Dpp1 inhibitors with polycyclic linkers and uses thereof

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or deuterated forms thereof, wherein R0 , L and R1 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a disease that is treatable by administration of a DPP1 inhibitor.

Description

This document provides compounds of formula (I) or pharmaceutically acceptable salts or deuterated forms thereof, wherein R0, L, and R1 are defined herein. This document also provides pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts or deuterated forms thereof, and methods of using compounds of formula (I) or pharmaceutically acceptable salts or deuterated forms thereof to, for example, treat diseases treatable by administration of DPP1 inhibitors. Abstract

Claims

CLAIMS 1. A compound of formula (I)or a pharmaceutically acceptable salt or deuterated form thereof, wherein: R0is • 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R8, or • 5-12-membered polycyclic heterocyclyl containing 1-3 heteroatoms selected from N, S, or O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R8, each R8is independently selected from H, halogen, oxo, cyano, hydroxyl, NH2, NH(C1- 6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, C1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy, halogenated C1-6alkoxy, C1-6 alkylene-carbocyclyl, or C1-6 alkylene-heteroaryl; L is polycyclic cycloalkylene, polycyclic arylene, or polycyclic heteroarylene, wherein a first atom of a first ring of the polycyclic arylene or heteroarylene is connected toand a second atom of a second ring of the polycyclic arylene or heteroarylene is connected to R1; wherein L is independently substituted by 0-4 R10;each R10is independently =O, halogen, C1-6alkyl, C1-6alkoxy, S-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, cyano, hydroxy, NH2, -NH-C1-6 alkyl, N(C1-6alkyl)2, COOH, COC1-6 alkyl, COOC1-6alkyl, CON1-6alkyl, CON(C1-6alkyl)2, NHCOC1-6alkyl, or heterocycle; wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycle are independently optionally substituted with 1-3 substituents selected from halogen, cyano, hydroxyl, NH2 and COOH; R1is • 5-12 membered carbocyclyl optionally substituted with 1-3 Rg, • 6-18 membered aryl optionally substituted with 1-3 Rg, • 5-12 membered monocyclic heterocyclyl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 Rg, • 5-12 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the monocyclic heteroaryl is optionally substituted with 1-3 Rg, • 7-14 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 Rg, or • 7-20 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 Rg, each Rgis independently selected from hydrogen, SF5, =O, halogen, cyano, hydroxyl, nitro, NH2, -COOH, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyloxy, C2-6alkenyloxy, C 2-6 alkynyloxy, C3- 6 cycloalkyl, C2-6 alkenyl, C2-5 alkynyl, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -COC1-6alkyl, -COOC1- 6 alkyl, -CONH2, -CONHC1-6 alkyl, -CONHC3-6 cycloalkyl, -CON(C1-6 alkyl)2, -NHCOC1- 6alkyl, -NHCOC3-5cycloalkyl, -P(O)(C1-6 alkyl), -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, -S(O)2C3- 6cycloalkyl, -SO2-3-7 membered heterocyclyl, -S(O)NH2, -S(O)NHC1-6 alkyl, -S(O)N(C1-6 alkyl)2, -S(O)2NH2, -OSO2-C1-6alkyl, C1-6alkylene-O-C1-6alkyl, C3-8 -cycloalkenyloxy, aryl, heteroaryl, 3-7-membered heterocycle containing 1-3 heteroatoms selected from N, S and O, and the Rgis optionally further substituted with 1-3 groups selected from C1-6 alkyl, C1-6 haloalkyl, C1-6-alkylene-OH, -CONH2, NH2, C1-6 alkoxy, hydroxyl, -COOH, halogen, or a 5- 7-membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the 5- 7-membered heterocycle is optionally substituted with 1-2 groups selected from =O, halogen, cyano, C1-6 alkyl, and C1-6 haloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is 5-12 membered monocyclic heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the monocyclic heterocycle is optionally substituted with 1-3 R8.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0isX1 and X2 are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1and X2are not CR12R13; X3 is O, S, NH, or N(C1-6alkyl); R8is H, halogen, oxo, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, C1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy or halogenated C1- 6alkoxy; R12is H, halogen, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, C1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy or halogenated C1-6alkoxy R13is independently H, halogen or C1-C6 alkyl; RAis H, C1-6alkyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl, or RAand RBare taken together to form a heterocyclyl; and m is 0, 1, 2 or 3.

