldehyde (400 mg, 2.90 mmol, 1.00 equiv), PPh.sub.3 (1.14 mg, 1.50 equiv) were added to the reaction mixture. A solution of DIAD (867 mg, 4.29 mmol, 1.50 equiv) in tetrahydrofuran (30 mL) was then added to the reaction mixture dropwise. The resulting solution was stirred for 18 h at 25 C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with PE:EA (15:1) as eluent. This resulted in 425 mg (50%) of methyl cis-3-(2-formyl-3-hydroxyphenoxymethyl)cyclohexane-1-carboxylate (Compound 3) as a colorless oil.

(150) Step 5

(151) Into a 50-mL round-bottom flask, was placed a solution of methyl cis-3-(2-formyl-3-hydroxyphenoxymethyl)cyclohexane-1-carboxylate (450 mg, 1.54 mmol, 1.00 equiv) in methanol (50 mL). This was followed by the addition of a solution of sodium hydroxide (2.9 g, 72.50 mmol, 50.00 equiv) in water (20 mL) dropwise in 20 min. The resulting solution was stirred overnight at 25 C. The pH value of the solution was adjusted to 4 with HCl (aq.) (3 mol/L). The resulting solution was extracted with 350 mL of ethyl acetate, and the combined organic layers were concentrated under vacuum. This resulted in 410 mg (91%) of cis-3-(2-formyl-3-hydroxyphenoxymethyl)cyclohexane-1-carboxylic acid as a light-yellow solid.

(152) .sup.1H NMR (300 MHz, CDCl.sub.3) 11.94 (s, 1H), 11.36 (brs, 1H), 10.35 (s, 1H), 7.42-7.36 (t, J=8.4 Hz, 1H), 6.53-6.5 (d, J=8.4 Hz, 1H), 6.36-6.33 (d, J=8.4 Hz, 1H), 3.93-3.78 (m, 2H), 2.48-2.36 (m, 1H), 2.21-2.06 (m, 2H), 1.95-1.88 (m, 3H), 1.48-1.27 (m, 3H), 1.18-1.08 (m, 1H); MS (ESI) m/z 279 [M+H].sup.+.

Example 6

Synthesis of 2-hydroxy-6-((3,4,5,6-tetrahydro-[1,1-biphenyl]-2-yl)methoxy)-benzaldehyde (Compound 10)

(153) ##STR00585##
Step 1

(154) Into a 1000-mL 3-necked round-bottom flask, was placed a solution of ethyl2-oxocyclohexane-1-carboxylate (40 g, 235.01 mmol, 1.00 equiv) in dichloromethane (400 mL). This was followed by the addition of DIPEA (92 mL, 2.40 equiv) dropwise with stirring at 78 C. The mixture was stirred for 10 min at 78 C. To this was added Tf.sub.2O (44.4 mL, 1.20 equiv) dropwise at 78 C. The resulting solution was stirred overnight at room temperature, and then it was washed with 3300 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10) as eluent. This resulted in 70 g (crude) of ethyl2-[(trifluoromethane)sulfonyloxy]cyclohex-1-ene-1-carboxylate as a yellow oil

(155) Step 2

(156) Into a 500-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl2-[(trifluoromethane)sulfonyloxy]cyclohex-1-ene-1-carboxylate (40 g, 132.33 mmol, 1.10 equiv) in a solvent mixture of toluene and ethanol (150/50 mL). Phenylboronic acid (15 g, 123.02 mmol, 1.00 equiv), sodium carbonate(2M) (50 mL), and Pd(dppf)Cl.sub.2 (5 g, 6.83 mmol, 0.05 equiv) were added to the reaction mixture. The resulting solution was stirred for 2 h at 80 C., and then it was diluted with 200 ml of ethyl acetate. The resulting mixture was washed with 2200 mL of brine, and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:100-1:10) as eluent to furnish 23 g (81%) of ethyl2-phenylcyclohex-1-ene-1-carboxylate as a yellow oil.

(157) Step 3

(158) Into a 500-mL three neck round-bottom flask, was placed a solution of ethyl2-phenylcyclohex-1-ene-1-carboxylate (22 g, 95.53 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (200 mL). This was followed by the addition of LAH (5.5 g, 144.93 mmol, 1.50 equiv) batchwise at 0 C. The mixture was stirred for 10 min at 0 C., and 3 h at room temperature. The reaction was then quenched with 5 mL of water at 0 C., followed by 15 mL of NaOH (15%), and another 5 mL of water. The mixture was stirred at rt for 1 h. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) as eluent. This resulted in 14 g (78%) of (2-phenylcyclohex-1-en-1-yl)methanol as a colorless oil. .sup.1H NMR (300 MHz, CDCl.sub.3) 7.32 (m, 2H), 7.20 (m, 3H), 4.49 (m, 1H), 3.72 (d, J=5.1 Hz, 2H), 2.21 (m, 4H), 1.65 (m, 4H).

(159) Step 4

(160) Into a 100-mL round-bottom flask, was placed a solution of (2-phenylcyclohex-1-en-1-yl)methanol (4 g, 21.25 mmol, 1.00 equiv) in thionyl chloride (10 mL). The resulting solution was stirred for 2 h at 65 C., and then it was concentrated under vacuum. This resulted in 3.5 g (80%) of [2-(chloromethyl)cyclohex-1-en-1-yl]benzene as a yellow oil.

(161) Step 5

(162) Into a 100-mL round-bottom flask, was placed a solution of [2-(chloromethyl)cyclohex-1-en-1-yl]benzene (1 g, 4.84 mmol, 1.00 equiv) in CH.sub.3CN (30 mL). Potassium carbonate (2.03 g, 14.69 mmol, 3.00 equiv), KI (160 mg, 0.96 mmol, 0.20 equiv), and 2,6-dihydroxybenzaldehyde (1 g, 7.24 mmol, 1.50 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 60 C., and then it was concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1:100-1:50) as eluent. This resulted in 380 mg (25%) of 2-hydroxy-6-[(2-phenylcyclohex-1-en-1-yl)methoxy]benzaldehyde as a yellow oil. .sup.1HNMR (300 MHz, CDCl.sub.3) 11.94 (s, 1H), 10.38 (s, 1H), 7.17-7.39 (m, 6H), 6.48 (d, J=8.4 Hz, 1H), 6.12 (d, J=8.4 Hz, 1H), 4.41 (s, 2H), 2.36 (m, 4H), 1.79 (m, 4H); MS (ESI) m/z 309 [M+H].sup.+.

