HETEROARYL PLASMA KALLIKREIN INHIBITORS

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.

Claims

1. A compound of Formula (I): ##STR00121## or a pharmaceutically acceptable salt thereof, wherein: Het.sup.A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het.sup.A is substituted with 0-4 R.sup.A groups; each R.sup.A is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O).sub.2R, —C(O)N(R).sub.2, —NO.sub.2, —N(R)—N(R).sub.2, —N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —OR, —OC(O)R, —OC(O)N(R).sub.2, —SR, —S(O)R, —S(O).sub.2R, —S(O)N(R).sub.2, —S(O).sub.2N(R).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; L is an optionally substituted C.sub.1-6 hydrocarbon chain, wherein 1-3 methylene units are independently replaced with -Cy-, —C(R).sub.2— —O—, —NR—, —C(O)—, —S(O).sub.2—, —C(O)NR—, —NRC(O)—, —S(O).sub.2NR—, and —NRS(O).sub.2—; -Cy- is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; R′ and R″ are independently selected from hydrogen, halogen, —OR, —NR.sub.2, —SR, and optionally substituted C.sub.1-6 aliphatic; wherein R′ may be taken together with a monocyclic Het.sup.A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O).sub.2R, —C(O)N(R).sub.2, —NO.sub.2, —N(R)—N(R).sub.2, —N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —OR, —OC(O)R, —OC(O)N(R).sub.2, —SR, —S(O)R, —S(O).sub.2R, —S(O)N(R).sub.2, —S(O).sub.2N(R).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; n is 0 or 1.

2. The compound according to claim 1, wherein when L is —(CR.sub.2).sub.mNRC(O)— and m is 0 to 2 (e.g., 0 or 2), one of the following (a), (b), or (c) applies: (a) n is 0; (b) at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is CN; or (c) R.sup.1 is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

3. The compound according to claim 1, wherein L is selected from the group consisting of —C(R).sub.2NRC(O)-#, —C(R).sub.2C(O)NRC(R).sub.2-#, —C(R).sub.2NRC(O)C(R).sub.2-#, —C(R).sub.2NRC(R).sub.2-#, —C(R).sub.2C(R).sub.2NRC(R).sub.2-#, —C(O)NRC(R).sub.2-#, —C(R).sub.2C(O)NR-#, —NRC(O)C(R).sub.2-#, —CR.sub.2C(O)NRC(R).sub.2-#, —SO.sub.2NRC(R).sub.2-#, and —C(R).sub.2NRSO.sub.2-#, wherein # represents the point of attachment to Het.sup.A.

4. The compound according to claim 1, wherein when L is —C(R).sub.2NRC(O)-# or —C(R).sub.2C(O)NR-#, one of the following (a), (b), or (c) applies: (a) n is 0; (b) at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is CN; or (c) R.sup.1 is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

5. The compound according to claim 1, wherein the compound has a structure of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), ##STR00122## or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound has a structure of Formula (II): ##STR00123## or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound has a structure of Formula (II-a) or Formula (II-b): ##STR00124## or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R′ is taken together with a monocyclic Het.sup.A to form an optionally substituted fused ring and the compound has a structure of Formula (III): ##STR00125## wherein R.sup.fus is fused with Het.sup.A to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound has a structure of Formula (III-a) or Formula (III-b): ##STR00126## or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, wherein Het.sup.A is a 5-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het.sup.A is substituted with 0-2 R.sup.A groups.

11. The compound according to claim 1, wherein Het.sup.A is selected from: ##STR00127## wherein * represents to point of attachment to L.

12. The compound according to claim 1, wherein a single instance of R.sup.A is C.sub.1-6 aliphatic substituted with halogen.

13. The compound of claim 1, wherein the compound is any one of compounds I-1 through I-20, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

15. A method of treating a plasma kallikrein-mediated disease or disorder using a compound of claim 1.

16. The method of claim 15, wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

17. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound of claim 1.

Description

V. EXEMPLARY EMBODIMENTS

[0154] The present disclosure contemplates, among other things, the following numbered embodiments: [0155] 1. A compound of Formula (I):

##STR00015##

or a pharmaceutically acceptable salt thereof,
wherein: [0156] Het.sup.A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het.sup.A is substituted with 0-4 R.sup.A groups; [0157] each R.sup.A is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O).sub.2R, —C(O)N(R).sub.2, —NO.sub.2, —N(R)—N(R).sub.2, —N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —OR, —OC(O)R, —OC(O)N(R).sub.2, —SR, —S(O)R, —S(O).sub.2R, —S(O)N(R).sub.2, —S(O).sub.2N(R).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; [0158] L is an optionally substituted C.sub.1-6 hydrocarbon chain, wherein 1-3 methylene units are independently replaced with -Cy-, —C(R).sub.2— —O—, —NR—, —C(O)—, —S(O).sub.2—, —C(O)NR—, —NRC(O)—, —S(O).sub.2NR—, and —NRS(O).sub.2—; [0159] Cy- is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; [0160] R′ and R″ are independently selected from hydrogen, halogen, —OR, —NR.sub.2, —SR, and optionally substituted C.sub.1-6 aliphatic; wherein R′ may be taken together with a monocyclic Het.sup.A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; [0161] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O).sub.2R, —C(O)N(R).sub.2, —NO.sub.2, —N(R)—N(R).sub.2, —N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —OR, —OC(O)R, —OC(O)N(R).sub.2, —SR, —S(O)R, —S(O).sub.2R, —S(O)N(R).sub.2, —S(O).sub.2N(R).sub.2, or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; and [0162] each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; [0163] or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; [0164] n is 0 or 1. [0165] 2. The compound according to embodiment 1, wherein when L is —(CR.sub.2).sub.mNRC(O)— and m [0166] is 0 to 2 (e.g., 0 or 2), one of the following (a), (b), or (c) applies: [0167] (a) n is 0; [0168] (b) at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is CN; or [0169] (c) R′ is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid. [0170] 3. The compound according to any one of the preceding embodiments, wherein L is selected from the group consisting of —C(R).sub.2NRC(O)-#, —C(R).sub.2C(O)NRC(R).sub.2-#, —C(R).sub.2NRC(O)C(R).sub.2-#, —C(R).sub.2NRC(R).sub.2-#, —C(R).sub.2C(R).sub.2NRC(R).sub.2-#, —C(O)NRC(R).sub.2-#, —C(R).sub.2C(O)NR-#, —NRC(O)C(R).sub.2-#, —CR.sub.2C(O)NRC(R).sub.2-#, —SO.sub.2NRC(R).sub.2-#, and —C(R).sub.2NRSO.sub.2-#, wherein # represents the point of attachment to Het.sup.A. [0171] 4. The compound according to any one of the preceding embodiments, wherein L is selected from the group consisting of —C(R).sub.2NRC(O)-#, —C(R).sub.2C(O)NRC(R).sub.2-#, —C(R).sub.2NRC(R).sub.2-#, —C(R).sub.2C(R).sub.2NRC(R).sub.2-#, —C(O)NRC(R).sub.2-#, —C(R).sub.2C(O)NR-#, —CR.sub.2C(O)NRC(R).sub.2-#, —SO.sub.2NRC(R).sub.2-#, and —C(R).sub.2NRSO.sub.2-#, wherein # represents the point of attachment to Het.sup.A. [0172] 5. The compound according to any one of the preceding embodiments, wherein L is selected from the group consisting of —C(R).sub.2C(O)NRC(R).sub.2-#, —C(R).sub.2NRC(R).sub.2-#, —C(R).sub.2C(R).sub.2NRC(R).sub.2-#, —C(O)NRC(R).sub.2-#, —C(R).sub.2C(O)NRC(R).sub.2-#, —SO.sub.2NRC(R).sub.2-#, and —C(R).sub.2NRSO.sub.2-#, wherein # represents the point of attachment to Het.sup.A. [0173] 6. The compound according to any one of the preceding embodiments, wherein L is other than —C(R).sub.2NRC(O)-# or —C(R).sub.2C(O)NR-#. [0174] 7. The compound according to any one of the preceding embodiments, wherein L is other than —CH.sub.2NRC(O)-# or —CH.sub.2C(O)NR-#. [0175] 8. The compound according to any one of the preceding embodiments, wherein when L is —C(R).sub.2NRC(O)-# or —C(R).sub.2C(O)NR-#, one of the following (a), (b), or (c) applies: [0176] (a) n is 0; [0177] (b) at least one of R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is CN; or [0178] (c) R.sup.1 is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid. [0179] 9. The compound according to any one of the preceding embodiments, wherein when L is —C(R).sub.2NRC(O)-# or —C(R).sub.2C(O)NR-#, n is 0. [0180] 10. The compound according to any one of the preceding embodiments, wherein when L is —C(R).sub.2NRC(O)-# or —C(R).sub.2C(O)NR-#, R′ is taken together with a monocyclic Het.sup.A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0181] 11. The compound according to any one of the preceding embodiments, wherein when L is —CH.sub.2NRC(O)-# or —CH.sub.2C(O)NR-#, R′ is taken together with a monocyclic Het.sup.A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0182] 12. The compound according to any one of the preceding embodiments, wherein when L is —(CR.sub.2).sub.mNRC(O)— and m is 0, 1, or 2, then n is 0. [0183] 13. The compound according to any one of the preceding embodiments, wherein when L is —(CR.sub.2).sub.mNRC(O)— and m is 0 to 2 (e.g., 0 or 2), R′ is taken together with a monocyclic Het.sup.A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0184] 14. The compound according to any one of the preceding embodiments, wherein L is —C(R).sub.2C(O)NRC(R).sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0185] 15. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2C(O)NHCH(CF.sub.3)-#. [0186] 16. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2C(O)NHCH(CH.sub.3)-# [0187] 17. The compound according to any one of the preceding embodiments, wherein L is —C(R).sub.2NRC(R).sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0188] 18. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2NHCH(CF.sub.3)-#. [0189] 19. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2NHCH.sub.2-#. [0190] 20. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2NHCH(CH.sub.3)-#. [0191] 21. The compound according to any one of the preceding embodiments, wherein L is —CH(CF.sub.3)NHCH.sub.2-#. [0192] 22. The compound according to any one of the preceding embodiments, wherein L is —C(R).sub.2NRSO.sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0193] 23. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2NHSO.sub.2-#. [0194] 24. The compound according to any one of the preceding embodiments, wherein L is —SO.sub.2NRC(R).sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0195] 25. The compound according to any one of the preceding embodiments, wherein L is —SO.sub.2NHCH.sub.2-#. [0196] 26. The compound according to any one of the preceding embodiments, wherein L is —SO.sub.2NHCH(CH.sub.3)-#. [0197] 27. The compound according to any one of the preceding embodiments, wherein L is —C(O)NRC(R).sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0198] 28. The compound according to any one of the preceding embodiments, wherein L is —C(O)NHCH.sub.2-#. [0199] 29. The compound according to any one of the preceding embodiments, wherein L is —C(R).sub.2C(O)NRC(R).sub.2-#, wherein each R is independently hydrogen or C.sub.1-3 aliphatic optionally substituted with halogen. [0200] 30. The compound according to any one of the preceding embodiments, wherein L is —CH.sub.2C(O)NHCH.sub.2-#. [0201] 31. The compound according to any one of the preceding embodiments, wherein the compound has a structure of Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d),

##STR00016##

or a pharmaceutically acceptable salt thereof. [0202] 32. The compound according to any one of the preceding embodiments, wherein the compound has a structure of Formula (II):

##STR00017##

or a pharmaceutically acceptable salt thereof. [0203] 33. The compound according to any one of the preceding embodiments, wherein the compound has a structure of Formula (II-a) or Formula (II-b):

##STR00018##

or a pharmaceutically acceptable salt thereof. [0204] 34. The compound according to any one of the preceding embodiments, wherein R′ is taken together with a monocyclic Het.sup.A to form an optionally substituted fused ring and the compound has a structure of Formula (III):