4. The compound of claim 3, or a pharmaceutically acceptable salt or deuterated form thereof, wherein5. The compound of claim 3 or 4, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, X1 and X2 are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1 and X2 are not CR12R13; each R8is independently selected from H, halogen, oxo, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, C1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2,C1-6alkoxy or halogenated C1-6alkoxy; and R12is H, halogen, C1-6 alkyl; and each R13is independently H, halogen or C1-C6 alkyl.

6. The compound of claim 3, or a pharmaceutically acceptable salt or deuterated form thereof, whereinX1 and X2 are independently O, S, NH, N(C1-6alkyl), or CR12R13, wherein at least one of X1 and X2 are not CR12R13; X3 is O, S, NH, or N(C1-6alkyl); RAis H, C1-6alkyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; and RBis C1-6alkyl, C2-6alkenyl, C1-6alkylene-carbocyclyl, or C1-6alkylene-heteroaryl; or RAand RBare taken together to form a heterocyclyl; R12is H, halogen, C1-6 alkyl; each R13is independently H, halogen or C1-C6 alkyl.

7. The compound of claim 5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein1-6alkoxy.

8. The compound of claim 1 or 2, wherein, each n1, n2 and n3 is independently an integer from 0-3, and the total sum of n1, n2 and n3 is ≤ 4, X1 and X2 are independently O, S, NR6or CR12R13, wherein at least one of the X1 and X2 is not CR12R13; each R6, R12and R13is independently H, halo, or C1-C6alkyl.

9. The compound of any one of claim 1-8, or a pharmaceutically acceptable salt or11. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is 5-12-membered polycyclic heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the polycyclic heterocycle is optionally substituted with 1-3 R8.

12. The compound of claim 1 or 11, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is • 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R8, • 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R8, or • 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the bridge heterocycle is optionally substituted with 1-3 R8.

13. The compound of any one of claims 1, 11, or 12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is 5-12 membered spiro heterocycle containing 1-3 heteroatoms selected from N, S, or O, wherein the spiro heterocycle is optionally substituted with 1-3 R8.

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is, wherein m1 and m2 are each independently 0, 1, or 2, provided that both m1 and m2 are not 0, or both m1 and m2 are not 2, and p is 1 or 2.

15. The compound of any one of claims 12-14, or a pharmaceutically acceptable salt or deuterated form thereof, wherein,.

16. The compound of claim 1, 11, or 12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is 5-12 membered fused heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the fused heterocycle is optionally substituted with 1-3 R8.

17. The compound of claim 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is, m4 is 0 or 1, m5 is 1 or 2, X2is O, S, NH, N(C1-6alkyl), or CR12R13, R12is selected from H, halogen, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy or halogenated C1-6alkoxy; R13is independently H, F, Cl, Br, I or C1-C6 alkyl.

18. The compound of claim 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is, X2 is O, S, NH, N(C1-6alkyl), or CR12R13R12is H, halogen, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy or halogenated C1-6alkoxy; R13is H, halogen or C1-C6 alkyl; each m and m’ is independently an integer from 0-3, and the total sum of m and m’ is ≤ 3.

19. The compound of claim 17, or a pharmaceutically acceptable salt or deuterated form.

20. The compound of claim 12 or 16, or a pharmaceutically acceptable salt or deuterated form thereof, whereinX2 is O, S, NH, N(C1-6alkyl), or CR12R13, R12is H, halogen, C1-6 alkyl, R13is H, halogen or C1-C6 alkyl, and each m and m’ is independently an integer from 0-3, and the total sum of mc and mc’ is ≤ 3.

21. The compound of claim 20, or a pharmaceutically acceptable salt or deuterated form thereof, wherein22. The compound of claim 21, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

23. The compound of claim 20, or a pharmaceutically acceptable salt or deuterated form thereof, the wherein R0is24. The compound of claim 18, or a pharmaceutically acceptable salt or deuterated form thereof, the wherein, X2 is O, S, NH, N(C1-6alkyl), or CR12R13R12is H, halogen, C1-6 alkyl; and R13is H, halogen or C1-C6 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

26. The compound of claim 11 or 12, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is 7-12 membered bridged heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the bridged heterocycle is optionally substituted with 1-3 R8.

27. The compound of claim 26, or a pharmaceutically acceptable salt or deuterated formwhich is optionally substituted with 1-4 R8, wherein A is a bond, -O-, -O-CH2-, -CH2-O-CH2-, -CH2OCH2CH2-, -CH2-, -CH2CH2-, or -CH2NH- , B is N or CH, m4is 0 or 1, p1is 0, 1, or 2, q1is 1, 2, or 3.

28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt or deuterated ,29. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein,.

30. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 5-12 membered carbocyclyl optionally substituted with 1-3 Rggroup.