Example 7

Synthesis of 2-hydroxy-6-((2-phenylcyclohexyl)methoxy)benzaldehyde (Compound 11)

(163) ##STR00586##
Step 1

(164) Into a 50-mL round-bottom flask, was placed a solution of (2-phenylcyclohex-1-en-1-yl)methanol (1 g, 5.31 mmol, 1.00 equiv) in methanol (20 mL). 10% Palladium on carbon (1 g) was added to the reaction mixture. The resulting solution was stirred overnight at room temperature under hydrogen atmosphere (1 atm). The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 1 g (89%) of (2-phenylcyclohexyl)methanol as a yellow oil.

(165) Step 2

(166) Into a 50-mL round-bottom flask, was placed a solution of (2-phenylcyclohexyl)methanol (550 mg, 2.89 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). PPh.sub.3 (1.14 g, 4.35 mmol, 1.50 equiv), 2,6-dihydroxybenzaldehyde (480 mg, 3.48 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (877 mg, 4.34 mmol, 1.50 equiv) in tetrahydrofuran (5 mL) dropwise with stirring at 0 C. The resulting solution was stirred overnight at room temperature, and then it was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10) as eluent. This resulted in 190 mg (21%) of 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde as a light yellow oil. .sup.1HNMR (300 MHz, CDCl.sub.3) 9.91 (s, 1H), 7.32 (m, 6H), 6.43 (d, J=8.4 Hz, 1H), 6.09 (d, J=8.4 Hz, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 3.02 (m, 1H), 2.51 (m, 1H), 1.42-2.09 (m, 8H); MS (ESI) m/z 311 [M+H].sup.+.

Example 8

Synthesis of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohex-1-en-1-yl)methoxy)benzaldehyde

(167) ##STR00587##
Step 1

(168) Into a 1000-mL 3-necked round-bottom flask, was placed a solution of ethyl2-oxocyclohexane-1-carboxylate (40 g, 235.01 mmol, 1.00 equiv) in dichloromethane (400 mL). This was followed by the addition of DIPEA (92 mL, 2.40 equiv) dropwise with stirring at 78 C. The mixture was stirred for 10 min at 78 C. To this was added Tf.sub.2O (44.4 mL, 1.20 equiv) dropwise at 78 C. The resulting solution was stirred overnight at room temperature, and then it was washed with 3300 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:10) as eluent. This resulted in 70 g (crude) of ethyl2-[(trifluoromethane)sulfonyloxy]cyclohex-1-ene-1-carboxylate as a yellow oil.

(169) Step 2

(170) Into a 1000-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19 g, 80.47 mmol, 1.00 equiv) in toluene (363 mL). Pd(dppf)Cl.sub.2 (2.98 g, 4.07 mmol, 0.05 equiv), sodium carbonate(2M) (121 mL, 3.00 equiv), and ethyl2-[(trifluoromethane)sulfonyloxy]cyclohex-1-ene-1-carboxylate (26.74 g, 88.46 mmol, 1.10 equiv) in ethanol (121 mL) were added to the reaction mixture. The resulting solution was stirred for 2 h at 80 C. in an oil bath, and then it was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 2200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:20) as eluent to furnish 12.73 g (51%) of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohex-1-ene-1-carboxylate as a red oil.

(171) Step 3

(172) Into a 500-mL round-bottom flask, was placed a suspension of LiAlH.sub.4 (5.52 g, 145.26 mmol, 3.00 equiv) in tetrahydrofuran (200 mL). This was followed by the addition of a solution of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohex-1-ene-1-carboxylate (12.73 g, 48.52 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 2 h at 0 C. in an ice/salt bath. The reaction was then quenched by the addition of 5.52 mL of water and 5.52 mL of 10% aq.NaOH. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE:EA (20:1-5:1) as eluent to yield 6.6 g (59%) of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohex-1-en-1-yl]methanol as a white solid.

(173) Step 4

(174) Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohex-1-en-1-yl]methanol (700 mg, 3.18 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). 2,6-Dihydroxybenzaldehyde (445 mg, 3.22 mmol, 1.00 equiv) and triphenylphosphine (1.08 g, 4.12 mmol, 1.30 equiv) were added to the reaction mixture. This was followed by the addition of DIAD (838 mg, 3.20 mmol, 1.30 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 4 h at room temperature, and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.1% TFA and MeCN (65% MeCN up to 85% in 8 min, up to 95% in 2 min, down to 65% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 415.6 mg (28%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohex-1-en-1-yl]methoxy)benzaldehyde as a white solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 10.26 (s, 1H), 7.43 (m, 2H), 6.47 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 6.04 (d, J=1.5 Hz, 1H), 4.35 (m, 1H), 4.29 (s, 2H), 2.31 (m, 2H), 2.19 (m, 2H), 1.72 (m, 4H), 1.26 (d, J=6.6 Hz, 6H); MS (ESI) m/z 341 [M+H].sup.+.

Example 9

Synthesis of cis-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde (Compound 174a), trans-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde (Compound 174b), and 3-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde (Compound 374)

(175) The title compounds are prepared according to scheme XI below.

(176) Ethyl2-oxocyclohexane-1-carboxylate 11.5 is converted to the triflate intermediate 11.6 by treating with a triflic anhydride in the presence of Hunig's base (Step 1). Suzuki coupling of triflate 11.6 with boronic ester 11.7 affords cyclohexene carboxylate 11.8 (Step 2). Ar in Scheme XI represents 2-propylpyrazol-3-yl. The cyclohexene carboxylate 11.8 is divided in two portions. Using the first portion, subsequent reduction of the ester group by DIBAL gives the corresponding alcohol 11.9-OH (Step 3). Further reaction of the alcohol 11.9-OH with mesyl chloride produces the corresponding 10-OMs mesylate (Step 5).

