Tricyclic piperidine compounds
09765092 · 2017-09-19
Assignee
Inventors
- Daniel Bur (Allschwil, CH)
- Corinna Grisostomi (Allschwil, CH)
- Oliver Nayler (Allschwil, CH)
- Lubos Remen (Allschwil, CH)
- Magali Vercauteren (Allschwil, CH)
- Richard Welford (Allschwil, CH)
Cpc classification
A61P1/04
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61P7/04
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
A61P1/16
HUMAN NECESSITIES
A61P15/00
HUMAN NECESSITIES
A61P7/02
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to compounds of the formula (I) ##STR00001##
wherein R, R.sup.1a, R.sup.1b, R.sup.2, R.sup.3, and X are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), to methods for the preparation of such compounds of formula (I), and especially to their use as TPH modulators.
Claims
1. A compound of Formula (I) ##STR00013## wherein X represents CH, or N; R represents hydrogen, (C.sub.1-4)alkyl, (C.sub.3-6)cycloalkyl, or (C.sub.1-3)trifluoroalkyl; R.sup.1a and R.sup.1b independently represent hydrogen, methyl, ethyl; or R.sup.1a and R.sup.1b together with the carbon atom to which they are attached to form a cyclopropyl ring; R.sup.2 represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.3-6)cycloalkyl, optionally comprising one or two ring oxygen atoms; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; cyano; —(CH.sub.2).sub.n—NR.sup.21R.sup.22, wherein n represents the integer 0 or 1; and R.sup.21 and R.sup.22 independently represent hydrogen or (C.sub.1-3)alkyl; or R.sup.21 and R.sup.22 together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated ring, wherein said ring optionally comprises one ring oxygen atom, and wherein said ring is optionally substituted with one or two fluorine substituents; carboxy; —CO—NR.sup.23R.sup.24, wherein R.sup.23 and R.sup.24 independently represent hydrogen or (C.sub.1-4)alkyl; —CO—(C.sub.1-4)alkoxy; —NR.sup.25—CO—R.sup.26, wherein R.sup.25 represents hydrogen or (C.sub.1-4)alkyl; and R.sup.26 represents (C.sub.1-4)alkyl or a group —NR.sup.27R.sup.28 wherein R.sup.27 and R.sup.28 independently represent hydrogen or (C.sub.1-4)alkyl; hydroxy-(C.sub.1-4)alkyl; (C.sub.1-3)alkoxy-(C.sub.1-4)alkyl; hydroxy-(C.sub.1-4)alkoxy; (C.sub.1-3)alkoxy-(C.sub.2-4)alkoxy; phenyl; 5-membered heteroaryl; or 3-methoxy-oxetan-3-yl; R.sup.3 represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from: —NR.sup.4—SO.sub.2—Y—R.sup.5, wherein R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents a direct bond; and R.sup.5 represents (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents —NR.sup.Y— wherein R.sup.Y represents hydrogen or (C.sub.1-3)alkyl; and R.sup.5 represents (C.sub.1-4)alkyl; or R.sup.4 and R.sup.5 together with the nitrogen and the —SO.sub.2—Y-group to which they are attached to form a 5-, 6-, or 7-membered ring, wherein Y represents a direct bond or —NR.sup.Y— wherein R.sup.Y represents (C.sub.1-3)alkyl; —CO—NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen, (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or R.sup.6 represents hydrogen and R.sup.7 represents hydroxy, methoxy, or cyano; —SO.sub.2—R.sup.8 wherein R.sup.8 represents (C.sub.1-5)alkyl, —(C.sub.2-4)alkylene-CO—(C.sub.1-3)alkoxy, or —NR.sup.81R.sup.82, wherein R.sup.81 and R.sup.82 independently represent hydrogen or (C.sub.1-4)alkyl; (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; (C.sub.3-6)cycloalkyl optionally mono-substituted with dimethylamino; halogen; cyano; (C.sub.1-3)alkoxy-(C.sub.1-4)alkyl; (C.sub.1-3)alkoxy-(C.sub.2-4)alkoxy; —CO—(C.sub.1-4)alkoxy; 5-membered heteroaryl; —(CH.sub.2).sub.m—NR.sup.9R.sup.10; wherein m represents the integer 0 or 1; and R.sup.9 and R.sup.10 independently represent hydrogen, (C.sub.1-4)alkyl, (C.sub.2-3)fluoroalkyl, hydroxy-(C.sub.2-4)alkyl, or (C.sub.1-4)alkoxy-(C.sub.2-4)alkyl; or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached to form a saturated 4- to 7-membered monocyclic ring or a saturated 7- or 8-membered bicyclic bridged or fused ring system; wherein independently said ring or ring system optionally comprises an oxygen ring atom or a group —NR.sup.11— wherein R.sup.11 represents (C.sub.1-4)alkyl; and wherein said ring or ring system independently is optionally substituted with: one or two fluorine substituents; or one or two methyl substituents; or one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen atom; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein the absolute configuration of the carbon atom carrying the substituent R.sup.2 is as depicted in Formula (I.sub.E): ##STR00014## or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R.sup.1a and R.sup.1b both represent hydrogen; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein X represents N; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, wherein R represents (C.sub.1-4)alkyl, (C.sub.3-6)cycloalkyl, or (C.sub.1-3)trifluoroalkyl; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, wherein R.sup.2 represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.3-6)cycloalkyl, optionally comprising one or two ring oxygen atoms; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; —(CH.sub.2).sub.n—NR.sup.21R.sup.22, wherein n represents the integer 0 or 1; and R.sup.21 and R.sup.22 independently represent hydrogen or (C.sub.1-3)alkyl; or n represents the integer 0; and R.sup.21 and R.sup.22 together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated ring, wherein said ring optionally comprises one ring oxygen atom, and wherein said ring is optionally substituted with one or two fluorine substituents; carboxy; —CO—NR.sup.23R.sup.24, wherein R.sup.23 and R.sup.24 independently represent hydrogen or (C.sub.1-4)alkyl; —CO—(C.sub.1-4)alkoxy; —NR.sup.25—CO—R.sup.26, wherein R.sup.25 represents hydrogen or (C.sub.1-4)alkyl; and R.sup.26 represents (C.sub.1-4)alkyl or a group —NR.sup.27R.sup.28 wherein R.sup.27 and R.sup.28 independently represent hydrogen or (C.sub.1-4)alkyl; hydroxy-(C.sub.1-4)alkyl; hydroxy-(C.sub.2-4)alkoxy; phenyl; tetrazolyl; or 3-methoxy-oxetan-3-yl; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, wherein R.sup.2 represents phenyl, wherein said phenyl is mono-, di-, or tri-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.3-6)cycloalkyl; (C.sub.1-3)fluoroalkyl; or halogen; or R.sup.2 represents 5- or 6-membered heteroaryl, wherein said heteroaryl is mono-, or di-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl ; (C.sub.3-6)cycloalkyl; (C.sub.1-3)fluoroalkyl ; or halogen; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, wherein R.sup.3 represents a fragment ##STR00015## wherein Z.sup.1 and Z.sup.2 independently represent CH or N; R.sup.3a represents: —NR.sup.4—SO.sub.2—Y—R.sup.5, wherein R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents a direct bond; and R.sup.5 represents (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents —NR.sup.Y— wherein R.sup.Y represents hydrogen or (C.sub.1-3)alkyl; and R.sup.5 represents (C.sub.1-4)alkyl; or R.sup.4 and R.sup.5 together with the nitrogen and the —SO.sub.2—Y-group to which they are attached to form a 5-, 6-, or 7-membered ring, wherein Y represents a direct bond or —NR.sup.Y— wherein R.sup.Y represents (C.sub.1-3)alkyl; —CO—NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen, (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; —SO.sub.2—R.sup.8 wherein R.sup.8 represents —NR.sup.81R.sup.82, wherein R.sup.81 and R.sup.82 independently represent hydrogen or (C.sub.1-4)alkyl; (C.sub.1-4)alkyl; (C.sub.1-3)fluoroalkyl; (C.sub.3-6)cycloalkyl optionally mono-substituted with dimethylamino; halogen; cyano; —CO—(C.sub.1-4)alkoxy; 5-membered heteroaryl; —(CH.sub.2).sub.mNR.sup.9R.sup.10; wherein m represents the integer 0 or 1; and R.sup.9 and R.sup.10 independently represent hydrogen, (C.sub.1-4)alkyl, (C.sub.2-3)fluoroalkyl, hydroxy-(C.sub.2-4)alkyl, or (C.sub.1-4)alkoxy-(C.sub.2-4)alkyl; or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached to form a saturated 4- to 7-membered monocyclic ring or a saturated 7- or 8-membered bicyclic bridged or fused ring system; wherein independently said ring or ring system optionally comprises an oxygen ring atom or a group —NR.sup.11— wherein R.sup.11 represents (C.sub.1-4)alkyl; and wherein said ring or ring system independently is optionally substituted with: one or two fluorine substituents; or one or two methyl substituents; or one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen atom; and R.sup.3b represents (C.sub.1-4)alkyl; halogen; (C.sub.3-6)cycloalkyl; or (C.sub.1-3)fluoroalkyl; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8, wherein Z.sup.1 represents N and Z.sup.2 represents CH; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 8, wherein R.sub.3arepresents: —NR.sup.41—SO.sub.2—R.sup.51, wherein R.sup.41 represents hydrogen or (C.sub.1-3)alkyl; and R.sup.51 represents (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or —NR.sup.43—SO.sub.2—R.sup.53, wherein R.sup.43 and R.sup.53 together with the nitrogen and the —SO.sub.2-group to which they are attached to form a 5-, 6-, or 7-membered ring; —CO—NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen, (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; R.sup.3b represents (C.sub.1-4)alkyl; halogen; or (C.sub.3-6)cycloalkyl; or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, wherein R.sup.3 represents 2-chloro-4-(dimethylcarbamoyl)-phenyl; or R.sup.3 represents 2-chloro-6-(carbamoyl)-pyridin-3-yl, 2-chloro-6-(methyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(dimethyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(diethyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(cyclopropyl-(methyl)-carbamoyl)-pyridin-3-yl, 6-(cyclopropyl-carbamoyl)-2-ethyl-pyridin-3-yl, 2-chloro-6-(methylsulfonamido)-pyridin-3-yl, 2-chloro-6-(N-methyl-methylsulfonamido)-pyridin-3-yl, 2-chloro-6-(1,1-dioxo-isothiazolidin-2-yl)-pyridin-3-yl, 2-chloro-6-(cyclopropylsulfonamido)-pyridin-3-yl, 2-chloro-6-((N-methylsulfamoyl)amino)-pyridin-3-yl, 2-chloro-6-((N,N-dimethylsulfamoyl)amino)-pyridin-3-yl, 2-ethyl-6-(methylsulfonamido)-pyridin-3-yl, or 6-(1,1-dioxo-isothiazolidin-2-yl)-2-ethyl-pyridin-3-yl; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein said compound is: 1-(5-(3,4-dimethoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(naphthalen-2-yloxy)ethanone; 1-(5-(2-cyclopropylpyrimidin-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 2-(2-chloro-4-morpholinophenoxy)-1-(5-(2-cyclopropyl-pyrimidin-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(2-cyclopropyl-4-methylpyrimidin-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 2-(2-chloro-4-morpholinophenoxy)-1-(5-(2-cyclopropyl-4-methylpyrimidin-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(3-phenyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(2-phenyloxazol-4-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(2-phenyloxazol-4-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophen-2-yl)acetamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2 ′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-4,5-difluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; 1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2-((2-fluoro-6-morpholinopyridin-3-yl)oxy)ethanone; 2-((2-chloro-5-fluoro-6-iodopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-5-fluoropyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)ethanone; 4-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-3-methylbenzenesulfonamide; 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methylamino)pyridin-3-yl)oxy)ethanone; 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)ethanone; 6-chloro-5-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; 3-chloro-4-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-((dimethylamino)methyl)thiazol-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-4-carboxamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(2-hydroxypropan-2-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(2-hydroxypropan-2-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; Methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylate; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)-thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-5-fluoropyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-Chloro-4-(trifluoromethyl)phenoxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-Chloro-5-(2-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methane-sulfonamide; 2-((2-Chloropyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)-thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-Chloro-5-(2-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; 2-((4-chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; Methyl 1-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-1H-pyrazole-3-carboxylate; 1-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethyl-1H-pyrazole-3-carboxamide; (R)-6-chloro-N,N-diethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; (R)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 4-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-3-methylbenzenesulfonamide; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 2-(4-(aminomethyl)-2-chlorophenoxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)-1-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide; 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluoro-thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; (R)-6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide a); 5-(6-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-6-cyanopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-((2-chloropyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy) acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 6-chloro-5-(2-(5-(3-fluoro-5-(methylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 6-chloro-5-(2-(5-(3-fluoro-5-(methylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; 5-(6-(2-((2-chloro-5-fluoropyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide; Methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylate; Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate; Ethyl 2-(6-(2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate; Ethyl 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenolxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate; Methyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate; Methyl 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate; Methyl 2-(6-(2-((2-chloro-6-(cyclopropanesulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate; Methyl 2-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate; Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)oxazole-4-carboxylate; 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; Ethyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-2-carboxylate; Ethyl 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-2-carboxylate; Ethyl 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-2-carboxylate; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(3-chloro-4-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)phenyl)methanesulfonamide; (R)-2-((2-chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (R)-2-((2-chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-N-cyclopropyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; (R)-N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N-methylmethanesulfonamide; (R)-N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; (R)-2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (R)-2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (R)-N-(4-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyrimidin-2-yl)methanesulfonamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (R)-N-(5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-methoxypyridin-2-yl)methanesulfonamide; 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; 3-chloro-4-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 3-chloro-4-(2-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (R)-6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone; 1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)ethanone; 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; N-(6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(3-chloro-4-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)phenyl)methanesulfonamide; 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-2-carboxamide; 5-(6-(2-((2-chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-2-carboxamide; 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-2-carboxamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; N-(6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2-oxoethoxy)pyridin-2-1)methanesulfonamide; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-((dimethylamino)-methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone; 2-(6-(2-((2-Chloro-6-(methylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetra-hydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide; 2-(6-(2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide; 2-(6-(2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide; 2-(6-(2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide; 2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide; 4-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carboxylic acid; N-(6-chloro-5-(2-(2-methyl-5-(thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone; Methyl 3-((6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)sulfonyl)propanoate; 6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridine-2-sulfonamide; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((2-hydroxyethyl)-(methyl)amino)pyridin-3-yl)oxy)ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((2-methoxyethyl)(methyl)-amino)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone; N-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-cyclopropanesulfonamide; 1-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)pyrrolidin-2-one; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)-pyridin-3-yl)oxy)ethanone; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((3S,5S)-3,5-dimethylpiperidin-1-yl)pyridin-3-yl)oxy)ethanone; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; 2-((6-amino-2-chloropyridin-3-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone; 6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-(cyanomethyl)picolinamide; 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-hydroxy-picolinamide; 3-Chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzamide; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methylamino)pyridin-3-yl)oxy)ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-cyclopropylpyridin-3-yl)oxy)-ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-(3,3-difluoroazetidin-1-yl)phenoxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-morpholinophenoxy)ethanone; N-(3-Chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)phenyl)cyclopropanesulfonamide; Methyl 5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-1-ethyl-1H-pyrazole-3-carboxylate; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)oxy)ethanone; 2-((6-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-chloropyridin-3-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-cyclopropylphenoxy)-ethanone; 1-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)piperazin-2-one; 2-((4-chloro-2-(trifluoromethyl)pyrimidin-5-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone; 2-((4-chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methoxypicolinamide; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2,4-dimethylpyrimidin-5-yl)oxy)ethanone; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-cyclopropyl-N-methylpicolinamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N-methylmethanesulfonamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N′,N′-dimethyl-sulfamide; N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N′-methyl-sulfamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)ethanone; Methyl 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinate; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; 6-Chloro-5-(2-(5-(5-(dimethylcarbamoyl)furan-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 5-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylfuran-2-carboxamide; Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate; 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(5-(methylcarbamoyl)furan-2-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylfuran-2-carboxamide; 2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyloxazole-4-carboxamide; 2-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylthiazole-4-carboxamide; 2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylthiazole-4-carboxamide; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-(hydroxymethyl)-thiophen-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid; 1-(4-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-yl)-3-ethylurea; 2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxamide; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone; 2-(2-chloro-4-morpholinophenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(3-methoxyoxetan-3-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-(ethylamino)-1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(2-Amino-5-fluorothiazol-4-yl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone; 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-methyl-phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; (S)-N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamideb); 6-chloro-5-(2-(5-(4-(difluoromethoxy)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(2,4-difluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(2,5-difluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(3-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(2-methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2,4-difluorophenoxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4-fluoro-2-methylphenoxy)ethanone; 2-((2-chloropyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yeethanone; 4-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzenesulfonamide; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-(trifluoromethyl)pyridin-3-yl)oxy)ethanone; 4-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-3-methylbenzenesulfonamide; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(dimethylamino)-2-methylpyridin-3-yl)oxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; (5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)(1-((2-ethyl-6-methylpyridin-3-yl)oxy)cyclopropyl)methanone; 2-(2-chloro-4-fluorophenoxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; Methyl 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinate; 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; N-(6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2,4-dimethylpyrimidin-5-yl)oxy)ethanone; 6-chloro-N-cyclopropyl-5-(2-(5-(4-cyclopropyl-2-fluoro-phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2,6-dimethylpyridin-3-yl)oxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-fluoropyridin-3-yl)oxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-methylpyridin-3-yl)oxy)ethanone; 2-(4-chloro-2-ethylphenoxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone; 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(2-phenylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 6-chloro-5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; N-(6-chloro-5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)-1-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 6-chloro-5-(2-(5-(2,3-difluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 1-(5-(4-(2H-Tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone; 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-diethyl-4-fluorothiophene-2-carboxamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-(3-methoxyoxetan-3-yl)thiazol-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2,4-dimethyloxazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2,5-dimethyloxazol-4-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; N-(6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-N-cyclopropyl-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; 2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N-methylmethanesulfonamide; N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; (R)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-((dimethylamino)-methyl)thiophen-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloropyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5-(1H-tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)ethanone; N-cyclopropyl-6-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(6-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2-ethyl-4-methylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2-isopropyl-4-methylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(5-(2-(5-(2,5-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2,5-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(5-fluoro-3-methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(2-methyl-5-(4-methyl-2-(trifluoromethyl)thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(4-((dimethylamino)methyl) thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl) ethanone; 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridine-3-yl)oxy)-1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 5-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[21,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyl-thiophene-3-carboxamide; 5-(6-(2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide; 5-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5 ,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4, 5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide; 5-(6-(2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide; 6-Chloro-5-(2-(5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethyl-picolinamide; 6-Chloro-5-(2-(5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methyl-picolinamide; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 1-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile; 1-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 1-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone; (S)-1-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanonec); 2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-ethyl-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(2,4-dimethylthiazol-5-yl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone; N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(trifluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 1-(5-(3 ,4-dimethoxyphenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(naphthalen-2-yloxy)ethanone; 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(543 ,4-dimethoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2,4-dichlorophenoxy)-1-(5-(3,4-dimethoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)ethanone; 2-((2-ethylpyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloropyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)ethanone; 2-(2-ethyl-4-fluorophenoxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)ethanone; 2-((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyloxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyloxy)-ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2,4-dichlorophenoxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4-chloro-2-methylphenoxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloropyridin-3-yl)oxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-oxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)ethanone; 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(isoquinolin-7-yloxy)ethanone; 2-(2-chloro-3-(trifluoromethyl)phenoxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2,4-dichlorophenoxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(1-phenyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyl-oxy)ethanone; 1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyl-oxy)ethanone; 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone, 2-((2-ethylpyridin-3-yl)oxy)-1-(5-(1-phenyl-1 H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2,4-dichlorophenoxy)-1-(5-(thieno[2,3-b]pyridin-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(thieno[2,3-b]-pyridin-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloropyridin-3-yl)oxy)-1-(5-(thieno[2,3-b]pyridin-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(thieno[2,3-b]pyridin-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yeethanone; 2-(2-chloro-5-methylphenoxy)-1-(5-(thieno[2,3-b]-pyridin-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; ((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-ethylphenoxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-(difluoromethyl)-2-fluorophenyl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone; 1-(5-(4-(difluoromethyl)-2-fluorophenyl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 2-((2-chloropyridin-3-yl)oxy)-1-(5-(4-(difluoromethyl)-2-fluorophenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoropyridin-3-yl)-7,8 -dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-(trifluoromethyl)-phenoxy)ethanone; 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyloxy)ethanone; 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyloxy)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((5-chloro-1-methyl-4-(trifluoromethyl)-1 H-pyrazol-3-yl)oxy)-1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; ((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(2-fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(isoquinolin-7-yloxy)ethanone; 2-(2-ethyl-4-fluorophenoxy)-1-(5-(2-fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-ethyl-4-fluorophenoxy)ethanone; 1-((5R)-5-(4-chloro-2-fluorophenyl)-4a,5-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(7H)-yl)-2-(2-chloro-4-morpholinophenoxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4-chloro-2-methylphenoxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloropyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone; 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(3,5-dimethylisoxazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone; 2-(2,4-dichlorophenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3,5-di-methylisoxazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(4-chloro-2-methylphenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-Aethanone; 2-(4-chloro-2-ethylphenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinonitrile; N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide; 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide; N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(3-chloro-4-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro-thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)phenyl)methanesulfonamide; 5-(6-(2-(2-chloro-4-(methylsulfonamido)phenoxy)-acetyl)-5,6,7,8-tetrahydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide; 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluoro-thiophen-2-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide; N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3-]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone; N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-ethyl-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-cyclopropyl-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpicolinamide; N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 1-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone, N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide; 1-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone; (S)-N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamided); N-(6-chloro-5-(2-(2-(difluoromethyl)-5-(2-fluoro-4-methylphenyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-cyclopropyl-5-(2-(2-(difluoromethyl)-5-(2,4-dimethylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-ethylpicolinamide; 1-(2-(difluoromethyl)-5-(2,4-dimethylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-cyclopropylpyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(1-(5-(4-chloro-2-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6-carbonyl)cyclopropoxy)pyridin-2-yl)methanesulfonamide; 5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,6-dicyclopropylpicolinamide; N-(6-chloro-5-((1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-methyl-1-oxopropan-2-yl)oxy)pyridin-2-yl)methanesulfonamide; 6-chloro-5-(1-(5-(4-chloro-2-fluorophenyl)-2-methyl-5 ,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6-carbonyl)cyclopropoxy)-N,N-dimethylpicolinamide; 6-chloro-5-((1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-methyl-1-oxopropan-2-yl)oxy)-N,N-dimethylpicolinamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)ethan-1-one; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpyridine-2-sulfonamide; 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpyridine-2-sulfonamide; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((1-methyl-1 H-indo1-4-yl)oxy)ethan-1-one; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((7-methoxy-2-methylquinolin-4-yl)oxy)ethan-1-one; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((7-chloro-8-methylquinolin-4-yl)oxy)ethan-1-one; 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((5,8-difluoroquinolin-4-yl)oxy)ethan-1-one; N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-4-ethylpyrimidin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(5-(2-(5-(4-(aminomethyl)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloropyridin-2-yl)methanesulfonamide; 5-(2-(5-(4-(aminomethyl)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloro-N-cyclopropylpicolinamide; methyl-4-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-3-fluorobenzoate; methyl-4-(6-(2-((2-chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-3-fluorobenzoate; N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-methoxypropan-2-yl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-methoxypropan-2-yl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-(methoxymethyl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(methoxymethyl)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-methoxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-methoxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide; N-(6-Chloro-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide; 1-(5-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-6-morpholinopyridin-3-yl)oxy)ethan-1-one; or 1-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethan-1-one; or a pharmaceutically acceptable salt thereof.