31. The compound of claim 30, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is, , , each of which is optionally substituted with 1-3 Rg.

32. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 6-18 membered aryl optionally substituted with 1-3 Rg.

33. The compound of claim 32, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, wherein L is attached to R1by replacing any hydrogen atom of R1, and wherein each R1is optionally substituted with 1-3 Rg.

34. The compound of claim 32, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

35. The compound of claim 34, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

36. The compound of claim 34 or 35, or a pharmaceutically acceptable salt or deuterated.

37. The compound of claim 34, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

38. The compound of claim 37, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

39. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 5-12 membered monocyclic heterocyclyl containing heteroatoms selected from N, S or O, wherein the monocyclic heterocyclyl is optionally substituted with 1-3 Rggroup.

40. The compound of claim 39, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, wherein each one of R1is optionally substituted with 1-3 Rg.

41. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 5-12 membered monocyclic heteroaryl containing heteroatoms selected from N, S or O, wherein each one of the monocyclic heteroaryl is optionally substituted with 1-3 Rggroup.

42. The compound of claim 41, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is ,, , , each of which is optionally substituted with 1-3 Rggroup.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each Rgis independently H, halogen, C1-C6 alkyl, OSO2C1-6alkyl, or CN.

44. The compound of claim 42 or 43, or a pharmaceutically acceptable salt or deuterated form.

45. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 7-14 membered bicyclic heteroaryl containing heteroatoms selected from N, S or O, wherein the bicyclic heteroaryl is optionally substituted with 1-4 Rggroup.

46. The compound of claim 1 or 45, or a pharmaceutically acceptable salt or deuterated form thereof, wherein Rgis R6or R7, wherein each R6is independently selected from H, C1-6 alkyl, -COC1-6 alkyl, C2-6 alkenyl, C2- 6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH;each R7is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl,C2- 6 alkynyl, C3-6cycloalkyl, cyano, hydroxyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, COOH, COC1-6 alkyl, COOC1-6 alkyl, CONHC1-6 alkyl, CON(C1-6 alkyl)2, NHCOC1-6 alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH.

47. The compound of claim 45, or a pharmaceutically acceptable salt or deuterated form, each of which is optionally substituted with 1-3 Rggroup.

48. The compound of claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, wherein Y is independently O, S, CHR6or NR6; and R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by OH, O-C1-6alkyl, N(C1-6alkyl)2, cycloalkyl, or heterocyclyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

50. The compound of claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, X4is NR6O CR7CR14R15S S(O) or S(O)Q is CH or N, each R6is independently selected from H, C1-6 alkyl, -COC1-6 alkyl, C2-6 alkenyl, C2- 6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; each R7is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl,C2- 6 alkynyl, C3-6cycloalkyl, cyano, hydroxyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, COOH, COC1-6 alkyl, COOC1-6 alkyl, CONHC1-6 alkyl, CON(C1-6 alkyl)2, NHCOC1-6 alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; R14and R15are each independently selected from H, halogen, C1-6 alkyl, C1-6alkoxy, C2-6 alkenyl, C2-6 alkynyl, C2-6alkenyloxy, C 2-6 alkynyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and - COOH; alternatively, R14and R15form =O.

51. The compound of any one of claims 45-46, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, each X4is independently NR6, O, CR14R15, S, S(O) or S(O)2,each R6is independently selected from H, C1-6 alkyl, -COC1-6 alkyl, C2-6 alkenyl, C2- 6alkynyl and C3-6cycloalkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; each R7is independently selected from H, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl,C2- 6 alkynyl, C3-6cycloalkyl, cyano, hydroxyl, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, COOH, COC1-6 alkyl, COOC1-6 alkyl, CONHC1-6 alkyl, CON(C1-6 alkyl)2, NHCOC1-6 alkyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycle groups within R7are optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; R14and R15are each independently selected from H, halogen, C1-6 alkyl, C1-6alkoxy, C2-6 alkenyl, C2-6 alkynyl, C2-6alkenyloxy, C 2-6 alkynyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl, and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and - COOH; alternatively, R14and R15form =O.

52. The compound of claim 50, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each X4is independently O, S, NR6or CR14R15; R6is C1-6alkyl optionally substituted by 1, 2 or 3 F, or by OH, O-C1-6alkyl, N(C1-6alkyl)2, cycloalkyl, or heterocyclyl; R7is H, halo or C1-6alkyl, R14and R15are independently H, halo or C1-6alkyl.

53. The compound of claim 52 or 53, or a pharmaceutically acceptable salt or deuterated form thereof, wherein each X4is independently NH, O, S, CHF, or CHF2.