(177) Using the second portion of cyclohexene carboxylate 11.8, the double bond is reduced first to give the cis-cyclohexane 11.11-cis carboxylate under palladium catalyzed hydrogenation conditions (Step 4). Reduction of the ester group of 11.11-cis by LAH yields cis-alcohol 11.12-OH-cis (Step 7). Conversion of the alcohol 11.12-OH-cis the corresponding chloride 11.13-Cl-cis is conducted via reaction with thionyl chloride (Step 8). The cis-cyclohexane carboxylate 11.11-cis can also be isomerized to the thermodynamically more stable trans-isomer 11.11-trans by the treatment with an alcoholic ethoxide solution. Analogously, transformation of 11.11-trans ester to 11.12-trans alcohol and 11.13-Cl-trans is conducted by applying conditions of Step 7 and Step 8 as for the corresponding cis-isomers.

(178) ##STR00588##

(179) 3-hydroxypicolinaldehyde 11.3 (0.1-2 mmol) is combined with with substituted methylene alcohol 11.9-OH (0.8 to 1.2 eq) and PPh.sub.3 (1-1.5 eq) in anhydrous THF (1-10 mL) and stirred under nitrogen until complete dissolution occurs. The solution is cooled to 0 C. in an ice bath and DIAD (1.1 eq) in THF is added dropwise over a 20 min period (Method A). The ice bath is allowed to room temperature over 90 min and the mixture is stirred at room temperature for 2-48 hours. The mixture is stirred for an additional 10 min, and is then filtered through a pad of silica. The silica is washed with ethyl acetate 2-20 mL. The combined filtrates are evaporated and the residue is dried in vacuo. The residue is purified by flash silica gel chromatography to provide 3-[[2-(2-propylpyrazol-3-yl)cyclohexen-1-yl]methoxy]pyridine-2-carbaldehyde (Compound 374).

(180) 3-hydroxypicolinaldehyde 11.3 (0.1-2 mmol, 1-4 eq.), substituted methylene chloride 11.13-Cl-cis (1 eq), and K.sub.2CO.sub.3 (2-5 eq.) in acetonitrile (5 mL) is stirred at RT or heated up to 120 C. for 0.5-8 h under nitrogen atmosphere. Aqeuous NH.sub.4Cl is added at 0 C. and pH is adjusted to 7. The reaction mixture is partitioned between dichloromethane and aqueous sodium chloride. The organic layer is separated and dried, and the solvent is removed under vacuum to afford crude product. The crude product is purified by automated silica gel column chromatography using ethyl acetate/hexanes to afford cis-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde (Compound 174a). The same procedure is used to prepare trans-3-[[2-(2-propylpyrazol-3-yl)cyclohexyl]methoxy]pyridine-2-carbaldehyde (Compound 174b) and other cis- and trans-cyclohexane substituted pyridine-carbaldehydes listed in Table 1.

Example 10

Preparation of Compound Intermediates

(181) General method AMitsunobu coupling. A hydroxyl(hetero)arylaldehyde derivative (0.1-2 mmol) mixture with substituted methylene alcohol (0.8 to 1.2 eq) and (polymer-supported) PPh.sub.3 (1-1.5 eq) in anhydrous THF (1-10 mL) was stirred under nitrogen until complete dissolution. The solution was cooled to 0 C. on ice bath and DIAD or DEAD (1.1 eq) in THF or toluene was added dropwise over a 1-20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 2-48 hours. The mixture was filtered through a pad of silica. The silica was washed with ethyl acetate 2-20 mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was purified by preparative HPLC or flash silica gel chromatography.

Preparation of 2,6-dihydroxybenzaldehyde (INT-1)

(182) ##STR00589##

(183) Into a 3000-mL three neck round-bottom flask, was placed a solution of AlCl.sub.3 (240 g, 1.80 mol, 3.00 equiv) in dichloromethane (1200 mL). A solution of 2,6-dimethoxybenzaldehyde (100 g, 601.78 mmol, 1.00 equiv) in dichloromethane (800 ml) was added to the reaction mixture dropwise at 0 C. The resulting solution was stirred overnight at room temperature, and then it was quenched with 200 mL of diluted HCl (2M). The resulting solution was extracted with 2200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) as eluent to furnish 40 g (48%) of 2,6-dihydroxybenzaldehyde as a yellow solid. .sup.1HNMR (300 MHz, DMSO-d.sub.6) 11.25 (s, 2H), 10.25 (s, 1H), 7.36 (m, 1H), 6.36 (d, J=8.4 Hz 2H); MS (ESI) m/z 139 [M+H].sup.+.

Preparation of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (INT-2)

(184) ##STR00590##
Step 1.

(185) A three-necked round-bottom flask equipped with mechanical stirrer was charged with 0.22 mol of NaH (50% suspension in mineral oil) under nitrogen atmosphere. NaH was washed with 2 portions (100 mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 10.1, dissolved in 100 mL of diethyl ether was added dropwise and the mixture was left under stirring at rt for 30 min. Then 0.18 mol of MOMCl was slowly added. After 1 h under stirring at rt, 250 mL of water was added and the organic layer was extracted with diethyl ether. The extracts were washed with brine, dried (Na.sub.2SO.sub.4), then concentrated to give the crude product that was purified by silica gel chromatography to give compound 10.2 (93% yield).

(186) Step 2.