13. A phaunaceutical composition comprising, as active principle, one or more compounds according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, formulated as a medicament.
15. A method of treating a disease or disorder comprising administering to a subject in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a lung disease.
16. A process for preparing a compound of formula (I) according to claim 1, comprising acylating a compound of foiiiiula (IV) with an acid of structure (2): ##STR00016## wherein R.sup.2 X, R.sup.3 R.sup.1a and R.sup.1b are as defined the compound of formula (I) according to claim 1.
17. A compound of the formula (IV): ##STR00017## wherein R.sup.2 and X are as defined for the compounds of formula (I) according to claim 1.
18. The method according to claim 15, wherein the lung disease is interstitial lung disease, chronic obstructive pulmonary disease, pulmonary embolism, or pulmonary hypertension.
19. The method according to claim 15, wherein the lung disease is pulmonary arterial hypertension, radiation pneumonitis, asthma, or adult respiratory distress syndrome.
20. A method of treating a disease or disorder comprising administering to a subject in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is inflammatory bowel disease, postinfectious irritable bowel syndrome, coeliac disease, idiopathic constipation, or irritable bowel syndrome.
21. A method of treating a disease or disorder comprising administering to a subject in need thereof a compound according to claim 1 or a phannaceutically acceptable salt thereof, wherein the disease or disorder is breast cancer, prostate cancer, or a neuroendocrine tumor with elevated serotonin secretion.
22. A method of treating a disease or disorder comprising administering to a subject in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is multiple sclerosis or systemic sclerosis.
23. The compound according to claim 2, wherein X represents N; or a phaitnaceutically acceptable salt thereof.
24. The compound according to claim 3, wherein R represents (C.sub.1-4)alkyl, (C.sub.3-6)cycloalkyl, or (C.sub.1-3)trifluoroalkyl; or a pharmaceutically acceptable salt thereof.
25. The compound according to claim 24, wherein R.sup.2 represents aryl or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.3-6)cycloalkyl, optionally containing one or two ring oxygen atoms; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; —(CH.sub.2).sub.n—NR.sup.21R.sup.22, wherein n represents the integer 0 or 1; and R.sup.21 and R.sup.22 independently represent hydrogen or (C.sub.1-3)alkyl; or n represents the integer 0; and R.sup.21 and R.sup.22 together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated ring, wherein said ring optionally contains one ring oxygen atom, and wherein said ring is optionally substituted with one or two fluorine substituents; carboxy; —CO—NR.sup.23R.sup.24, wherein R.sup.23 and R.sup.24 independently represent hydrogen or (C.sub.1-4)alkyl; —CO—(C.sub.1-4)alkoxy; —NR.sup.25—CO—R.sup.26, wherein R.sup.25 represents hydrogen or (C.sub.1-4)alkyl; and R.sup.26 represents (C.sub.1-4)alkyl or a group —NR.sup.27R.sup.28 wherein R.sup.27 and R.sup.28 independently represent hydrogen or (C.sub.1-4)alkyl; hydroxy-(C.sub.1-4)alkyl; hydroxy-(C.sub.2-4)alkoxy; phenyl; tetrazolyl; or 3-methoxy-oxetan-3-yl; or a pharmaceutically acceptable salt thereof.
26. The compound according to claim 24, wherein R.sup.2 represents phenyl, wherein said phenyl is mono-, di-, or tri-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.3-6)cycloalkyl; (C.sub.1-3)fluoroalkyl; or halogen; or R.sup.2 represents 5- or 6-membered heteroaryl, wherein said heteroaryl is mono-, or di-substituted, wherein the substituents are independently selected from: (C.sub.1-4)alkyl; (C.sub.3-6)cycloalkyl; (C.sub.1-3)fluoroalkyl; or halogen; or a pharmaceutically acceptable salt thereof.
27. The compound according to claim 25, wherein R.sup.3 represents a fragment ##STR00018## wherein Z.sup.1 and Z.sup.2 independently represent CH or N; R.sup.3a represents: —NR.sup.4—SO.sub.2—Y—R.sup.5, wherein R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents a direct bond; and R.sup.5 represents (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or R.sup.4 represents hydrogen or (C.sub.1-3)alkyl; Y represents —NR.sup.Y— wherein R.sup.Y represents hydrogen or (C.sub.1-3)alkyl; and R.sup.5 represents (C.sub.1-4)alkyl; or R.sup.4 and R.sup.5 together with the nitrogen and the —SO.sub.2—Y-group to which they are attached to form a 5-, 6-, or 7-membered ring, wherein Y represents a direct bond or —NR.sup.Y— wherein R.sup.Y represents (C.sub.1-3)alkyl; —CO—NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen, (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; —SO.sub.2—R.sup.8 wherein R.sup.8 represents —NR.sup.81R.sup.82, wherein R.sup.81 and R.sup.82 independently represent hydrogen or (C.sub.1-4)alkyl; (C.sub.1-4)alkyl; (C.sub.1-3)fluoroalkyl; (C.sub.3-6)cycloalkyl optionally mono-substituted with dimethylamino; halogen; cyano; —CO—(C.sub.1-4)alkoxy; 5-membered heteroaryl; —(CH.sub.2).sub.m—NR.sup.9R.sup.10; wherein m represents the integer 0 or 1; and R.sup.9 and R.sup.10 independently represent hydrogen, (C.sub.1-4)alkyl, (C.sub.2-3)fluoroalkyl, hydroxy-(C.sub.2-4)alkyl, or (C.sub.1-4)alkoxy-(C.sub.2-4)alkyl, or R.sup.9 and R.sup.10 together with the nitrogen to which they are attached to form a saturated 4- to 7-membered monocyclic ring or a saturated 7- or 8-membered bicyclic bridged or fused ring system; wherein independently said ring or ring system optionally contains an oxygen ring atom or a group —NR.sup.11— wherein R.sup.11 represents (C.sub.1-4)alkyl; and wherein said ring or ring system independently is optionally substituted with: one or two fluorine substituents; or one or two methyl substituents; or one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen atom; and R.sup.3b represents (C.sub.1-4)alkyl; halogen; (C.sub.3-6)cycloalkyl; or (C.sub.1-3)fluoroalkyl; or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 27, wherein Z.sup.1 represents N and Z.sup.2 represents CH; or a pharmaceutically acceptable salt thereof.
29. The compound according to claim 27, wherein R.sup.3a represents: —NR.sup.41—SO.sub.2—R.sup.51, wherein R.sup.41 represents hydrogen or (C.sub.1-3)alkyl; and R51 represents (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; or —NR.sup.43—SO.sub.2—R.sup.53, wherein R.sup.43 and R.sup.53 together with the nitrogen and the —SO.sub.2-group to which they are attached to form a 5-, 6-, or 7-membered ring; —CO—NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen, (C.sub.1-4)alkyl, or (C.sub.3-6)cycloalkyl; R.sup.3b represents (C.sub.1-4)alkyl; halogen; or (C.sub.3-6)cycloalkyl; or a pharmaceutically acceptable salt thereof.
30. The compound according to claim 26, wherein R.sup.3 represents 2-chloro-4-(dimethylcarbamoyl)-phenyl; or R.sup.3 represents 2-chloro-6-(carbamoyl)-pyridin-3-yl, 2-chloro-6-(methyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(dimethyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(diethyl-carbamoyl)-pyridin-3-yl, 2-chloro-6-(cyclopropyl-(methyl)-carbamoyl)-pyridin-3-yl, 6-(cyclopropyl-carbamoyl)-2-ethyl-pyridin-3-yl, 2-chloro-6-(methylsulfonamido)-pyridin-3-yl, 2-chloro-6-(N-methyl-methylsulfonamido)-pyridin-3-yl, 2-chloro-6-(1,1-dioxo-isothiazolidin-2-yl)-pyridin-3-yl, 2-chloro-6-(cyclopropylsulfonamido)-pyridin-3-yl, 2-chloro-6-((N-methylsulfamoyl)amino)-pyridin-3-yl, 2-chloro-6-((N,N-dimethylsulfamoyl)amino)-pyridin-3-yl, 2-ethyl-6-(methylsulfonamido)-pyridin-3-yl, or 6-(1,1-dioxo-isothiazolidin-2-yl)-2-ethyl-pyridin-3-yl; or a pharmaceutically acceptable salt thereof.
Description
EXPERIMENTAL SECTION
(1) Abbreviations (as Used Herein and in the Description Above) aq. aqueous Bu butyl (such as in nBuLi=n-butyl lithium) CC column chromatography on silica gel conc. Concentrated DCC 1,3-dicyclohexylcarbodiimide DCM dichloromethane DIPEA N-ethyldiisopropylamine DME 1,2-dimethoxyethane DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide DTT dithiothreitol EA ethyl acetate E. coli. Escherichia coli Eq (molar) equivalent(s) Et ethyl EtOH ethanol FC flash chromatography h hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HOBt 1-hydroxybenzotriazole hydrate HPLC high performance liquid chromatography LC liquid chromatography M molarity [mol L.sup.−1] Me methyl MeCN acetonitrile MeOH methanol MS mass spectroscopy min. minute(s) N normality NFSI N-fluorobenzenesulfonimide NaOtBu sodium tert. (tertiary) butoxide org. organic Pd/C palladium on carbon Ph phenyl PTSA p-Toluenesulfonic acid rt room temperature Sat. Saturated TBAF tetrabutylammonium fluoride TBME tert-butylmethylether TBTU 0-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate tBu tert-butyl=tertiary butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMSCl trimethylsilyl chloride Tris tris(hydroxymethyl)aminomethane t.sub.R retention time
(2) I. Chemistry
(3) The following examples illustrate the preparation of biologically active compounds of the invention but do not at all limit the scope thereof.
(4) General: All temperatures are stated in degrees Celsius (° C.). Unless otherwise indicated, the reactions take place at RT under an nitrogen atmosphere and are run in a flame dried round-bottomed flask equipped with a magnetic stir bar.
(5) Characterization Methods Used:
(6) The LC-MS and GC-MS retention times have been obtained using the following elution conditions:
(7) A) LC-MS (A):
(8) Zorbax SB-Aq, 3.5 μm, 4.6×50 mm column thermostated at 40° C. The two elution solvents were as follows: solvent A=water+0.04% TFA; solvent B=acetonitrile. The eluent flow rate was 4.5 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):
(9) TABLE-US-00001 t (min) 0 0.08 1.07 1.57 1.67 1.70 Solvent A (%) 95 95 5 5 95 95 Solvent B (%) 5 5 95 95 5 5
(10) B) LC-MS (B):
(11) Waters Atlantis T3, 5 μm, 4.6×30 mm column thermostated at 40° C. The two elution solvents were as follows: solvent A=water+0.04% TFA; solvent B=acetonitrile. The eluent flow rate was 4.5 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):
(12) TABLE-US-00002 t (min) 0 0.08 1.07 1.57 1.67 1.70 Solvent A (%) 95 95 5 5 95 95 Solvent B (%) 5 5 95 95 5 5
(13) D) GC-MS (A)
(14) Zebron ZB-5 MS, 15 m×0.25 mm ID, 0.25 μm film, 2.0 mL/min. The carrier gas is Helium and the chemical ionization occurs with CH.sub.4 as reagent gas. Temp. gradient: 60−300° C. from 0 to 4.0 min and 300° C. isotherm from 4.0 to 5.0 min.
(15) Non-Chiral Preparative Methods Used:
(16) The purifications by preparative LC-MS have been performed using the conditions described hereafter.
(17) E) Preparative LC-MS (I):
(18) A X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: solvent A=water+0.5% NH.sub.4OH; solvent B=acetonitrile. The eluent flow rate was 75 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):
(19) TABLE-US-00003 t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 90 90 5 5 90 90 Solvent B (%) 10 10 95 95 10 10
(20) Chiral Preparative LC-MS Methods Used:
(21) The separation of selected enantiomers has been performed using chiral column chromatography using the conditions described hereafter.
(22) F) Chiral Preparative LC-MS (I):
(23) ChiralPack IC, 5 μm, 250×4.6 mm was used. The two elution solvents were as follows: solvent A=0.05% diethylamine in heptane; solvent B=0.05% diethylamine in EtOH. The eluent flow rate was 0.8 mL/min. The elution was done using 10% of the solvent A and 90% of the solvent B.
(24) G) Chiral Preparative LC-MS (II):
(25) ChiralPack AS-H, 5 μm, 250×4.6 mm was used. The two elution solvents were as follows: solvent A==0.05% diethylamine in heptane; solvent B=0.05% diethylamine in EtOH. The eluent flow rate was 1 mL/min. The elution was done using 50% of the solvent A and 50% of the solvent B.
(26) H) Chiral Preparative LC-MS (III):
(27) ChiralPack IC, 5 μm, 250×4.6 mm was used. The two elution solvents were as follows: solvent A=0.1% diethylamine in MeOH; solvent B=THF. The eluent flow rate was 1.2 mL/min. The elution was done using 30% of the solvent A and 70% of the solvent B.
(28) I) Chiral Preparative LC-MS (IV):
(29) ChiralPack AD-H, 5 μm, 250×4.6 mm was used. The two elution solvents were as follows: solvent A=0.05% diethylamine in heptane; solvent B=0.05% diethylamine in EtOH. The eluent flow rate was 0.8 mL/min. The elution was done using 90% of the solvent A and 10% of the solvent B.
(30) Preparation of the Compounds of Structure 1
(31) Method A
(32) All intermediates of the structure 1 have been prepared in analogy to the following procedure:
(33) A solution of 2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanamine (50 mg), 3,4-di-methoxybenzaldehyde (33 mg) and TFA (4 μl) in toluene (2 mL) was stirred at 80° C. for 15 h. The mixture was diluted with 1N aq. NaOH and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: DCM, solvent B: 7N NH.sub.3 in MeOH, gradient in % B: 1 to 3, flow rate: 9 mL/min) to afford 47 mg of colourless solid. LC-MS (A) t.sub.R=0.50 min; [M+H].sup.+: 331.14.
(34) Preparation of the Compounds of Formula (I)
(35) Method B
Example 1.1.1
1-(5-(3,4-dimethoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(naphthalen-2-yloxy)ethanone
(36) To a solution of (2-naphtoxy)acetic acid (14.6 mg) in DCM (2 mL) was added DMAP (2.5 mg), HOBT (12 mg), EDCl (23 mg) and DIPEA (40 μl). The reaction mixture was stirred for min. The 5-(3,4-dimethoxyphenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo [4,5-c]pyridine (24 mg) was added and the mixture was stirred for 15 h. The mixture was diluted with water, the layers were separated and the org. phase was further washed with water. The combined aq. layers were extracted with DCM. The combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 19.6 mg of colourless oil. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 515.11.
(37) Method C
Example 1.2.1
2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)yl) ethanone
(38) To a solution of 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)acetic acid (TFA salt) (22 mg) in DMF (1 mL) was added TBTU (19 mg). The mixture was stirred for 30 min. The 5-(2-fluoropyridin-3-yl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine (16 mg) and DIPEA (28 μl) were added and the mixture was stirred for 30 min. The crude was purified by preparative LC-MS (I) to afford 17 mg of orange oil. LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: 558.02.
(39) Following examples were synthesized starting from the appropriate acid derivative and amine following the method B or C. LC-MS data are listed in table 1 below. The LC-MS conditions used were LC-MS (A).