54. The compound of any one of claims 52-53, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is.

55. The compound of any one of claims 52-53, or a pharmaceutically acceptable salt ordeuterated form thereof, wherein R1is .

56. The compound of any one of claims 45-46 or 51, or a pharmaceutically acceptable salt or57. The compound of any one of claims 45-46, 51 or 56 or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is.

58. The compound of claim 45 or 46, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is optionally substituted with 1-4 R6or R7group, wherein ring C is a 7-8 membered heterocycle comprising 1-3 heteroatoms selected from O, S and N.

59. The compound of claim 58, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is, each of which is optionally substituted with 1-4 R6or R7.

60. The compound of claim 58 or 59, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

61. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 7-20 membered tricyclic heteroaryl containing heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 Rg, wherein Rgis R6, R7, R11, R14or R15.

62. The compound of claim 1 or 61, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 7-20 membered spiro tricyclic heteroaryl containing heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 Rg.

63. The compound of any one of claims 61-62, or a pharmaceutically acceptable salt or deuterated form thereof, wherein,, each R6is independently selected from H, C1-6 alkyl, -COC1-6 alkyl, C2-6 alkenyl, C2- 6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; and, R14and R15are each independently selected from H, halogen, C1-6 alkyl, C1-6alkoxy, C2-6 alkenyl, C2-6 alkynyl, C2-6alkenyloxy, C 2-6 alkynyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and - COOH; alternatively, R14and R15form =O.

64. The compound of claim 62-63, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, wherein W, X4 and Y2 are each independently CH or N, provided that a maximum of one of W, X4 and Y2 can be N; D-E is N(H)-C(=O), N(C1-6alkyl)-C(=O), CH2CH2, C(=O)-O or CH2-O; R11is H, C1-6alkyl, alkylene-O-alkyl, or heterocyclyl; and i and j are each independently 1, 2 or 3; provided that the sum of i+j is 2, 3 or 4.

65. The compound of any one of claims 61-64, or a pharmaceutically acceptable salt or66. The compound of any one of claims 61-65, or a pharmaceutically acceptable salt or67. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is 7-20 membered fused tricyclic heteroaryl containing heteroatoms selected from N, S or O, wherein the tricyclic heteroaryl is optionally substituted with 1-5 Rg.

68. The compound of claim 1 or 67, or a pharmaceutically acceptable salt or deuterated form thereof, whereinoptionally substituted with 1-5 Rg, wherein X5and X6are each independently selected from single bond, -C(R14R15)-O-, -C(R14R15)- C(R14R15)-, -OC(R14R15)-, -C(R14R15)-, -O-, and -NR6-; R14and R15are each independently selected from H, halogen, C1-6 alkyl, C1-6alkoxy, C2-6 alkenyl, C2-6alkynyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, cyano, hydroxyl, NH2, COOH, -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, -S(O)2C3-6cycloalkyl, -SO2-3- 7 membered heterocyclyl and a 4-7 membered heterocycle containing 1-3 heteroatoms selected from N, S or O, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and heterocycle is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and - COOH; each R6is independently selected from H, C1-6 alkyl, -COC1-6 alkyl, C2-6 alkenyl, C2- 6alkynyl, C3-6cycloalkyl or alkylene-O-alkyl; wherein the alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with 1-3 groups selected from halogen, cyano, hydroxyl, NH2 and COOH; Ring D is selected from aryl and 5-8 membered heteroaryl containing 1-3 heteroatoms, wherein aryl and said 5-8 membered heteroaryl containing 1-3 heteroatoms each independently optionally substituted with 1-3 Rg, provided when ring D is aryl, X5and X6are not both -C(R14R15)-C(R14R15)- or- C(R14R15)-.

69. The compound of claim 68, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is,optionally substituted with 1-5 Rg.

70. The compound of claim 68 or 69, or a pharmaceutically acceptable salt or deuterated form thereof, wherein Ring D ir , each of which is optionally substituted with 1-3 Rggroup.

71. The compound of any one of claims 68-70, or a pharmaceutically acceptable salt or,.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt or deuterated form thereof wherein L is a polycyclic cycloalkylene73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic cycloalkylene comprises 4-10 carbon atoms.

74. The compound of any one of claims 1-73, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic cycloalkylene is connected to R1at a first quaternary carbon of the polycyclic cycloalkylene and independently connected tothrough a second quaternary carbon of the polycyclic cycloalkylene.

75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic cycloalkylene is,76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic cycloalkylene is,77. The compound of any one of claims 1-76, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L is a polycyclic heteroarylene substituted by 0-4 R10.