##STR00019##

wherein R.sup.fus is fused with Het.sup.A to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or a pharmaceutically acceptable salt thereof [0205] 35. The compound according to any one of the preceding embodiments, wherein the compound has a structure of Formula (III-a) or Formula (III-b):

##STR00020##

or a pharmaceutically acceptable salt thereof. [0206] 36. The compound according to any one of the preceding embodiments, wherein Het.sup.A is a 5-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het.sup.A is substituted with 0-2 R.sup.A groups. [0207] 37. The compound according to any one of the preceding embodiments, wherein Het.sup.A is a 5-membered monocyclic heteroarylene having 2-3 heteroatoms selected from nitrogen, wherein Het.sup.A is substituted with 0-2 R.sup.A groups. [0208] 38. The compound according to any one of the preceding embodiments, wherein Het.sup.A is pyrazolediyl substituted with 0-2 R.sup.A groups. [0209] 39. The compound according to any one of the preceding embodiments, wherein Het.sup.A is triazolediyl substituted with 0-1 R.sup.A groups. [0210] 40. The compound according to any one of the preceding embodiments, wherein Het.sup.A is an unsubstituted pyrazolediyl. [0211] 41. The compound according to any one of the preceding embodiments, wherein Het.sup.A is an unsubstituted 1,2,3-triazolediyl. [0212] 42. The compound according to any one of the preceding embodiments, wherein Het.sup.A is selected from:

##STR00021##

wherein * represents to point of attachment to L. [0213] 43. The compound according to any one of the preceding embodiments, wherein a single instance of R.sup.A is C.sub.1-6 aliphatic substituted with halogen. [0214] 44. The compound according to any one of the preceding embodiments, wherein R′ and R″ are each hydrogen. [0215] 45. The compound according to any one of the preceding embodiments, wherein R″ is hydrogen and R′ is taken together with a monocyclic Het.sup.A to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0216] 46. The compound according to any one of the preceding embodiments, wherein n is 1, R″ is hydrogen and R′ is taken together with a monocyclic Het.sup.A to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0217] 47. The compound according to any one of the preceding embodiments, wherein n is 1, R″ is hydrogen and R′ is taken together with a monocyclic Het.sup.A to form a fused 8-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0218] 48. The compound according to any one of the preceding embodiments, wherein when n is 0, Het.sup.A is a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. [0219] 49. The compound according to any one of the preceding embodiments, wherein n is 0. [0220] 50. The compound according to any one of the preceding embodiments, wherein n is 1. [0221] 51. The compound according to any one of the preceding embodiments, wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, and R.sup.9 are hydrogen. [0222] 52. The compound according to any one of the preceding embodiments, wherein each of R′, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, and R.sup.9 are hydrogen. [0223] 53. The compound according to any one of the preceding embodiments, wherein each of R′, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, and R.sup.9 are hydrogen. [0224] 54. The compound according to any one of the preceding embodiments, wherein R.sup.1 is an optionally substituted group selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. [0225] 55. The compound according to any one of the preceding embodiments, wherein R.sup.1 is an optionally substituted 5-membered heteroaryl having 2-4 heteroatoms selected from oxygen or nitrogen. [0226] 56. The compound according to any one of the preceding embodiments, wherein R.sup.1 is an optionally substituted piperizinyl or an optionally substituted triazolyl. [0227] 57. The compound according to any one of the preceding embodiments, wherein R.sup.1 is optionally substituted C.sub.1-6 aliphatic. [0228] 58. The compound according to any one of the preceding embodiments, wherein substituents on an optionally substituted R.sup.1 group are independently halogen, —(CH.sub.2).sub.0-4R.sup.o, —(CH.sub.2).sub.0-4OR.sup.o; and —(CH.sub.2).sub.0-4C(O)OR.sup.o, wherein each R.sup.o is independently hydrogen, C.sub.1-6 aliphatic, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0229] 59. The compound according to any one of the preceding embodiments, wherein R.sup.5 and R.sup.6 are each independently halogen. [0230] 60. The compound according to any one of the preceding embodiments, wherein R.sup.5 is F and R.sup.6 is Cl. [0231] 61. The compound according to any one of the preceding embodiments, wherein R.sup.6 is Cl or CN. [0232] 62. The compound of any one of the preceding embodiments, wherein the compound is any one of compounds I-1 through 1-20, or a pharmaceutically acceptable salt thereof. [0233] 63. A pharmaceutical composition comprising a compound of any one of the preceding embodiments. [0234] 64. The pharmaceutical composition comprising a compound of any one of the preceding embodiments, further comprising a pharmaceutically acceptable excipient. [0235] 65. The pharmaceutical composition of any one of embodiments 63-64, wherein the composition is suitable for oral administration. [0236] 66. The pharmaceutical composition of any one of embodiments 63-64, wherein the composition is suitable for administration by injection. [0237] 67. A method of treating a plasma kallikrein-mediated disease or disorder using a compound or composition of any one of the preceding embodiments. [0238] 68. The method of embodiment 67, wherein the disease or disorder is hereditary angioedema or diabetic macular edema. [0239] 69. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound or composition of any one of the preceding embodiments.

EXEMPLIFICATION

Synthesis of Intermediates

Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic Acid

[0240] ##STR00022##

[0241] Synthesis of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. To a stirred suspension of (S)-2-methylpropane-2-sulfinamide (5.00 g, 41.3 mmol) and cesium carbonate (20.2 g, 61.9 mmol) in dichloromethane (100 mL) was added a solution of 4-chloropicolinaldehyde (5.84 g, 41.3 mmol) in dichloromethane (20 mL) dropwise over a period of 10 min at room temperature. The solution was stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (100 mL×3). The combined organic layers were dried (MgSO.sub.4) and concentrated to give the product (N-((4-chloropyridin-2-yl) methylene)-2-methylpropane-2-sulfinamide, 10.1 g, quant.) as a brown oil. LCMS RT=1.738 min [M+H].sup.+ 246.9, 95% purity.

[0242] Synthesis of 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate. To a stirred solution of lithium diisopropylamide (2M in tetrahydrofuran, 43 mL, 86 mmol) in anhydrous tetrahydrofuran (100 mL), was added dropwise a solution of butyl acetate (9.40 g, 81 mmol) in tetrahydrofuran (20 mL) at −78° C. under nitrogen atmosphere. After stirring for 30 min, a solution of N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (10.0 g, 41 mmol) in tetrahydrofuran (30 mL) was added at this temperature. After stirring for an additional 2 h at −78° C., the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried (Na.sub.2SO.sub.4), concentrated and purified by flash chromatography (eluent 50% petroleum ether/ethyl acetate) to give the product (butyl 3-((tert-butylsulfinyl)amino)-3-(4-chloropyridin-2-yl)propanoate, 9.0 g, 61%) as a white solid. LCMS RT=1.338 min [M+H].sup.+ 361, 95% purity.

[0243] Synthesis of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate. To a solution of butyl 3-(4-chloropyridin-2-yl)-3-(1,1-dimethylethylsulfinamido)propanoate (3.5 g, 9.7 mmol) in 1,4-dioxane (30 mL) was added a solution of hydrochloric acid (4 M in 1,4-dioxane, 10 mL, 40 mmol). The mixture was stirred at room temperature for 4 h then concentrated to give the crude oil (4.3 g) which was used into next step without purification. LCMS RT=1.187 min [M+H].sup.+ 257, 80% purity.

[0244] Synthesis of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate. A solution of butyl 3-amino-3-(4-chloropyridin-2-yl)propanoate (2.6 g, 10.2 mmol) in formic acid (10 mL) was stirred at reflux for 4 h. The reaction mixture was then concentrated to give the crude product as a dark oil (3.0 g) which was used in the next step without purification. LCMS RT=1.05 min [M+H].sup.+ 285, 83% purity

[0245] Synthesis of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate. A solution of butyl 3-(4-chloropyridin-2-yl)-3-formamidopropanoate (500 mg, 1.76 mmol) in phosphorus(V) oxychloride (5.0 mL) was stirred at 80° C. for 1 h. The mixture was evaporated, the residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (50 mL×3). The combined organic layers were concentrated and purified by flash chromatography (eluent 70% ethyl acetate/petroleum ether) to give the product (butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate, 290 mg, 62%). LCMS RT=1.18 min [M+H].sup.+ 267, 95% purity.

[0246] Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid. To a stirred solution of butyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate (310 mg, 1.16 mmol) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide (139 mg, 5.8 mmol) and the mixture was stirred at room temperature for 16 h. The pH was adjusted to 6 by adding aqueous 1M hydrochloric acid and extracted with dichloromethane/methanol (10/1, 50 mL×5). Combined organic layers were dried and concentrated to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid, 200 mg, 82%) which was used in the next step without purification. LCMS RT=0.901 min [M+H]′ 211, 95% purity

Synthesis of Methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate

[0247] ##STR00023##

[0248] Acetyl chloride (0.42 mL, 5.9 mmol) was added to a stirred solution of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (250 mg, 1.2 mmol) in methanol (5.0 mL) at 0° C. then warmed to room temperature and stirred for 18 h. The mixture was concentrated in vacuo. The residue was dissolved in a mixture of saturated aqueous sodium bicarbonate solution (25 mL) and water (25 mL) and extracted with methanol/dichloromethane (1:9, 3×50 mL). The combined organic layers were dried (MgSO.sub.4), filtered and evaporated in vacuo to yield the product (methyl 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetate, 310 mg, quant.) as a cream solid.

[0249] .sup.1H NMR (400 MHz, DMSO): δ, ppm 9.23 (1H, s), 8.52 (1H, dd, J=1.0, 7.5 Hz), 8.08-8.07 (1H, m), 7.03 (1H, dd, J=2.0, 7.5 Hz), 4.17 (2H, s), 3.67 (3H, s).

Synthesis of 2-(7-chloroimidazo[1,5-c]pyridin-1-yl)acetamide

[0250] ##STR00024##

[0251] A mixture of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (500 mg, 2.4 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (550 mg, 2.9 mmol), 1-hydroxybenzotriazole hydrate (380 mg, 2.9 mmol), N,N-diisopropylethylamine (2.5 mL, 14 mmol) and ammonium carbonate (1.1 g, 12 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylformamide (4.0 mL) was stirred at 60° C. for 18 h. The mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate solution (100 mL), dried (MgSO.sub.4), filtered and evaporated in vacuo. The residue was triturated with diethyl ether:dichloromethane (9:1) to give the product (2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetamide, 0.20 g, 40%) as a yellow solid.

[0252] .sup.1H NMR (400 MHz, DMSO): δ, ppm 8.36-8.33 (2H, m), 7.79-7.77 (1H, m), 7.45-7.38 (1H, m), 6.99-6.92 (1H, m), 6.68 (1H, dd, J=2.0, 7.3 Hz), 3.66 (2H, s).

Synthesis of Ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

[0253] Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO).sub.2 (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol) and K.sub.3PO.sub.4 (372 g, 1.755 mol) in toluene/H.sub.2O (1.2 L/0.12 L) was stirred at 90° C. for 14 h under N.sub.2. The reaction was concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA=1/2) to give the 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS [M+H].sup.+: 135.1.

[0254] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95° C. for 13 h. The reaction was concentrated to remove the EtOH. The pH of the residue was adjusted to 9 by addition of aqueous NaHCO.sub.3 and extracted with EtOAc (1 L×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (EA) to give the 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H].sup.+: 207.1.

[0255] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN.sub.3 (18.8 g, 290 mmol). The resulting reaction was stirred at RT for 2 h. The reaction was diluted with H.sub.2O (500 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA=2/1) to give the 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H].sup.+: 214.1.

[0256] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO.sub.4 (2.6 g, 16.35 mmol) and sodium ascorbate (3.3 g, 16.35 mmol) in H.sub.2O/t-BuOH (150 mL/150 mL) was stirred at RT for 3 h. Yellow solid was precipitated after 3 h and the mixture was filtered. The cake was dried to give the ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H].sup.+: 312.1.

Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde

[0257] Synthesis of 4-chloro-3-fluoropicolinaldehyde. To a solution of 2, 2, 6, 6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL THF was added n-Butyllithium (2.4 M in hexane, 100 mL, 240 mmol) dropwise at 0° C. The reaction mixture was cooled to −78° C. after stirring at 0° C. for 1 h and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at −78° C. for 2 h, a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at −78° C. for another 1 h. The reaction was quenched with H.sub.2O (50 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over with anhydrous magnesium sulphate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to afford 4-chloro-3-fluoropicolinaldehyde (26.0 g, yield: 71%). ESI-MS [M+H].sup.+: 160.1.

[0258] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixtutre, 163.0 mmol) in DCM (100 mL) was added cesium carbonate (96.0 g, 293.3 mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at RT. The reaction mixture was stirred for 3 h at RT. After the reaction was complete, the reaction mixture was filtrated and washed with DCM three times. To the combined mixture was added MeOH (40 mL), and then the resulting mixture was cooled to 0° C. by ice-water bath. Sodium borohydride (15.5 g, 409.0 mmol) was added slowly in portions. The reaction mixture was warmed up to RT and stirred at this temperature for 2 h. The reaction was quenched with H.sub.2O carefully. The resulting mixture was extracted with DCM (100 mL×3), the combined organic solvent was dried by sodium sulfate, filtered, and concentrated to get crude N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (43.3 g, crude) as yellow solid. ESI-MS [M+H].sup.+: 265.1.

[0259] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (about 162.4 mmol) in ethyl acetate (100 mL) was added a solution of hydrochloride acid in ethyl acetate (3 M, 200 mL). The resulting reaction mixture was stirred at RT for 3 h. After the reaction was completed, the reaction mixture was filtered to give the crude product, which was washed with ethyl acetate and dried in vacuum to afford (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, 78%, mixture) as a pink solid. .sup.1H NMR (400 MHz, DMSO) δ 8.75 (br, 3H), 8.47 (d, J=5.2 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 4.28-4.26 (m, 2H).

[0260] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at RT. The resulting reaction mixture was stirred at 70° C. overnight. After the reaction was complete, the reaction mixture was filtered, the solid was washed with DCM three times. The combined organic solvent was washed with brine, dried by sodium sulfate, filtrated, and concentrated to afford N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude), which was used in the next step directly without purification. ESI-MS [M+H].sup.+: 189.1.

[0261] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, about 126.89 mmol) in dry acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 eq), and the resulting reaction mixture was stirred at reflux for 3 h. After the reaction was completed, the reaction mixture was cooled down to RT, and then poured into H.sub.2O (200 mL) carefully. The pH was adjusted to 8 with saturated sodium bicarbonate, and then the resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with brine, dried over sodium sulphate, filtrated, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to afford 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H].sup.+: 171.1.

[0262] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde. A solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (9.0 g, 52.6 mmol) in dry DMF (12 mL) was cooled with an ice-water bath to 0-5° C. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 eq) was added dropwise, and then the reaction mixture was stirred at 100° C. for 2 h. After the reaction was completed, the reaction mixture was cooled down to RT and poured into saturated sodium bicarbonate aqueous (200 mL) carefully. The resulting mixture was stirred at RT for 2 h and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by recrystallization (petroleum ether/ethyl acetate=1/1) to afford 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, yield: 47%) as a brown solid. ESI-MS [M+H].sup.+: 181.1.

Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic Acid

[0263] Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc).sub.2 (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol) and K.sub.3PO.sub.4 (18.5 g, 87.3 mmol) in toluene/H.sub.2O (100 mL/10 mL) was stirred at 95° C. for 12 h under nitrogen. Then the reaction mixture was quenched with H.sub.2O (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude residue which was purified by silica gel chromatography (PE/EtOAc=1/1) to give the 5-cyclopropylpyridin-2-amine as yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H].sup.+: 135.2.

[0264] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at RT. The resulting reaction was stirred at 85° C. for 2 h. The solution was quenched with H.sub.2O (60 mL), adjusted to pH 8 by adding saturated NaHCO.sub.3 solution, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified with prep-TLC (PE/EtOAc=1/1) to give the 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield:39%) as a light yellow oil. ESI-MS [M+H].sup.+: 207.2.

[0265] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and Cs.sub.2CO.sub.3 (6.32 g, 19.38 mmol) at RT. The resulting reaction was stirred at RT for 12 h. H.sub.2O (150 mL) was added to the reaction and then the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH=20/1) to give the ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H].sup.+: 311.2.

[0266] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl) methyl)-1H-pyrazole-4-carboxylate (1.2 g, 3.87 mmol) in THF (20 mL) and H.sub.2O (10 mL) was added LiOH (464 mg, 19.35 mmol). The mixture was stirred at RT for 16 h. Most of the THF was removed and the pH was adjusted to 4-5 by adding HCl (1 M). The resulting precipitate was collected and dried to give the 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.0 g, yield: 91%). ESI-MS [M+H].sup.+: 283.2.

Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile

[0267] Synthesis of tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate. To a solution of (7-bromoimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride salt (2 g, 7.66 mmol) in DCM (30 mL) was added triethylamine (4.3 mL, 30.6 mmol) and di-tert-butyl dicarbonate (3.5 mL, 15.3 mmol). The mixture was stirred at RT for 2 h. TLC showed that the reaction was completed. The mixture was concentrated, dissolved in ethyl acetate, washed with saturated ammonium chloride. The organic layer was concentrated, purified by column chromatography (DCM/MeOH=10/1) to give tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (2 g, yield: 80%) as a yellow oil. ESI-MS [M+H].sup.+: 326.1.

[0268] Synthesis of tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate. To a solution of tert-butyl ((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (200 mg, 0.615 mmol) in DMF (3 mL) was added 1,1′-bis(diphenylphosphino)ferrocene (64 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium (Pd.sub.2(dba).sub.3, 55 mg, 0.06 mmol) and zinc cyanide (144 mg, 1.23 mmol). The mixture was stirred at 150° C. in microwave reactor for 1 h and concentrated. The residue was purified by column chromatography (DCM/MeOH=10/1) to give tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (117 mg, yield: 70%) as a yellow oil. ESI-MS [M+H].sup.+: 273.1.

[0269] Synthesis of 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile. A mixture of tert-butyl ((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)carbamate (270 mg, 0.99 mmol) and hydrochloride in ethyl acetate (3 M, 20 mL) was stirred at RT for 2 h and then filtered to give the crude product which was washed with ethyl acetate and dried in vacuum to afford 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (201.3 mg, quant.) as a yellow solid. ESI-MS [M−NH.sub.2].sup.+: 156.0. Purity: 96.3%.

Synthesis of Ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

[0270] Synthesis of 5-cyclopropylpyridin-2-amine. A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO).sub.2 (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol) and K.sub.3PO.sub.4 (372 g, 1.755 mol) in toluene/H.sub.2O (1.2 L/0.12 L) was stirred at 90° C. for 14 h under N.sub.2. The reaction was concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA=1/2) to give the 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS [M+H].sup.+: 135.1.

[0271] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95° C. for 13 h. The reaction was concentrated to remove the EtOH. The pH of the residue was adjusted to 9 by addition of aqueous NaHCO.sub.3 and extracted with EtOAc (1 L×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (EA) to give the 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H].sup.+: 207.1.

[0272] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN.sub.3 (18.8 g, 290 mmol). The resulting reaction was stirred at RT for 2 h. The reaction was diluted with H.sub.2O (500 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EA=2/1) to give the 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H].sup.+: 214.1.

[0273] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO.sub.4 (2.6 g, 16.35 mmol) and sodium ascorbate (3.3 g, 16.35 mmol) in H.sub.2O/t-BuOH (150 mL/150 mL) was stirred at RT for 3 h. Yellow solid was precipitated after 3 h and the mixture was filtered. The cake was dried to give the ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, yield: 57%) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H].sup.+: 312.1.

[0274] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride

[0275] Synthesis of 4-chloro-3-fluoropicolinaldehyde. To a solution of 2, 2, 6, 6-tetramethylpiperidine (35.4 g, 250.88 mmol) in 200 mL THF was added n-Butyllithium (2.4 M in hexane, 100 mL, 240 mmol) dropwise at 0° C. The reaction mixture was cooled to −78° C. after stirring at 0° C. for 1 h and a solution of 4-chloro-3-fluoropyridine (30.0 g, 228.08 mmol) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at −78° C. for 2 h, a solution of DMF (17.5 g, 239.48 mmol) in THF (50 mL) was added dropwise, and the resulting reaction mixture was stirred at −78° C. for another 1 h. The reaction was quenched with H.sub.2O (50 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over with anhydrous magnesium sulphate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to afford 4-chloro-3-fluoropicolinaldehyde (26.0 g, yield: 71%). ESI-MS [M+H].sup.+: 160.1.

[0276] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of 4-chloro-3-fluoropicolinaldehyde (26.0 g, mixture, 163.0 mmol) in DCM (100 mL) was added cesium carbonate (96.0 g, 293.3 mmol) and 2-methylpropane-2-sulfinamide (19.8 g, 163.0 mmol) at RT. The reaction mixture was stirred for 3 h at RT. After the reaction was complete, the reaction mixture was filtrated and washed with DCM three times. To the combined mixture was added MeOH (40 mL), and then the resulting mixture was cooled to 0° C. by ice-water bath. Sodium borohydride (15.5 g, 409.0 mmol) was added slowly in portions. The reaction mixture was warmed up to RT and stirred at this temperature for 2 h. The reaction was quenched with H.sub.2O carefully. The resulting mixture was extracted with DCM (100 mL×3), the combined organic solvent was dried by sodium sulfate, filtered, and concentrated to get crude N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (43.3 g, crude) as yellow solid. ESI-MS [M+H].sup.+: 265.1.

[0277] Synthesis of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (about 162.4 mmol) in ethyl acetate (100 mL) was added a solution of hydrochloride acid in ethyl acetate (3 M, 200 mL). The resulting reaction mixture was stirred at RT for 3 h. After the reaction was completed, the reaction mixture was filtered to give the crude product, which was washed with ethyl acetate and dried in vacuum to afford (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, 78%, mixture) as a pink solid. .sup.1H NMR (400 MHz, DMSO) δ 8.75 (br, 3H), 8.47 (d, J=5.2 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 4.28-4.26 (m, 2H).

[0278] Synthesis of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide. To a solution of (4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (25.0 g, mixture, 127.0 mmol) in THF (200 mL) was added triethylamine (38.5 g, 380.6 mmol) and ethyl formate (100 mL) at RT. The resulting reaction mixture was stirred at 70° C. overnight. After the reaction was complete, the reaction mixture was filtered, the solid was washed with DCM three times. The combined organic solvent was washed with brine, dried by sodium sulfate, filtrated, and concentrated to afford N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude), which was used in the next step directly without purification. ESI-MS [M+H].sup.+: 189.1.

[0279] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine. To a solution of N-((4-chloro-3-fluoropyridin-2-yl)methyl)formamide (crude, about 126.89 mmol) in dry acetonitrile (200 mL) was added phosphoryl trichloride (18 mL, 1.5 eq), and the resulting reaction mixture was stirred at reflux for 3 h. After the reaction was completed, the reaction mixture was cooled down to RT, and then poured into H.sub.2O (200 mL) carefully. The pH was adjusted to 8 with saturated sodium bicarbonate, and then the resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with brine, dried over sodium sulphate, filtrated, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate) to afford 7-chloroimidazo[1,5-a]pyridine (12.0 g, yield: 56%) as a white solid. ESI-MS [M+H].sup.+: 171.1.