(40) TABLE-US-00004 TABLE 1 Example Name t.sub.R [M + H].sup.+ IC.sub.50 [nM] 1.1.1 1-(5-(3,4-dimethoxyphenyl)-2-methyl-7,8-dihydro- 0.90 515.11 10 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- (naphthalen-2-yloxy)ethanone 1.2.1 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2- 0.60 558.02 208 fluoropyridin-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)yl)ethanone 1.3.1 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoro-4- 0.84 585.60 4 methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.3.2 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2- 0.78 586.77 9 fluoro-4-methoxyphenyl)-2-methyl-7,8-dihydro-[1,3,4] thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.3.3 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-methoxyphenyl)-2- 0.85 570.99 10 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide 1.3.4 N-(6-chloro-5-(2-(5-(2-fluoro-4-methoxyphenyl)-2-methyl-7,8- 0.80 580.94 8 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.4.1 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.70 591.04 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)ethanone 1.4.2 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.70 500.13 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.4.3 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.92 576.00 4 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2- chloro-4-morpholinophenoxy)ethanone 1.4.4 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.92 577.78 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-morpholinopyridin-3-yl)oxy)ethanone 1.4.5 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.68 486.10 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethylpyridin-3-yl)oxy)ethanone 1.4.6 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.94 536.08 11 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (difluoromethyl)-2-ethylpyridin-3-yl)oxy)ethanone 1.4.7 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.93 534.89 6 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(dimethylamino)pyridin-3-yl)oxy)ethanone 1.4.8 Methyl 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.87 549.96 32 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinate 1.4.9 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.90 516.77 36 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinonitrile 1.4.10 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.95 617.75 8 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-iodopyridin-3-yl)oxy)ethanone 1.4.19 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.81 535.35 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.4.21 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.85 549.37 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N-methylpicolinamide 1.4.24 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.93 515.76 11 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)benzonitrile 1.4.31 Methyl 5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.83 533.03 40 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-1-ethyl-1H-pyrazole-3-carboxylate 1.4.36 2-((4-chloro-2-(trifluoromethyl)pyrimidin-5-yl)oxy)-1-(5-(4-chloro- 0.95 560.89 38 2-fluorophenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.4.38 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.99 602.93 3 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3- yl)oxy)ethanone 1.4.39 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.84 584.75 5 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.4.40 2-((4-chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)-1-(5-(4-chloro- 0.93 535.79 4 2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.4.42 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.82 562.85 18 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.4.43 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.93 591.14 35 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3- yl)oxy)ethanone 1.4.44 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.70 575.16 51 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3- yl)oxy)ethanone 1.4.45 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.80 486.88 98 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- ((2,4-dimethylpyrimidin-5-yl)oxy)ethanone 1.4.46 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.87 589.16 16 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N-cyclopropyl-N-methylpicolinamide 1.4.47 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.88 559.13 10 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)etha-none 1.4.48 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.89 599.05 10 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)-N-methylmethanesulfonamide 1.4.49 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.88 611.04 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)ethanone 1.4.50 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.88 614.06 78 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)-N′,N′-dimethyl-sulfamide 1.4.51 N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.85 579.11 12 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2- oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 1.4.52 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.83 599.75 38 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)-N′-methyl-sulfamide 1.4.53 N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.87 591.94 22 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-6-cyclopropylpyridin-2-yl)methanesulfonamide 1.4.54 N-(6-chloro-5-(1-(5-(4-chloro-2-fluorophenyl)-2-methyl-5,6,7,8- 0.89 610.97 37 tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6- carbonyl)cyclopropoxy)pyridin-2-yl)methanesulfonamide 1.4.55 5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.93 581.12 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,6-dicyclopropylpicolinamide 1.4.56 N-(6-chloro-5-((1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8- 0.91 612.89 567 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-methyl-1-oxopropan-2-yl)oxy)pyridin-2- yl)methanesulfonamide 1.4.57 6-chloro-5-(1-(5-(4-chloro-2-fluorophenyl)-2-methyl-5,6,7,8- 0.89 588.95 39 tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6- carbonyl)cyclopropoxy)-N,N-dimethylpicolinamide 1.4.58 6-chloro-5-((1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.91 590.99 55 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- methyl-1-oxopropan-2-yl)oxy)-N,N-dimethylpicolinamide 1.4.59 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.85 569.94 27 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)ethan-1-one 1.4.60 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.8 584.89 36 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N-methylpyridine-2-sulfonamide 1.4.61 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.91 598.91 37 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpyridine-2-sulfonamide 1.4.62 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.92 510.16 15 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((1- methyl-1H-indol-4-yl)oxy)ethan-1-one 1.4.63 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.74 552.12 65 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((7- methoxy-2-methylquinolin-4-yl)oxy)ethan-1-one 1.4.64 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.79 556.09 255 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((7- chloro-8-methylquinolin-4-yl)oxy)ethan-1-one 1.4.65 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.84 544.11 31 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- ((5,8-difluoroquinolin-4-yl)oxy)ethan-1-one 1.5.1 2-(2-chloro-4-morpholinophenoxy)-1-(5-(3,5-dimethylisoxazol-4- 0.82 543.02 22 yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.5.2 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3,5- 0.82 544.36 9 dimethylisoxazol-4-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.6.1 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.95 499.09 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2,4- difluorophenoxy)ethanone 1.6.2 2-(2-chloro-4-fluorophenoxy)-1-(5-(4-cyclopropyl-2- 0.97 515.05 10 fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.6.3 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.69 492.16 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- ((2,6-dimethylpyridin-3-yl)oxy)ethanone 1.6.4 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.93 532.05 68 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (trifluoromethyl)pyridin-3-yl)oxy)ethanone 1.6.5 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.87 481.74 89 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- fluoropyridin-3-yl)oxy)ethanone 1.6.6 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.68 478.14 25 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- methylpyridin-3-yl)oxy)ethanone 1.6.7 2-(4-chloro-2-ethylphenoxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)- 1.03 525.07 7 2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.6.8 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.72 506.14 23 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.6.9 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.71 492.13 457 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethylpyridin-3-yl)oxy)ethanone 1.6.10 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.98 494.96 6 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4- fluoro-2-methylphenoxy)ethanone 1.6.11 2-((2-chloropyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2-fluorophenyl)- 0.89 497.65 14 2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.6.12 4-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.80 542.03 390 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)benzenesulfonamide 1.6.13 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.81 531.91 4 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- (trifluoromethyl)pyridin-3-yl)oxy)ethanone 1.6.14 4-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.83 556.03 45 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-3-methylbenzenesulfonamide 1.6.15 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.72 521.37 6 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (dimethylamino)-2-methylpyridin-3-yl)oxy)ethanone 1.6.16 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.75 547.46 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone 1.6.17 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2- 0.94 583.48 3 fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.6.18 (5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.75 532.28 186 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)(1-((2- ethyl-6-methylpyridin-3-yl)oxy)cyclopropyl)methanone 1.6.19 2-chloro-3-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8- 0.77 514.35 250 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridine-1-oxide 1.6.20 3-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.85 522.45 94 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-2-ethyl-6-methylpyridine-1-oxide 1.6.21 Methyl 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl- 0.90 555.91 8 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinate 1.6.22 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(4- 0.96 540.90 3 cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.6.23 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8- 0.92 522.90 8 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinonitrile 1.6.24 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(4- 0.98 566.39 7 cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.6.25 6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8- 0.85 568.90 4 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.6.26 N-(6-chloro-5-(2-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8- 0.86 591.07 12 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.6.27 1-(5-(4-cyclopropyl-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.83 492.97 161 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- ((2,4-dimethylpyrimidin-5-yl)oxy)ethanone 1.6.28 6-chloro-N-cyclopropyl-5-(2-(5-(4-cyclopropyl-2-fluoro-phenyl)-2- 0.89 595.21 18 methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide 1.6.29 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(4-cyclopropyl- 0.90 565.20 17 2-fluorophenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.7.1 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol- 0.71 525.82 337 5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.7.2 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(2- 0.78 617.10 32 morpholinothiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.7.3 2-((2-chloropyridin-3-yl)oxy)-1-(2-methyl-5-(2-morpholinothiazol- 0.69 532.29 338 5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.7.4 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(2-methyl-5-(2- 0.79 575.45 408 morpholinothiazol-5-yl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.8.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4- 0.67 588.10 18 ((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.8.2 1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8- 0.49 497.03 140 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-((2-ethylpyridin-3-yl)oxy)ethanone 1.8.3 2-(4-chloro-2-methylphenoxy)-1-(5-(4-((dimethylamino)methyl) 0.72 516.06 95 thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.8.4 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(4- 0.68 546.21 106 ((dimethylamino)methyl)thiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.8.5 2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridine-3- 0.75 614.00 25 yl)oxy)-1-(5-(4-((dimethylamino)methyl)thiophen-2-yl)-2-methyl- 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 1.10.1 1-(5-(2-cyclopropylpyrimidin-5-yl)-2-methyl-7,8-dihydro- 0.61 490.00 187 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.10.2 2-(2-chloro-4-morpholinophenoxy)-1-(5-(2-cyclopropyl-pyrimidin- 0.84 565.94 18 5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.10.3 1-(5-(2-cyclopropyl-4-methylpyrimidin-5-yl)-2-methyl-7,8- 0.62 504.38 38 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.10.4 2-(2-chloro-4-morpholinophenoxy)-1-(5-(2-cyclopropyl-4- 0.82 580.51 18 methylpyrimidin-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.11.1 2-(4-chloro-2-methylphenoxy)-1-(2-methyl-5-(3-phenyl-1,2,4- 1.02 521.02 35 oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.11.2 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(3-phenyl-1,2,4- 0.71 502.11 141 oxadiazol-5-yl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.11.3 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(3- 0.96 592.93 4 phenyl-1,2,4-oxadiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.12.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(2- 0.92 592.04 14 phenyloxazol-4-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.12.2 2-((2-ethylpyridin-3-yl)oxy)-1-(2-methyl-5-(2-phenyloxazol-4-yl)- 0.69 501.11 336 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 1.13.1 N-(5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.78 587.92 54 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophen-2-yl)acetamide 1.14.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3- 0.88 583.94 4 fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.2 1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.67 507.00 6 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.14.3 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(5- 0.93 567.00 17 cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.4 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl- 0.87 524.00 17 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinonitrile 1.14.5 1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.86 568.04 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2-((2- fluoro-6-morpholinopyridin-3-yl)oxy)ethanone 1.14.6 2-((2-chloro-5-fluoro-6-iodopyridin-3-yl)oxy)-1-(5-(5-cyclopropyl- 0.94 642.81 6 3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.7 2-((2-chloro-5-fluoropyridin-3-yl)oxy)-1-(5-(5-cyclopropyl-3- 0.87 516.89 25 fluoropyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.14.8 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl- 0.79 569.81 3 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.14.9 2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5- 0.92 602.03 4 cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.10 2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3- 0.97 609.99 4 yl)oxy)-1-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8- dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.11 2-((2-chloro-4,5-difluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5- 0.95 619.95 122 cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.12 2-((2-chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5- 0.91 601.98 41 cyclopropyl-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.14.13 N-(6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-2-methyl- 0.80 591.92 7 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.15.1 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(6- 0.94 564.39 58 (difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.15.2 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(6- 0.92 606.50 7 (difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.15.3 1-(5-(6-(difluoromethoxy)-4-methylpyridin-3-yl)-2-methyl-7,8- 0.70 529.25 156 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5c]pyridin-6(5H)- yl)-2-((2-ethyl-6-methylpyridin-3-yl)oxy)ethanone 1.16.1 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro- 0.79 535.79 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(dimethylamino)pyridin-3-yl)oxy)ethanone 1.16.2 4-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro- 0.65 550.82 74 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-3-methylbenzenesulfonamide 1.16.3 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro- 0.82 522.34 8 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(methylamino)pyridin-3-yl)oxy)ethanone 1.16.4 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro- 0.92 561.29 27 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)ethanone 1.16.5 6-chloro-5-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8- 0.87 518.36 35 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinonitrile 1.16.6 3-chloro-4-(2-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8- 0.89 517.39 13 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)benzonitrile 1.16.7 1-(5-(6-chloro-2-fluoropyridin-3-yl)-2-methyl-7,8-dihydro- 0.97 560.34 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2- chloro-4-(trifluoromethyl)phenoxy)ethanone 1.17.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4- 0.65 588.94 62 ((dimethylamino)methyl)thiazol-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.18.1 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl- 0.78 603.22 14 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-N,N-dimethylthiazole-4-carboxamide 1.19.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(2- 0.77 561.21 6 hydroxypropan-2-yl)thiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.20.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(2- 0.82 588.92 12 hydroxypropan-2-yl)thiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.21.1 Methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.88 589.44 5 methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene- 3-carboxylate 1.23.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3- 0.87 550.38 2 fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.23.2 4-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.76 522.35 89 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-3-methylbenzenesulfonamide 1.23.3 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(3- 0.92 532.30 20 fluorothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.23.4 N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.79 556.81 7 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 1.23.5 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3-fluorothiophen-2- 0.97 530.99 9 yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.23.6 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.78 534.86 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.23.7 2-(4-(aminomethyl)-2-chlorophenoxy)-1-(5-(3-fluorothiophen-2- 0.89 488.08 38 yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.23.8 2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)-1-(5-(3- 0.92 555.03 6 fluorothiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.23.9 N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.83 582.87 14 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide 1.23.10 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.81 520.81 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N-methylpicolinamide 1.23.11 2-((4-chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)-1-(5-(3- 0.89 507.85 6 fluorothiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.23.12 Methyl 1-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8- 0.79 504.88 265 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-1H-pyrazole-3-carboxylate 1.23.13 1-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.75 517.88 103 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethyl-1H-pyrazole-3-carboxamide 1.23.14 (R)-6-chloro-N,N-diethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2- 0.86 563.04 19 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide 1.23.15 (R)-2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(3- 0.84 530.83 20 fluorothiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.24.1 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl- 0.83 620.56 2 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide 1.24.2 5-(6-(2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetyl)-2- 0.88 603.46 22 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N- dimethylthiophene-2-carboxamide 1.24.3 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl- 0.92 602.45 8 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide 1.24.4 5-(6-(2-((2-chloro-6-cyanopyridin-3-yl)oxy)acetyl)-2-methyl- 0.81 560.33 46 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide 1.24.5 5-(6-(2-((2-chloropyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8- 0.76 535.35 64 tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)- 4-fluoro-N,N-dimethylthiophene-2-carboxamide 1.24.6 5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3- 0.88 625.76 5 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N- dimethylthiophene-2-carboxamide 1.24.7 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2-yl)- 0.74 605.86 5 2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.24.8 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl-5,6,7,8- 0.85 558.90 14 tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)- 4-fluoro-N,N-dimethylthiophene-2-carboxamide 1.24.9 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)- 0.75 628.06 6 2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N,N- dimethylthiophene-2-carboxamide 1.24.10 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluoro-thiophen-2-yl)- 0.76 591.90 20 2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide 1.24.11 (R)-6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluorothiophen-2- 0.74 605.86 4 yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide .sup.a) 1.25.1 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl- 0.80 606.52 5 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide 1.25.2 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl- 0.90 587.91 10 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide 1.25.3 5-(6-(2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetyl)-2- 0.86 588.91 35 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methyl thiophene-2-carboxamide 1.25.4 6-chloro-5-(2-(5-(3-fluoro-5-(methylcarbamoyl)thiophen-2-yl)-2- 0.71 591.97 6 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.25.5 5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3- 0.85 611.95 7 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene- 2-carboxamide 1.25.6 6-chloro-5-(2-(5-(3-fluoro-5-(methylcarbamoyl)thiophen-2-yl)-2- 0.70 563.90 8 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide 1.25.7 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)- 0.72 613.93 7 2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluoro-N-methylthiophene- 2-carboxamide 1.25.8 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl-5,6,7,8- 0.82 544.77 43 tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)- 4-fluoro-N-methylthiophene-2-carboxamide 1.25.9 5-(6-(2-((2-chloro-5-fluoropyridin-3-yl)oxy)acetyl)-2-methyl- 0.77 538.81 47 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-4-fluoro-N-methylthiophene-2-carboxamide 1.26.1 Methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.84 573.44 10 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylate 1.27.1 Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.86 604.53 7 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate 1.27.2 Ethyl 2-(6-(2-((2-chloro-6-(trifluoromethyl)pyridin-3- 0.91 587.05 500 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate 1.27.3 Ethyl 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenolxy)acetyl)-2- 0.95 586.06 245 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate 1.28.1 Methyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.86 590.45 7 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate 1.28.2 Methyl 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2- 0.96 572.01 40 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxylate 1.28.3 Methyl 2-(6-(2-((2-chloro-6-(cyclopropanesulfonamido)pyridin-3- 0.81 625.87 45 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5- carboxylate 1.28.4 Methyl 2-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3- 0.90 596.10 17 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5- carboxylate 1.29.1 Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.84 588.00 20 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)oxazole-4-carboxylate 1.30.1 Ethyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.87 604.15 9 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-2-carboxylate 1.30.2 Ethyl 5-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2- 0.96 586.05 442 methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-2-carboxylate 1.30.3 Ethyl 5-(6-(2-(2-chloro-4-cyanophenoxy)acetyl)-2-methyl- 0.88 543.00 371 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)thiazole-2-carboxylate 1.31.1 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3-fluoro-5- 0.93 540.02 14 methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.31.2 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5- 0.83 558.09 5 methylpyridin-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.31.3 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.82 497.86 36 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinonitrile 1.31.4 3-chloro-4-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.85 497.03 49 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)benzonitrile 1.31.5 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5- 0.89 541.02 21 methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.6 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.77 529.67 7 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N-methylpicolinamide 1.31.7 6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.73 543.86 6 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.31.8 N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.75 565.87 9 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.31.9 N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.79 591.95 21 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide 1.31.10 N-(3-chloro-4-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.76 564.59 11 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)phenyl)methanesulfonamide 1.31.11 (R)-2-((2-chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3- 0.85 572.20 23 yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.12 (R)-2-((2-chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3- 0.63 556.20 217 yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.13 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(3-fluoro-5- 0.79 539.93 16 methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.14 6-chloro-N-cyclopropyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2- 0.78 570.21 32 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide 1.31.15 (R)-N-(6-chloro-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl- 0.83 580.08 9 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-N- methylmethanesulfonamide 1.31.16 (R)-N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl- 0.77 560.15 18 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.31.17 (R)-2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3- 0.81 592.08 8 yl)oxy)-1-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.18 (R)-2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)-1-(5-(3-fluoro-5- 0.83 502.06 49 methylpyridin-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.31.19 (R)-N-(4-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl- 0.74 560.92 51 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyrimidin-2-yl)methanesulfonamide 1.31.20 (R)-N-(5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2-methyl-7,8- 0.72 561.87 77 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-methoxypyridin-2-yl)methanesulfonamide 1.32.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5-(4- 0.82 545.78 2 methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.32.2 3-chloro-4-(2-(2-methyl-5-(4-methylthiazol-5-yl)-7,8-dihydro- 0.84 484.82 83 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)benzonitrile 1.32.3 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(2-methyl-5-(4- 0.93 527.93 10 methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.32.4 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(2-methyl-5-(4- 0.87 528.84 21 methylthiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.32.5 (R)-6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(4-methylthiazol-5- 0.71 532.93 43 yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinamide 1.33.1 1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.90 577.63 2 dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone 1.33.2 1-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.93 583.77 4 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)ethanone 1.33.3 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.79 563.78 6 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.33.4 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.77 535.81 7 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinamide 1.33.5 6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.81 549.80 6 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N-methylpicolinamide 1.33.6 N-(6-chloro-5-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.79 585.85 6 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.33.7 N-(3-chloro-4-(2-(5-(5-chloro-3-fluoropyridin-2-yl)-2-methyl-7,8- 0.82 584.82 13 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)phenyl)methanesulfonamide 1.34.1 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl- 0.83 602.91 6 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-N,N-dimethylthiazole-2-carboxamide 1.34.2 5-(6-(2-((2-chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetyl)- 0.72 588.81 9 2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-2- carboxamide 1.34.3 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)- 0.74 610.69 104 2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-2- carboxamide 1.35.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoropyridin- 0.80 543.87 6 2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.35.2 6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.69 529.67 45 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.35.3 6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.72 515.85 29 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N-methylpicolinamide 1.35.4 N-(6-chloro-5-(2-(5-(3-fluoropyridin-2-yl)-2-methyl-7,8-dihydro- 0.71 551.83 35 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2- oxoethoxy)pyridin-2-l)methanesulfonamide 1.39.1 N-(6-chloro-5-(2-(2-methyl-5-(thiazol-5-yl)-7,8-dihydro- 0.71 539.75 101 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 1.39.2 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(thiazol-5-yl)-7,8- 0.69 518.14 69 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)picolinamide 1.39.3 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(2-methyl-5- 0.79 532.03 5 (thiazol-5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 1.42.1 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(5- 0.67 557.87 49 (methylcarbamoyl)furan-2-yl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.42.2 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl- 0.76 571.90 11 5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-5-yl)-N-methylfuran-2-carboxamide 1.47.1 1-(4-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2- 0.77 618.18 18 methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2- yl)-3-ethylurea 1.50.