(187) A three-necked round-bottom flask was charged with 110 mL of n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine (TMEDA) under nitrogen atmosphere. The mixture was cooled to 10 C. and 0.079 mol of bis-phenyl ether 10.2 was slowly added. The resulting mixture was left under magnetic stirring at 10 C. for 2 h. Then the temperature was raised to 0 C. and 0.067 mol of DMF was added dropwise. After 1 h, aqueous HCl was added until the pH was acidic; the mixture was then extracted with ethyl ether. The combined extracts were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated to give aldehyde 10.3 (84%). 2,6-bis(methoxymethoxy)benzaldehyde (10.3): mp 58-59 C. (n-hexane); IR (KBr) n: 1685 (CO) cm.sup.1; .sup.1H-NMR (400 MHz, CDCl.sub.3) 3.51 (s, 6H, 2OCH.sub.3), 5.28 (s, 4H, 2OCH.sub.2O), 6.84 (d, 2H, J=8.40 Hz, H-3, H-5), 7.41 (t, 1H, J=8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc'd for C.sub.11H.sub.14O.sub.5: C, 58.40; H, 6.24. Found: C, 57.98; H, 6.20.

(188) Step 3.

(189) To a solution of 2,6-bis(methoxymethoxy)benzaldehyde 10.3 (15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N.sub.2) was added conc HCl (12N, 7 mL) under N.sub.2, then it was further stirred under N.sub.2 for 1.5 h. To the solution were added brine (100 mL) and ether (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2200 mL). The combined organics were washed with brine, dried and concentrated to give crude product, which was purified by column (300 g, hexanes/EtOAc=85:15) to give the desired product (9.9 g, 97%) as a yellow liquid.

Example 11

Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)methoxy)benzaldehyde (compound 571) and 2,6-dihydroxy-3-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)methyl)benzaldehyde (compound 572)

(190) ##STR00591##
Step 1.

(191) Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl2-oxocyclopentane-1-carboxylate (46.8 g, 299.66 mmol, 1.00 equiv) in dichloromethane (200 mL). This was followed by the addition of TEA (43.8 mL) dropwise with stirring at 78 C. in 30 min. To this was added (trifluoromethane)sulfonyl trifluoromethanesulfonate (52.2 mL) dropwise with stirring at 78 C. in 1 h. The resulting solution was stirred for 5 h at room temperature, and then it was quenched by the addition of 100 mL of water. The resulting solution was extracted with 250 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to provide 82.3 g (95%) of ethyl2-[(trifluoromethane)sulfonyloxy]cyclopent-1-ene-1-carboxylate as a light yellow oil.

(192) Step 2.

(193) Into a 250-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl2-[(trifluoromethane)sulfonyloxy]cyclopent-1-ene-1-carboxylate (3.0 g, 10.41 mmol, 1.00 equiv) in toluene (60 mL). 1-(Propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.95 g, 12.49 mmol, 1.20 equiv), Pd(dppf)Cl.sub.2 (425 mg, 0.58 mmol, 0.06 equiv), 2N sodium carbonate aqueous solution (20 mL) and ethanol (20 mL) were added to the reaction. The resulting solution was stirred for 5 h at 80 C., and then it was quenched with 30 mL of water. The resulting solution was extracted with 330 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent to yield 1.38 g (53%) of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-ene-1-carboxylate as a light yellow oil.

(194) Step 3.

(195) Into a 30-mL round-bottom flask, was placed a solution of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-ene-1-carboxylate (600 mg, 2.42 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). LAH (186 mg, 4.90 mmol, 2.03 equiv) was added to the reaction solution. The resulting solution was stirred for 3 h at room temperature, and then it was quenched by the addition of 20 mL of water. The resulting solution was extracted with 320 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) as eluent to yield 0.492 g (99%) of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-en-1-yl]methanol as a light yellow oil.

(196) Step 4 (Method A).

(197) Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-en-1-yl]methanol (300 mg, 1.45 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). 2,6-Dihydroxybenzaldehyde (201 mg, 1.46 mmol, 1.00 equiv) and PPh.sub.3 (458 mg, 1.75 mmol, 1.20 equiv) were added to the reaction. This was followed by the addition of DIAD (353 mg, 1.75 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 5 h at room temperature, and then it was quenched by the addition of 20 mL of water. The resulting solution was extracted with 315 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (65.0% MeCN up to 85.0% in 10 min, up to 95.0% in 3 min, down to 65.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This provided 26.5 mg (4%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-en-1-yl]methoxy)benzaldehyde (compound 571) trifluoroacetic acid salt as a white solid and 58.5 mg (9%) of 2,6-dihydroxy-3-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-en-1-yl]methyl)benzaldehyde trifluoroacetic acid salt as a yellow solid (compound 572).

(198) Compound 571: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.74 (s, 1H), 10.10 (s, 1H), 7.45-7.49 (t, 2H), 6.47-6.53 (m, 2H), 6.12 (s, 1H), 4.64 (s, 2H), 4.35-4.41 (t, 1H), 2.67-2.70 (t, 4H), 1.98-2.05 (s, 2H), 1.31 (s, 6H); MS (ESI) m/z 327 [M+H].sup.+.

(199) Compound 572: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.92 (s, 1H), 10.77 (s, 1H), 10.24 (s, 1H), 7.44 (s, 1H), 7.09 (s, 1H), 6.38 (d, 1H), 6.07 (s, 1H), 4.32-4.39 (t, 1H), 3.19 (s, 2H), 2.60 (s, 2H), 2.33 (s, 2H), 1.90 (s, 3H), 1.34 (s, 6H); MS (ESI) m/z 327 [M+H].sup.+.

Example 12

Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl)-methoxy)benzaldehyde (Compound 573)

(200) ##STR00592##
Step 1.

(201) Into a 50-mL round-bottom flask, was placed a solution of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopent-1-ene-1-carboxylate (780 mg, 3.14 mmol, 1.00 equiv) in ethanol (20 mL). 10% Palladium on carbon (0.5 g) was added to the reaction mixture. The resulting solution was stirred for 48 h at room temperature under 1 atm of hydrogen gas. The solids were filtered out. The resulting mixture was concentrated under vacuum. This provided 0.6375 g (81%) of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopentane-1-carboxylate as a yellow oil.

(202) Step 2.