78. The compound of claim 77, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene comprises 8-12 ring atoms and is substituted by 0-4 R10.

79. The compound of any one of claims 77-78, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene comprises 8-10 ring atoms and is substituted by 0-4 R10.

80. The compound of any one of claims 77-79, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene comprises 8-9 ring atoms and is substituted by 0-4 R10.

81. The compound of claim 77, or a pharmaceutically acceptable salt or deuterated formwherein ring B is a heteroaryl ring.

82. The compound of any one of claims 77-81, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene comprises 9 ring atoms and 1 or 2 heteroatoms selected from O, N, or S, and the polycyclic heteroarylene is substituted by 0-4 R10.

83. The compound of any one of claims 77-82, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene issubstituted by 0-4 R10, wherein X′ is O, S, NH or N(C1-6 alkyl).

84. The compound of any one of claims 77-83, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is benzothienylene, indolylene or benzofuranylene substituted by 0-4 R10.

85. The compound of any one of claims 77-84, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is,, each of which is substituted by 0-4 R10.

86. The compound of claim 85, or a pharmaceutically acceptable salt or deuterated form87. The compound of claim 85, or a pharmaceutically acceptable salt or deuterated form thereof, whereinattached to the 5-membered ring of,88. The compound of any one of claims 77-87, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is,.

89. The compound of any one of claims 77-88, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is,90. The compound of any one of claims 77-87, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L isR10.

91. The compound of any one of claims 90, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L issubstituted by one R10.

92. The compound of any one of claims 90 or 91, or a pharmaceutically acceptable salt ordeuterated form thereof, wherein R10 is halo.

93. The compound of any one of claims 90-92, or a pharmaceutically acceptable salt or94. The compound of any one of claims 90-93, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L is.

95. The compound of any one of claims 77-80, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene comprises 8 ring atoms and 1 or 2 heteroatoms selected from O, N, or S, and the polycyclic heteroarylene is substituted by 0-4 R10.

96. The compound of any one of claims 77-80 or 95, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is, wherein each of ring E and ring F is 5-membered heteroaryl or 5-membered heterocyclyl comprising 1-3 heteroatoms selected from O, N or S.

97. The compound of any one of claims 77-80 or 95-96, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is, wherein each of ring E and ring F is 5-membered heteroaryl comprising 1-3 heteroatoms selected from O, N or S.

98. The compound of any one of claims 77-80 or 95-96, or a pharmaceutically acceptable salt ,.

99. The compound of any one of claims 77-80, 95-96 or 98, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the polycyclic heteroarylene is, 100. The compound of any one of claim 1-71, or a pharmaceutically acceptable salt or deuterated form thereof, wherein L is polycyclic arylene.

101. The compound of claim 100, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

102. The compound of claim 100 or 101, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

103. The compound of any one of claims 1-71, wherein the compound is of Formula (II),or a pharmaceutically acceptable salt or deuterated form thereof.

104. The compound of any one of claims 1-71, wherein the compound is of Formula (III),or a pharmaceutically acceptable salt or deuterated form thereof.

105. The compound of any one of claims 1-71, wherein the compound is of Formula (IV),or a pharmaceutically acceptable salt or deuterated form thereof.

106. The compound of claim 1, wherein the compound is of Formula (V),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10is substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

107. The compound of claim 1, wherein the compound is of Formula (VI),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10is substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

108. The compound of claim 1, wherein the compound is of Formula (VII),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10can be substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

109. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0.

110. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1 and R10is halo.

111. The compound of any one of claims 103-108 or 110, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1 and R10is F.

112. The compound of any one of claims 1-111, or a pharmaceutically acceptable salt or deuterated form thereof, wherein ,X is O, S or CF2; Y is O or S; Q is CH or N; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F, OH, OC1- 3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is H, F, Cl or CH3.

113. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, whereinX is O, S or CF2; Y is O or S; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F, OH, OC1- 3alkyl, N(C1-3alkyl)2, cyclopropyl, or tetrahydropyran; and R7is H, F, Cl or CH3.

114. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

115. The compound of claim 114, or a pharmaceutically acceptable salt or deuterated form thereof, wherein, X is O; R6is C1-3alkyl; and R7is H.

116. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, whereinX is O; R6is C1-3alkyl, wherein said C1-3alkyl is optionally substituted by 1, 2 or 3 F; and R7is H.

117. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein,X is O; R6is C1-3alkyl; and R7is H.

118. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein.

119. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

120. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is.