[0280] Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde. A solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (9.0 g, 52.6 mmol) in dry DMF (12 mL) was cooled with an ice-water bath to 0-5° C. Phosphorus oxychloride (7.4 g, 78.9 mmol, 1.5 eq) was added dropwise, and then the reaction mixture was stirred at 100° C. for 2 h. After the reaction was completed, the reaction mixture was cooled down to RT and poured into saturated sodium bicarbonate aqueous (200 mL) carefully. The resulting mixture was stirred at RT for 2 h and extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by recrystallization (petroleum ether/ethyl acetate=1/1) to afford 7-chloroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, yield: 47%) as a brown solid. ESI-MS [M+H].sup.+: 181.1.

[0281] Synthesis of (Z)—N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide. To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (5.2 g, 26.19 mmol) and 2-methylpropane-2-sulfinamide (3.2 g, 26.71 mmol) in THF (200 mL) was added tetraethoxytitanium (15.0 g, 65.50 mol). The reaction mixture was stirred at reflux overnight. After the reaction was completed, the reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate) to give (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 98%) as a white solid. ESI-MS [M+H].sup.+: 302.1.

[0282] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide. To a solution of (E)-N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methylene)-2-methylpropane-2-sulfinamide (7.77 g, 25.75 mmol) in MeOH (200 mL) was added sodium borohydride (2.44 g, 64.37 mmol) slowly. The resulting reaction mixture was stirred at RT for 3 h. After the reaction was completed, the reaction was quenched with H.sub.2O (50 mL). The resulting mixture was extracted with ethyl acetate (200 mL×3), the combined organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated in vacuum to afford N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 99%) as a white solid. ESI-MS [M+H].sup.+: 304.1.

[0283] Synthesis of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride. A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-2-methylpropane-2-sulfinamide (7.77 g, 25.5 mmol) and hydrochloride acid in ethyl acetate (3 M, 100 mL) was stirred at RT for 2 h, and then the reaction mixture was filtered to give the crude product, which was washed with ethyl acetate and dried in vacuum to afford (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride salt (6.03 g, quant.) as a white solid. ESI-MS [M−NH.sub.2].sup.+: 182.9. .sup.1H NMR (400 MHz, DMSO): δ 8.64 (d, J=2.0 Hz, 1H), 8.44 (br, 3H), 8.33 (d, J=7.2 Hz, 1H), 6.92 (t, J=6.8 Hz, 1H), 4.26-4.22 (m, 2H).

Synthesis of Ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate

[0284] Synthesis of 5-cyclopropylpyridin-2-amine. A solution of 5-bromopyridin-2-amine (5 g, 29.1 mmol), cyclopropylboronic acid (3.75 g, 43.6 mmol), Pd(OAc).sub.2 (651 mg, 2.91 mmol), SPhos (1.19 g, 2.91 mmol) and K.sub.3PO.sub.4 (18.5 g, 87.3 mmol) in toluene/H.sub.2O (100 mL/10 mL) was stirred at 95° C. for 12 h under nitrogen. Then the reaction mixture was quenched with H.sub.2O (50 mL) and extracted with DCM (200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude residue which was purified by silica gel chromatography (PE/EtOAc=1/1) to give the 5-cyclopropylpyridin-2-amine as yellow solid (3.8 g, 97.4% yield). ESI-MS [M+H].sup.+: 135.2.

[0285] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. To a solution 5-cyclopropyl-4-methylpyridin-2-amine (500 mg, 3.70 mmol) in DMF (10 mL) was added 1,3-dichloropropan-2-one (1409 mg, 11.1 mmol) at RT. The resulting reaction was stirred at 85° C. for 2 h. The solution was quenched with H.sub.2O (60 mL), adjusted to pH 8 by adding saturated NaHCO.sub.3 solution, and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified with prep-TLC (PE/EtOAc=1/1) to give the 2-(chloromethyl)-6-cyclopropyl-7-methylimidazo[1,2-a]pyridine (300 mg, yield:39%) as a light yellow oil. ESI-MS [M+H].sup.+: 207.2.

[0286] Synthesis of ethyl 14(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate. To a solution 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 9.70 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-4-carboxylate (906 mg, 6.46 mmol) and Cs.sub.2CO.sub.3 (6.32 g, 19.38 mmol) at RT. The resulting reaction was stirred at RT for 12 h. H.sub.2O (150 mL) was added to the reaction and then the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH=20/1) to give the ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (1.5 g, yield: 75%) as a white solid. ESI-MS [M+H].sup.+: 311.2.

Synthesis of Tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

[0287] Synthesis of 3-bromo-5-cyclopropylpyridin-2-amine. To a solution of 5-cyclopropylpyridin-2-amine (8.08 g, 60 mmol) in MeCN (200 mL) was added NBS (11.72 g, 66 mmol) in portions at 0° C. during 30 min. The mixture was stirred at 0° C. for additional 30 min and then concentrated to give the crude, which was purified by silica gel chromatography (PE/EA=5/1 to 4/1) to afford 3-bromo-5-cyclopropylpyridin-2-amine as a white solid (8.23 g, yield: 64%). ESI-MS [M+H].sup.+: 212.8,

Synthesis of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0288] A solution of 3-bromo-5-cyclopropylpyridin-2-amine (8.23 g, 38.6 mmol) and 1,3-dichloropropan-2-one (7.46 g, 57.9 mmol) in EtOAc (80 mL) was stirred at 70° C. for 48° C. The reaction mixture was diluted with EtOAc (300 mL) and washed with saturate aqueous NaHCO.sub.3 (100 mL). The organic layer was washed brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo to give the crude, which was purified with silica gel (EtOAc/PE=1/2) to give (8 g, yield: 72.3%) as a yellow solid. ESI-MS [M+H].sup.+: 284.8

Synthesis of 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine

[0289] To a solution of 8-bromo-2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (1 g, 3.5 mmol) in DMF (15 mL) was added NaN.sub.3 (230 mg, 3.5 mmol). The resulting mixture was stirred at 50° C. for 24 h under nitrogen. H.sub.2O (50 mL) was added to the reaction, extracted with EtOAc (50 mL×3). The combined organic layers were washed brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo to give 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude), which was used into next step without further purification. ESI-MS [M+H].sup.+: 292.0.

[0290] Synthesis of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. To a solution 2-(azidomethyl)-8-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.1 g, crude from previous step) and tert-butyl propiolate (860 mg, 6.8 mmol) in t-BuOH/H.sub.2O (15 mL/15 mL) was added CuSO.sub.4 (170 mg, 0.68 mmol), sodium ascorbate (180 mg, 1.02 mmol). The reaction mixture was stirred at RT for 12 h. The mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE/EtOAc=1/2) to give tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (500 mg, 34% over 2 steps) as brown oil. ESI-MS [M+H].sup.+: 417.7.

Example 1

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1)

[0291] ##STR00025##

Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0292] ##STR00026##

[0293] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at −60° C. The mixture was stirred at room temperature for 3 h and then quenched with saturated aq. NaHCO.sub.3 solution (300 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc from 0 to 80%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) as an off-white solid. ESI-MS [M+H].sup.+: 270.1

Synthesis of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0294] ##STR00027##

[0295] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (5 g, 18.6 mmol) and DPPA (10.2 g, 37.2 mmol) in DCM (80 mL) was added DBU (11.3 g, 74.4 mmol) dropwise at 0° C. After stirring at room temperature for 18 h, the reaction was quenched with saturated aqueous NH.sub.4Cl (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (70 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (PE/EtOAc from 0 to 50%) to give 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, yield: 36.6%) as a white solid. [M+H].sup.+: 295.2

Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine

[0296] ##STR00028##

[0297] A mixture of 2-((4-(azidomethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (2 g, 6.8 mmol) and Pd/C (200 mg) in THF (80 mL) was stirred at room temperature under H.sub.2 atmosphere for 18 h. The reaction mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated in vacuo to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (1 g, yield: 54.9%) as a yellow solid. [M+H]+: 269.2

Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1)

[0298] ##STR00029##

[0299] A mixture of 2-(7-chloro-1,8a-dihydroimidazo[1,5-a]pyridin-1-yl)acetic acid (40 mg, 0.19 mmol), HATU (110 mg, 0.29 mmol), DIPEA (74 mg, 0.57 mmol) and (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (51 mg, 0.19 mmol) in DMF (3 mL) was stirred at rt for 18 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (DCM/MeOH=20/1) to provide 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (50 mg, yield: 57%) as a white solid. ESI-MS: [M+H].sup.+ 461.2.

[0300] 1H NMR (400 MHz, DMSO) δ 8.45-8.42 (m, 1H), 8.36 (s, 1H), 8.29-8.27 (m, 2H), 7.89 (s, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.02 (d, J=9.4 Hz, 1H), 6.63-6.61 (m, 1H), 5.63 (s, 2H), 4.27 (d, J=5.6 Hz, 2H), 3.66 (s, 2H), 1.97-1.90 (m, 1H), 0.95-0.90 (m, 2H), 0.70-0.66 (m, 2H).

Example 2

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (I-2)

[0301] ##STR00030##

Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol

[0302] ##STR00031##

[0303] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (510 mg, 3 mmol) in DMF (15 mL) was added TFAA (1.58 g, 7.5 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3 h, then H.sub.2O (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified with silica gel column (PE/EtOAc=1/1) to provide 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-one (400 mg, yield: 50%) as a yellow solid. ESI-MS [M+H]+: 267.0.

Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol

[0304] ##STR00032##

[0305] To a solution of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-one (50 mg, 0.19 mmol) in MeOH (10 mL) at 0° C. was added NaBH.sub.4 (29 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 2 h, then H.sub.2O (20 mL) was added. The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by Prep-TLC (DCM/MeOH=10/1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol as a white solid (46 mg, 90.2%). ESI-MS [M+H]+: 269.0.

Synthesis of 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine

[0306] ##STR00033##

[0307] To a solution 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoroethan-1-ol (46 mg, 0.17 mmol) in DCM (10 mL) was added SOCl.sub.2 (0.5 mL). The resulting mixture was heated to 50° C. and stirred for 12 h. The reaction mixture was concentrated in vacuo to give 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (49 mg crude), which was used in the next step without further purification. (49 mg crude). ESI-MS [M+H]+: 288.1

Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine

[0308] ##STR00034##

[0309] To a solution of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (46 mg, 0.17 mmol) and triethylamine (174 mg, 1.72 mmol) in DCM (5 mL) was added 7-chloro-1-(1-chloro-2,2,2-trifluoroethyl)-8-fluoroimidazo[1,5-a]pyridine (46 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was poured into H.sub.2O (20 mL) and extracted with DCM (25 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by prep-HPLC to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine as a white solid (6 mg, 7%). ESI-MS [M+H]+: 519.1.

[0310] 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=7.5 Hz, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.01 (d, J=9.4 Hz, 1H), 6.89 (t, J=7.0 Hz, 1H), 5.55 (s, 2H), 5.42-5.34 (m, 1H), 3.82-3.71 (m, 2H), 1.95-1.90 (m, 1H), 0.93-0.90 (m, 2H), 0.70-0.66 (m, 2H).

Example 3

7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (I-3)

[0311] ##STR00035##

Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic Acid

[0312] ##STR00036##

[0313] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (0.3 g, 1.5 mmol) in H.sub.2O (5 mL) and t-BuOH (10 mL) was added NaH.sub.2PO.sub.4 (0.4 g, 3.0 mmol) and NaClO.sub.2 (0.3 g, 3.0 mmol). The mixture was stirred at room temperature for 48 h. Water (30 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel chromatography (DCM/MeOH=10/1) to give 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (0.15 g, yield: 46.6%) as a white solid. ESI-MS [M+H].sup.+: 215.0.

Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide

[0314] ##STR00037##

[0315] To a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carboxylic acid (60 mg, 0.28 mmol) in DMF (5 mL) was added (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (75 mg, 0.28 mmol), HOBt (56.7 mg, 0.42 mmol), EDCI (80.6 mg, 0.42 mmol) and DIPEA (108.4 mg, 0.84 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give the crude, which was purified by Prep-HPLC to give 7-chloro-N-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (30 mg, yield: 23.1%) as a white solid. ESI-MS [M+H]+: 465.1.