(203) Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopentane-1-carboxylate (637.5 mg, 2.55 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). LAH (194 mg, 5.11 mmol, 2.01 equiv) was added to the reaction. The resulting solution was stirred for 2 h at room temperature, and then it was quenched by the addition of 5 mL of water. The resulting solution was extracted with 35 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This provided 0.446 g (84%) of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopentyl]methanol as a yellow oil.

(204) Step 3 (Method A).

(205) Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopentyl]methanol (446 mg, 2.14 mmol, 1.00 equiv), 2,6-dihydroxybenzaldehyde (296 mg, 2.14 mmol, 1.00 equiv), and PPh.sub.3 (674 mg, 2.57 mmol, 1.20 equiv) in tetrahydrofuran (30 mL). This was followed by the addition of DIAD (519 mg, 2.57 mmol, 1.20 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 5 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 315 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (500 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (65.0% MeCN up to 85.0% in 10 min, up to 95.0% in 2 min, down to 65.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This provided 189.5 mg (20%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclopentyl]methoxy)benzaldehyde; trifluoroacetic acid as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.74 (s, 1H), 10.05 (s, 1H), 7.45 (t, 1H), 7.32 (s, 1H), 6.47 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 6.04 (s, 1H), 4.64 (s, 1H), 3.76 (t, 1H), 3.62 (t, 1H), 3.48 (m, 1H), 2.71 (s, 1H), 2.00 (m, 2H), 1.98 (s, 2H), 1.88 (Ss, 2H), 1.33 (s, 6H); MS (ESI) m/z 329 [M+H].sup.+.

Example 13

Preparation of 2-hydroxy-6-((2-(2-methoxypyridin-3-yl)cyclopent-1-en-1-yl)methoxy)benzaldehyde (Compound 574)

(206) ##STR00593##
Step 1.

(207) Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed ethyl2-[(trifluoromethane)sulfonyloxy]cyclopent-1-ene-1-carboxylate (1.44 g, 5.00 mmol, 1.00 equiv), (2-methoxypyridin-3-yl)boronic acid (1.07 g, 7.00 mmol, 1.40 equiv), toluene (30 mL), ethanol (10 mL), and sodium carbonate (2M in H.sub.2O) (10 mL). This was followed by the addition of Pd(dppf)(DCM)Cl.sub.2 (327 mg, 0.08 equiv). The resulting solution was stirred for 3 h at 100 C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 330 mL of ethyl acetate. The combined organic layers were washed with 280 mL of water and 180 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:8) as eluent to furnish 1.12 g (91%) of ethyl2-(2-methoxypyridin-3-yl)cyclopent-1-ene-1-carboxylate as a colorless oil.

(208) Step 2.

(209) Into a 50-mL round-bottom flask, was placed a solution of ethyl2-(2-methoxypyridin-3-yl)cyclopent-1-ene-1-carboxylate (570 mg, 2.30 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LAH (220 mg, 5.80 mmol, 2.50 equiv) at 0 C. The resulting solution was stirred for 3 h at room temperature, and then it was quenched with 10 mL of 2.5M NaOH aq. The resulting solution was extracted with 330 mL of ethyl acetate. The combined organic layers were washed with 140 mL of water and 140 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:6) as eluent to furnish 428 mg (90%) of [2-(2-methoxypyridin-3-yl)cyclopent-1-en-1-yl]methanol as a colorless oil.

(210) Step 3 (Method A).

(211) Into a 50-mL round-bottom flask, was placed a solution of [2-(2-methoxypyridin-3-yl)cyclopent-1-en-1-yl]methanol (428 mg, 2.09 mmol, 1.00 equiv), 2,6-dihydroxybenzaldehyde (374 mg, 2.71 mmol, 1.30 equiv), PPh.sub.3 (709 mg, 2.70 mmol, 1.30 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of DIAD (546 mg, 2.70 mmol, 1.30 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 30 min at 0 C. and for an additional hour at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 340 mL of ethyl acetate. The combined organic layers were washed with 130 mL of water and 130 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:8) as eluent. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (50.0% MeCN up to 75.0% in 10 min, up to 95.0% in 2 min, down to 50.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This provided 140 mg (21%) of 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclopent-1-en-1-yl]methoxy]benzaldehyde as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.98 (s, 1H), 8.08 (dd, J=5.4 Hz, 2.0 Hz, 1H), 7.51 (dd, J=5.4 Hz, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.69-6.96 (m, 1H), 6.44 (dd, J=16.0 Hz, 8.4 Hz, 1H), 6.73 (s, 2H), 3.80 (s, 3H), 2.72-2.61 (m, 4H), 1.98-1.92 (m, 2H); MS (ESI) m/z 326.2 [M+H].sup.+.

Example 14

Preparation of 2-hydroxy-6-((2-(2-methoxypyridin-3-yl)cyclopentyl)methoxy)-benzaldehyde (Compound 575)

(212) ##STR00594##
Step 1.

(213) Into a 50-mL round-bottom flask, was placed ethyl2-(2-methoxypyridin-3-yl)cyclopent-1-ene-1-carboxylate (530 mg, 2.14 mmol, 1.00 equiv), Palladium on carbon (200 mg) and ethanol (15 mL). The resulting solution was stirred for 18 h at room temperature under hydrogen atmosphere. The solids were filtered out. The resulting mixture was concentrated under vacuum. This provided 534 mg (100%) of ethyl2-(2-methoxypyridin-3-yl)cyclopentane-1-carboxylate as a colorless oil.

(214) Step 2.

(215) Into a 50-mL round-bottom flask, was placed a solution of ethyl2-(2-methoxypyridin-3-yl)cyclopentane-1-carboxylate (534 mg, 2.14 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of LAH (200 mg, 5.27 mmol, 2.50 equiv), in one portion at 0 C. The resulting solution was stirred for 30 min at 0 C. and for an additional 3 h at room temperature. The reaction was then quenched by the addition of 15 mL of 2.5M NaOH aq. The resulting solution was extracted with 340 mL of ethyl acetate. The combined organic layers were washed with 140 mL of water and 140 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) as eluent to yield 415 mg (93%) of [2-(2-methoxypyridin-3-yl)cyclopentyl]methanol as a colorless oil.