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-(3- 0.85 616.96 6 methoxyoxetan-3-yl)thiophen-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.53.1 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(2-fluoro-4- 0.87 539.16 9 methylphenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.53.2 N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-methyl-7,8- 0.82 565.12 12 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.53.3 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-methyl-phenyl)-2- 0.85 569.23 15 methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide 1.53.4 (S)-N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-methyl-7,8- 0.82 564.95 8 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide.sup.b) 1.54.1 6-chloro-5-(2-(5-(4-(difluoromethoxy)-2-fluorophenyl)-2-methyl- 0.83 594.91 14 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.55.1 6-chloro-5-(2-(5-(2,4-difluorophenyl)-2-methyl-7,8-dihydro- 0.80 546.87 19 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.56.1 6-chloro-5-(2-(5-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl- 0.86 596.92 15 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.57.1 6-chloro-5-(2-(5-(2,5-difluorophenyl)-2-methyl-7,8-dihydro- 0.79 546.83 30 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.58.1 6-chloro-5-(2-(5-(3-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.82 562.76 42 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.59.1 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(2-methylthiazol-5-yl)- 0.70 531.81 37 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinamide 1.60.1 6-chloro-N,N-dimethyl-5-(2-(2-methyl-5-(2-phenylthiazol-5-yl)- 0.84 593.74 14 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinamide 1.61.1 6-chloro-5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8- 0.83 560.73 7 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-N,N-dimethylpicolinamide 1.61.2 N-(6-chloro-5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8- 0.83 583.16 34 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.61.3 2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1- 0.89 609.94 5 (5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.61.4 2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)-1-(5-(2,3-difluoro-4- 0.92 519.05 49 methylphenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.61.5 N-(5-(2-(5-(2,3-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro- 0.85 576.91 9 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 1.62.1 6-chloro-5-(2-(5-(2,3-difluorophenyl)-2-methyl-7,8-dihydro- 0.79 546.81 65 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.64.1 5-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)- 0.81 656.16 21 2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-diethyl-4- fluorothiophene-2-carboxamide 1.65.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-(3- 0.81 617.92 208 methoxyoxetan-3-yl)thiazol-2-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.66.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2,4- 0.81 543.96 13 dimethyloxazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.67.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2,5- 0.80 544.19 25 dimethyloxazol-4-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 1.68.1 6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- 0.71 545.51 20 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 1.68.2 N-(6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8- 0.73 567.97 9 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.68.3 2-((2-chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)-1-(5-(2,4- 0.79 541.87 9 dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.68.4 6-chloro-N-cyclopropyl-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2- 0.76 571.92 19 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methylpicolinamide 1.68.5 2-((2-chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)-1- 0.80 593.68 5 (5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 1.68.6 N-(6-chloro-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8- 0.81 581.91 6 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)-N-methylmethanesulfonamide 1.68.7 N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- 0.77 561.76 11 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2- oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 1.68.8 (R)-1-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- 0.81 587.97 5 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone 1.68.9 N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-methyl-7,8-dihydro- 0.73 562.96 66 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-4-ethylpyrimidin-2-yl)methanesulfonamide 1.71.1 N-cyclopropyl-6-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl- 0.89 541.04 12 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)picolinamide 1.71.2 N-(6-ethyl-5-(2-(5-(3-fluorothiophen-2-yl)-2-methyl-7,8-dihydro- 0.80 550.86 7 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 1.72.1 N-(6-chloro-5-(2-(5-(2-ethyl-4-methylthiazol-5-yl)-2-methyl-7,8- 0.77 581.86 22 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.73.1 N-(6-chloro-5-(2-(5-(2-isopropyl-4-methylthiazol-5-yl)-2-methyl- 0.80 595.88 60 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.74.1 N-(5-(2-(5-(2,5-difluoro-4-methylphenyl)-2-methyl-7,8-dihydro- 0.84 576.94 25 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 1.74.2 N-(6-chloro-5-(2-(5-(2,5-difluoro-4-methylphenyl)-2-methyl-7,8- 0.83 582.96 18 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.75.1 N-(6-chloro-5-(2-(5-(5-fluoro-3-methylpyridin-2-yl)-2-methyl-7,8- 0.78 565.91 9 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 1.76.1 N-(6-chloro-5-(2-(2-methyl-5-(4-methyl-2-(trifluoromethyl)thiazol- 0.87 621.87 20 5-yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.77.1 N-(6-chloro-5-(2-(5-(2-fluoro-4-(trifluoromethoxy)phenyl)-2- 0.87 634.86 13 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.77.2 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4- 0.92 624.81 28 (trifluoromethoxy)phenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.78.1 N-(5-(2-(5-(4-(aminomethyl)-2-fluorophenyl)-2-methyl-7,8- 0.79 575.99 10 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-chloropyridin-2-yl)methanesulfonamide 1.78.2 5-(2-(5-(4-(aminomethyl)-2-fluorophenyl)-2-methyl-7,8-dihydro- 0.84 566.08 18 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-6-chloro-N-cyclopropylpicolinamide 1.79.1 methyl-4-(6-(2-((2-chloro-6-(methylsulfonamido)pyridin-3- 0.81 610.90 17 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-3- fluorobenzoate 1.79.2 methyl-4-(6-(2-((2-chloro-6-(cyclopropylcarbamoyl)pyridin-3- 0.86 598.86 21 yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-3- fluorobenzoate 1.80.1 N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)-2- 0.75 609.10 98 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.80.2 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-hydroxypropan-2- 0.80 599.32 65 yl)phenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.81.1 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-methoxypropan-2- 0.89 613.16 27 yl)phenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.81.2 N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-methoxypropan-2-yl)phenyl)- 0.83 623.12 132 2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.82.1 N-(6-chloro-5-(2-(5-(2-fluoro-4-(methoxymethyl)phenyl)-2- 0.79 595.09 17 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.82.2 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4- 0.85 585.13 14 (methoxymethyl)phenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.83.1 6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2- 0.84 615.15 24 methoxyethoxy)phenyl)-2-methyl-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinamide 1.83.2 N-(6-chloro-5-(2-(5-(2-fluoro-4-(2-methoxyethoxy)phenyl)-2- 0.79 625.11 18 methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2- yl)methanesulfonamide 1.85.1 1-(5-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)-2-methyl-7,8-dihydro- 0.85 603.50 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-morpholinopyridin-3-yl)oxy)ethan-1-one 2.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro- 0.82 570.99 11 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 2.1.2 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro- 0.92 502.10 31 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)benzonitrile 2.1.3 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydro-[1,3,4]thia- 0.87 547.02 8 diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6- (oxazol-2-yl)pyridin-3-yl)oxy)ethanone 3.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8- 0.87 598.81 13 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 3.1.2 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro- 0.96 529.63 15 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)benzonitrile 3.1.3 1-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro- 0.92 572.79 12 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone 3.1.4 1-(5-(4-chloro-2-fluorophenyl)-2-ethyl-7,8-dihydro- 0.73 603.84 10 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)ethanone 4.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8- 0.88 610.79 16 dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 4.1.2 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8- 0.97 541.76 23 dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)benzonitrile 4.1.3 1-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro- 0.93 584.81 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)ethanone 4.1.4 1-(5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-7,8-dihydro- 0.74 615.83 12 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)ethanone 5.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)- 0.90 638.83 50 7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 5.1.2 N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8- 0.92 633.09 32 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 5.1.3 1-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8-dihydro- 0.97 658.84 10 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone 5.1.4 (S)-1-(5-(4-chloro-2-fluorophenyl)-2-(trifluoromethyl)-7,8- 0.97 658.90 7 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3- yl)oxy)ethanone.sup.c) 5.2.1 2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)-1- 0.92 639.93 13 (5-(3-fluoro-5-methylpyridin-2-yl)-2-(trifluoromethyl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 5.2.2 N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2- 0.87 613.89 42 (trifluoromethyl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 5.3.1 N-(6-ethyl-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(trifluoromethyl)- 0.91 612.90 28 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 5.4.1 1-(5-(2,4-dimethylthiazol-5-yl)-2-(trifluoromethyl)-7,8-dihydro- 0.90 641.81 25 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone 5.4.2 N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(trifluoromethyl)-7,8- 0.84 615.88 27 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 6.1.1 1-(5-(3,4-dimethoxyphenyl)-7,8-dihydrothiazolo- 0.77 500.12 4 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(naphthalen-2- yloxy)ethanone 6.1.2 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(3,4- 0.57 583.07 5 dimethoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 6.1.3 2-(2,4-dichlorophenoxy)-1-(5-(3,4-dimethoxyphenyl)-7,8- 0.79 518.04 7 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.2.1 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoropyridin- 0.55 542.06 12 3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.2.2 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]- 0.76 477.11 81 imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-(trifluoromethyl)- phenoxy)ethanone 6.2.3 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]- 0.71 423.04 52 imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyloxy)ethanone 6.2.4 1-(5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]- 0.72 422.94 266 imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyloxy)ethanone 6.2.5 2-(4-chloro-2-methylphenoxy)-1-(5-(2-fluoropyridin-3-yl)-7,8- 0.78 456.93 26 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.2.6 2-((5-chloro-1-methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)-1- 0.77 514.88 419 (5-(2-fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 6.2.7 ((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2- 0.53 542.96 235 fluoropyridin-3-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 6.3.1 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(2-fluoro-4- 0.61 570.97 5 methoxyphenyl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 6.3.2 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(2- 0.58 572.02 9 fluoro-4-methoxyphenyl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.3.3 1-(5-(2-fluoro-4-methoxyphenyl)-7,8- 0.57 488.97 4 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- (isoquinolin-7-yloxy)ethanone 6.3.4 2-(2-ethyl-4-fluorophenoxy)-1-(5-(2-fluoro-4-methoxyphenyl)- 0.83 484.11 8 7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.4.1 1-(5-(4-chloro-2-fluorophenyl)-7,8- 0.87 478.07 14 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2- ethyl-4-fluorophenoxy)ethanone 6.4.2 1-((5R)-5-(4-chloro-2-fluorophenyl)-4a,5-dihydro- 0.81 560.88 4 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(7H)-yl)-2-(2-chloro-4- morpholinophenoxy)ethanone 6.4.3 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo- 0.88 490.03 6 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4-chloro-2- methylphenoxy)ethanone 6.4.4 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo- 0.75 477.01 13 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloropyridin-3- yl)oxy)ethanone 6.4.5 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo- 0.62 575.92 7 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6- (morpholinomethyl)pyridin-3-yl)oxy)ethanone 6.4.6 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo- 0.81 561.45 4 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6- morpholinopyridin-3-yl)oxy)ethanone 6.4.7 1-(5-(4-chloro-2-fluorophenyl)-7,8-dihydrothiazolo- 0.60 471.05 6 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethylpyridin-3- yl)oxy)ethanone 6.4.8 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-7,8- 0.73 569.77 3 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 6.5.1 1-(5-(3,5-dimethylisoxazol-4-yl)-7,8-dihydrothiazolo- 0.54 451.97 117 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6- methylpyridin-3-yl)oxy)ethanone 6.5.2 2-(2,4-dichlorophenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-7,8- 0.80 476.81 61 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.5.3 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(3,5-di- 0.83 510.89 85 methylisoxazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5- c]pyridin-6(5H)-yl)ethanone 6.5.4 2-(4-chloro-2-methylphenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)- 0.80 456.92 27 7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)ethanone 6.5.5 2-(4-chloro-2-ethylphenoxy)-1-(5-(3,5-dimethylisoxazol-4-yl)-7,8- 0.84 471.10 135 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.6.1 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(4-cyclopropyl-2- 0.82 568.05 4 fluorophenyl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.7.1 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(5- 0.82 551.97 11 cyclopropyl-3-fluoropyridin-2-yl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.7.2 6-chloro-5-(2-(5-(5-cyclopropyl-3-fluoropyridin-2-yl)-7,8- 0.76 508.95 17 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)picolinonitrile 6.8.1 N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro- 0.73 567.82 15 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)cyclopropanesulfonamide 6.8.2 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro- 0.67 519.81 5 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)- N,N-dimethylpicolinamide 6.8.3 6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro- 0.70 505.84 9 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N- methylpicolinamide 6.8.4 N-(6-chloro-5-(2-(5-(3-fluorothiophen-2-yl)-7,8- 0.69 541.79 7 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 6.8.5 N-(3-chloro-4-(2-(5-(3-fluorothiophen-2-yl)-7,8-dihydro- 0.70 540.59 9 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)phenyl)methanesulfonamide 6.9.1 5-(6-(2-(2-chloro-4-(methylsulfonamido)phenoxy)-acetyl)- 0.67 611.70 2 5,6,7,8-tetrahydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4- fluoro-N,N-dimethylthiophene-2-carboxamide 6.9.2 6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)-3-fluoro-thiophen-2-yl)- 0.64 590.93 5 7,8-dihydrothiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)-N,N-dimethylpicolinamide 6.10.1 2-(4-chloro-2-methylphenoxy)-1-(5-(2-fluoro-4-methyl-phenyl)- 0.79 470.12 5 7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)ethanone 6.10.2 2-((2-ethylpyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8- 0.51 451.15 7 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)ethanone 6.10.3 2-((2-chloropyridin-3-yl)oxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8- 0.60 457.09 14 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)ethanone 6.10.4 2-(2-ethyl-4-fluorophenoxy)-1-(5-(2-fluoro-4-methyl-phenyl)-7,8- 0.85 468.14 6 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-6(5H)- yl)ethanone 6.11.1 2-((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(2-fluoro-4- 0.86 518.95 10 (trifluoromethyl)phenyl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.12.1 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.82 461.09 26 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyloxy)ethanone 6.12.2 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.83 461.11 115 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyloxy)-ethanone 6.12.3 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.88 514.80 20 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2,4- dichlorophenoxy)ethanone 6.12.4 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.88 494.89 36 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(4-chloro-2- methylphenoxy)ethanone 6.12.5 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.89 548.87 28 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-3- (trifluoromethyl)phenoxy)ethanone 6.12.6 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.74 481.64 101 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloropyridin-3- yl)oxy)ethanone 6.12.7 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.86 552.87 62 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((4-chloro-1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl)-oxy)ethanone 6.12.8 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.62 580.99 43 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6- (morpholinomethyl)pyridin-3-yl)oxy)ethanone 6.12.9 1-(5-(benzo[d]thiazol-2-yl)-7,8-dihydrothiazolo- 0.61 497.68 12 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(isoquinolin-7- yloxy)ethanone 6.13.1 2-(2-chloro-3-(trifluoromethyl)phenoxy)-1-(5-(1-phenyl-1H- 0.84 557.97 75 pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.13.2 2-(2,4-dichlorophenoxy)-1-(5-(1-phenyl-1H-pyrazol-4-yl)-7,8- 0.82 524.02 50 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.13.3 1-(5-(1-phenyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo- 0.77 470.17 53 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(p-tolyl-oxy)ethanone 6.13.4 1-(5-(1-phenyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo- 0.78 470.16 236 [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(o-tolyl-oxy)ethanone 6.13.5 2-(2-chloro-4-(morpholinomethyl)phenoxy)-1-(5-(1-phenyl-1H- 0.61 589.05 7 pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.13.6 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5-(1- 0.59 590.07 28 phenyl-1H-pyrazol-4-yl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.13.7 2-(4-chloro-2-methylphenoxy)-1-(5-(1-phenyl-1H-pyrazol-4-yl)- 0.82 504.09 26 7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.13.8 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(1-phenyl-1H- 0.85 558.03 80 pyrazol-4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.13.9 2-((2-ethylpyridin-3-yl)oxy)-1-(5-(1-phenyl-1H-pyrazol-4-yl)-7,8- 0.57 485.15 123 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.14.1 2-(2,4-dichlorophenoxy)-1-(5-(thieno[2,3-b]pyridin-2-yl)-7,8- 0.83 514.80 25 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.14.2 2-(4-chloro-2-methylphenoxy)-1-(5-(thieno[2,3-b]-pyridin-2-yl)- 0.83 494.87 39 7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.14.3 2-((2-chloropyridin-3-yl)oxy)-1-(5-(thieno[2,3-b]pyridin-2-yl)-7,8- 0.69 481.67 67 dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.14.4 2-((2-chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)-1-(5- 0.58 580.98 38 (thieno[2,3-b]pyridin-2-yl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 6.14.5 2-(2-chloro-5-methylphenoxy)-1-(5-(thieno[2,3-b]-pyridin-2-yl)- 0.81 495.06 43 7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.15.1 ((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(1,3,5-trimethyl-1H- 0.68 464.97 149 pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.15.2 2-(2-chloro-4-(trifluoromethyl)phenoxy)-1-(5-(1,3,5-trimethyl-1H- 0.78 524.05 48 pyrazol-4-yl)-7,8-dihydrothiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.15.3 2-(4-chloro-2-methylphenoxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol- 0.74 470.12 20 4-yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.15.4 2-(4-chloro-2-ethylphenoxy)-1-(5-(1,3,5-trimethyl-1H-pyrazol-4- 0.78 484.10 102 yl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 6.16.1 1-(5-(4-(difluoromethyl)-2-fluorophenyl)-7,8-dihydro- 0.60 487.09 14 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2- ethylpyridin-3-yl)oxy)ethanone 6.16.2 1-(5-(4-(difluoromethyl)-2-fluorophenyl)-7,8-dihydro- 0.81 500.88 8 thiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-ethyl-6- methylpyridin-3-yl)oxy)ethanone 6.16.3 2-((2-chloropyridin-3-yl)oxy)-1-(5-(4-(difluoromethyl)-2- 0.74 493.01 15 fluorophenyl)-7,8-dihydrothiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)ethanone 6.17.1 2-((2-ethyl-6-methylpyridin-3-yl)oxy)-1-(5-(2-methyl-6- 0.62 516.11 194 (trifluoromethyl)pyridin-3-yl)-7,8-dihydrothiazolo- [2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone 7.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)- 0.85 602.84 8 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3-]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 7.1.2 N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-7,8- 0.86 596.88 8 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 7.1.3 1-(5-(4-chloro-2-fluorophenyl)-2-(fluoromethyl)-7,8-dihydro- 0.91 622.88 6 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethan-1- one 7.2.1 2-((6-(1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)-1- 0.85 603.95 9 (5-(3-fluoro-5-methylpyridin-2-yl)-2-(fluoromethyl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)ethanone 7.2.2 N-(6-ethyl-5-(2-(5-(3-fluoro-5-methylpyridin-2-yl)-2- 0.79 577.83 20 (fluoromethyl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide 7.3.1 N-(6-chloro-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(fluoromethyl)- 0.84 582.89 8 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 7.3.2 N-(6-ethyl-5-(2-(5-(2-fluoro-4-methylphenyl)-2-(fluoromethyl)- 0.85 576.87 12 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 7.4.1 N-cyclopropyl-5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)- 0.84 570.00 7 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)-6-ethylpicolinamide 7.4.2 N-(5-(2-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)-7,8- 0.76 579.91 7 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 7.4.3 1-(5-(2,4-dimethylthiazol-5-yl)-2-(fluoromethyl)-7,8-dihydro- 0.82 605.91 8 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone 8.1.1 N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)- 0.88 620.83 19 7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 8.1.2 N-(5-(2-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8- 0.89 614.91 10 dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)- yl)-2-oxoethoxy)-6-ethylpyridin-2-yl)methanesulfonamide 8.1.3 1-(5-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7,8-dihydro- 0.94 640.75 7 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone 8.1.4 (S)-N-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2- 0.88 620.82 12 (difluoromethyl)-7,8-dihydro- [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2- oxoethoxy)pyridin-2-yl)methanesulfonamide.sup.d) 8.2.1 N-(6-chloro-5-(2-(2-(difluoromethyl)-5-(2-fluoro-4-methylphenyl)- 0.87 600.84 24 7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide 8.3.1 N-cyclopropyl-5-(2-(2-(difluoromethyl)-5-(2,4-dimethylthiazol-5- 0.87 587.96 11 yl)-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin- 6(5H)-yl)-2-oxoethoxy)-6-ethylpicolinamide 8.3.2 1-(2-(difluoromethyl)-5-(2,4-dimethylthiazol-5-yl)-7,8-dihydro- 0.86 623.91 13 [1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((6- (1,1-dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)ethanone .sup.a) isolated by chiral separation of the corresponding racemic mixture (example 1.24.7) by the chiral preparative LC-MS (III); .sup.b)prepared from the corresponding enantiomerically pure amine of the structure 1, which has been isolated by chiral separation of the corresponding racemic mixture by the preparative LC-MS (I); .sup.c)prepared from the corresponding enantiomerically pure amine of the structure 1, which has been isolated by chiral separation of the corresponding racemic mixture by the preparative LC-MS (IV); .sup.d)prepared from the corresponding enantiomerically pure amine of the structure 1, which has been isolated by chiral separation of the corresponding racemic mixture by the preparative LC-MS (II);
Synthesis of Aldehydes of Structure 3
Aldehyde 1: 4-Chloro-2-fluorobenzaldehyde
(4-Chloro-2-fluorophenyl)methanol
(41) To a solution of 4-chloro-2-fluorobenzoic acid (300 mg) in THF (15 mL) was added at 0° C. LiAlH.sub.4 (130 mg). The suspension was stirred at 0° C. for 16 h. The reaction mixture was diluted with EA and aq. solution of potassium sodium tartrat and stirred for 1 h at rt. The layers were separated and the org. phase was further washed with water. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: DCM, solvent B: 3N ammonia in MeOH, gradient in % B: 0 to 5, flow rate: 6.0 mL/min) to afford 224 mg of colourless oil. LC-MS (A) t.sub.R=0.68 min; [M+H].sup.+: not visible.
4-Chloro-2-fluorobenzaldehyde
(42) To a solution of (4-chloro-2-fluorophenyl)methanol (222 mg) in MeCN (20 mL) was added MnO.sub.2 (480 mg). The mixture was stirred for 24 h. The mixture was filtered over celite, the org. layer was dried over MgSO.sub.4 and evaporated in vacuo. The crude aldehyde was used without purification in the next step. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: not visible.
Aldehyde 2: 4-Cyclopropyl-2-fluorobenzaldehyde
Methyl 4-bromo-2-fluorobenzoate
(43) A solution of 4-bromo-2-fluorobenzoyl chloride (15 mL) in MeOH (200 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo. The residue was diluted with DCM and sat. aq. NaHCO.sub.3. The layers were separated, the aq. layer was extracted with DCM, the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (25 g of a white solid) was used without purification in the next step. LC-MS (A) t.sub.R=0.84 min; [M+H].sup.+: not visible.
Methyl 4-cyclopropyl-2-fluorobenzoate
(44) To a solution of methyl 4-bromo-2-fluorobenzoate (25 g) in THF (500 mL) were added potassium cyclopropyltrifluoroborate (15.9 g), cesium carbonate (105 g) and water (50 mL). The solution was degassed under argon and (1,1′-bis(diphenylphosphino)ferrocene) dichloropalladium (II) dichloromethane adduct (8.8 g) was finally added. The reaction mixture was stirred at 70° C. overnight. The mixture was diluted with water and TBME, the layers were separated. The aq. layer was extracted with TBME and the combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 350 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 20, flow rate: 100 mL/min) to afford 19.2 g of yellow oil. LC-MS (A) t.sub.R=0.87 min; [M+H].sup.+: 195.45.
4-Cyclopropyl-2-fluorobenzaldehyde
(45) This aldehyde has been prepared from methyl 4-cyclopropyl-2-fluorobenzoate according to the reduction/oxidation procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.83 min; [M+H].sup.+: not visible.
Aldehyde 3: 5-Cyclopropyl-3-fluoropicolinaldehyde
(46) This aldehyde has been prepared from (5-cyclopropyl-3-fluoropyridin-2-yl)methanol according to the procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: 166.25.
Aldehyde 4: 6-Chloro-2-fluoronicotinaldehyde
(47) To a solution of diisopropylamine (5.26 mL) in THF (70 mL) was added at −78° C. nBuLi 1.6M in hexanes (21.6 mL). The mixture was stirred at 0° C. for 45 min. 2-Chloro-6-fluoropyridine (3.5 g) in THF (36 mL) was added dropwise at −78° C. over 1 h under nitrogen to the previous mixture and the reaction mixture was stirred at −78° C. for 1.5 h. DMF (4.12 mL) was added dropwise over 1 h and the reaction mixture was stirred an additional 1.5 h. HCl 2M in diethylether (45 mL) was added slowly at −78° C., water (30 mL) was added and the layers were separated. The aq. phase was extracted with EA and the combined org. layers were washed with sat. aq. NaCl, dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude (4.4 g of an orange solid) was used without purification in the next step. GC-MS (A): t.sub.R=1.55 min; [M+H].sup.+: 159.80.
Aldehyde 5: 4-((Dimethylamino)methyl)thiazole-2-carbaldehyde
4-Bromo-2-(dimethoxymethyl)thiazole
(48) To a solution of 4-bromothiazole-2-carboxaldehyde (200 mg) in MeOH (3.5 mL) were added trimethylorthoformate (0.57 mL) and PTSA (165 mg). The reaction mixture was stirred under reflux overnight. The mixture was diluted with sat. aq. NaHCO.sub.3 and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with 1N aq. NaOH and sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 1, flow rate: 7 mL/min) to afford 178 mg of yellow oil. LC-MS (A) t.sub.R=0.71 min; [M+H].sup.+: 238.09.
2-(Dimethoxymethyl)thiazole-4-carbaldehyde
(49) To a solution of 4-bromo-2-(dimethoxymethyl)thiazole in diethyl ether (3 mL) was added at −78° C. nBuLi 1.6M in hexanes (0.55 mL). The mixture was stirred at −78° C. for 15 min. DMF (0.57 mL) in diethyl ether (1 mL) was added dropwise and the reaction mixture was stirred at rt overnight. The mixture was diluted with sat. aq. NH.sub.4Cl and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 1, flow rate: 10 mL/min) to afford 39 mg of a yellow oil. LC-MS (A) t.sub.R=0.55 min; [M+H].sup.+: 188.09.
1-(2-(Dimethoxymethyl)thiazol-4-yl)-N,N-dimethylmethanamine
(50) To a solution of 2-(dimethoxymethyl)thiazole-4-carbaldehyde (39 mg) in MeOH (1 mL) was added dimethylamine in ethanol (0.038 mL). The reaction mixture was stirred at rt overnight. Sodium borohydride (12 mg) was added and the resulting mixture was stirred at rt for 2 h. The mixture was diluted with 1N aq. NaOH and EA, the layers were separated and the aq. layer was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (31 mg of a yellow oil) was used without purification in the next step. LC-MS (A) t.sub.R=0.41 min; [M+H].sup.+: 217.04.
4-((Dimethylamino)methyl)thiazole-2-carbaldehyde
(51) To a solution of 1-(2-(dimethoxymethyl)thiazol-4-yl)-N,N-dimethylmethanamine (31 mg) in THF (2.7 mL) was added at 0° C. 1N aq. HCl (0.39 mL). The reaction mixture was stirred at rt overnight. The mixture was diluted with 1N aq. NaOH and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (47 mg of a yellow oil) was used without purification in the next step. LC-MS (A) t.sub.R=0.17 min; [M+H].sup.+: 171.20.
Aldehyde 6: 4-(Hydroxymethyl)thiophene-2-carbaldehyde
5-(1, 3-Dioxolan-2-yl)thiophene-3-carbaldehyde
(52) This compound has been prepared from 2-(4-bromothien-2-yl)-1,3-dioxolane according to the procedure described for aldehyde 5 (second step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: not visible.
(5-(1,3-Dioxolan-2-yl)thiophen-3-yl)methanol
(53) To a solution of 5-(1,3-dioxolan-2-yl)thiophene-3-carbaldehyde (425 mg) in MeOH (2 mL) was added at 0° C. NaBH.sub.4 (96 mg). The reaction mixture was stirred at 0° C. for 10 min and rt for 30 min. The mixture was evaporated in vacuo, the residue was diluted with EA and washed with sat. aq. NaCl. The org. layer was dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 14, flow rate: 10 mL/min) to afford 230 mg of a colourless oil. LC-MS (A) t.sub.R=0.51 min; [M+H].sup.+: 187.33.
4-(Hydroxymethyl)thiophene-2-carbaldehyde
(54) This aldehyde has been prepared from (5-(1,3-dioxolan-2-yl)thiophen-3-yl)methanol according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.44 min; [M+H].sup.+: not visible.