[0316] 1H NMR (400 MHz, DMSO) δ 8.63 (t, J=6.0 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.40-8.31 (m, 2H), 8.19 (s, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 6.94-7.06 (m, 2H), 5.63 (s, 2H), 4.50 (d, J=6.0 Hz, 2H), 1.84-1.98 (m, 1H), 0.97-0.86 (m, 2H), 0.73-0.62 (m, 2H).

Example 4

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-4)

[0317] ##STR00038##

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide

[0318] ##STR00039##

[0319] To a solution of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (1.06 g, 5.3 mmol) and DIPEA (1.33 mL, 7.5 mmol) in THF (15 mL) was added a solution of 1H-pyrazole-4-sulfonyl chloride (250 mg, 1.5 mmol) in DMSO (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by silica gel chromatography (eluent: DCM/MeOH=10/1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide as a yellow solid. (70 mg, yield: 14.2%), ESI-MS [M+H]+: 330.2

Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-N-(2-fluoro-3-methoxy-6-(1H-tetrazol-1-yl)benzyl)-1H-pyrazole-4-sulfonamide

[0320] ##STR00040##

[0321] A mixture of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1H-pyrazole-4-sulfonamide (70 mg, 0.21 mmol), 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (43 mg, 0.21 mmol) and Cs.sub.2CO.sub.3 (205 mg, 0.63 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. Water (25 mL) was added and the mixture was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by Prep-HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide as a white solid (7 mg, 6.7%). ESI-MS [M+H]+: 500.1, Purity: 99.75%(214 nm), 99.89% (254 nm).

[0322] 1H NMR (400 MHz, DMSO) δ 8.41 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 8.19-8.17 (m, 2H), 7.78-7.77 (m, 2H), 7.66 (s, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.01 (dd, J=9.4, 1.7 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 5.42 (s, 2H), 4.23 (d, J=5.5 Hz, 2H), 1.97-1.87 (m, 1H), 0.95-0.90 (m, 2H), 0.70-0.66 (m, 2H).

Example 5

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide (I-5)

[0323] ##STR00041##

Synthesis ((Benzylthio)ethynyl)trimethylsilane

[0324] ##STR00042##

[0325] To a solution of ethynyltrimethylsilane (9.8 g, 100 mmol) in dry Et.sub.2O (150 mL) was added n-BuLi (42 mL, 2.4 M solution in hexane, 100.8 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 15 min. Then S (3.2 g, 100 mmol) was added and the reaction mixture was stirred at −78° C. for another 15 min. The reaction was allowed to warm to room temperature and stirred for 1 h until the S was consumed, then cooled to 0° C. BnBr (17.1 g, 100 mmol) was added and the resulting mixture was stirred at room temperature for 14 h. The reaction was concentrated in vacuo to give the crude, which was purified by silica gel chromatography (eluent: PE) to give ((benzylthio)ethynyl)trimethylsilane as a yellow oil (20 g, 91%). 1H NMR (400 MHz, CDCl.sub.3) δ 7.25-7.13 (m, 5H), 3.80 (s, 2H), 0.00 (s, 9H).

Synthesis Benzyl(ethynyl)sulfane

[0326] ##STR00043##

[0327] To a solution of ((benzylthio)ethynyl)trimethylsilane (20 g, 90.9 mmol) in THF (50 mL) was added TBAF (75 mL, 1 M solution in THF, 75 mmol). The resulting solution was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NH.sub.4Cl (100 mL) and extracted with Et.sub.2O (100 mL×2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give benzyl(ethynyl)sulfane, which was used in the next step without further purification. (12 g, crude yield: 91%)

[0328] 1H NMR (400 MHz, CDCl.sub.3) δ 7.35-7.26 (m, 5H), 3.96 (s, 2H), 2.82 (s, 1H).

Synthesis Benzyl(ethynyl)sulfane

[0329] ##STR00044##

[0330] To a solution of benzyl(ethynyl)sulfane (4 g, 27 mmol) and 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (6.9 g, 32.4 mmol) in tBuOH/H.sub.2O (40 mL/40 mL) was added CuSO.sub.4 (2.1 g, 13.2 mmol) and sodium ascorbate (2.61 g, 13.2 mmol). The reaction was stirred at room temperature for 12 h. H.sub.2O (150 mL) was added and the mixture was extracted with DCM (150 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (DCM/MeOH=15/1) to give 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine as a black solid. (3.5 g, 36%). ESI-MS [M+H]+: 362.2

Synthesis 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl Chloride

[0331] ##STR00045##

[0332] To a solution of 2-((4-(benzylthio)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (500 mg. 1.39 mmol) in AcOH/H.sub.2O (15 mL/5 mL) was added NCS (197 mg, 1.39 mmol). The reaction was stirred at room temperature for 2 h. Additional NCS (197 mg, 1.39 mmol) was added to the reaction. The resulting reaction mixture was stirred for another 3 h. The mixture was concentrated in vacuo to give the crude, which was used in the next step without further purification (650 mg crude). ESI-MS [M+H]+: 338.0

Synthesis N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide

[0333] ##STR00046##

[0334] To a mixture of (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (100 mg, 0.42 mmol) and DIPEA (774 mg, 6 mmol) in dry THF (15 mL) was added 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl chloride (650 mg crude from previous step) in 5 mL THF at 0° C. The reaction was stirred at room temperature for 1 h. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by Prep-HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonamide as a white solid. (18 mg, yield: 2.6% over 2 steps) ESI-MS [M+H]+: 501.1, Purity: 99.78%(214 nm), 100% (254 nm)

[0335] 1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 7.20-7.10 (m, 2H), 7.03-7.00 (m, 2H), 6.85 (d, J=3.6 Hz, 1H), 5.85-5.56 (m, 2H), 2.50 (s, 1H), 1.97-1.92 (m, 2H), 1.23-1.16 (m, 2H), 0.95-0.87 (m, 2H), 0.70-0.66 (m, 2H).

Example 6

7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-6)

[0336] ##STR00047##

Synthesis of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine

[0337] ##STR00048##

[0338] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine (1.7 g, 10 mmol), NIS (2.5 g, 11 mmol) and TFA (342 mg, 3.0 mmol) in MeCN (15 mL) was stirred at 60° C. for 4 h. The reaction was cooled to 0° C., quenched with saturated aqueous NaHCO.sub.3 (50 mL), and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM=1/20) to give 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.5 g, yield: 50%) as yellow oil. ESI-MS [M+H]+: 297.0.

Synthesis of 7-chloro-8-fluoro-1-(4-methoxybenzyl)thio)imidazo[1,5-a]pyridine

[0339] ##STR00049##

[0340] A mixture of 7-chloro-8-fluoro-1-iodoimidazo[1,5-a]pyridine (1.18 g, 4.0 mmol), (4-methoxyphenyl)methanethiol (0.74 g, 4.8 mmol), Xantphos (116 mg, 0.2 mmol), Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol) and DIPEA (1.03 g, 8.0 mmol) in dioxane (15 mL) was stirred at 100° C. for 18 h. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude, which was purified with silica gel chromatography (eluent: MeOH/DCM=1/20) to give 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (1.2 g, yield: 93%) as yellow oil. ESI-MS [M+H]+: 323.0.

Synthesis of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl Chloride

[0341] ##STR00050##

[0342] To the mixture of 7-chloro-8-fluoro-1-((4-methoxybenzyl)thio)imidazo[1,5-a]pyridine (644 mg, 2.0 mmol) in AcOH/H.sub.2O (4.5 mL/1.5 mL) was added NCS (266 mg, 2.0 mmol). After stirring at room temperature for 2 h, a second portion of NCS (266 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for another 2 h. Then the reaction was quenched with saturated aqueous NaHCO.sub.3 (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na.sub.2SO.sub.4 and concentrated give crude 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (700 mg, crude) as a brown oil which was used in next step directly without further purification. ESI-MS [M+H].sup.+: 269.0.

Synthesis of 7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide

[0343] ##STR00051##

[0344] A mixture of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (150 mg, 0.56 mmol), (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanamine (150 mg, 0.56 mmol) and DIPEA (217 mg, 1.68 mmol) in DMF (100 mL) was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO.sub.3 (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude, which was purified by Prep-HPLC to give 7-chloro-N-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (11 mg, 4% yield) as a light-yellow solid. ESI-MS [M+H].sup.+: 501.1.

[0345] 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.43-8.34 (m, 2H), 8.22 (s, 1H), 7.82 (d, J=7.9 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 7.07-7.01 (m, 2H), 5.57 (s, 2H), 4.18 (s, 2H), 1.99-1.92 (m, 1H), 0.95-0.89 (m, 2H), 0.72-0.68 (m, 2H).

Example 7

7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7)

[0346] ##STR00052##

Synthesis of 7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide

[0347] To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (70 mg, 0.248 mmol) and triethylamine (75 mg, 0.743 mmol) in DMF (3 mL) was added a solution of 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-sulfonyl chloride (100 mg, 0.373 mmol) in 3 mL DMF at 0° C. The reaction mixture was stirred at RT for 8 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed by brine (30 mL), dried over Na.sub.2SO.sub.4, and concentrated to give the crude which was purified by Prep-HPLC to afford 7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide[1,5-a]pyridine-1-sulfonamide (5.4 mg, yield: 4.3%) as a white solid. ESI-MS: [M+H].sup.+, 515.1, Purity: 97.25% (214 nm); 98.25%(254 nm).

[0348] 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=2.1 Hz, 1H), 8.37-8.35 (m, 2H), 8.19 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.45 (d, J=9.4 Hz, 1H), 7.07-7.01 (m, 2H), 5.62-5.46 (m, 2H), 4.59-4.53 (m, 1H), 1.97-1.91 (m, 1H), 1.33 (d, J=7.0 Hz, 3H), 0.94-0.91 (m, 2H), 0.71-0.67 (m, 2H).

##STR00053##

Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol

[0349] ##STR00054##

[0350] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then the reaction mixture was quenched with saturated aq. NH.sub.4Cl solution (50 mL) and extracted with EtOAc (30 mL×5). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 5%) to afford 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+H].sup.+: 284.1

Synthesis of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0351] ##STR00055##

[0352] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl.sub.2 (1.0 mL) at 0° C. and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated afford crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used in the next step directly without further purification. ESI-MS [M+H].sup.+: 302.1

Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0353] ##STR00056##

[0354] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) and NaN.sub.3 (344 mg, 5.30 mmol) in DMF (10 mL) was stirred at RT for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 3%) to afford 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, yield: 46% over 2 steps) as a yellow oil. ESI-MS [M+H].sup.+: 309.2.

Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

[0355] ##STR00057##

[0356] A mixture of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, 0.81 mmol) and Pd/C (50 mg) in THF (10 mL) was stirred under hydrogen atmosphere at RT for 18 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated to afford crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, yield: 66%) as a yellow oil which was used in the next step directly without further purification. ESI-MS [M+H].sup.+: 283.2

Example 8

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (I-8)

[0357] ##STR00058## ##STR00059##

Synthesis of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol

[0358] ##STR00060##

[0359] To the mixture of 6-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (1.86 g, 10.0 mmol) in THF (30 mL) was added vinylmagnesium bromide (15 mL, 15.0 mmol), maintaining a temperature below −60° C. The reaction mixture was stirred at −60° C. for 2 h, then quenched with saturated aqueous NH.sub.4Cl (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the crude, which was purified by flash column chromatography (eluent: DCM/MeOH=10/1) to give 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.6 g, yield: 75%) as a pale yellow solid. ESI-MS [M+H]+: 215.2.