121. The compound of any one of claims 105-120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is methyl.

122. The compound of any one of claims 105-120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is ethyl.

123. The compound of any one of claims 105-120, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is propyl.

124. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is. 125.The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

126. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1is. 127.The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (VIII):or a pharmaceutically acceptable salt or deuterated form thereof.

128. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (IX),or a pharmaceutically acceptable salt or deuterated form thereof.

129. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (X),or a pharmaceutically acceptable salt or deuterated form thereof.

130. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (XI),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10can be substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

131. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (XII),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10can be substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

132. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (XIII),or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0 or 1, and R10can be substituted on the phenyl ring or the thiophenyl ring of the benzothienylene ring.

133. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is of Formula (XVI),or a pharmaceutically acceptable salt or deuterated form thereof, wherein each of ring E and Ring F is 5-membered heteroarylene or 5-membered heterocyclylene, n is 0 or 1, and R10is substituted on the ring E or ring F. ,.

135. The compound of claim 133 or 134, wherein.

136. The compound of any one of claims 133-135, wherein R10is halo.

137. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof,, wherein the compound is of Formula (XVII),or a pharmaceutically acceptable salt or deuterated form thereof, wherein X’ is O, S, NH or N(C1-6 alkyl), n is 0 or 1, and R10is substituted on the phenyl ring or the 5-membered ring of.

138. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof,, wherein the compound is of Formula (XVIII),or a pharmaceutically acceptable salt or deuterated form thereof, wherein X’ is O, S, NH or N(C1-6 alkyl), n is 0 or 1, and R10is substituted on the phenyl ring or the 5-membered ring o.

139. The compound of any one of claims 120-138, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0.

140. The compound of any one of claims 120-138, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1 and R10is halo.

141. The compound of any one of claims 120-138 or 140, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1 and R10is F.

142. The compound of any one of claims 127-141, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

143. The compound of any one of claims 127-142, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is C1-3 alkyl.

144. The compound of any one of claims 127-143, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R7 is H.

145. The compound of any one of claims 127-144, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O, R6is C1-3 alkyl and R7 is H.

146. The compound of any one of claims 1-145, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

147. The compound of any one of claims 1-146, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

148. The compound of any one of claims 146-147, wherein R8is H.

149. The compound of any one of claims 1-145, or a pharmaceutically acceptable salt or.

150. The compound of any one of claims 1-145 or 149, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

151. The compound of claim 150, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

152. The compound of any one of claims 150-151, or a pharmaceutically acceptable salt ordeuterated form thereof, wherein R0is , wherein each R8is independently selected from H, halogen, oxo, cyano, hydroxyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)2, COOH, C1-6 alkyl, C1-6 alkyl-OH, -CONH2, -S(=O)NH2, -S(O)2NH2, C1-6alkoxy or halogenated C1- 6alkoxy.

153. The compound of any one of claims 150-152, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is, wherein each R8is independently selected from H, halogen, C1-6 alkyl, C1-6alkoxy or halogenated C1-6alkoxy.

154. The compound of claim 150, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

155. The compound of claim 150, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

156. The compound of claim 150, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

157. The compound of any one of claims 1 or 149-156, or a pharmaceutically acceptable salt or deuterated form thereof, wherein at least one R8is H.

158. The compound of any one of claims 1 or 149-156, or a pharmaceutically acceptable salt or deuterated form thereof, wherein at least one R8is methoxy.

159. The compound of any one of claims 1 or 149-156, or a pharmaceutically acceptable salt or deuterated form thereof, wherein at least one R8is ethoxy.

160. The compound of any one of claims 1 or 149-156, or a pharmaceutically acceptable salt or deuterated form thereof, wherein at least one R8is OH.

161. The compound of any one of claims 1-148, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

162. The compound of any one of claims 1-148 or 161, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

163. The compound of any one of claims 1-148 or 161, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

164. The compound of any one of claims 149-150, or a pharmaceutically acceptable salt or ,165. The compound of any one of claims 149-153 or 164, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is:

166. The compound of any one of claims 149-153 or 164-165, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is.

167. The compound of any one of claims 149-153 or 164-165, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R0is:.

168. The compound of any one of claims 149-153 or 164-165, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

169. The compound of claim 164, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

170. The compound of claim 164, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

171. The compound of claim 164, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

172. The compound of any one of claims 1-145 or 149, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

173. The compound of claim 172, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

174. The compound of any one of claims 149 or 172-173, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RAis H or C1-6alkyl.

175. The compound of claim 174, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RAis H.

176. The compound of claim 174, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RAis methyl.

177. The compound of any one of claims 149 or 172-176, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis C1-6alkyl, C2-6 alkenyl, C1-6alkylene- carbocyclyl, or C1-6alkylene-heteroaryl.