Aldehyde 7: Methyl 5-formylthiophene-3-carboxylate
Methyl 5-(1, 3-dioxolan-2-yl)thiophene-3-carboxylate
(55) To a solution of 2-(4-bromothien-2-yl)-1,3-dioxolane (5 g) in diethyl ether (200 mL) was added at −78° C. nBuLi 1.6M in hexanes (16 mL) under nitrogen. The mixture was stirred at −78° C. for 15 min. Methyl chloroformate (16.6 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1 h under nitrogen. The mixture was diluted with sat. aq. NH.sub.4Cl and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 5, flow rate: 30 mL/min) to afford 2.89 g of a colourless oil. LC-MS (A) t.sub.R=0.72 min; [M+H].sup.+: 214.85.
Methyl 5-form ylthiophene-3-carboxylate
(56) This aldehyde has been prepared from methyl 5-(1,3-dioxolan-2-yl)thiophene-3-carboxylate according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: not visible.
Aldehyde 8: Methyl 5-formylfuran-2-carboxylate
(57) To a solution of 5-formyl-2-furancarboxylic acid (180 mg) in DMF (4 mL) was added at 0° C. NaH (68 mg). The reaction mixture was stirred at rt for 30 min. Iodomethane (0.17 mL) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with 1N aq. HCl and EA. The layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 2, flow rate: 12 mL/min) to afford 140 mg of a white solid. LC-MS (A) t.sub.R=0.57 min; [M+H].sup.+: not visible.
Aldehyde 9: 3-Fluorothiophene-2-carbaldehyde
(58) This aldehyde has been prepared from 3-fluoro-2-thiophenecarboxylic acid according to the reduction/oxidation procedures described for aldehyde 1. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: not visible.
Aldehyde 10: 4-Fluoro-5-formyl-N-methylthiophene-2-carboxamide
2-(3-Fluorothiophen-2-yl)-1,3-dioxane
(59) To a solution of 3-fluorothiophene-2-carbaldehyde (7.3 g) in dioxane (80 mL) were added 1,3-propandiol (36.5 mL), molecular sieve 4A (20 g) and PTSA (3.84 g). The reaction mixture was stirred at rt overnight. The mixture was filtrated off and evaporated in vacuo. The residue was diluted with sat. aq. Na.sub.2CO.sub.3 and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Flash Master, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 20, flow rate: 30 mL/min) to afford 6.95 g of yellow oil. GC-MS (A) t.sub.R=2.20 min; [M+H].sup.+: 190.20.
5-(1,3-Dioxan-2-yl)-4-fluorothiophene-2-carboxylic acid
(60) To a solution of 2-(3-fluorothiophen-2-yl)-1,3-dioxane (500 mg) in THF (13 mL) was added at −78° C. tBuLi 1.7M in pentane (2.34 mL). The mixture was stirred at −40° C. for 1 h. The solution was added under nitrogen via a syringe into freshly crushed dry ice. The reaction mixture was stirred at −40° C. for 1 h and at rt overnight. The mixture was diluted with EA and 2N aq. HCl to maintain acidic pH. The layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 352 mg of white solid. LC-MS (A) t.sub.R=0.66 min; [M+H].sup.+: not visible.
5-(1,3-Dioxan-2-yl)-4-fluoro-N-methylthiophene-2-carboxamide
(61) To a solution of 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxylic acid (303 mg) in toluene (6.5 mL) under nitrogen were added a few drops of DMF and oxalyl chloride (0.17 mL). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated in vacuo and the residue was diluted in DCM (6.5 mL). Methylamine 2M in THF (3.3 mL) and DIPEA (0.67 mL) were added and the reaction mixture was stirred at rt under nitrogen for 1 h. The mixture was diluted with DCM and sat. aq. NaCl, the layers were separated and the aq. phase was washed with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 186 mg of white solid. LC-MS (A) t.sub.R=0.63 min; [M+H].sup.+: 246.04.
4-Fluoro-5-formyl-N-methylthiophene-2-carboxamide
(62) To a solution of 5-(1,3-dioxan-2-yl)-4-fluoro-N-methylthiophene-2-carboxamide (186 mg) in dioxane (4 mL) and water (4 mL) was added PTSA (144 mg). The reaction mixture was stirred at rt for 48 h. The mixture was diluted with EA and sat. aq. NaHCO.sub.3, the layers were separated and the aq. layer was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude compound (158 mg of a white solid) was used without purification in the next step. LC-MS (A) t.sub.R=0.55 min; [M+H].sup.+: not visible.
Aldehyde 11: 4-fluoro-5-formyl-N,N-dimethylthiophene-2-carboxamide
5-(1,3-Dioxan-2-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide
(63) This amide has been prepared from 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxylic acid according to the procedure described for aldehyde 10 (3. step) using dimethylamine 2M in THF instead of methylamine. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 260.05.
4-Fluoro-5-formyl-N,N-dimethylthiophene-2-carboxamide
(64) This aldehyde has been prepared from 5-(1,3-dioxan-2-yl)-4-fluoro-N,N-dimethylthiophene-2-carboxamide according to the procedure described for aldehyde 10 (3. step). LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 202.19.
Aldehyde 12: Ethyl 2-formylthiazole-4-carboxylate
2,2-Diethoxyethanethioamide
(65) To a solution of diethoxyacetonitrile (10.8 mL) in EtOH (455 mL) was added ammonium sulfide (330 mL). The reaction mixture was stirred at 50° C. for 4 h. The mixture was diluted with water and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude compound (11.01 g of a beige solid) was used without purification in the next step. LC-MS (B) t.sub.R=0.53 min; [M+H].sup.+: not visible.
Ethyl 2-(diethoxymethyl)thiazole-4-carboxylate
(66) To a solution of 2,2-diethoxyethanethioamide (9 g) in EtOH (90 mL) were added molecular sieve 3A (22 g) and ethylbromopyruvate (6.8 mL). The reaction mixture was stirred under reflux for 6.5 h. The mixture was evaporated in vacuo and the residue was diluted with EA. The molecular sieve was filtrated off and washed with EA. The org. layer was washed with NaHCO.sub.3, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude compound (14.3 g of a brown oil) was used without purification in the next step. LC-MS (B) t.sub.R=0.82 min; [M+H].sup.+: 260.12.
Ethyl 2-form ylthiazole-4-carboxylate
(67) To a solution of ethyl 2-(diethoxymethyl)thiazole-4-carboxylate (1 g) in acetone (70 mL) was added 1N aq. HCl (9.2 mL). The reaction mixture was stirred under reflux for 4 h. The mixture was evaporated in vacuo, the residue was diluted with EA and sat. aq. NaHCO.sub.3. The layers were separated, the aq. layer was washed with EA and the combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude compound (715 mg of a yellow solid) was used without purification in the next step. LC-MS (A) t.sub.R=0.63 min; [M+H].sup.+: not visible.
Aldehyde 13: Methyl 2-formylthiazole-5-carboxylate
Methyl 2-vinylthiazole-5-carboxylate
(68) To a solution of methyl 2-bromothiazole-5-carboxylate (1 g) in dioxane (10 mL) were added tributyl(vinyl)tin (1.45 mL), 2,6-di-tert-butyl-4-methylphenol (50 mg) and tetrakis(triphenyl phosphine)palladium (260 mg). The reaction mixture was stirred at 100° C. for 2 h. The suspension was filtrated off and washed with EA. The org. layer was evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 4, flow rate: 20 mL/min) to afford 696 mg of a yellow oil. LC-MS (A) t.sub.R=0.71 min; [M+H].sup.+: 170.06.
Methyl 2-form ylthiazole-5-carboxylate
(69) To a solution of methyl 2-vinylthiazole-5-carboxylate (695 mg) in dioxane (48 mL) and water (12 mL) were added sodium periodate (3.51 g), osmiumtetroxid (0.74 mL) and 2,6-lutidine (0.97 mL). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 5, flow rate: 20 mL/min) to afford 434 mg of a brown solid. LC-MS (A) t.sub.R=0.42 min; [M+H].sup.+: not visible.
Aldehyde 14: ethyl 2-formyloxazole-4-carboxylate
(E)-Ethyl 2-styryloxazole-4-carboxylate
(70) To a solution of cinnamamide (1 g) and NaHCO.sub.3 (2.49 g) in THF (20 mL) was added ethylbromopyruvate (1.38 mL). The reaction mixture was stirred under reflux overnight. The mixture was filtered through celite and evaporated in vacuo. The residue was diluted with THF (50 mL) and TFAA (3.3 mL) was added dropwise at rt overnight. The mixture was quenched with sat. aq. NaHCO.sub.3 (150 mL), the layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 25 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 5, flow rate: 20 mL/min) to afford 812 mg of a white solid. LC-MS (A) t.sub.R=0.88 min; [M+H].sup.+: 244.83.
Ethyl 2-formyloxazole-4-carboxylate
(71) To a solution of ethyl 2-styryloxazole-4-carboxylate (160 mg) in dioxane (7.5 mL) and water (2.3 mL) was added slowly sodium periodate (563 mg), osmiumtetroxid (0.12 mL) and 2,6-lutidine (0.15 mL). The reaction mixture was stirred at rt for 48 h. The mixture was diluted with water and washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 5, flow rate: 20 mL/min) to afford 434 mg of a brown solid. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent: DCM, flow rate: 10 mL/min) to afford 102 mg of a yellow solid. LC-MS (A) t.sub.R=0.39 min; [M+H].sup.+: not visible; [M+H+H.sub.2O]: 188.22.
Aldehyde 15: Ethyl 5-formylthiazole-2-carboxylate
2-Bromo-5-(1, 3-dioxolan-2-yl)thiazole
(72) To a solution of 2-bromo-1,3-thiazole-5-carboxaldehyde (5 g) in toluene (60 mL) were added ethylene glycol anhydrous (4 mL) and PTSA (326 mg). The reaction mixture was stirred under reflux for 2 h with a Dean-Stark apparatus. The mixture was diluted with 20% Na.sub.2CO.sub.3 in water and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 2, flow rate: 30 mL/min) to afford 3.42 g of a yellow oil. LC-MS (A) t.sub.R=0.68 min; [M+H].sup.+: 235.33.
Ethyl 5-(1, 3-dioxolan-2-yl)thiazole-2-carboxylate
(73) To a solution of 2-bromo-5-(1,3-dioxolan-2-yl)thiazole (3.42 g) in THF (35 mL) was added at −78° C. nBuLi 1.6M in hexanes (11.8 mL) under nitrogen. The mixture was stirred at −78° C. for 15 min. The solution was added to a sol. of ethyl chloroformate (3.46 mL) in THF (35 mL) via a cannula under argon at −78° C. and the reaction mixture was stirred at −78° C. for 15 min. The mixture was diluted with sat. aq. NH.sub.4Cl and EA, the layers were separated and the aq. phase was extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 15, flow rate: 35 mL/min) to afford 961 mg of a colourless oil. LC-MS (A) t.sub.R=0.69 min; [M+H].sup.+: 230.09.
Ethyl 5-form ylthiazole-2-carboxylate
(74) This aldehyde has been prepared from ethyl 5-(1,3-dioxolan-2-yl)thiazole-2-carboxylate according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 186.23.
Aldehyde 16: 3-Fluoro-5-methylpicolinaldehyde
(75) This aldehyde has been prepared from (3-fluoro-5-methylpyridin-2-yl)methanol according to the procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.55 min; [M+H].sup.+: 140.06.
Aldehyde 17: 5-Chloro-3-fluoropicolinaldehyde
Methyl 5-chloro-3-fluoropicolinate
(76) To a solution of 5-chloro-3-fluoropyridine-2-carboxylic acid (6 g) in MeOH (120 mL) was added (trimethylsilyl)diazomethane 2M in diethyl ether (48.6 mL). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated in vacuo. The crude compound (5.65 g of a brown solid) was used without purification in the next step. LC-MS (A) t.sub.R=0.64 min; [M+H].sup.+: 190.19.
(5-Chloro-3-fluoropyridin-2-yl)methanol
(77) To a solution of methyl 5-chloro-3-fluoropicolinate (1.05 g) in THF (25 mL) was added at 0° C. lithium borohydride 2M in THF (5.6 mL). The reaction mixture was stirred at 0° C. for 1 h. The mixture was diluted with sat. aq. NaHCO.sub.3 and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0 to 5, flow rate: 30 mL/min) to afford 2.70 g of a yellow solid. LC-MS (A) t.sub.R=0.50 min; [M+H].sup.+: 161.95.
5-Chloro-3-fluoropicolinaldehyde
(78) This aldehyde has been prepared from (5-chloro-3-fluoropyridin-2-yl)methanol according to the procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: not visible.
Aldehyde 18: 5-Formyl-N,N-dimethylthiazole-2-carboxamide
2-Bromo-5-(1, 3-dioxan-2-yl)thiazole
(79) This compound has been prepared from 2-bromo-1,3-thiazole-5-carboxaldehyde according to the procedure described for aldehyde 15 using 1,3-propandiol instead of ethylene glycol. LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 251.87.
5-(1,3-Dioxan-2-yl)thiazole-2-carboxylic acid
(80) To a solution of 2-bromo-5-(1,3-dioxan-2-yl)thiazole (535 mg) in diethyl ether (10 mL) was added at −78° C. nBuLi 1.6M in hexanes (1.5 mL) under nitrogen. The mixture was stirred at −78° C. for 15 min. CO.sub.2 (gas) was bubbled into the solution under nitrogen at −78° C. for 30 min. The mixture was acidified with 1N aq. HCl and diluted with TBME, the layers were separated and the aq. phase was extracted with TBME. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude compound (159 mg of a white solid) was used without purification in the next step. LC-MS (A) t.sub.R=0.46 min; [M+H].sup.+: 216.12 (contains 5-(1,3-dioxan-2-yl)thiazole: LC-MS (A) t.sub.R=0.53 min; [M+H].sup.+: 171.93.
5-(1,3-Dioxan-2-yl)-N,N-dimethylthiazole-2-carboxamide
(81) To a solution of 5-(1,3-dioxan-2-yl)thiazole-2-carboxylic acid (159 mg) in DMF (3 mL) were added PyBOP (404 mg), dimethylamine 2M in THF (0.93 mL) and DIPEA (0.38 mL). The reaction mixture was stirred at rt overnight. The mixture was diluted with EA and sat. aq. NH.sub.4Cl, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0, flow rate: 20 mL/min) to afford 205 mg of an orange oil. LC-MS (A) t.sub.R=0.63 min; [M+H].sup.+: 243.06 (contains traces of 5-(1,3-dioxan-2-yl)thiazole: LC-MS (A) t.sub.R=0.54 min; [M+H].sup.+: 172.10.)
5-Formyl-N,N-dimethylthiazole-2-carboxamide
(82) This aldehyde has been prepared from 5-(1,3-dioxan-2-yl)-N,N-dimethylthiazole-2-carboxamide according to the procedure described for aldehyde 5 (latest step). LC-MS (A): t.sub.R=0.54 min; [M+H].sup.+: 185.25 (contains traces of thiazole-5-carbaldehyde: LC-MS (A) t.sub.R=0.40 min; [M+H].sup.+: not visible.)
Aldehyde 19: 1-Ethyl-3-(2-formylthiazol-4-yl)urea
Ethyl 4-(3-ethylureido)thiazole-2-carboxylate
(83) To a solution of ethyl 2-amino-1,3-thiazole-4-carboxylate (1 g) in DMF (28 mL) were added ethylisocyanate (1.24 g) and DIPEA (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated in vacuo, diluted with water and DCM, the layers were separated and the aq. phase was washed with DCM. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4 dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 25 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0 to 5, flow rate: 35 mL/min) to afford 1.4 g of a yellow solid. LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 244.83.
1-Ethyl-3-(4-formylthiazol-2-yl)urea
(84) To a solution of ethyl 4-(3-ethylureido)thiazole-2-carboxylate (1.4 g) in THF (800 mL) was added LAH (368 mg). The reaction mixture was stirred at 0° C. for 1 h 30. Water was added, followed by 20% aq. NaOH and finally water. The mixture was stirred at rt for 30 min and filtrated over celite. The solution was evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 15, flow rate: 15 mL/min) to afford 248 mg of a yellow solid. LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: 200.11.
Aldehyde 20: 4-(3-Methoxyoxetan-3-yl)thiophene-2-carbaldehyde
3-(5-(1,3-Dioxolan-2-yl)thiophen-3-yl)oxetan-3-ol
(85) This compound has been prepared from 2-(4-bromothien-2-yl)-1,3-dioxolane according to the procedure described for aldehyde 5 using oxetane-3-one instead of DMF (2. step). LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: not visible.
2-(4-(3-Methoxyoxetan-3-yl)thiophen-2-yl)-1,3-dioxolane
(86) This compound has been prepared from 3-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)oxetan-3-ol according to the procedure described for aldehyde 8. LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: 242.80.
4-(3-Methoxyoxetan-3-yl)thiophene-2-carbaldehyde
(87) This aldehyde has been prepared from 2-(4-(3-methoxyoxetan-3-yl)thiophen-2-yl)-1,3-dioxolane according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: not visible.
Aldehyde 21: 5-Formyl-N-methylfuran-2-carboxamide
(88) This aldehyde has been prepared from 5-formyl-2-furancarboxylic acid according to the procedure described for aldehyde 18 (3. step). LC-MS (A): t.sub.R=0.44 min; [M+MeCN].sup.+: 195.26.
Aldehyde 22: Tert-butyl ethyl(5-formyl-1,4-dimethyl-1H-pyrazol-3-yl)carbamate
N-Ethyl-1,4-dimethyl-1H-pyrazol-3-amine
(89) To a solution of 1,4-dimethyl-1H-pyrazol-3-amine (500 mg) in Methanol (10 mL) were added acetaldehyde anhydrous (0.26 mL) and sodium cyanoborhydrid (368 mg). The reaction mixture was stirred at rt for 2 h 30. The mixture was diluted with EA and 1N aq. NaOH, the layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: NH.sub.3 7 N in MeOH, gradient in % B: 1, flow rate: 12 mL/min) to afford 230 mg of a brown solid. LC-MS (A) t.sub.R=0.38 min; [M+H].sup.+: 140.33.
Tert-butyl (1,4-dimethyl-1H-pyrazol-3-yl)(ethyl)carbamate
(90) To a solution of N-ethyl-1,4-dimethyl-1H-pyrazol-3-amine (230 mg) in DCM (2 mL) was added di-tert-butyl-dicarbonat (433 mg). The solution was cooled down to 0° C. and DIPEA (0.43 mL) was added slowly. The reaction mixture was stirred at 0° C. for 30 min and at rt overnight. The mixture was diluted with DCM and 1N aq. HCl, the layers were separated and the aq. phase was washed with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0 to 3, flow rate: 7 mL/min) to afford 350 mg of an orange oil. LC-MS (A) t.sub.R=0.79 min; [M+H].sup.+: 240.30.
Tert-butyl ethyl(5-formyl-1,4-dimethyl-1H-pyrazol-3-yl)carbamate
(91) To a solution of TMEDA (0.27 mL) in THF (2.5 mL was added under Argon at −60° C. nBuLi 1.6M in hexanes (1.10 mL). The mixture was stirred at −20° C. for 1 h. A solution of tert-butyl (1,4-dimethyl-1H-pyrazol-3-yl)(ethyl)carbamate (350 mg) in THF (2.5 mL) was added dropwise at −70° C. The mixture was stirred at −40° C. for 30 min and DMF (0.23 mL) in THF (2 mL) was added slowly at −70° C. The reaction mixture was stirred at −60° C. for 2 h. The mixture was diluted with EA and water, the layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 10, flow rate: 10 mL/min) to afford 50 mg of a yellow oil. LC-MS (A) t.sub.R=0.84 min; [M+H].sup.+: 268.37.
Aldehyde 23: 2,4-Difluorobenzaldehyde
Methyl 2, 4-difluorobenzoate
(92) This ester has been prepared from 2,4-difluorobenzoïc acid according to the procedure described for aldehyde 8. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: not visible.
2, 4-Difluorobenzaldehyde
(93) This aldehyde has been prepared from methyl 2,4-difluorobenzoate according to the reduction/oxidation procedures described for aldehyde 1. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: not visible.
Aldehyde 24: 2-Methylthiazole-5-carbaldehyde
(94) This aldehyde has been prepared from (2-methyl-1,3-thiazol-5-yl)methanol according to the oxidation procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 128.26.
Aldehyde 25: 4-(Difluoromethoxy)-2-fluorobenzaldehyde
(95) This aldehyde has been prepared from (4-(difluoromethoxy)-2-fluorophenyl)methanol according to the oxidation procedure described for aldehyde 1. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: not visible.
Aldehyde 26: N,N-Diethyl-4-fluoro-5-formylthiophene-2-carboxamide
5-(1,3-dioxan-2-yl)-N,N-diethyl-4-fluorothiophene-2-carboxamide
(96) To a solution of 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxylic acid (605 mg) in DMF (10 mL) was added TBTU (878 mg). The mixture was stirred at rt for 30 min. Diethylamine (0.54 mL) and DIPEA (1.34 mL) were added and the reaction mixture was stirred at rt overnight. TBTU (870 mg) was added and the reaction mixture was stirred at rt for 5 h. The mixture was diluted with EA and water, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 25, flow rate: 15 mL/min) to afford 520 mg of a colourless oil. LC-MS (A) t.sub.R=0.78 min; [M+H].sup.+: 288.07.
N,N-Diethyl-4-fluoro-5-formylthiophene-2-carboxamide
(97) This aldehyde has been prepared from 5-(1,3-dioxan-2-yl)-N,N-diethyl-4-fluorothiophene-2-carboxamide according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 230.13.
Aldehyde 27: 5-(3-methoxyoxetan-3-yl)thiazole-2-carbaldehyde
5-Bromo-2-vinylthiazole
(98) To a solution of 2,5-dibromothiazole (1 g) in dioxane (20 mL) were added tributyl(vinyl)tin (1.32 mL), 2,6-di-tert-butyl-4-methylphenol (46 mg) and tetrakis(triphenylphosphine)palladium (238 mg). The reaction mixture was stirred at 100° C. for 2 h. The mixture was filtrated and evaporated in vacuo. The residue was diluted with toluene and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 1, flow rate: 15 mL/min) to afford 208 mg of an orange oil. LC-MS (A) t.sub.R=0.76 min; [M+H].sup.+: not visible.