(216) Step 3 (Method A).

(217) Into a 50-mL round-bottom flask, was placed a solution of 2,6-dihydroxybenzaldehyde (416 mg, 3.01 mmol, 1.30 equiv), [2-(2-methoxypyridin-3-yl)cyclopentyl]methanol (480 mg, 2.32 mmol, 1.00 equiv), PPh.sub.3 (787 mg, 3.00 mmol, 1.30 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of DIAD (607 mg, 3.00 mmol, 1.30 equiv) dropwise with stirring at 0 C. The resulting solution was stirred for 30 min at 0 C. and for an additional 1 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 340 mL of ethyl acetate. The combined organic layers were washed with 140 mL of water and 120 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (61.0% MeCN up to 77.0% in 8 min, up to 95.0% in 2 min, down to 61.0% in 2 min); Detector, Waters2545 UvDector 254&220 nm. This provided 264 mg (35%) of 2-hydroxy-6-[[2-(2-methoxypyridin-3-yl)cyclopentyl]methoxy]benzaldehyde as a light yellow semi-solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 11.91 (s, 1H), 10.04 (s, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.4 Hz), 7.26 (d, J=8.4 Hz, 2H), 6.80-6.70 (m, 1H), 6.42 (d, J=8.4 Hz, 1H), 6.05 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.67-3.60 (m, 1H), 3.58-3.40 (m, 2H), 4.00-3.85 (m, 1H), 2.20-1.50 (m, 6H); MS (ESI) m/z 328.2 [M+H].sup.+.

Example 15

Preparation of 2-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)-methoxy)-6-hydroxybenzaldehyde (Compound 576)

(218) ##STR00595##
Step 1.

(219) trans-Ethyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexanecarboxylate. To a cooled (0 C.) solution of ethyl2-oxocyclohexanecarboxylate (0.64 g, 4.0 mmol) in dichloromethane (5 mL) was added triacetoxyborohydride (1.7 g, 8.0 mmol) followed by acetic acid (0.26 g, 4.4 mmol). The mixture was stirred at ambient temperature for 12 hours and then washed with saturated aqueous NaHCO.sub.3. The aqueous layer was extracted two times with CH2Cl2 and the combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. Purification by silica gel chromatography yielded trans-ethyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexanecarboxylate (0.65 g, 61% yield) as a clear oil. MS (ES) for C.sub.15H.sub.25NO.sub.3: 268 (MH.sup.+).

(220) Step 2.

(221) trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methanol. To a cooled (0 C.) solution of trans-ethyl2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexanecarboxylate (0.28 g, 1.0 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (3.2 mL, 1M in THF). The reaction mixture was stirred for 1 h and then 120 L of H.sub.2O was added followed by 120 L of 15% NaOH (aq) and then 360 L of additional H.sub.2O. The slurry was stirred for 1 h, filtered and the resulting residue was washed with ether. The combined organic layers were dried over MgSO.sub.4 and concentrated in vacuo. Purification by column chromotography (EtOAc/hexanes, 0-100%) provided trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methanol (0.20 g, 85% yield). MS (ES) for C.sub.13H.sub.23NO.sub.2: 226 (MH.sup.+).

(222) Step 3.

(223) trans-3-(2-(chloromethyl)cyclohexyl)-8-oxa-3-azabicyclo[3.2.1]octane. To a cooled (0 C.) solution of trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methanol (0.220 g, 0.98 mmol) in dichloromethane was added SOCl.sub.2 (0.58 g, 4.9 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene to provide trans-3-(2-(chloromethyl)cyclohexyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.24 g, 99%) as a clear oil. MS (ES) for C.sub.13H.sub.22ClNO: 244 (MH.sup.+).

(224) Step 4 (Method A).

(225) 2-((trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methoxy)-6-(methoxymethoxy)benzaldehyde. To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (0.24 g, 1.5 mmol) in DMF was added trans-3-(2-(chloromethyl)cyclohexyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.24 g, 0.97 mmol) and potassium carbonate (0.67 g, 4.8 mmol). The reaction mixture was heated (90 C.) for 30 minutes and partitioned between EtOAc and saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. Purification by silica gel chromatography provided 2-((trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methoxy)-6-(methoxymethoxy)benzaldehyde (0.23 g, 62%) as a clear oil. MS (ES) for C.sub.22H.sub.31NO.sub.5: 390 (MH.sup.+).

(226) Step 5.

(227) 2-(trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methoxy)-6-hydroxybenzaldehyde. To a solution of 2-((trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methoxy)-6-(methoxymethoxy)benzaldehyde (0.23 g, 0.59 mmol) in THF (5 mL) was added concentrated HCl (1 mL). The resulting solution was heated (50 C.) for 30 minutes and partitioned between EtOAc and saturated aqueous NaHCO.sub.3. The aqueous layer was extracted with EtOAc two times and the combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. Purification by silica gel chromatography provided 2-(trans-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)methoxy)-6-hydroxybenzaldehyde (0.180 mg, 88% yield) as a white powder. .sup.1H NMR (400 MHz, Chloroform-d) 11.95 (s, 1H), 10.34 (d, J=0.6 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 6.51 (dt, J=8.5, 0.7 Hz, 1H), 6.43 (dd, J=8.4, 0.8 Hz, 1H), 4.33-4.20 (m, 3H), 4.04 (dd, J=10.4, 9.3 Hz, 1H), 2.78 (dt, J=11.2, 1.8 Hz, 1H), 2.70 (dt, J=10.9, 1.7 Hz, 1H), 2.51 (dt, J=10.8, 4.1 Hz, 1H), 2.32-2.17 (m, 3H), 2.14-1.71 (m, 8H), 1.51-1.20 (m, 4H), 1.19-1.02 (m, 1H). MS (ES) for C.sub.20H.sub.27NO.sub.4: 346 (MH.sup.+).

Example 16

Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)cyclohept-1-en-1-yl)methoxy)-benzaldehyde (Compound 577)

(228) ##STR00596##
Step 1.