178. The compound of claim 177, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis C1-6alkyl, C1-6alkylene-aryl or -C1-6alkylene-5-6 membered heteroaryl.

179. The compound of claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

180. The compound of claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

181. The compound of claim 172 or 173, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

182. The compound of any one of claims 177-181, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis methyl.

183. The compound of any one of claims 177-181, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis ethyl.

184. The compound of any one of claims 177-181, wherein RBis H.

185. The compound of claim 180, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

186. The compound of claim 181, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

187. The compound of claim 182, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

188. The compound of any one of claims 185-187, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis methyl.

189. The compound of any one of claims 185-187, or a pharmaceutically acceptable salt or deuterated form thereof, wherein RBis ethyl.

190. The compound of any one of claims 172-178, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X3 is O.

191. The compound of any one of claims 1-145, or a pharmaceutically acceptable salt or deuterated form thereof, wherein.

192. The compound of any one of claims 127-191, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is C1-3 alkyl.

193. The compound of claim 192, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R6is CH3.

194. The compound of any one of claims 127-193, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R7is H.

195. The compound of any one of claims 127-194, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R10is -H or -F.

196. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the compound is selected from Table 1.

197. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-196, or a pharmaceutically acceptable salt or deuterated form thereof and a pharmaceutically acceptable adjuvant, diluent or carrier.

198. A method for treating an obstructive disease of the airway in a patient in need thereof, comprising, administering to the patient an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

199. The method of claim 198, wherein the obstructive disease of the airway is asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer’s lung and related diseases, hypersensitivity pneumonitis, lung fibrosis, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, iatrogenic cough, acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever), nasal polyposis; acute viral infection including the common cold, and infection due to a respiratory virus, acute lung injury, or acute respiratory distress syndrome (ARDS).

200. The method of claim 199, wherein the obstructive disease of the airway is asthma.

201. The method of claim 199, wherein the obstructive disease of the airway is acute respiratory distress syndrome (ARDS).

202. The method of claim 199, wherein the obstructive disease of the airway is bronchitis.

203. The method of claim 199, wherein the obstructive disease of the airway is lung fibrosis.

204. The method of claim 199, wherein the obstructive disease of the airway is emphysema.

205. The method of claim 199, wherein the obstructive disease of the airway is cystic fibrosis (CF).

206. The method of claim 199, wherein the obstructive disease of the airway is bronchiectasis.

207. The method of claim 199, wherein the obstructive disease of the airway is sarcoidosis.

208. The method of claim 199, wherein the obstructive disease of the airway is alpha-1 antitrypsin (A1AT) deficiency.

209. The method of claim 199, wherein the obstructive disease of the airway is farmer’s lung.

210. The method of claim 199, wherein the obstructive disease of the airway is hypersensitivity pneumonitis.

211. The method of claim 199, wherein the obstructive disease of the airway is a complication of lung transplantation.

212. The method of claim 199, wherein the obstructive disease of the airway is a vasculitic or thrombotic disorder of the lung vasulature.

213. The method of claim 199, wherein the obstructive disease of the airway is pulmonary hypertension.

214. The method of claim 199, wherein the obstructive disease of the airway is iatrogenic cough.

215. The method of claim 199, wherein the obstructive disease of the airway is acute rhinitis.

216. The method of claim 199, wherein the obstructive disease of the airway is chronic rhinitis.

217. The method of claim 199, wherein the obstructive disease of the airway is rhinitis medicamentosa or vasomotor rhinitis.

218. The method of claim 199, wherein the obstructive disease of the airway is nasal polyposis.

219. The method of claim 199, wherein the obstructive disease of the airway is COPD.

220. The method of claim 200, wherein the asthma is bronchial, allergic, intrinsic, extrinsic, exercise-induced or drug-induced asthma.

221. The method of claim 200, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

222. The method of claim 203, wherein the lung fibrosis is idiopathic pulmonary fibrosis, cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, or fibrosis complicating anti-neoplastic therapy or chronic infection.

223. The method of claim 206, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

224. The method of claim 206, wherein the bronchiectasis is associated with cystic fi25.

225. The method of claim 213, wherein the pulmonary hypertension is pulmonary arterial hypertension.

226. The method of claim 213, wherein the pulmonary hypertension is pulmonary hypertension due to left heart disease.

227. The method of claim 213, wherein the pulmonary hypertension is pulmonary hypertension associated with chronic lung disease.