3-(2-Vinylthiazol-5-yl)oxetan-3-ol
(99) This compound has been prepared from 5-bromo-2-vinylthiazole according to the procedure described for aldehyde 20 (1. step). (LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 184.23.
5-(3-methoxyoxetan-3-yl)-2-vinylthiazole
(100) This compound has been prepared from 3-(2-vinylthiazol-5-yl)oxetan-3-ol according to the procedure described for aldehyde 20 (2. step). LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 198.22.
5-(3-methoxyoxetan-3-yl)thiazole-2-carbaldehyde
(101) This aldehyde has been prepared from 5-(3-methoxyoxetan-3-yl)-2-vinylthiazole according to the procedure described for aldehyde 13 (2. step). LC-MS (A): t.sub.R=0.58 min; [M+H].sup.+: not visible.
Aldehyde 28: 4-Fluoro-5-formylthiophene-2-carbonitrile
5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxamide
(102) This compound has been prepared according to the procedure described for aldehyde 26 (1. step) from 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxylic acid using ammonia instead of diethylamine. LC-MS (A): t.sub.R=0.58 min; [M+H].sup.+: 232.10.
5-(1,3-Dioxan-2-yl)-4-fluorothiophene-2-carbonitrile
(103) This compound has been prepared from 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carboxamide according to the procedure described for example 1.63.1 (4. step). LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: not visible.
4-Fluoro-5-formylthiophene-2-carbonitrile
(104) This aldehyde has been prepared from 5-(1,3-dioxan-2-yl)-4-fluorothiophene-2-carbonitrile according to the procedure described for aldehyde 5 (5. step). LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: not visible.
Aldehyde 29: 4-(2-Hydroxypropan-2-yl)thiophene-2-carbaldehyde
2-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)propan-2-ol
(105) This compound has been prepared from (2 2-(4-bromothiophen-2-yl)-1,3-dioxolane according to the procedure described for aldehyde 6 (1. step) using actetone instead of DMF. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 215.34.
4-(2-Hydroxypropan-2-yl)thiophene-2-carbaldehyde
(106) This aldehyde has been prepared from 2-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)propan-2-ol according to the procedure described for aldehyde (4. step). LC-MS (A): t.sub.R=0.57 min; [M+H].sup.+: not visible.
Aldehyde 30: 2-Ethyl-4-methylthiazole-5-carbaldehyde
(107) This compound has been prepared from (2-ethyl-4-methylthiazol-5-yl)methanol according to the procedure described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: 156.11.
Aldehyde 31: 2-Isopropyl-4-methylthiazole-5-carbaldehyde
Methyl 2-isopropyl-4-methylthiazole-5-carboxylate
(108) This compound has been prepared from 2-isopropyl-4-methylthiazole-5-carboxylic acid according to the procedure described for aldehyde 17 (1. step). LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 200.21.
(2-Isopropyl-4-methylthiazol-5-yl)methanol
(109) This compound has been prepared from methyl 2-isopropyl-4-methylthiazole-5-carboxylate according to the procedure described for aldehyde 23 (2. step). LC-MS (A): t.sub.R=0.41 min; [M+H].sup.+: 172.01.
2-Isopropyl-4-methylthiazole-5-carbaldehyde
(110) This compound has been prepared from (2-isopropyl-4-methylthiazol-5-yl)methanol according to the procedure described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 170.23.
Aldehyde 32: 2,5-Difluoro-4-methylbenzaldehyde
(111) This compound has been prepared from 1-bromo-2,5-difluoro-4-methylbenzene according to the procedure described for aldehyde 5 (2. step) using THF instead of Et.sub.2O as a solvent. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: not visible.
Aldehyde 33: 5-Fluoro-3-methylpicolinaldehyde
(112) This compound has been prepared from (5-fluoro-3-methylpyridin-2-yl)methanol according to the procedure described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 140.31.
Aldehyde 34: 4-Methyl-2-(trifluoromethyl)thiazole-5-carbaldehyde
(113) This compound has been prepared from (4-methyl-2-(trifluoromethyl)thiazol-5-yl)methanol according to the procedure described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: not visible
Aldehyde 35: 2-Fluoro-4-(2-hydroxypropan-2-yl)benzaldehyde
Methyl 4-(dimethoxymethyl)-3-fluorobenzoate
(114) This compound has been prepared from methyl 3-fluoro-4-formylbenzoate according to the procedure described for aldehyde 5 (1. step). LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: not visible.
2-(4-(Dimethoxymethyl)-3-fluorophenyl)propan-2-ol
(115) To a solution of methyl 4-(dimethoxymethyl)-3-fluorobenzoate (400 mg) was at −78° C. added methylmagnesium bromide 3M in Et.sub.2O (730 mL) and the mixture was stirred at rt for 4 h.
(116) The reaction mixture was diluted with rochelle salt, EA and water. The layers were separated and the water phase was extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 5 to 15, flow rate: 10 mL/min) to afford 330 mg of a yellowish oil. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: not visible.
2-Fluoro-4-(2-hydroxypropan-2-yl)benzaldehyde
(117) This compound has been prepared from 2-(4-(dimethoxymethyl)-3-fluorophenyl)propan-2-ol according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: not visible.
Aldehyde 36: 2-Fluoro-4-(2-methoxypropan-2-yl)benzaldehyde
1-(Dimethoxymethyl)-2-fluoro-4-(2-methoxypropan-2-yl)benzene
(118) This compound has been prepared from 2-(4-(dimethoxymethyl)-3-fluorophenyl)propan-2-ol according to the procedure described for aldehyde 8. LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: not visible.
2-Fluoro-4-(2-methoxypropan-2-yl)benzaldehyde
(119) This compound has been prepared from 1-(dimethoxymethyl)-2-fluoro-4-(2-methoxypropan-2-yl)benzene according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: not visible.
Aldehyde 37: 2-Fluoro-4-(methoxymethyl)benzaldehyde
(4-(Dimethoxymethyl)-3-fluorophenyl)methanol
(120) This compound has been prepared from 2-(4-(dimethoxymethyl)-3-fluorophenyl)propan-2-ol according to the procedure described for aldehyde 1 (1. step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: not visible.
1-(Dimethoxymethyl)-2-fluoro-4-(methoxymethyl)benzene
(121) This compound has been prepared from (4-(dimethoxymethyl)-3-fluorophenyl)methanol according to the procedure described for aldehyde 36 (1. step). LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: not visible.
2-Fluoro-4-(methoxymethyl)benzaldehyde
(122) This compound has been prepared from 1-(dimethoxymethyl)-2-fluoro-4-(methoxymethyl)benzene according to the procedure described for aldehyde 5 (4. step). LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: not visible.
Aldehyde 38: 2-Fluoro-4-(2-methoxyethoxy)benzaldehyde
(123) A solution of 2-fluoro-4-hydroxybenzaldehyde (200 mg), K.sub.2CO.sub.3 (592 mg) and 1-bromo-2-methoxyethane in DMF (5 mL) was stirred at 60° C. for 2 h. The reaction mixture was diluted at rt with DCM and water. The layers were separated and the water phase was extracted with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude brown oil (330 mg) was used in the next step without purification LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 199.15.
Aldehyde 39: 5-(1,3-Dioxolan-2-yl)thiophene-3-carbaldehyde
(124) This compound has been prepared from 2-(4-bromothiophen-2-yl)-1,3-dioxolane according to the procedure described for aldehyde 5 (2. step). LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: not visible.
Synthesis of amines of Structure 4
Amine 1: 2-(2-(Difluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanamine
5-(Difluoromethyl)-1,3,4-thiadiazol-2-amine
(125) A solution of thiosemicarbazide (4.8 g) and difluoroacetonitrile (4.0 g) in TFA (35 mL) was stirred at 60° C. for 4 h. The reaction mixture was diluted with sat. aq. NaHCO.sub.3, sat. aq. K.sub.2CO.sub.3 and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by FC (solvent A: heptane, solvent B: EA, gradient in % B: 10 to 90%) to afford 6.9 g of a colourless solid. LC-MS (A): t.sub.R=0.40 min; [M+H].sup.+: 152.10.
2-(2-(Difluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanamine
(126) A mixture of 5-(difluoromethyl)-1,3,4-thiadiazol-2-amine (6.7 g) and 2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione (15.7 g) in EtOH (120 mL) was stirred at 78° C. overnight. Hydrazine monohydrate (10.5 mL) was added and the reaction mixture was stirred at this temperature for 20 min. The mixture was filtrated off and the solution was evaporated in vacuo. The crude was purified by FC (solvent A: DCM, solvent B: 7N ammonia in MeOH, gradient in % B: 0 to 4%) to afford 4.7 g of a yellowish solid. LC-MS (A): t.sub.R=0.42 min; [M+H].sup.+: 219.06.
Amine 2: 2-(2-(Fluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethan-1-amine
(127) This compound has been prepared from corresponding starting materials according to the procedure described for amine 1. LC-MS (A): t.sub.R=0.35 min; [M+H].sup.+: 201.10.
Amine 3: 2-(2-(Trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethan-1-amine
Ethyl 2-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetate
(128) A mixture of 5-(trifluoromethyl)-1,3,4-thiadiazol-2-amine (50 g) and ethyl 4-chloro-3-oxobutanoate (121 mL) in EtOH (250 mL) was stirred at 100° C. for one week. About 50% of the solvent was evaporated in. vacuo. The solid was filtrated off and washed with EtOH. The crude (17 g of a colourless solid) was used in the next step without purification. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 280.02
2-(2-(Trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethan-1-ol
(129) To a solution of ethyl 2-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetate (6 g) and CoCl.sub.2 (5.6 g) in ethanol (120 mL) and THF (90 mL) was added at 0° C. NaBH.sub.4 (2.5 g) and the mixture was stirred at rt for 23 h. Additional NaBH.sub.4 (0.82 g) was added and the mixture was stirred for 1.5 days. Aq. sat. NH.sub.4Cl was added and the mixture was stirred for 25 min at rt. The mixture was diluted with 25% aq. NH.sub.4OH, water and DCM. The layers were separated and the water phase was extracted with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 70 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0 to 3, flow rate: 35 mL/min) to afford 2.0 g of a brown solid. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 238.05.
2-(2-(Trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethyl methanesulfonate
(130) To a solution of 2-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethan-1-ol (4.6 g) in DCM (50 mL) was added at 0° C. DIPEA (5 mL) and after 5 min methanesulfonyl chloride (1.8 mL). The mixture was stirred at 0° C. for 15 min. The mixture was diluted with ag. sat NH.sub.4Cl and water. The layers were separated and the water phase was extracted with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (6.1 g of a yellowish oil) was in the next step without purification. LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 315.93.
6-(2-Azidoethyl)-2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole
(131) A mixture of 2-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethyl methanesulfonate (6.1 g) and Natrium azide (7.56 g) in DMF (60 mL) was stirred at 60° C. for 3 h. The reaction mixture was diluted with water and EA. The layers were separated and the water phase was extracted with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (5.1 g of a brown oil) was in the next step without purification. LC-MS (A): t.sub.R=0.83 min; [M+H].sup.+: 263.02.
2-(2-(Trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethan-1-amine
(132) To a mixture of 6-(2-azidoethyl)-2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole (5.1 g) in THF (250 mL) was added water (0.9 mL) and polymer-supported triphenylphosphine (15.3). The mixture was stirred at rt for 19 h. Additional polymer-supported triphenylphosphine (2.5 g) was added and the mixture was stirred for 24 h. The mixture was filtrated off through celite and the solvent was evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: 3N NH.sub.3 in MeOH, gradient in % B: 1 to 5, flow rate: 30 mL/min) to afford 2.7 g of a beige solid. LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 237.05.
Synthesis of acids of Structure 2
Acid 1: 2-((2-Ethyl-6-methylpyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-ethyl-6-methylpyridin-3-yl)oxy)acetate
(133) To a solution of 2-ethyl-3-hydroxy-6-methylpyridine (2 g) in THF (40 mL) was added NaH (763 mg) portionwise at 0° C. After 30 min tert-butyl bromoacetate (2.15 mL) was added and the mixture was stirred overnight at rt. The reaction mixture was diluted with EA and sat. aq. NH.sub.4Cl. The layers were separated and the org. phase was washed with sat. aq. NaCl. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 5, flow rate: 30 mL/min) to afford 3.90 g of a colourless oil. LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 252.10.
2-((2-Ethyl-6-methylpyridin-3-yl)oxy)acetic acid
(134) To a solution of tert-butyl 2-((2-ethyl-6-methylpyridin-3-yl)oxy)acetate (3.90 g) in DCM (50 mL) was added TFA (14 mL) at 0° C. and the reaction was stirred for 2.5 h at rt. The mixture was evaporated in vacuo. The crude product was washed with Et.sub.2O. The crude product (3.9 g of a white solid) was used in the next step without purification. LC-MS (A): t.sub.R=0.37 min; [M+H].sup.+: 196.13.
Acid 2: 2-(2-Chloro-4-morpholinophenoxy)acetic acid
4-Bromo-2-chloro-1-(methoxymethoxy)benzene
(135) To a solution of 4-bromo-chlorophenol (1.1 g) in DCM (55 mL) was added at 0° C. DIPEA (1.36 mL) and chloromethyl methyl ether (0.44 mL). The mixture was stirred at 0° C. for 1 h and overnight at rt. The reaction mixture was diluted with EA and 1N aq. KHSO.sub.4. The layers were separated and the org. phase was washed with water and sat. aq. NaCl. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (1.43 g of a colourless oil) was used in the next step without purification. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: not visible.
4-(3-Chloro-4-(methoxymethoxy)phenyl)morpholine
(136) A solution of 4-bromo-2-chloro-1-(methoxymethoxy)benzene (1.43 g), morpholine (0.65 mL), sodium tert-butoxide (765 mg), 2-biphenyl di-tert-butylphosphine (679 mg) and tris(dibenzy lidenaceton)dipalladium (52 mg) in toluene (50 mL) was stirred under nitrogen at 80° C. for 3 h. The mixture was filtered through celite and evaporated in vacuo. The crude was purified by CC (Flash Master, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B:0 to 4, flow rate: 15 mL/min) to afford 1.18 g of an yellow oil. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: 257.97.
2-Chloro-4-morpholinophenol hydrochloride
(137) To a solution of 4-(3-chloro-4-(methoxymethoxy)phenyl)morpholine (900 mg) in EA (7 mL) and MeOH (1.8 mL) was added a solution of HCl 4M in dioxane (1.7 mL) and the mixture was stirred at rt overnight. The mixture was evaporated in vacuo. The resulting oil was suspended in diethyl ether and sonicated. The solid was filtrated off and dried in vacuo to afford 852 mg of a beige solid. LC-MS (A): t.sub.R=0.54 min; [M+H].sup.+: 214.01.
Tert-butyl 2-(2-chloro-4-morpholinophenoxy)acetate
(138) This ester has been prepared from 2-chloro-4-morpholinophenol hydrochloride according to the procedure described for acid 1 (1. step). LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: 328.13.
2-(2-Chloro-4-morpholinophenoxy)acetic acid
(139) This acid has been prepared from tert-butyl 2-(2-chloro-4-morpholinophenoxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 272.02.
Acid 3: 2-((2-Ethylpyridin-3-yl)oxy)acetic acid
2-Bromopyridin-3-yl acetate
(140) A solution of 2-bromo-3-pyridinol (3 g) in acetic anhydride (90 mL) was stirred at 140° C. for 5 min. The mixture was evaporated in vacuo. The residue was diluted with DCM and sat. aq. NaHCO.sub.3. The layers were separated, the aq. phase was washed with DCM and the combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 3, flow rate: 30 mL/min) to afford 3.35 g of an orange oil. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 216.95.
2-(2-(Trimethylsilyl)ethyl)pyridin-3-yl acetate
(141) To a solution of 2-bromopyridin-3-yl acetate (3.32 g) in THF (90 mL) were added triethylamine (11.8 mL), trimethylsilylacetylene (6.9 mL), copper iodid (150 mg) and bis(triphenyl-phosphin)palladium(II)-dichlorid (1.62 g). The reaction mixture was stirred at rt for 35 min. The mixture was diluted with EA and water. The layers were separated, the org. phase was washed with sat. aq. NH.sub.4Cl. and sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 70 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 6 to 40, flow rate: 35 mL/min) to afford 2.78 g of an brown oil. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 234.04.
2-Ethynylpyridin-3-ol
(142) To a solution of 2-(2-(trimethylsilyl)ethyl)pyridin-3-yl acetate (2.78 g) in THF (40 mL) was added at 0° C. TBAF 1M in THF (18 mL). The reaction mixture was stirred at 0° C. for 50 min. The mixture was diluted with EA and water. The layers were separated, the org. phase was washed with sat. aq. NH.sub.4Cl. and sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 4, flow rate: 30 mL/min) to afford 0.77 g of a yellow solid. LC-MS (A): t.sub.R=0.31 min; [M+H].sup.+: 120.33.
2-Ethylpyridin-3-ol
(143) To a solution of 2-ethynylpyridin-3-ol (0.77 g) in EtOH (10 mL) was added platinoxid (IV) (110 mg). The reaction mixture was stirred under hydrogen at rt for 1 h 40. The mixture was filtered through celite, washed with EtOH and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 0 to 7, flow rate: 30 mL/min) to afford 0.995 g of a yellow solid. LC-MS (A): t.sub.R=0.31 min; [M+H].sup.+: 124.05.
Tert-butyl 2-((2-ethylpyridin-3-yl)oxy)acetate
(144) This ester has been prepared from 2-ethylpyridin-3-ol according to the procedure described for acid 1 (1. step). LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 238.19.
2-((2-Ethylpyridin-3-yl)oxy)acetic acid
(145) This acid has been prepared from tert-butyl 2-((2-ethylpyridin-3-yl)oxy)acetate. according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.29 min; [M+H].sup.+: 182.16.
Acid 4: 2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetic acid
2-Chloro-6-iodo-3-(methoxymethoxy)pyridine
(146) To a solution of 2-chloro-6-iodo-3-pyridinol (5 g) in DCM (100 mL) were added at 0° C. DIPEA (5 mL) and chloromethyl methyl ether (1.7 mL). The reaction mixture was stirred at 0° C. for 1 h. The mixture was washed with 1M aq. KHSO.sub.4. The layers were separated, the aq. phase was washed with DCM and the combined org. layers were washed with sat. aq. NaCl., dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 2, flow rate: 15 mL/min) to afford 5.52 g of a colourless oil. LC-MS (A): t.sub.R=0.83 min; [M+H].sup.+: 299.99.
4-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)morpholine
(147) To a solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (5.95 g) in DMSO (100 mL) were added morpholine (8.57 mL), copper iodide (3.71 g), L-proline (4.04 g) and potassium carbonate (6.19 g). The mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with sat. aq. NaCl and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 5, flow rate: 30 mL/min) to afford 4.14 g of a colourless oil. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 258.90.
2-Chloro-6-morpholinopyridin-3-ol hydrochloride
(148) This alcohol has been prepared from 4-(6-chloro-5-(methoxymethoxy)pyridin-2-yl)morpholine according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 215.14.
Tert-butyl 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetate
(149) This ester has been prepared from 2-chloro-6-morpholinopyridin-3-ol dihydrochloride according to the procedure described for acid 1 using DMF instead of THF. LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: 328.98.
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetic acid
(150) This acid has been prepared from tert-butyl 2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: 273.04.
Acid 5: 2-((2-Chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)acetic acid
6-Chloro-5-(methoxymethoxy)-N-methylpyridin-2-amine
(151) A solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (1 g) in methylamine 40% in water (35 mL) and copper (106 mg) was stirred at 100° C. for 1 h 45. The reaction mixture was diluted with EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude was recrystallized in EA and a few drops of heptane to afford 400 mg of a brown solid. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 203.20.
N-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)-2,2,2-trifluoro-N-methylacetamide
(152) To a solution of 6-chloro-5-(methoxymethoxy)-N-methylpyridin-2-amine (61 mg) in DCM (3 mL) were added trifluoroacetic anhydride (63 μl) and DIPEA (103 μl). The mixture was stirred at 0° C. for 1 h and at rt for 1.5 h. The mixture was diluted with DCM and 1N aq. HCl. The layers were separated, the org. phase was washed with water and sat. aq. NaCl. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Flash Master, 2 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 5, flow rate: 6 mL/min) to afford 76 mg of a yellow oil. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 299.03.
2-Chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-ol
(153) To a solution of N-(6-chloro-5-(methoxymethoxy)pyridin-2-yl)-2,2,2-trifluoro-N-methyl acetamide (80 mg) in THF (1.5 mL) was added borane-methyl sulfide complex, 2M in THF (1.34 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was evaporated in vacuo, the residue was diluted with EA and 1N aq. NaOH. The layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude alcohol (72 mg) was used in the next step without purification. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 240.98.
Tert-butyl 2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)acetate
(154) This ester has been prepared from 2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-ol according to the procedure described for acid 4 (1. step). LC-MS (A): t.sub.R=0.99 min; [M+H].sup.+: 354.91.
2-((2-Chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)acetic acid
(155) This acid has been prepared from tert-butyl 2-((2-chloro-6-(methyl(2,2,2-trifluoroethyl)amino)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 299.08.
Acid 6: 2-((2-Chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
4-(6-Chloro-3-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine
(156) To a solution of 4-(6-chloro-5-(methoxymethoxy)pyridin-2-yl)morpholine (3 g) in THF (58 mL) was added dropwise at −78° C. nBuLi 1.6M in hexanes (8 mL) under nitrogen. The mixture was stirred at −78° C. for 1 h. N-fluorobenzenesulfonimide (4.48 g) was added and the reaction mixture was stirred at −78° C. for 1 h and then at rt overnight. The mixture was diluted with EA and water. The layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Flash Master, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 10 to 20, flow rate: 30 mL/min) to afford 112 mg of a yellow oil. LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 277.02.
2-Chloro-5-fluoro-6-morpholinopyridin-3-ol hydrochloride
(157) This alcohol has been prepared from 4-(6-chloro-3-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 233.04.