Synthesis of Methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0360] ##STR00061##

[0361] A mixture of 1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)prop-2-en-1-ol (1.2 g, 5.6 mmol), methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.25 g, 6.7 mmol), Pd(OAc).sub.2 (125 mg, 0.56 mmol), (o-MeC.sub.6H.sub.4).sub.3P (170 mg, 0.56 mmol) and DIPEA (2.2 g, 16.8 mmol) in DMA (20 mL) was degassed with N.sub.2 and stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and water (100 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and concentrated in vacuo to give the crude, which was purified by flash column chromatography (eluent: DCM/MeOH=15/1) to afford methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate as an off-white solid (900 mg, yield: 34%). ESI-MS [M+H]+: 468.2.

Synthesis of Methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate

[0362] ##STR00062##

[0363] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (500 mg, 1.07 mmol) in TFA/DCM (3.5 mL/10 mL) was stirred at 50° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated to give a residue, which was diluted with saturated aqueous NaHCO.sub.3 (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by flash column chromatography (eluent: DCM/MeoH=15/1) to afford methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate as a yellow solid (300 mg, yield: 83%). ESI-MS [M+H]+: 338.1.

Synthesis of Methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate

[0364] ##STR00063##

[0365] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-oxopropyl)-1H-imidazole-4-carboxylate (0.3 g, 0.89 mmol) in MeOH (15 mL) at 0° C. was added NaBH.sub.4 (67 mg, 1.78 mmol) slowly. The reaction mixture was stirred at room temperature for 2 h. Water (50 mL) was added and the mixture was and extracted with DCM/MeOH (10/1, 30 mL×3). The combined organic layers were washed with brine (20 mL) and concentrated in vacuo to give the crude, which was purified by flash column chromatography (eluent: DCM/MeOH=8/1) to afford methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate as a white solid (220 mg, yield: 73%). ESI-MS [M+H]+: 341.1.

Synthesis of Methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

[0366] ##STR00064##

[0367] To a mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (100 mg, 0.29 mmol) and PPh.sub.3 (152 mg, 0.58 mmol) in THF (5 mL) at 0° C. was added DIAD (118 mg, 0.58 mmol). The mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with water (30 mL) and extracted with DCM/MeOH (10/1, 30 mL×3). The combined organic layers were washed with brine (30 mL) and concentrated to give the crude, which was purified by flash column chromatography (eluent: DCM/MeOH=10/1) to afford methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate as a colorless oil (25 mg, yield: 26%). ESI-MS [M+H]+: 323.1.

Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic Acid

[0368] ##STR00065##

[0369] A mixture of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate (25 mg, 0.078 mmol) and LiOH.H.sub.2O (16 mg, 0.390 mmol) in EtOH/THF/H.sub.2O (1.5 mL/1.5 mL/0.5 mL) was stirred at 35° C. for 18 h. The reaction mixture was adjusted to pH 5 by addition of HCl (1N) and concentrated to afford 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, crude) as a white solid which was used into next step without further purification. ESI-MS [M+H]+: 309.2.

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

[0370] ##STR00066##

[0371] A mixture of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylic acid (40 mg, 0.13 mmol crude), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (30 mg, 0.13 mmol), HOBT (17.5 mg, 0.13 mmol), EDCI (25 mg, 0.13 mmol) and DIPEA (50 mg, 0.39 mmol) in DMF (1 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by prep-HPLC to afford N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide as white solid (10 mg, yield: 15.7%). ESI-MS [M+H]+: 490.2.

[0372] 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=2.4 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.96 (t, J=5.4 Hz, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.02-6.99 (m, 1H), 6.76-6.74 (m, 1H), 5.58-5.54 (m, 1H), 4.66 (d, J=5.4 Hz, 2H), 2.93-2.82 (m, 3H), 2.78-2.70 (m, 1H), 1.94-1.89 (m, 1H), 0.92-0.89 (m, 2H), 0.70-0.65 (m, 2H).

Synthesis of Methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound 3)

[0373] ##STR00067##

Synthesis of Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0374] To a stirred solution of methyl 1H-imidazole-4-carboxylate (4 g, 31.75 mmol) in dry DMF (75 mL) was added NaH (1.46 g, 60% suspension in paraffin oil, 36.5 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then treated dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (6.32 g, 38.1 mmol). The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was quenched with ice water (80 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by silica gel chromatography (eluent: MeOH/DCM=1/20) to provide methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (6.8 g, yield: 84%) as a white solid. ESI-MS [M+H]+: 257.2.

Synthesis of Methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate

[0375] ##STR00068##

[0376] To a stirred solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5.0 g, 19.5 mmol) in carbon tetrachloride (50 mL) was added NBS (3.47 g, 19.5 mmol) and AIBN (160 mg, 5 mol %) at room temperature. The reaction mixture was heated at 60° C. for 3 h, then cooled to room temperature and filtered through a small pad of celite. The filtrate was concentrated in vacuo to give a light yellow colored residue, which was dissolved in EtOAc (100 mL) and washed with 10% aqueous NaHCO.sub.3 (100 mL) solution. The organic layer was washed with brine (70 mL), dried over Na.sub.2SO.sub.4 and concentrated to give crude compound. The crude material was purified by silica gel chromatography (eluent: PE/EtOAc=2/1) to provide methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (4 g, yield: 61.5%). ESI-MS [M+H]+: 355.2.

Example 9

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (I-9)

[0377] ##STR00069##

Synthesis of Methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate

[0378] ##STR00070##

[0379] To a solution of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-hydroxypropyl)-1H-imidazole-4-carboxylate (200 mg, 0.59 mmol) in DCM (4 mL) at 0° C. was added triethylamine (119.3 mg, 1.18 mmol) and MSCI (101.2 g, 0.88 mmol). After stirring at 0° C. for 2 h, the reaction was concentrated in vacuo to give methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, yield: 98%) as a black solid which was used in the subsequent step without further purification. ESI-MS [M+H].sup.+: 419.1.

Synthesis of Methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate

[0380] ##STR00071##

[0381] A mixture of methyl 2-(3-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-3-((methylsulfonyl)oxy)propyl)-1H-imidazole-4-carboxylate (240 mg, 0.57 mmol) and Cs.sub.2CO.sub.3 (557 mg, 1.71 mmol) in DMF (15 mL) was stirred at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude, which was purified by silica gel chromatography (EtOAc/PE=1/1) to give methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate (102 mg, yield: 55.7%) as a yellow solid. ESI-MS [M+H].sup.+: 323.1.

Synthesis of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic Acid

[0382] ##STR00072##

[0383] To a solution of methyl 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylate (102 mg, 0.32 mmol) in MeOH (1 mL) and THF (1 mL) was added LiOH (31.6 mg, 1.32 mmol) and H.sub.2O (0.5 mL). The reaction mixture was stirred at room temperature for 12 h. The mixture was adjusted pH 5 with 1N HCl and then extracted with EtOAc (30 mL×3). The combined organic layers were concentrated to give 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid (65 mg, yield:67%) as a white solid which was used in the subsequent reaction without further purification. ESI-MS [M+H]+: 309.1.

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide

[0384] ##STR00073##

[0385] To a solution of 5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxylic acid (65 mg, 0.21 mmol) in DMF (2 mL) was added (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (64.7 mg, 0.27 mmol), HATU (102.6 mg, 0.27 mmol), and DIPEA (387 mg, 3.0 mmol). The reaction mixture was stirred at room temperature for 4 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the crude, which was purified by Prep-HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (32 mg, yield: 50%) as a white solid. ESI-MS [M+H]+: 490.2. Purity: 98.98% (214 nm), 99.54% (254 nm).

[0386] 1H NMR (400 MHz, DMSO) δ 8.48 (t, J=5.3 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.34 (d, J=9.3 Hz, 1H), 6.98-6.95 (m, 1H), 6.78-6.71 (m, 1H), 5.86 (d, J=7.6 Hz, 1H), 4.68-4.65 (m, 1H), 4.51-4.46 (m, 1H), 3.02-2.88 (m, 2H), 2.81-2.71 (m, 1H), 2.69-2.59 (m, 1H), 1.95-1.88 (m, 1H), 0.95-0.86 (m, 2H), 0.71-0.62 (m, 2H).

Example 10

N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10)

[0387] ##STR00074##

[0388] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol), 1-(aminomethyl)imidazo[1,5-a]pyridine-7-carbonitrile (55 mg, 0.32 mmol) and HATU (120 mg, 0.31 mmol) in DMF (2 mL) was added DIPEA (81 mg, 0.63 mmol). The resulting reaction was stirred at room temperature for 12 h. H.sub.2O (25 mL) was added and the mixture was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the crude product which was purified by Prep-TLC (DMC/MeOH=10/1) to give N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide as a white solid (22 mg, yield: 24%). ESI-MS [M+H]+: 437.2.

[0389] 1H NMR (400 MHz, DMSO) δ 8.65 (t, J=5.7 Hz, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.40-8.37 (m, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.39 (d, J=9.3 Hz, 1H), 7.01-6.97 (m, 1H), 6.85-6.81 (m, 1H), 5.39 (s, 2H), 4.63 (d, J=5.7 Hz, 2H), 1.94-1.88 (m, 1H), 0.93-0.88 (m, 2H), 0.68-0.64 (m, 2H).

Example 11

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-11)

[0390] ##STR00075##

Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0391] ##STR00076##

[0392] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (10.0 g, 33.7 mmol) in THF (100 mL) was added DIBAL-H (67.3 mL, 67.3 mmol) at −60° C. The mixture was stirred at room temperature for 3 h and then quenched with saturated aq. NaHCO.sub.3 solution (300 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc from 0 to 20%) to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (7.5 g, yield: 82%) as an off-white solid. ESI-MS [M+H].sup.+: 270.1

Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde

[0393] ##STR00077##

[0394] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.12 mmol) and MnO.sub.2 (963 mg, 11.2 mmol) in DCM (10 mL) was stirred at room temperature for 18 h. The reaction mixture was then filtered and concentrated in vacuo to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (220 mg, yield: 74%) as a yellow solid which was used in the next step without purification. ESI-MS [M+H].sup.+: 268.1

Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine

[0395] ##STR00078##

[0396] A mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (100 mg, 0.37 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (88 mg, 0.37 mmol) and triethylamine (37 mg, 0.37 mmol) in MeOH (5 mL) was stirred at room temperature for 16 h. NaBH(OAc).sub.3 (157 mg, 0.74 mmol) was added and the mixture was stirred at room temperature for another 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by Prep-TLC (MeOH/DCM=1/15) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5.5 mg, yield: 3.3%) as a white solid. ESI-MS [M+H]+: 451.1.

[0397] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.1 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.00 (d, J=9.4 Hz, 1H), 6.73 (t, J=6.9 Hz, 1H), 5.62 (s, 2H), 3.92 (s, 2H), 3.74 (s, 2H), 1.97-1.88 (m, 1H), 0.97-0.87 (m, 2H), 0.72-0.62 (m, 2H).