(229) Into a 50-mL 3-necked round-bottom flask, was placed a solution of methyl2-oxocycloheptane-1-carboxylate (1 g, 5.88 mmol, 1.00 equiv) in dichloromethane (10 mL). This was followed by the addition of DIPEA (2.3 mL, 2.40 equiv) dropwise with stirring at 78 C. The mixture was stirred for 10 mins at 78 C. To this was added Tf2O (1.1 mL, 1.20 equiv) dropwise with stirring at 78 C. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 250 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:401:4) as eluent. This provided 1.1 g (62%) of methyl2-[(trifluoromethane)sulfonyloxy]cyclohept-1-ene-1-carboxylate as a brown oil.

(230) Step 2.

(231) Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed 1-(propan-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (771 mg, 3.27 mmol, 1.10 equiv), methyl2-[(trifluoromethane)sulfonyloxy]cyclohept-1-ene-1-carboxylate (900 mg, 2.98 mmol, 1.00 equiv), Tol (19.8 mL), ethanol (6.6 mL), water (6.6 mL), sodium carbonate (940.6 mg, 8.87 mmol, 2.98 equiv), and Pd(dppf)Cl2 (183.2 mg, 0.25 mmol, 0.08 equiv). The resulting solution was stirred overnight at 90 C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) as eluent. This provided 632 mg (81%) of methyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohept-1-ene-1-carboxylate as a brown oil.

(232) Step 3.

(233) Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohept-1-ene-1-carboxylate (553 mg, 2.11 mmol, 1.00 equiv) in tetrahydrofuran (9.2 mL). This was followed by the addition of LAH (243.2 mg, 6.41 mmol, 3.04 equiv) at 0 C. The resulting solution was stirred for 0.5 h at 0 C. in a water/ice bath. The reaction was then quenched by the addition of 2.3 mL of EA. The resulting solution was diluted with 50 mL of H.sub.2O. The resulting solution was extracted with 3100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This provided 464 mg (94%) of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohept-1-en-1-yl]methanol as a yellow oil.

(234) Step 4.

(235) Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohept-1-en-1-yl]methanol (273 mg, 1.16 mmol, 1.00 equiv) in dichloromethane (10 mL). This was followed by the addition of thionyl chloride (0.25 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 0.5 h at 0 C. in a water/ice bath. The resulting mixture was concentrated under vacuum. This provided 295 mg (100%) of 5-[2-(chloromethyl)cyclohept-1-en-1-yl]-1-(propan-2-yl)-1H-pyrazole as a yellow oil.

(236) Step 5.

(237) Into a 100-mL round-bottom flask, was placed 2,6-dihydroxybenzaldehyde (241.5 mg, 1.75 mmol, 1.50 equiv), 5-[2-(chloromethyl)cyclohept-1-en-1-yl]-1-(propan-2-yl)-1H-pyrazole (295.2 mg, 1.17 mmol, 1.00 equiv), potassium carbonate (194.5 mg, 1.41 mmol, 1.21 equiv), DMSO (3.2 mL), NaI (16.2 mg, 0.10 equiv). The resulting solution was stirred for 1.5 h at 55 C. and overnight at room temperature. The resulting solution was diluted with 100 mL of 1M HCl. The resulting solution was extracted with 3200 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, Gemini-NX C18 AXAI Packed, 21.2*150 mm 5 um 11 nm; mobile phase, WATER WITH 0.05% TFA and MeCN (5.0% MeCN up to 35.0% in 10 min); Detector, nm. This provided 100.3 mg (24%) of 2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]cyclohept-1-en-1-yl]methoxy)benzaldehyde as a brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.37 (s, 1H), 7.76 (s, 1H), 7.36 (t, 1H, J=8.4 Hz), 6.55 (d, 1H, J=8.4 Hz), 6.16 (d, 1H, J=8.0 Hz), 6.10 (s, 1H), 4.52-4.46 (m, 1H), 4.32-4.25 (brs, 1H), 2.62-2.50 (m, 3H), 2.45-2.41 (m, 1H), 1.95-1.91 (m, 2H), 1.68-1.66 (m, 4H), 1.53 (d, 3H, J=6.8 Hz), 1.45 (d, 3H, J=6.4 Hz); MS (ESI) m/z 355.4 [M+H].sup.+.

(238) In Vitro Testing

Example 17

Modulation of Hemoglobin Oxygen Affinity by Substituted Benzaldehyde CompoundsAssay Procedure

(239) Oxygen equilibrium curves (OEC) in purified Hemoglobin S (HbS) were measured by the change in p50, the partial pressure of oxygen at which the heme binding sites in the HbS sample are 50% saturated with oxygen. HbS was purified by a modified procedure (Antonini and Brunori, 1971; Hemoglobin and Myoglobin in their Reactions with Ligands; North Holland Publishing Company; Amsterdam, London) from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Oxygen equilibrium curves were carried out with a HEMOX analyzer, (TCS Scientific, New Hope, Pa.). Five hundred L of 250 M purified HbS were diluted into 4.5 mL of HEMOX buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) resulting in a final hemoglobin concentration of 25 M. The compounds were added at the final desired concentrations. The mixture was incubated for 45 min at 37 C. and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the absorbance of deoxy-Hb was recorded as a function of the solution pO.sub.2. The oxygen equilibrium data was then fit to the Hill Model to obtain values for p50. The deoxygenation curves for both HbS alone (control) and HbS in the presence of compound were collected with the TCS software. The p50 for purified Hbs was typically 13.81.6. Delta p50 values were obtained from the p50 value for control minus the p50 value for HbS treated with compound divided by the p50 value for the control. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.

Example 18

Modulation of Hemoglobin Oxygen Affinity by Substituted Benzaldehyde CompoundsAssay Results

(240) The compounds of Table 1 that were where tested in the assay above were all found to have positive delta p50 values. Delta p50% is calculated from [[p50(HbS)-p50(HbS treated with compound)]/p50(HbS)]100. Table 2 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29 and ++ indicates a delta p50% of 30 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 30 M.