228. A method for treating cystic fibrosis in a patient in need thereof, comprising, administering to the patient an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

229. The method of claim 228, wherein the treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

230. The method of claim 229, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEV1), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), or increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF(25-75%)), as compared to the respective value for the patient prior treatment.

231. The method of claim 229 or 230, wherein the lung function is measured by spirometry.

232. A method for treating bronchiectasis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

233. The method of claim 232, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

234. The method of claim 232, wherein the bronchiectasis is associated with cystic fibrosis.

235. The method of any one of claims 232-234, wherein treating comprises improving the lung function of the patient, as compared to the lung function of the patient prior to treatment.

236. The method of claim 235, wherein improving lung function of the patient comprises increasing the patient’s forced expiratory volume in 1 second (FEV1), increasing the patient’s forced vital capacity (FVC), increasing the patient’s peak expiratory flow rate (PEFR), or increasing the patient’s forced expiratory flow between 25% and 75% of FVC (FEF(25-75%)), as compared to the respective value for the patient prior to treatment.

237. The method of claim 235-236, wherein the lung function is measured by spirometry.

238. The method of any one of claims 232-234, wherein treating comprises decreasing the rate of pulmonary exacerbation, as compared to the rate of pulmonary exacerbation of the patient prior to treatment.

239. The method of any one of claims 232-238, wherein treating comprises increasing the time to first pulmonary exacerbation, as compared to an untreated patient.

240. The method of claim 238 or 239, wherein the pulmonary exacerbation is characterized by three or more of the following symptoms exhibited for at least 48 hours by the patient: (1) increased cough; (2) increased sputum volume or change in sputum consistency; (3) increased sputum purulence; (4) increased breathlessness and / or decreased exercise tolerance; (5) fatigue and / or malaise; (6) hemoptysis.

241. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

242. The method of claim 241, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

243. The method of claim 241, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

244. The method of any one of claims 241-242, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

245. The method of any one of claims 241-244, wherein treating comprises reducing, diminishing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

246. The method of claim 245, wherein the one or more symptoms of CRS is nasal congestion; nasal obstruction; nasal discharge; post-nasal drip; facial pressure; facial pain; facial fullness; reduced smell; depression; mucosal edema; mucopurulent discharge; obstruction of the middle meatus; mucosal changes within the ostiomeatal complex and sinuses; or rhinorrhea.

247. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

248. The method of claim 247, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

249. The method of claim 247, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

250. The method of claim 247, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

251. A method for treating cancer in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

252. The method of claim 251, wherein the cancer is a metastatic cancer.

253. The method of claim 252, wherein the metastatic cancer is breast to lung metastatic cancer.

254. The method of claim 252, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

255. The method of claim 252, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

256. The method of claim 252, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, the pancreas, the stomach, the lung, the liver, the kidney, or the spleen.

257. The method of claim 252, wherein the metastatic cancer comprises metastasis of stomach cancer to the mesentery, the spleen, the pancreas, the lung, the liver, the adrenal gland, or the ovary.

258. The method of claim 252, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or the kidney.

259. The method of claim 252, wherein the metastatic cancer comprises metastasis of lymphoma to the kidney, ovary, liver, bladder, or the spleen.

260. A method for treating lupus nephritis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

261. A method for treating rheumatoid arthritis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

262. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

263. The method of claim 262, wherein the inflammatory bowel disease (IBD) is Crohn’s disease.

264. The method of claim 262, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

265. A method for treating an anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

266. The method of claim 265, wherein the ANCA associated disease is granulomatosis with polyangiitis (GPA).

267. The method of claim 265, wherein the ANCA associated disease is microscopic polyangiitis (MPA).

268. A method for treating a disease in a patient in need thereof comprising, administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197, wherein the disease is giant cell arteritis, polyarteritis nodosa, anti- GBM disease (Goodpasture’s), systemic scleroderma, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic ulcers, Duchenne muscular dystrophy, bronchiolitis obliterans, atopic dermatitis, pyoderma gangrenosum, sweet’s syndrome, dermatomyositis / polymyositis, neutrophilic dermatoses, thrombosis, bronchopulmonary dysplasia, amyotrophic lateral sclerosis, sickle cell anemia, psoriasis, or a ventilator-induced lung injury.

269. A method for treating a heart failure in a patient in need thereof, comprising administering to the patient, an effective amount of a compound of any one of claims 1-196, or the composition of claim 197.

270. The method of claim 269, wherein the heart failure is heart failure with reduced ejection fraction.

271. The method of claim 269, wherein the heart failure is heart failure with preserved ejection fraction.

272. A compound selected from Table 1, or a pharmaceutically acceptable salt or deuterated form thereof.