Example 12

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (I-12)

[0398] ##STR00079##

Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol

[0399] ##STR00080##

[0400] To a mixture of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (2.0 g, 7.5 mmol) in THF (30 mL) was added MeMgBr (30.0 mL, 30.0 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Then the reaction mixture was quenched with saturated aq. NH.sub.4Cl solution (50 mL) and extracted with EtOAc (30 mL×5). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 5%) to afford 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (1.5 g, yield: 71%) as a yellow oil. ESI-MS [M+H].sup.+: 284.1

Synthesis of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0401] ##STR00081##

[0402] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ol (500 mg, 1.77 mmol) in DCM (10 mL) was added SOCl.sub.2 (1.0 mL) at 0° C. and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated afford crude 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) as a yellow oil, which was used in the next step directly without further purification. ESI-MS [M+H].sup.+: 302.1

Synthesis of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0403] ##STR00082##

[0404] A mixture of 2-((4-(1-chloroethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (600 mg, crude) and NaN.sub.3 (344 mg, 5.30 mmol) in DMF (10 mL) was stirred at RT for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 3%) to afford 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, yield: 46% over 2 steps) as a yellow oil. ESI-MS [M+H].sup.+: 309.2

Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

[0405] ##STR00083##

[0406] A mixture of 2-((4-(1-azidoethyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (250 mg, 0.81 mmol) and Pd/C (50 mg) in THF (10 mL) was stirred under hydrogen atmosphere at RT for 18 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated to afford crude 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (150 mg, yield: 66%) as a yellow oil which was used in the next step directly without further purification. ESI-MS [M+H].sup.+: 283.2

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine

[0407] ##STR00084##

[0408] To a solution of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (80 mg, 0.284 mmol) in MeOH (4 mL) was added 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (51 mg, 0.256 mmol) and triethylamine (57.5 mg, 0.568 mmol). The mixture was stirred at RT for 4 h. NaBH.sub.4 (11 mg, 0.291 mmol) was added and the reaction mixture was stirred at RT for another 3 h. Water (40 mL) was added and the mixture was extracted with EA (30 ml×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by Prep-TLC (DCM:MeOH=10:1) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (18 mg, yield: 13.6%) as a yellow solid. ESI-MS [M+H]+: 465.2

[0409] 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 8.17 (d, J=7.4 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.04-6.98 (m, 1H), 6.74-6.69 (m, 1H), 5.62 (s, 2H), 3.96-3.89 (m, 1H), 3.86 (s, 2H), 1.97-1.88 (m, 1H), 1.31 (d, J=6.6 Hz, 3H), 0.95-0.89 (m, 2H), 0.70-0.64 (m, 2H).

Example 13

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (I-13)

Synthesis of 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide

[0410] ##STR00085##

[0411] The mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (37.1 mg, 0.131 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (60 mg, 0.285 mmol), HATU (100.07 mg, 0.263 mmol), DIPEA (114.2 mg, 0.885 mmol) in DMF (4 mL) was stirred at rt for 16 h. Water (50 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (30 mL) and concentrated. The residue was purified by Prep-HPLC to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (40 mg, yield: 47.7%) as a white solid. ESI-MS [M+H]+: 475.2.

[0412] 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 8.31-8.24 (m, 2H), 7.90 (s, 1H), 7.83 (s, 1H), 7.75-7.70 (m, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.05-6.98 (m, 1H), 6.65-6.58 (m, 1H), 5.62 (s, 2H), 5.06-4.97 (m, 1H), 3.65 (s, 2H), 1.98-1.89 (m, 1H), 1.39 (d, J=7.0 Hz, 3H), 0.95-0.89 (m, 2H), 0.71-0.65 (m, 2H).

Example 14

Methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-14)

[0413] ##STR00086##

[0414] Synthesis of methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

##STR00087##

[0415] To a stirred solution of tert-butyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.7 g, 6.45 mmol) in MeOH (50 mL) was added conc. H.sub.2SO.sub.4 (1 mL) dropwise at room temperature. The mixture was heated to reflux for 16 h, then cooled to room temperature, diluted with water (50 mL), and concentrated in vacuo to remove MeOH. The residue was adjusted to pH=9-10 by addition of sat. aq. NaHCO.sub.3. The resulting precipitate was collected by filtration and dried in vacuo to give methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (2.0 g, yield: 82%) as a light brown solid. ESI-MS [M+H].sup.+: 376.0.

Synthesis of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0416] ##STR00088##

[0417] To a stirred solution of methyl 1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.59 mmol) in MeOH (10 mL) and THF (10 mL) was added NaBH.sub.4 (693 mg, 18.32 mmol) in portions at 0° C. The mixture was stirred at room temperature for 8 h, then quenched with sat. aq. NH.sub.4Cl (30 mL) and concentrated in vacuo to remove MeOH and THF. The residue was extracted with DCM (40 mL×3). The combined organics were washed with brine (80 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, yield: 91%) as a light brown solid which was used directly in next step without further purification. ESI-MS [M+H]+: 348.0.

Synthesis of Methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

[0418] ##STR00089##

[0419] A mixture of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (500 mg, 1.44 mmol), Pd(dppf)Cl.sub.2 (105 mg, 0.143 mmol) and triethylamine (729 mg, 7.218 mmol) in MeOH (20 mL) was refluxed for 16 h, then cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM/MeOH=20/1) to afford methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (400 mg, yield: 85%) as a yellow solid. ESI-MS [M+H].sup.+: 328.1.

Synthesis of Methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate

[0420] ##STR00090##

[0421] A mixture of methyl 6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (400 mg, 1.22 mmol) and MnO.sub.2 (2.12 g, 24.4 mmol) in DCM (15 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to afford methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (180 mg, yield: 45%) as a yellow solid. ESI-MS [M+H].sup.+: 326.1.

Synthesis of Methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate

[0422] ##STR00091##

[0423] A mixture of methyl 6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (180 mg, 0.553 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (144 mg, 0.721 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h. NaBH.sub.3CN (174 mg, 2.77 mmol) was added and the reaction mixture was stirred at room temperature for another 3 h. The reaction mixture was concentrated in vacuo, then diluted with water (40 mL) and extracted with DCM/MeOH (50 mL×3, v/v 10/1). The combined organics were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to give methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (130 mg, yield: 46%) as a pale solid. ESI-MS [M+H].sup.+: 509.2.

[0424] .sup.1H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.47 (s, 1H), 8.20 (d, J=7.4 Hz, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.61 (d, J=1.6 Hz, 1H), 6.76 (t, J=6.9 Hz, 1H), 5.70 (s, 2H), 4.07 (s, 2H), 3.92 (s, 2H), 3.84 (s, 3H), 2.03-1.94 (m, 1H), 0.96-0.90 (m, 2H), 0.71-0.65 (m, 2H).

Example 15

2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic Acid (I-15)

[0425] ##STR00092##

[0426] To a solution of methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (110 mg, 0.216 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (18 mg, 0.429 mmol). The mixture was stirred at 40° C. for 1 h. The reaction mixture was diluted with water (20 mL), acidified to pH=5-6 by addition of HCl (2 M), and concentrated in vacuo. The residue was purified by prep-HPLC to give 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (50 mg, yield: 47%) as a white solid. ESI-MS [M+H].sup.+: 495.1.

[0427] .sup.1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 6.76 (t, J=6.8 Hz, 1H), 5.75 (s, 2H), 4.04 (s, 2H), 3.89 (s, 2H), 2.06-1.98 (m, 1H), 1.00-0.93 (m, 2H), 0.74-0.68 (d, 2H).

Example 16

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (I-16)

[0428] ##STR00093## ##STR00094##

Synthesis of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol

[0429] ##STR00095##

[0430] To a solution of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxylate (600 mg, 1.94 mmol) in THF (20 mL) was added LiAlH.sub.4 (221 mg, 5.81 mmol) slowly at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 5 h. The mixture was quenched with Na.sub.2SO.sub.4-10H.sub.2O and diluted with EtOAc (50 mL). The resulting suspension was filtered and the filtrate was concentrated in vacuo to give (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol as a yellow solid (588 mg, crude) which was used directly in next step without further purification. ESI-MS [M+H].sup.+: 269.2.

Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

[0431] ##STR00096##

[0432] A mixture of (1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanol (588 mg, 2.19 mmol) and MnO.sub.2 (1.7 g, 19.54 mmol) in DCM (20 mL) was stirred at RT for 72 h. The mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by Prep-TLC (DCM:MeOH=20:1) to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde as a yellow oil (365 mg, yield: 63%). ESI-MS [M+H].sup.+: 267.1.

Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde

[0433] ##STR00097##

[0434] To a solution of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carbaldehyde (365 mg, 1.37 mmol) and CsF (584 mg, 3.845 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (312 mg, 2.19 mmol) at room temperature. The mixture was stirred at 60° C. for 16 h under nitrogen. Then the mixture was diluted with EtOAc (50 mL) and washed with water (30 mL×3). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-ol as a yellow solid (430 mg, yield: 93.5%) which was used directly in next step without further purification. ESI-MS [M+H].sup.+: 337.2.

Synthesis of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0435] ##STR00098##

[0436] To a mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-ol (430 mg, 1.27 mmol) in DCM (5 mL) was added SOCl.sub.2 (1.0 mL) at 0° C. The reaction mixture was stirred at rt for 2 h. The mixture was concentrated to give 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, crude) as a yellow solid which was used directly in the next step without further purification. ESI-MS [M+H].sup.+: 355.1.

Synthesis of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine

[0437] ##STR00099##

[0438] A mixture of 2-((4-(1-chloro-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.27 mmol) and NaN.sub.3 (165 mg, 2.54 mmol) in DMSO (5 mL) was stirred at 80° C. under N.sub.2 for 16 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with water (30 mL×3). The organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine as a yellow solid (450 mg, crude) which was used directly in the next step without further purification. ESI-MS [M+H].sup.+: 362.2.

Synthesis of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine

[0439] ##STR00100##

[0440] A mixture of 2-((4-(1-azido-2,2,2-trifluoroethyl)-1H-pyrazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine (450 mg, 1.25 mmol) and Pd/C (50 mg) in dry THF (10.0 mL) was stirred at room temperature under H.sub.2 for 16 h. Upon completion, the reaction mixture was filtered and the filtrate concentrated in vacuo to give (1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (400 mg, crude) as a light yellow oil which was used directly in the next step without further purification. ESI-MS [M+H]+: 336.1.

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine

[0441] ##STR00101##

[0442] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol) and 7-chloro-8-fluoroimidazo[1,5-a]pyridine-1-carbaldehyde (29.5 mg, 0.15 mmol) in MeOH/AcOH (5.0 mL/0.1 mL) was stirred at room temperature for 4 h. Then the reaction mixture was cooled to 0° C. and NaBH.sub.4 (8.6 mg, 0.227 mmol) was added. The reaction mixture was stirred at RT for another 1 h, then concentrated in vacuo and purified by Prep-HPLC to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (19.8 mg, yield: 25.49%) as a light yellow solid. ESI-MS [M+H]+: 518.1.

[0443] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.4 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J=7.4 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.48 (s, 1H), 7.41 (d, J=9.3 Hz, 1H), 7.00 (dd, J=9.4, 1.8 Hz, 1H), 6.78-6.68 (m, 1H), 5.37 (s, 2H), 4.48-4.40 (m, 1H), 3.97-3.87 (m, 2H), 2.73-2.64 (m, 1H), 1.98-1.86 (m, 1H), 0.99-0.86 (m, 2H), 0.75-0.60 (m, 2H).

Example 17

Ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-17a)

3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic Acid (I-17b)

[0444] ##STR00102##

Synthesis of Ethyl (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)acrylate

[0445] ##STR00103##

[0446] A mixture of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (1.4 g, 4.0 mmol), ethyl acrylate (0.81 g, 8.1 mmol), Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol), (o-MeC.sub.6H.sub.4).sub.3P (365 mg, 1.2 mmol) and triethylamine (1.2 g, 12.0 mmol) in MeCN (20 mL) was stirred at 90° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (50 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by flash column chromatography (PE/EtOAc from 0 to 30%) to give ethyl (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)acrylate (0.4 g, yield: 27%) as a brown solid.

Synthesis of Ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate

[0447] ##STR00104##

[0448] To a solution of ethyl (E)-3-(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)acrylate (400 mg, 1.09 mmol) in MeOH (10 mL) was added CuCl (162 mg, 1.63 mmol) and NaBH.sub.4 (245 mg, 6.48 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then quenched with water (50 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was dissolved in DCM (10 mL). MnO.sub.2 (1.9 g, 21.8 mmol) was added and the mixture was stirred at room temperature for 18 h, then filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc from 0 to 20%) to give ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, yield: 40%) as a colorless oil.