Tert-butyl 2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)acetate
(158) This ester has been prepared from 2-chloro-5-fluoro-6-morpholinopyridin-3-ol hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 347.04.
2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
(159) This acid has been prepared from tert-butyl 2-((2-chloro-5-fluoro-6-morpholinopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 291.08.
Acid 7: 2-((2-Chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
4-(6-Chloro-4-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine
(160) This compound has been isolated as second product by the synthesis of 4-(6-chloro-3-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 277.07.
2-Chloro-4-fluoro-6-morpholinopyridin-3-ol hydrochloride
(161) This alcohol has been prepared from 4-(6-chloro-4-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 233.05.
Tert-butyl 2-((2-chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)acetate
(162) This ester has been prepared from 2-chloro-4-fluoro-6-morpholinopyridin-3-ol hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 347.05.
2-((2-Chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
(163) This acid has been prepared from tert-butyl 2-((2-chloro-4-fluoro-6-morpholinopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 291.03.
Acid 8: 2-((2-Chloro-3,4-difluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
4-(6-Chloro-3, 4-difluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine
(164) This compound has been isolated as third product by the synthesis of 4-(6-chloro-3-fluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 295.08.
2-Chloro-3,4-difluoro-6-morpholinopyridin-3-ol hydrochloride
(165) This alcohol has been prepared from 4-(6-chloro-3,4-difluoro-5-(methoxymethoxy)pyridin-2-yl)morpholine according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: 250.98.
Tert-butyl 2-((2-chloro-3, 4-difluoro-6-morpholinopyridin-3-yl)oxy)acetate
(166) This ester has been prepared from 2-chloro-3,4-difluoro-6-morpholinopyridin-3-ol hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 364.99.
2-((2-chloro-3,4-difluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
(167) This acid has been prepared from tert-butyl 2-((2-chloro-3,4-difluoro-6-morpholinopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: 309.09.
Acid 9: 2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate
(168) This ester has been prepared from 2-chloro-6-iodo-3-pyridinol according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 369.66.
Tert-butyl 2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate
(169) To a solution of tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate (7.07 g) in DMF (150 mL) were added methansulfonamide (1.80 g), copper iodide (550 mg), (trans)-N,N′-dimethyl-1,2-cyclohexanediamine (0.90 mL) and potassium carbonate (5.3 g). The reaction mixture was stirred at 100° C. for 1 h 45. The reaction mixture was diluted at rt with EA and sat. aq. NH.sub.4Cl. The layers were separated, the aq. phase was washed with EA and the combined org. layers were washed with sat. aq. NaCl, dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 100 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 25, flow rate: 40 mL/min) to afford 3.01 g of a white solid. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 337.04.
2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetic acid
(170) This acid has been prepared from tert-butyl 2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.53 min; [M+H].sup.+: 281.06.
Acid 10: 2-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetate
(171) This ester has been prepared from 2-chloro-6-(trifluoromethyl)pyridin-3-ol according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 312.15.
2-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid
(172) This acid has been prepared from tert-butyl 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 256.01.
Acid 11: 2-((2-Chloro-6-cyanopyridin-3-yl)oxy)acetic acid
6-Chloro-5-(methoxymethoxy)picolinic acid
(173) To a solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (5.85 g) in toluene (80 mL) under nitrogen was added at −78° C. nBuLi 1.6M in hexanes (16 mL) under nitrogen. The mixture was stirred at −78° C. for 30 min. The reaction mixture was poured into CO.sub.2 (s). After the addition, 1N aq. NaOH (30 mL) was added and the aq. layer was extracted with diethyl ether. The layers were separated, the aq. phase was acidified at 0° C. with 2N aq. HCl until pH 1 and washed with DCM. The org. layer was dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (3.73 g of a beige solid) was used in the next step without purification. LC-MS (A): t.sub.R=0.58 min; [M+H].sup.+: 217.98.
6-Chloro-5-(methoxymethoxy)picolinamide
(174) To a solution of 6-chloro-5-(methoxymethoxy)picolinic acid (3.6 g) in THF (80 mL) were added at 0° C. triethylamine (6 mL) and methylchloroformate (3 mL). The mixture was stirred at 0° C. for 30 min. Ammonium hydroxide 25% in water (20 mL) was added and the reaction mixture was stirred at rt for 10 min. The reaction mixture was diluted with EA and water. The layers were separated, the org. phase was washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 3, flow rate: 35 mL/min) to afford 2.4 g of a white solid. LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 217.03.
6-Chloro-5-(methoxymethoxy)picolinonitrile
(175) To a solution of 6-chloro-5-(methoxymethoxy)picolinamide (2.4 g) in DCM (100 mL) was added Burgess reagent (6 g). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with DCM and sat. aq. NaHCO.sub.3. The layers were separated, the org. phase was washed with water and sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 20, flow rate: 30 mL/min) to afford 1.72 g of a colourless oil. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: not visible.
6-Chloro-5-hydroxypicolinonitrile hydrochloride
(176) This alcohol has been prepared from 6-Chloro-5-(methoxymethoxy)picolinonitrile according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: not visible.
Tert-butyl 2-((2-chloro-6-cyanopyridin-3-yl)oxy)acetate
(177) This ester has been prepared from 6-chloro-5-hydroxypicolinonitrile hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: not visible.
2-((2-Chloro-6-cyanopyridin-3-yl)oxy)acetic acid
(178) This acid has been prepared from tert-butyl 2-((2-chloro-6-cyanopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: not visible.
Acid 12: 2-((2-Fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
2-Fluoro-6-iodopyridin-3-ol
(179) To a solution of 2-fluoro-3-hydroxypyridine (500 mg) in water (22 mL) were added potassium carbonate (599 mg) and iodine (660 mg). The reaction mixture was stirred at rt overnight. A solution of sat. aq. sodium thiosulfate was added, then 2N aq. HCl and the mixture was extracted with EA. The layers were separated, the org. layer was dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 10, flow rate: 15 mL/min) to afford 220 mg of a yellow solid. GC-MS (A): t.sub.R=2.13 min; [M+H].sup.+: 239.90.
Tert-butyl 2-((2-fluoro-6-iodopyridin-3-yl)oxy)acetate
(180) This ester has been prepared from 2-fluoro-6-iodopyridin-3-ol according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 353.76.
Tert-butyl 2-((2-fluoro-6-morpholinopyridin-3-yl)oxy)acetate
(181) This compound has been prepared from tert-butyl 2-((2-fluoro-6-iodopyridin-3-yl)oxy)acetate according to the procedure described for acid 4 (2. step). LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 313.27.
2-((2-Fluoro-6-morpholinopyridin-3-yl)oxy)acetic acid
(182) This acid has been prepared from tert-butyl 2-((2-fluoro-6-morpholinopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 257.16.
Acid 13: 2-((2-Chloro-5-fluoro-6-iodopyridin-3-yl)oxy)acetic acid
2-Chloro-5-fluoro-6-iodopyridin-3-ol
(183) This compound has been prepared from 2-chloro-5-fluoro-pyridin-3-ol according to the procedure described for acid 12 (1. step). LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 331.80.
Tert-butyl 2-((2-chloro-5-fluoro-6-iodopyridin-3-yl)oxy)acetate
(184) This ester has been prepared from 2-chloro-5-fluoro-6-iodopyridin-3-ol according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.96 min; [M+H].sup.+: 387.88.
2-((2-Chloro-5-fluoro-6-iodopyridin-3-yl)oxy)acetic acid
(185) This acid has been prepared from tert-butyl 2-((2-chloro-5-fluoro-6-iodopyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 331.80.
Acid 14: 2-((2-Chloro-5-fluoropyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-5-fluoropyridin-3-yl)oxy)acetate
(186) This ester has been prepared from 2-chloro-5-fluoropyridin-3-ol according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 262.10.
2-((2-Chloro-5-fluoropyridin-3-yl)oxy)acetic acid
(187) This acid has been prepared from tert-butyl 2-((2-chloro-5-fluoropyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.56 min; [M+H].sup.+: 206.01.
Acid 15: 2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetic acid
6-Chloro-5-(methoxymethoxy)-N,N-dimethylpicolinamide
(188) To a solution of 6-chloro-5-(methoxymethoxy)picolinic acid (213 mg) in DMF (5 mL) were added TBTU (330 mg), dimethylamine 2M in THF (0.46 mL) and DIPEA (0.5 mL). The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with EA and sat. aq. NH.sub.4Cl. The layers were separated, the aq. phase was washed with EA, the combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 35, flow rate: 10 mL/min) to afford 220 mg of a yellow solid. LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: 245.08.
6-Chloro-5-hydroxy-N,N-dimethylpicolinamide hydrochloride
(189) This alcohol has been prepared from 6-chloro-5-(methoxymethoxy)-N,N-dimethyl-picolinamide according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 201.10.
Tert-butyl 2-((2-chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetate
(190) This ester has been prepared from 6-chloro-5-hydroxy-N,N-dimethylpicolinamide hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 315.09.
2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetic acid
(191) This acid has been prepared from tert-butyl 2-((2-chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 258.96.
Acid 16: 2-((2-Chloro-6-(dimethylamino)pyridin-3-yl)oxy)acetic acid
6-Chloro-5-(methoxymethoxy)-N,N-dimethylpyridin-2-amine
(192) To a solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (1 g) in DMSO (17 mL) were added dimethylamine 2M in THF (8.35 mL), copper iodide (636 mg), L-proline (692 mg) and potassium carbonate (1.06 g). The mixture was stirred at 70° C. for 2 h. The reaction mixture was diluted with sat. aq. NaCl and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 10, flow rate: 20 mL/min) to afford 556 mg of a yellow oil. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 217.34.
2-Chloro-6-(dimethylamino)pyridin-3-ol hydrochloride
(193) This alcohol has been prepared from 6-chloro-5-(methoxymethoxy)-N,N-dimethylpyridin-2-amine according to the procedure described for acid 2 (3. step). LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: 173.09.
Tert-butyl 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)acetate
(194) This ester has been prepared from 2-chloro-6-(dimethylamino)pyridin-3-ol hydrochloride according to the procedure described for acid 4 (4. step). LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 287.02.
2-((2-Chloro-6-(dimethylamino)pyridin-3-yl)oxy)acetic acid
(195) This acid has been prepared from tert-butyl 2-((2-chloro-6-(dimethylamino)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 231.25.
Acid 17: 2-((2-Chloro-6-(methylamino)pyridin-3-yl)oxy)acetic acid, sodium salt
Methyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate
(196) To a solution of 2-chloro-6-iodo-3-pyridinol (400 g) in THF (20 mL) were added NaH (79 mg) and methyl bromoacetate (0.16 mL). The reaction mixture was stirred in microwave at 100° C. for 2 h. The mixture was diluted with EA and sat. aq. NaCl. The layers were separated and the aq. phase was washed with EA. The combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude (525 mg of a beige oil) was used without further purification in the next step. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 328.14.
Methyl 2-((2-chloro-6-(methylamino)pyridin-3-yl)oxy)acetate
(197) To a solution of methyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate (200 mg) in DMSO (1 mL) were added methylamine 2M in THF (0.37 mL), copper iodide (116 mg), L-proline (122 mg) and potassium carbonate (194 mg). The mixture was stirred at 80° C. for 3 h. The reaction mixture was diluted with sat. aq. NaCl and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 40 mg of a white solid. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 230.99.
2-((2-Chloro-6-(methylamino)pyridin-3-yl)oxy)acetic acid, sodium salt
(198) To a solution of methyl 2-((2-chloro-6-(methylamino)pyridin-3-yl)oxy)acetate (40 mg) in methanol (1 mL) was added 1N aq. NaOH (0.2 mL). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated in vacuo. The crude (48 mg of a white salt) was used in the next step without purification. LC-MS (A): t.sub.R=0.54 min; [M+H].sup.+: 217.18.
Acid 18: 2-(2-Chloro-4-cyanophenoxy)acetic acid
3-Chloro-4-hydroxybenzonitrile
(199) To a solution of 3-chloro-4-methoxybenzonitrile (4.25 g) in DCM (85 mL) was added a −78° C. dropwise 1M sol. of BBr.sub.3 in DCM (50.7 mL). The reaction mixture was stirred at −78° C. for 10 min and at RT overnight. The mixture was then stirred at 40° C. for 4.5 d and additional BBr.sub.3 sol. (26 mL) was added on the first, second and third day respectively. The reaction mixture was carefully quenched with water, the solid precipitate was filtrated off. The layers were separated, the aq. phase was washed with DCM and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 0 to 40, flow rate: 30 mL/min) to afford 3.17 g of a brown oil. LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: not visible.
Methyl 2-(2-chloro-4-cyanophenoxy)acetate
(200) This ester has been prepared from 3-chloro-4-hydroxybenzonitrile according to the procedure described for acid 17 (1. step). LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: not visible.
2-(2-chloro-4-cyanophenoxy)acetic acid
(201) This acid has been prepared from methyl from 2-(2-chloro-4-cyanophenoxy)acetate according to the procedure described for acid 17 (3. step). LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: not visible.
Acid 19: 2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetic acid
(202) This compound was prepared from 2-chloro-4-(trifluoromethyl)phenol according to the procedures described for acid 18 (steps 2-3). LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: not visible.
Acid 20: 2-((2-Chloropyridin-3-yl)oxy)acetic acid
(203) This compound was prepared from 2-chloropyridin-3-ol according to the procedures described for acid 18. LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 188.18.
Acid 21: 2-((6-(3,3-Difluoroazetidin-1-yl)-2-chlororopyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((6-(3,3-difluoroazetidin-1-yl)-2-chloropyridin-3-yl)oxy)acetate
(204) This compound was prepared from tert-butyl 2-((2-fluoro-6-iodopyridin-3-yl)oxy)acetate according to the procedures described for acid 4 (2. step) using 3,3-difluoroazetidine instead of morholine and DMF instead of DMSO as a solvent. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 334.92.
2-((6-(3,3-Difluoroazetidin-1-yl)-2-chloropyridin-3-yl)oxy)acetic acid
(205) This compound was prepared from tert-butyl 2-((6-(3,3-difluoroazetidin-1-yl)-2-fluoropyridin-3-yl)oxy)acetate according to the procedures described for acid 1 (2. step). LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 279.03.
Acid 22: 2-((2-Chloro-6-(methylcarbamoyl)pyridin-3-yl)oxy)acetic acid
(206) This compound was prepared from 6-chloro-5-(methoxymethoxy)picolinic acid according to the procedures described for acid 15 using methylamine instead of dimethylamine fo the amide coupling. LC-MS (A): t.sub.R=0.53 min; [M+H].sup.+: 318.19.
Acid 23: 2-((2-Chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)acetic acid 2-Chloro-6-(hydroxymethyl)pyridin-3-ol
(207) To a solution of 2-chloropyridin-3-ol (25 g) and NaHCO.sub.3 (2.92 g) in water (22.5 mL) was added at 90° C. aq. 37%-solution of formaldehyde portionwise (4×1.2 mL during 6 h) and the mixture was stirred for 26 h. Water was added (20 mL) at rt followed by addition of 1N aq. sol. of HCl (100 mL) to maintain the pH=1. The solid precipitate was filtrated off. The aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude material (3.0 g) of was used in the next step without purification LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 160.20.
6-Chloro-5-hydroxypicolinaldehyde
(208) This compound was prepared from 2-chloro-6-(hydroxymethyl)pyridin-3-ol according to the procedures described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: not visible.
2-Chloro-6-(morpholinomethyl)pyridin-3-ol
(209) To a solution of 6-chloro-5-hydroxypicolinaldehyde (530 mg) and morpholine (0.75 mL) in MeCN (40 mL) was added natriumtriacetoxyborhydrid (1.4 g). The mixture was stirred at RT for 14.5 h. The reaction mixture was diluted with sat. aq. NaHCO.sub.3 and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: 7N NH.sub.3 in MeOH, gradient in % B: 0.5, flow rate: 20 mL/min) to afford 503 mg of a yellow oil. LC-MS (A): t.sub.R=0.36 min; [M+H].sup.+: 229.14.
2-((2-Chloro-6-(morpholinomethyl)pyridin-3-yl)oxy)acetic acid
(210) This compound was prepared from 2-chloro-6-(morpholinomethyl)pyridin-3-ol in 2 steps according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.37 min; [M+H].sup.+: 287.12.
Acid 24: 2-(2-Chloro-4-(morpholinomethyl)phenoxy)acetic acid
Tert-butyl 2-(2-chloro-4-formylphenoxy)acetate
(211) To a solution of 3-chlor-4-hydroxybenzaldehyde (12.84 g) in MeCN was added Nal (1.23 g) and K.sub.2CO.sub.3 (12.47 g). The mixture was stirred at 80° C. for 45 min. Tert-butyl bromoacetate (8 g) was added dropwise and the mixture was stirred at 80° C. for 15 h. After cooling to the RT was the reaction mixture diluted with water and DCM. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over Na.sub.2SO.sub.4, filtrated off and evaporated in vacuo. The crude was used without further purification in the next step. LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: not visible.
Tert-butyl 2-(2-chloro-4-(morpholinomethyl)phenoxy)acetate
(212) This compound was prepared from tert-butyl 2-(2-chloro-4-formylphenoxy)acetate according to the procedure described for acid 23 (3. step). LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 342.18.
2-(2-Chloro-4-(morpholinomethyl)phenoxy)acetic acid
(213) This compound was prepared from tert-butyl 2-(2-chloro-4-(morpholinomethyl)phenoxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.44 min; [M+H].sup.+: 286.15.
Acid 25: 2-((4-Chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)acetic acid
4-Chloro-5-methoxy-N,N-dimethylpyrimidin-2-amine
(214) To a solution of 4-chloro-5-methoxy-N,N-dimethylpyrimidin-2-amine (253 mg) in DMF (8 mL) was added at 0° C. NaH (86 mg) portionwise. After 30 min MeI (0.25 mL) was added and the reaction was stirred at RT for 1 h. The reaction mixture was diluted with sat. aq. NH.sub.4Cl and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: heptane, solvent B: EA, gradient in % B: 1 to 8, flow rate: 10 mL/min) to afford 123 mg of a yellow oil. LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 188.25.
4-Chloro-2-(dimethylamino)pyrimidin-5-ol
(215) This compound was prepared from 4-chloro-5-methoxy-N,N-dimethylpyrimidin-2-amine according to the procedure described for acid 18 (1. step). LC-MS (A): t.sub.R=0.58 min; [M+H].sup.+: 174.07.
2-((4-Chloro-2-(dimethylamino)pyrimidin-5-yl)oxy)acetic acid
(216) This compound was prepared from 4-chloro-2-(dimethylamino)pyrimidin-5-ol according to the procedures described for acid 1 (1. and 2. step). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 232.04.
Acid 26: 2-((6-Carbamoyl-2-chloropyridin-3-yl)oxy)acetic acid
Methyl 6-chloro-5-(methoxymethoxy)picolinate
(217) To a solution of 6-chloro-5-(methoxymethoxy)picolinic acid (1.63 g) in MeOH (60 mL) was added dropwise at RT a 2.0 M solution of trimethylsilyldiazomethane in hexane (18.8 mL). The mixture was stirred at RT. Two other portions of trimethylsilyldiazomethane solution were added: (1.9 mL after 2 h and 1.9 mL after additional 3 h). 3 h after the last addition was the solvent evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: heptane, solvent B: EA, gradient in % B: 1 to 9, flow rate: 30 mL/min) to afford 1.3 g of a yellow oil. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 232.09.
Methyl 5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropicolinate
(218) This compound was prepared from methyl 6-chloro-5-(methoxymethoxy)picolinate according to the procedures described for acid 2 (3. and 4. step). LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 302.16.
Tert-butyl 2-((6-carbamoyl-2-chloropyridin-3-yl)oxy)acetate
(219) A solution of methyl 5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropicolinate (500 mg) in aq. ammoniumhydroxid (10 mL) was stirred at 35° C. for 3.5 h. The solid precipitate was filtrated off and washed with water and dried. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: heptane, solvent B: EA, gradient in % B: 1 to 70, flow rate: 10 mL/min) to afford 430 mg of a white solid. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: 287.14.
2-((6-Carbamoyl-2-chloropyridin-3-yl)oxy)acetic acid
(220) This compound was prepared from tert-butyl 2-((6-carbamoyl-2-chloropyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.49 min; [M+H].sup.+: 231.11.
Acid 27: 2-(2-Chloro-4-fluorophenoxy)acetic acid
(221) This compound was prepared from 2-chloro-4-fluorophenol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: not visible.
Acid 28: 2-(4-Fluoro-2-methylphenoxy)acetic acid
(222) This compound was prepared from 4-fluoro-2-methylphenol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: not visible.
Acid 29: 2-(2,4-Difluorophenoxy)acetic acid
(223) This compound was prepared from 2,4-difluorophenol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: not visible.
Acid 30: 2-(2-Chloro-4-(methylsulfonamido)phenoxy)acetic acid
(224) This compound was prepared from 2-chloro-4-iodophenol according to the procedures described for acid 9. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: not visible.
Acid 31: 2-((2-Chloro-6-iodopyridin-3-yl)oxy)acetic acid
(225) This compound was prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy) according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 313.82.
Acid 32: 2-((2,6-Dimethylpyridin-3-yl)oxy)acetic acid
(226) This compound was prepared from 2,6-dimethylpyridin-3-ol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.29 min; [M+H].sup.+: 182.26.
Acid 33: 2-((2-Methylpyridin-3-yl)oxy)acetic acid
(227) This compound was prepared from 2-methylpyridin-3-ol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.18 min; [M+H].sup.+: 168.22.
Acid 34: 2-((2-Fluoropyridin-3-yl)oxy)acetic acid
(228) This compound was prepared from 2-fluoropyridin-3-ol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.46 min; [M+H].sup.+: 171.96.