(241) TABLE-US-00002 TABLE 2 delta p50 Compound delta p50 1 ++ 2 ++ 3 ++ 4 ++ 5 ++ 6 ++ 7 ++ 8 + 9 +

Example 19

Polymerization Assay

(242) Polymerization assays are carried out in vitro using purified HBS exchanged into 1.8 M potassium phosphate buffer at pH 7.4. Using a slightly modified protocol (Antonini and Brunori, 1971), HbS is purified by the CRO VIRUSYS, from blood obtained from homozygous sickle cell patients through the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. Compounds are prepared in 100% DMSO and a desired amount is added to 50 M of purified HBS at a final DMSO concentration of 0.3%. Final potassium phosphate concentration is adjusted to 1.8 M using a combination of 2.5 M potassium phosphate stock solution and water at pH 7.4. The reaction mixture is incubated for an hour at 37 C. and then transferred into a 24-well plate for deoxygenation in a glove box containing 99.5% nitrogen and 0.5% oxygen. The 24-well plate is not covered and incubated at 4 C. on a plate cooler inside the glove box for one and a half hours. Fifty L of the reaction mixture is transferred into a 96-well plate and the absorbance at 700 nm is measured every minute for one hour at 37 C. in a plate reader located inside the glove box. A plot of the absorbance against time is fitted using a Boltzman sigmoidal fit and the delay time (from zero to time at half Vmax) is measured. To compare and rank compounds, delay times are expressed as percent delay (% DT), which is defined as the difference in delay times for HBS/compound and HBS alone multiplied by 100 and divided by the delay time for HBS alone.

(243) Compounds listed below have been tested in the polymerization assay. Activity ranges are defined by the number of dagger () symbols indicated. denotes activity 40% but 80%; denotes activity >80% but 120%; denotes activity >120% but 140%; denotes activity >160%.

(244) TABLE-US-00003 TABLE 3 delta Delay Compound % delta Delay 1 2 3 4 5 6 7 8 10 11

Example 20

R/T Assay

(245) A relaxed-to-tense transition assay (R/T assay) was used to determine the ability of substituted benzaldehyde compounds to maintain the high-oxygen affinity relaxed (R) state of hemoglobin under deoxygenated conditions. This ability can be expressed as a delta R value (i.e., the change in the time-period of the R state after hemoglobin is treated with a compound, as compared to the period without treatment with the compound). Delta R is the % R to remaining after the compounds treatment compared with no treatment (e.g. if R % without treatment is 8% while with treatment with a target compound is 48% R at 30 M, then % R is 40% for that compound.

(246) A mixture of HbS/A was purified from blood obtained from homozygous sickle cell patients though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. HbS/A (at a final concentration of 3 M) was incubated for 1 hr at 37 C. in presence or absence of compounds in 50 M potassium phosphate buffer, pH=7.4 and 30 M 2, 3 diphosphoglycerate (DPG) in 96 well plates in a final volume of 160 l. Compounds were added at different concentrations (3 M to 100 M final concentrations). Plates were covered with a Mylar film. After incubation was completed the Mylar cover was removed and the plates were placed in a Spectrostar Nano plate reader previously heated at 37 C. Five minutes later, N.sub.2 (flow rate=20 L/min) was flowed through the spectrophotometer. Spectroscopic measurements (300 nm to 700 nm) were taken every 5 min for 2 hours. Data analysis was performed by using linear regression from the data retrieved for all wavelengths.

(247) Table 4 below lists the delta R values where + indicates a delta R of between 0 and 30, ++ indicates a delta R of between 30 and 50, and +++ indicates a delta R of 50 or greater. Unless noted otherwise, the compounds in Table 2 were tested at 9 M.

(248) TABLE-US-00004 TABLE 4 delta R delta R Compound (%) 1 +++ 2 ++ 3 +++ 4 +++ 5 +++ 8 + 9 +++ 10 ++ 11 ++

Example 21

Whole Blood Assay

(249) Oxygen Equilibrium Curves (OEC) of whole blood before and after treatment with different concentrations of substituted benzaldehyde compounds were performed as follows using a HEMOX analyzer (TCS Scientific, New Hope, Pa.). Blood samples from homozygous sickle cell patients were obtained though the Hemoglobinopathy Center at Children's Hospital Oakland Research Institute (CHORI) with Institutional Review Board approval. The hematocrit was adjusted to 20% using autologous plasma and the blood samples were incubated for 1 hour at 37 C. in absence or presence of compounds. 100 l of these samples were added to 5 mL of Hemox buffer (30 mM TES, 130 mM NaCl, 5 mM KCl, pH=7.4) at 37 C. and then transferred to the Hemox sample chamber. The samples were saturated with oxygen by flushing with compressed air for 10 minutes. The samples were then flushed with pure nitrogen and the respective absorbances of oxy- and deoxy-Hb are recorded as a function of the solution pO2. The oxygen equilibrium data were then fitted to the Hill Model to obtain values for p50. The deoxygenation curves for both whole blood alone (control) and whole blood in the presence of the compound were collected with the TCS software.

(250) Table 5 below lists the delta p50% values where + indicates a delta p50% of between 0 and 29, ++ indicates a delta p50% of between 30 and 50, and +++ indicates a delta p50% of 50 or greater. The compounds in Table 2 were tested at 1000 M. A positive delta p50 value corresponds to a left shifted curve and a lower p50 value relative to control, indicating that the compound acts to modulate HbS to increase its affinity for oxygen.

(251) TABLE-US-00005 TABLE 5 delta p50% Values for Whole Blood Assay Compound delta p50% 1 + 2 ++ 3 + 4 + 5 ++ 6 + 7 + 10 ++

(252) All patents, patent applications, publications and presentations referred to herein are incorporated by reference in their entirety. Any conflict between any reference cited herein and the teaching of this specification is to be resolved in favor of the latter. Similarly, any conflict between an art-recognized definition of a word or phrase and a definition of the word or phrase as provided in this specification is to be resolved in favor of the latter.