Synthesis of Ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate

[0449] ##STR00105##

[0450] To a mixture of ethyl 3-(6-cyclopropyl-2-((4-formyl-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)propanoate (160 mg, 0.44 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (87 mg, 0.44 mmol) in EtOH (10 mL) was added a drop of AcOH. The reaction mixture was stirred at room temperature for 18 h. NaBH.sub.4 (50 mg, 1.32 mmol) was added and the mixture was stirred at room temperature for another 2 h. The reaction was quenched with sat. aq. NH.sub.4Cl (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by prep-HPLC to afford ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (120 mg, yield: 50%) as white solid. ESI-MS [M+H]+: 551.2.

[0451] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.4 Hz, 1H), 8.21 (d, J=1.3 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 6.83 (s, 1H), 6.75-6.70 (m, 1H), 5.64 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.92 (s, 2H), 3.74 (s, 2H), 3.07 (t, J=7.6 Hz, 2H), 2.77 (t, J=7.7 Hz, 2H), 1.92-1.84 (m, 1H), 1.13 (t, J=7.1 Hz, 3H), 0.93-0.87 (m, 2H), 0.68-0.62 (m, 2H).

Synthesis of 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic Acid

[0452] ##STR00106##

[0453] A mixture of ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (90 mg, 0.16 mmol) and LiOH.H.sub.2O (21 mg, 0.50 mmol) in EtOH/THF/H.sub.2O (3 mL/3 mL/2 mL) was stirred at room temperature for 2 h. The reaction mixture was adjusted to pH-5 by addition of HCl (2 M) and concentrated in vacuo. The residue was purified by prep-HPLC to afford 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (60 mg, yield: 71.5%) as a white solid. ESI-MS [M+H]+: 523.2. Purity: 95.01 (214 nm), 95.35 (254 nm).

[0454] 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.3 Hz, 1H), 8.18 (d, J=7.4 Hz, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 6.82 (s, 1H), 6.75-6.69 (m, 1H), 5.63 (s, 2H), 3.92 (s, 2H), 3.73 (s, 2H), 2.99 (t, J=7.7 Hz, 2H), 2.36 (t, J=7.7 Hz, 2H), 1.90-1.81 (m, 1H), 0.91-0.85 (m, 2H), 0.67-0.61 (m, 2H).

Example 18

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-18)

[0455] ##STR00107##

Synthesis of Tert-butyl(6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate

[0456] ##STR00108##

[0457] To a solution of (1-((8-bromo-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (450 mg, 1.3 mmol) in dioxane (10 mL) was added NH.sub.2Boc (227.6 mg, 1.95 mmol), Pd(OAc).sub.2 (29.1 mg, 0.13 mmol), Xantphos (75.1 mg, 0.13 mmol) and Cs.sub.2CO.sub.3 (1.27 g, 3.9 mmol) at RT. The mixture was stirred at 95° C. for 16 h under N.sub.2. The mixture was concentrated and purified by silica gel chromatography (DCM/MeOH=30/1) to give the product tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate as a white solid (90 mg, yield: 18%). ESI-MS [M+H].sup.+: 385.2.

Synthesis of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0458] ##STR00109##

[0459] A solution of tert-butyl (6-cyclopropyl-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)imidazo[1,2-a]pyridin-8-yl)carbamate (90 mg, 0.23 mmol) in HCl (4M in dioxane) (5.0 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo to give (14(8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (90 mg, crude) as a yellow solid which was used in the next step directly without further purification. ESI-MS [M+H]+: 285.1.

Synthesis of (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol

[0460] ##STR00110##

[0461] To a solution of (1-((8-amino-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (300 mg, 1.06 mmol) in pyridine (15 mL) was added N′-formylformohydrazide (280 mg, 3.18 mmol) and Et.sub.3N (749 mg, 7.42 mmol) at RT. Then the TMSCl (1.72 g, 15.9 mmol) was added at 0° C. under N.sub.2. The resulting solution was stirred at 100° C. for 18 h and then cooled to RT. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (DCM/MeOH=20/1-10/1) to give (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (150 mg, 42%) as a white solid. ESI-MS [M+H]+: 337.1.

Synthesis of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde

[0462] ##STR00111##

[0463] To a solution of (1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methanol (60 mg, 0.18 mmol) in DCM (5.0 mL) at RT was added MnO.sub.2 (157 mg, 1.8 mmol). The reaction mixture was stirred at RT for 18 h. Additional MnO.sub.2 (78 mg. 0.9 mmol) was added and the reaction mixture was stirred for another 3 h. Upon completion, the mixture was filtered and the filtrate was concentrated to give 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, crude) as a yellow solid which was used in the next step directly without further purification. ESI-MS [M+H]+: 335.1.

Synthesis of 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine

[0464] ##STR00112##

[0465] A mixture of 1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carbaldehyde (40 mg, 0.12 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine (30 mg, 0.15 mmol) in MeOH (5.0 mL) was added AcOH (0.1 mL) at RT. The reaction mixture was stirred at RT for 18 h. Then NaBH.sub.4 (8.5 mg, 0.22 mmol) was added and the mixture was stirred for another 4 h at RT. The mixture was then concentrated and the residue purified by Prep-TLC (DCM/MeOH=15:1) to give 1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (5 mg, 8%) as a light yellow solid. ESI-MS [M+H]+: 518.2.

[0466] 1H NMR (400 MHz, DMSO) δ 9.41 (s, 2H), 8.48 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 8.18 (d, J=7.4 Hz, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.45 (d, J=0.9 Hz, 1H), 6.73 (t, J=6.9 Hz, 1H), 5.71 (s, 2H), 3.94 (s, 2H), 3.77 (s, 2H), 2.01-1.96 (m, 1H), 1.80-1.72 (m, 1H), 1.02-0.95 (m, 2H), 0.86-0.77 (m, 2H).

Example 19

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (I-19)

[0467] ##STR00113##

[0468] A mixture of 1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (50 mg, 0.15 mmol), 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)acetic acid (31 mg, 0.15 mmol), EDCI (40.3 mg, 0.21 mmol), HOBt (28.4 mg, 0.21 mmol) and DIPEA (54.2 mg, 0.42 mmol) in DMF (3 mL) was stirred at RT for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL×3). The organic layer was concentrated and the residue was purified by Prep-HPLC to give 2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (23.9 mg, 30%) as a light yellow solid. ESI-MS [M+H]+: 528.1.

[0469] 1H NMR (400 MHz, DMSO) δ 9.11 (d, J=9.4 Hz, 1H), 8.35 (s, 1H), 8.32-8.25 (m, 2H), 7.92 (s, 1H), 7.74 (s, 1H), 7.73-7.72 (m, 1H), 7.58 (s, 1H), 7.41 (d, J=9.4 Hz, 1H), 7.00 (dd, J=9.4, 1.7 Hz, 1H), 6.63 (dd, J=7.5, 2.1 Hz, 1H), 5.80-5.64 (m, 1H), 5.39 (s, 2H), 3.78 (s, 2H), 2.01-1.87 (m, 1H), 1.00-0.85 (m, 2H), 0.79-0.53 (m, 2H).

Example 20

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20)

[0470] ##STR00114## ##STR00115##

Synthesis of 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine

[0471] ##STR00116##

[0472] To a mixture of 5-cyclopropyl-3-(4-methylpiperazin-1-yl)pyridin-2-amine (460 mg, 1.98 mmol) in DME (25 mL) was added 1,3-dichloropropan-2-one (620 mg, 5 mmol). The reaction was stirred at 90° C. for 16 h. The reaction mixture was concentrated in vacuo to give 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (400 mg, yield: 32%, crude) as a yellow solid which was used in next step directly without further purification. ESI-MS [M+H]+: 305.1.

Synthesis of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine

[0473] ##STR00117##

[0474] To a mixture of 2-(chloromethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (400 mg, 1.3 mmol) in DMF (5 mL) was added NaN.sub.3 (250 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 16 h. Water (50 mL) was added and the mixture was extracted with EtOAc (30 ml×3). The combined organic layers were washed with brine (30 ml), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 10%) to give 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (100 mg, yield: 25%) as a yellow solid. ESI-MS [M+H].sup.+: 312.1.

Synthesis of Tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate

[0475] ##STR00118##

[0476] To a mixture of 2-(azidomethyl)-6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine (100 mg, 0.32 mmol) in t-BuOH (5 mL) and H.sub.2O (5 mL) was added tert-butyl propiolate (52 mg, 0.42 mmol), CuSO.sub.4 (25 mg, 0.16 mmol) and sodium ascorbate (31 mg, 0.16 mmol). The reaction mixture was stirred at rt for 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/DCM from 0 to 10%) to give tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (20 mg, yield: 14%) as a yellow solid. ESI-MS [M+H].sup.+: 438.2.

Synthesis of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid

[0477] ##STR00119##

[0478] A mixture of tert-butyl 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (15 mg, 0.034 mmol) in dry DCM (3 mL) and TFA (0.6 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo to give 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (3 mg, yield: 23% crude) as a yellow solid which was used in next step directly without further purification. ESI-MS [M+H]+: 382.1.

Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-O-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

[0479] ##STR00120##

[0480] A mixture of 1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 mg, 0.05 mmol), (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (20 mg, 0.1 mmol), HOBT (10 mg, 0.074 mmol), EDCI (14 mg, 0.075 mmol) and DIPEA (32 mg, 0.25 mmol) in dry DMF (5 ml) was stirred at room temperature for 16 h. Water (50 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by Prep-TLC (MeOH/DCM=10%) to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (1 mg, yield: 14%) as a yellow solid. ESI-MS [M+H]+: 563.1.

[0481] 1H NMR (400 MHz, DMSO) δ 8.66 (t, J=5.4 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.16 (d, J=7.4 Hz, 1H), 7.86 (s, 1H), 7.67 (s, 1H), 6.75-6.68 (m, 1H), 6.16 (s, 1H), 5.67 (s, 2H), 4.65 (d, J=5.5 Hz, 2H), 3.46 (s, 4H), 2.56 (s, 4H), 2.27 (s, 3H), 1.84-1.80 (m, 1H), 0.84-0.79 (m, 2H), 0.64-0.50 (m, 2H).

Example 21

Inhibitory Activity of Exemplary Compounds Against Plasma Kallikrein

[0482] Example compounds were evaluated for inhibition of the human activated kallikrein enzyme in two formats of an assay employing a fluorogenic peptide substrate. In one assay format, the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 500 pM activated kallikrein enzyme, 300 uM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Prior to reaction initiation with substrate, enzyme and inhibitors were preincubated for 30 min at RT. After initiation with substrate, reactions were incubated for 10 min at RT and fluorescence emission at 460 nm from 380 nm excitation measured with a microplate reader. In another assay format, the concentrations of reagents were as follows: 20 mM Tris pH 7.5, 1 mM EDTA, 150 mM sodium chloride, 0.1% PEG-400, 0.1% Triton X-100, 5 pM activated kallikrein enzyme, 300 uM Pro-Phe-Arg-7-amido-4-methylcoumarin substrate. Prior to reaction initiation with substrate, enzyme and inhibitors were preincubated for 30 min at RT. After initiation with substrate, reactions were incubated for 18 h at RT and fluorescence emission at 460 nm from 380 nm excitation measured with a microplate reader.

[0483] Table 1 provides the results of the assay in the format with 500 pM activated kallikrein assay. For the compounds listed in Table 1, the EC.sub.50 values are reported according to the following ranges: A≤50 nM; 50 nM<B≤200 nM; 200 nM<C≤1000 nM; 1000 nM<D.

TABLE-US-00001 TABLE 1 Primary Dose Response Compound Assay: Average EC50 I-1 A I-2 D I-3 B I-4 C I-5 C I-6 A I-7 A I-8 A I-9 C I-10 A I-11 A I-12 B I-13 A I-14 A I-15 C I-16 A I-17a A I-17b A I-18 A I-19 B I-20 A

[0484] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.