Acid 35: 2-((2-(Trifluoromethyl)pyridin-3-yl)oxy)acetic acid 2-(Trifluoromethyl)pyridin-3-ol
(229) To a solution of 1.6M nBuLi in hexane (0.94 mL) in THF (2.7 mL) was added at −78° C. 2,2,6,6-tetramethylpiperidin (0.28 mL) followed by 2-trifluoromethylpyridine (0.14 mL). The reaction was stirred at −78° C. for 17 h. Trimethylborate (0.32 mL) was added and the reaction was stirred at −78° C. for 2 h. Peracetic acid was added (0.39 mL, 39% solution in AcOH) and the reaction mixture was allowed to warm to 0° C. under stirring for 3 h. The reaction mixture was diluted with sat. aq. Na.sub.2SO.sub.3 and DCM. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by FC (solvent A: DCM, solvent B: MeOH, gradient in % B: 2) to afford 114 mg of an orange oil. LC-MS (A): t.sub.R=0.46 min; [M+H].sup.+: 164.20.
2-((2-(Trifluoromethyl)pyridin-3-yl)oxy)acetic acid
(230) This compound was prepared from 2-(trifluoromethyl)pyridin-3-ol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.49 min; [M+H].sup.+: 221.98.
Acid 36: 2-((6-(Dimethylamino)-2-methylpyridin-3-yl)oxy)acetic acid 4, 6-Dibromo-2-methylpyridin-3-ol
(231) To a suspension of 2-methylpyridin-3-ol (500 mg) in MeCN (30 mL) was added at 0° C. NBS (1.7 g). The reaction was stirred at 0° C. for 2 h. The solvent was evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: 7N NH.sub.3 in MeOH, gradient in % B: 1 to 3, flow rate: 10 mL/min) to afford 1.0 g of a yellow solid. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 267.83.
6-Bromo-2-methylpyridin-3-ol
(232) To a solution of 4,6-dibromo-2-methylpyridin-3-ol (1.0 g) in THF (20 mL) was added at −78° C. 1.6M nBuLi in hexane (4.7 mL). The reaction was stirred for 2 h. Water was added (9 mL) and the reaction mixture was allowed to warm up to rt. The reaction mixture was diluted with sat. aq. NH.sub.4Cl and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: 7N NH.sub.3 in MeOH, gradient in % B: 1 to 3, flow rate: 10 mL/min) to afford 550 mg of a colourless solid. LC-MS (A): t.sub.R=0.58 min; [M+H].sup.+: 188.03.
2-((6-(Dimethylamino)-2-methylpyridin-3-yl)oxy)acetic acid
(233) This compound was prepared from 6-bromo-2-methylpyridin-3-ol according to the procedures described for acid 4 (1-5. step), using dimethylamine instead of morpholine in the Buchwald coupling. LC-MS (A): t.sub.R=0.40 min; [M+H].sup.+: 211.22.
Acid 37: 2-((2-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)oxy)acetic acid
3-(Methoxymethoxy)-2-methyl-6-(pyrrolidin-1-yl)pyridine
(234) This compound has been prepared from 6-bromo-3-(methoxymethoxy)-2-methylpyridine according to the procedure described for acid 2 (2. step) using pyrrolidine instead of morpholine in the Buchwald coupling. LC-MS (A): t.sub.R=0.54 min; [M+H].sup.+: 223.10.
2-((2-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)oxy)acetic acid
(235) This acid has been prepared from 3-(methoxymethoxy)-2-methyl-6-(pyrrolidin-1-yl)pyridine according to the procedures described for acid 2 (steps 3-5). LC-MS (A): t.sub.R=0.46 min; [M+H].sup.+: 237.29.
Acid 38: 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid
(236) This acid has been prepared from 6-(trifluoromethyl)pyridin-3-ol according to the procedures described for acid 1 (steps 1-2). LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 222.14.
Acid 39: 2-((2-Chloro-6-(methoxycarbonyl)pyridin-3-yl)oxy) acetic acid
2-((2-Chloro-6-(methoxycarbonyl)pyridin-3-yl)oxy) acetic acid
(237) This acid has been prepared from methyl 5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropicolinate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.55 min; [M+H].sup.+: 246.15.
Acid 40: 2-((4-Chloro-2-(trifluoromethyl)pyrimidin-5-yl)oxy)acetic acid
(238) This acid has been prepared from 4-chloro-5-methoxy-2-(trifluoromethyl)pyrimidine according to the procedures described for acid 25 (steps 2-4). LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: not visible.
Acid 41: 2-((1-Ethyl-3-(methoxycarbonyl)-1H-pyrazol-5-yl)oxy)acetic acid
Methyl 1-ethyl-5-hydroxy-1H-pyrazole-3-carboxylate
(239) To a solution of 1-ethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid (50 mg) in methanol (2 mL) was added PTSA (6 mg). The mixture was stirred at rt for 1 h and at 65° C. for 41 h. Methanol was evaporated in vacuo, the remaining aqueous layer was extracted twice with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 2 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 3, flow rate: 5 mL/min) to afford 43 mg of a white solid. LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 170.98.
2-((1-Ethyl-3-(methoxycarbonyl)-1H-pyrazol-5-yl)oxy)acetic acid
(240) This acid has been prepared from methyl 1-ethyl-5-hydroxy-1H-pyrazole-3-carboxylate according to the procedures described for acid 4 (steps 4-5). LC-MS (A): t.sub.R=0.53 min; [M+H].sup.+: 229.16.
Acid 42: 2-((2,4-Dimethylpyrimidin-5-yl)oxy)acetic acid
(241) This acid has been prepared from 2,4-dimethylpyrimidin-5-ol according to the procedures described for acid 4 (steps 4-5). LC-MS (A): t.sub.R=0.40 min; [M+H].sup.+: 183.16.
Acid 43: 2-((2-Chloro-6-(diethylcarbamoyl)pyridin-3-yl)oxy)acetic acid
(242) This acid has been prepared from 6-chloro-5-(methoxymethoxy)picolinic acid according to the procedures described for acid 15 (steps 1-4) using diethylamine instead of dimethylamine in the amide coupling. LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: 287.04.
Acid 44: 2-((2-Chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)acetic acid
2-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)oxazole
(243) To a solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (1 g) in DMF (10 mL) were added 2-(tri-n-butylstannyl)oxazole (2.4 g) and tetrakis(triphenylphosphine)palladium (20 mg). The mixture was stirred at 120° C. for 1 h. The solvent was evaporated in vacuo and the remaining crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 20, flow rate: 20 mL/min) to afford 420 mg of a white solid. LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: 240.96.
2-((2-Chloro-6-(oxazol-2-yl)pyridin-3-yl)oxy)acetic acid
(244) This acid has been prepared from 2-(6-chloro-5-(methoxymethoxy)pyridin-2-yl)oxazole according to the procedures described for acid 4 (steps 3-5). LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 255.14.
Acid 45: 2-((2-Chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3-yl)oxy)acetic acid
1-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)cyclopropanamine
(245) To a solution of 6-chloro-5-(methoxymethoxy)picolinonitrile (2.13 g) in diethyl ether (70 mL) cooled down to −75° C. were added ethylmagnesium bromide 3M in diethyl ether (8 mL) and titanium (IV) isopropoxide (3.5 mL). The mixture was stirred at −75° C. for 10 min. Boron trifluoride ethyl etherate (2.7 mL) was added at rt and the reaction mixture was stirred at rt for 40 min. The mixture was diluted with EA and 1N HCl until pH=1. The slurry was slipped into a 1N aq. NaOH solution and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (555 mg of a brown oil) was used in the next step without purification. LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 229.14.
1-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)-N,N-dimethylcyclopropanamine
(246) To a solution of 1-(6-chloro-5-(methoxymethoxy)pyridin-2-yl)cyclopropanamine (100 mg) in acetonitrile (4 mL) were added formaldehyde 36.5% in water (0.11 mL), acetic acid (0.025 mL) and sodium triacetoxyborohydrid (140 mg). The mixture was stirred at rt overnight. Additionally, formaldehyde (0.051 mL) and sodium triacetoxyborohydrid (140 mg) were added and the reaction mixture was stirred at rt for 30 min. The mixture was diluted with DCM and sat. aq. NaHCO.sub.3. The layers were separated and the aq. phase was washed twice with DCM. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 5, flow rate: 10 mL/min) to afford 77 mg of a yellow solid. LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: 257.10.
2-((2-Chloro-6-(1-(dimethylamino)cyclopropyl)pyridin-3-yl)oxy)acetic acid
(247) This acid has been prepared from 1-(6-Chloro-5-(methoxymethoxy)pyridin-2-yl)-N,N-dimethylcyclopropanamine according to the procedures described for acid 4 (steps 3-5). LC-MS (A): t.sub.R=0.42 min; [M+H].sup.+: 271.09.
Acid 46: 2-((2-Chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)acetate
(248) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to the procedure described for acid 4 (2. step) using 3-methyl-3-methoxyazetidin instead of morpholine in the Buchwald coupling. LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 343.14.
2-((2-Chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)acetic acid
(249) This acid has been prepared from tert-butyl 2-((2-chloro-6-(3-methoxy-3-methylazetidin-1-yl)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: 286.99.
Acid 47: 2-((2-Chloro-6-(cyclopropanesulfonamido)pyridin-3-yl)oxy)acetic acid
(250) This acid has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to the procedure described for acid 9 (2 and 3. step) using cyclopropanesulfonamide instead of methylsulfonamide in the Ulmann coupling. LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: 306.97.
Acid 48: 2-((2-chloro-6-(cyclopropyl(methyl)carbamoyl)pyridin-3-yl)oxy)acetic acid
6-Chloro-N-cyclopropyl-5-(methoxymethoxy)-N-methylpicolinamide
(251) This compound has been prepared from 6-chloro-5-(methoxymethoxy)picolinic acid according to procedures described for acid 15 (steps 1-4) using N-methylcyclopropanamine instead of dimethylamine in the amide coupling. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 285.15.
Acid 49: 2-((2-Chloro-6-(N-methylmethylsulfonamido)pyridin-3-yl)oxy)acetic acid
(252) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to procedures described for acid 9 (steps 2-3) using N-methylmethanesulfonamide instead of methanesulfonamide in the Ullmann coupling. LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 295.06.
Acid 50: 2-((2-Chloro-6-(N-methylmethylsulfonamido)pyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-ethyl-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate
(253) To solution of tert-butyl 2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate (192 mg) in dioxane (8 mL) was added at rt diethylzinc 1M in hexanes (0.855 mL), (1,1′-bis(diphenylphosphino) ferrocene) dichloropalladium (II) dichloromethane adduct (15 mg) and the mixture was stirred at 85° C. for 1.5 h. The reaction mixture was diluted with water and EA. The layers were separated, the aq. phase was washed with EA and the combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 180 mg of a white solid. LC-MS (A): t.sub.R=0.83 min; [M+H].sup.+: 331.26.
2-((2-Chloro-6-(N-methylmethylsulfonamido)pyridin-3-yl)oxy)acetic acid
(254) This acid has been prepared from tert-butyl 2-((2-ethyl-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate according to the procedures described for acid 1 (2. step). LC-MS (A): t.sub.R=0.55 min; [M+H].sup.+: 275.01.
Acid 51: 2 2-((2-Chloro-6-(1,1-dioxidoisothiazolidin-2-yl)pyridin-3-yl)oxy)acetic acid
(255) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to procedures described for acid 9 (2. step to 3. step) using isothiazolidine 1,1-dioxide instead of methanesulfonamide in the Ullmann coupling. LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 307.01.
Acid 52: 2 2-((2-Chloro-6-(((dimethylamino)methyl)amino)pyridin-3-yl)oxy)acetic acid
(256) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to procedures described for acid 9 (2. step to 3. step) using N,N-dimethylsulfamide instead of methanesulfonamide in the Ullmann coupling. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 310.10.
Acid 53: 2-((2-Chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)oxy)acetic acid
(257) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to procedures described for acid 9 (2. step to 3. step) using 1-methylpiperazine instead of methanesulfonamide in the Ullmann coupling. LC-MS (A): t.sub.R=0.45 min; [M+H].sup.+: 286.11.
Acid 54: 2-((6-(Difluoromethyl)-2-ethylpyridin-3-yl)oxy)acetic acid 2-Bromo-6-(hydroxymethyl)pyridin-3-ol
(258) This compound has been prepared from 2-bromopyridin-3-ol according to procedures described for acid 23 (1. step). LC-MS (A): t.sub.R=0.41 min; [M+H].sup.+: 204.10.
6-(Hydroxymethyl)-2-vinylpyridin-3-ol
(259) A solution of 2-bromo-6-(hydroxymethyl)pyridin-3-ol (1.5 g), vinylboronic anhydride pyridine complex (2.65 g), K.sub.2CO.sub.3 (2.03 g) and tetrakis(triphenylphosphine)palladium (0.85 g) in DME (50 mL) was stirred at 100° C. for 50 min. The mixture was filtrated off at rt over celite and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 7, flow rate: 10 mL/min) to afford 910 mg of a yellowish oil. LC-MS (A): t.sub.R=0.30 min; [M+H].sup.+: 152.01.
2-Ethyl-6-(hydroxymethyl)pyridin-3-ol
(260) A solution of 6-(hydroxymethyl)-2-vinylpyridin-3-ol (0.9 g) and Pd/C (90 mg) in MeOH (60 mL) was stirred under hydrogen (normal pressure) at rt for 15 min. The mixture was filtrated off over celite and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: DCM, solvent B: MeOH, gradient in % B: 1 to 7, flow rate: 20 mL/min) to afford 551 mg of a yellowish solid. LC-MS (A): t.sub.R=0.30 min; [M+H].sup.+: 154.07.
6-Ethyl-5-hydroxypicolinaldehyde
(261) This compound has been prepared from 2-ethyl-6-(hydroxymethyl)pyridin-3-ol according to procedures described for aldehyde 1 (2. step). LC-MS (A): t.sub.R=0.49 min; [M+H].sup.+: 152.06.
Tert-butyl 2-((2-ethyl-6-formylpyridin-3-yl)oxy)acetate
(262) This compound has been prepared from 6-ethyl-5-hydroxypicolinaldehyde according to procedures described for acid 1 (1. step). LC-MS (A): t.sub.R=0.87 min; [M+H].sup.+: 266.13.
Tert-butyl 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)oxy)acetate
(263) To a solution of tert-butyl 2-((2-ethyl-6-formylpyridin-3-yl)oxy)acetate (58 mg) in DCM (5 mL) was added at 0° C. DAST (64 μl) and the reaction was stirred at rt overnight. The mixture was diluted with DCM and sat. aq. NaHCO.sub.3. The layers were separated and the aq. phase was washed twice with DCM. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: EA, solvent B: heptane, gradient in % B: 1 to 4, flow rate: 10 mL/min) to afford 41 mg of a yellowish solid. LC-MS (A): t.sub.R=0.93 min; [M+H].sup.+: 288.18.
2-((6-(Difluoromethyl)-2-ethylpyridin-3-yl)oxy)acetic acid
(264) This compound has been prepared from tert-butyl 2-((6-(difluoromethyl)-2-ethylpyridin-3-yl)oxy)acetate according to procedures described for acid 1 (2. step). LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: 232.14.
Acid 55: 3-(Carboxymethoxy)-2-ethyl-6-methylpyridine 1-oxide
Methyl 2-((2-ethyl-6-methylpyridin-3-yl)oxy)acetate
(265) This compound has been prepared from 2-ethyl-6-methylpyridin-3-ol according to procedures described for acid 17 (1. step). LC-MS (A): t.sub.R=0.47 min; [M+H].sup.+: 210.07.
2-Ethyl-3-(2-methoxy-2-oxoethoxy)-6-methylpyridine 1-oxide
(266) A solution methyl 2-((2-ethyl-6-methylpyridin-3-yl)oxy)acetate (335 mg) and MCPBA (470 mg) in DCM (6 mL) was stirred at rt for 15 min. The mixture was evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: EA, solvent B: heptane, gradient in % B: 2 to 15, flow rate: 9 mL/min) to afford 314 mg of a colourless solid. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 226.30.
3-(Carboxymethoxy)-2-ethyl-6-methylpyridine 1-oxide
(267) A solution of 2-ethyl-3-(2-methoxy-2-oxoethoxy)-6-methylpyridine 1-oxide (210 mg) in MeOH (10 mL) and 2.5M aq. NaOH (1 mL) was stirred at rt for 30 min. The MeOH was evaporated in vacuo and the mixture was diluted with DCM and 3M aq. HCl. The layers were separated and the aq. phase was evaporated in vacuo. The colourless solid was treated with MeOH, filtrated off and evaporated in vacuo. The crude (200 mg) was used in the next step without purification. LC-MS (A): t.sub.R=0.47 min; [M+H].sup.+: 212.34.
Acid 56: 2-((4-Chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)acetic acid
Methyl 2-((4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)acetate
(268) This compound has been prepared from 4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol according to procedures described for acid 17 (1. step). LC-MS (A): t.sub.R=0.87 min; [M+H].sup.+: 272.97.
2-((4-Chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)acetic acid
(269) This compound has been prepared from methyl 2-((4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)acetate according to procedures described for acid 55 (3. step). LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 258.89.
Acid 57: 2-(Isoquinolin-7-yloxy)acetic acid
Ethyl 2-(isoquinolin-7-yloxy)acetate
(270) A solution of isoquinolin-7-ol (200 mg), ethyl bromoacetate (1.07 mL) and CsCO.sub.3 (1.8 g) in MeCN (2 mL) was stirred at rt for 48 h. The mixture was diluted with EA and aq. sat. NaCl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by FC (solvent: DCM/MeOH, 95/5) to afford 655 mg of a yellow oil. LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: 232.17.
2-(Isoquinolin-7-yloxy)acetic acid
(271) This compound has been prepared from ethyl 2-(isoquinolin-7-yloxy)acetate according to procedures described for acid 18 (3. step). LC-MS (A): t.sub.R=0.39 min; [M+H].sup.+: 204.21.
Acid 58: 2-(2-Ethyl-4-fluorophenoxy)acetic acid
(272) This compound was prepared from 2-ethyl-4-fluorophenol according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: not visible.
Acid 59: 2-(2-Chloro-3-(trifluoromethyl)phenoxy)acetic acid
(273) This compound was prepared from 2-chloro-3-(trifluoromethyl)phenol according to the procedures described for acid 18. LC-MS (A): t.sub.R=1.14 min; [M+H].sup.+: not visible.
Acid 60: 2-(2-Chloro-5-methylphenoxy)acetic acid
(274) This compound was prepared from 2-chloro-5-methylphenol according to the procedures described for acid 18. LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: not visible.
Acid 61: 2-((2-Chloro-4-ethylpyrimidin-5-yl)oxy)acetic acid 2-Chloro-4-ethyl-5-methoxypyrimidine
(275) To a solution of 2,4-dichloro-5-methoxypyrimidine (4 g) and iron(III) acetylacetonate (790 mg) in THF (40 mL) was added at 0° C. 2.0 M solution of ethylmagnesium chloride in THF (13.4 mL) and the mixture was stirred overnight at rt. The mixture was diluted with TBME and 1N HCl. The layers were separated and the aq. phase was washed twice with TBME. The combined org. layers were washed with aq. sat. NaHCO.sub.3 and with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 50 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 8, flow rate: 30 mL/min) to afford 2.8 g of a colourless solid. LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 173.02.
2-Chloro-4-ethylpyrimidin-5-ol
(276) This compound was prepared from 2-chloro-4-ethyl-5-methoxypyrimidine according to the procedures described for acid 18. LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 159.06.
Tert-butyl 2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)acetate
(277) This compound was prepared from 2-chloro-4-ethylpyrimidin-5-ol according to the procedures described for acid 4 (4. step). LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 273.11.
2-((2-Chloro-4-ethylpyrimidin-5-yl)oxy)acetic acid
(278) This compound has been prepared from tert-butyl 2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)acetate according to procedures described for acid 1 (2. step). LC-MS (A): t.sub.R=0.59 min; [M+H].sup.+: 217.04.
Acid 62: 2-((4-Ethyl-2-(methylsulfonamido)pyrimidin-5-yl)oxy)acetic acid
Tert-butyl 2-((4-ethyl-2-(methylthio)pyrimidin-5-yl)oxy)acetate
(279) A solution of tert-butyl 2-((2-chloro-4-ethylpyrimidin-5-yl)oxy)acetate (391 mg) and sodium thiomethoxide (160 mg) in THF (10 mL) was stirred at 60° C. for 24 h. The mixture was diluted with EA and aq. sat. NH.sub.4Cl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 20, flow rate: 10 mL/min) to afford 273 mg of a yellowish oil. LC-MS (A): t.sub.R=0.93 min; [M+H].sup.+: 285.10.
Tert-butyl 2-((4-ethyl-2-(methylsulfonyl)pyrimidin-5-yl)oxy)acetate
(280) To a solution of tert-butyl 2-((4-ethyl-2-(methylthio)pyrimidin-5-yl)oxy)acetate (270 mg) in DCM (20 mL) was added a 39%-solution peracetic acid in acetic acid (0.5 mL). The reaction mixture was stirred at rt and additional peracetic acid sol. was added (0.45 mL) was added after 90 min and 3 h respectively. The mixture was diluted with aq. sat. NaHCO.sub.3 and DCM. The layers were separated and the aq. phase was washed twice with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude solid (261 mg) was used in the next step without purification. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 317.06.
Tert-butyl 2-((4-ethyl-2-(methylsulfonamido)pyrimidin-5-yl)oxy)acetate
(281) A solution of tert-butyl 2-((4-ethyl-2-(methylsulfonyl)pyrimidin-5-yl)oxy)acetate (300 mg) and methanesulfonamide monopotassium salt (380 mg) in DMSO was stirred in a microwave station at 100° C. for 1 h. The mixture was diluted with aq. sat. NaHCO.sub.3 and EA. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 30, flow rate: 10 mL/min) to afford 58 mg of a colourless solid. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 332.06.
2-((4-Ethyl-2-(methylsulfonamido)pyrimidin-5-yl)oxy)acetic acid
(282) This compound has been prepared from tert-butyl 2-((4-ethyl-2-(methylsulfonamido)pyrimidin-5-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 276.06.
Acid 63: 2-((2-Methoxy-6-(methylsulfonamido)pyridin-3-yl)oxy)acetic acid
6-Iodo-2-methoxy-3-(methoxymethoxy)pyridine
(283) A solution of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (400 mg) and sodium methoxide (97 mg) in DMSO (12 mLmL) was stirred at 90° C. for 90 min. The mixture was diluted with EA and aq. sat. NH.sub.4Cl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 10 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 12, flow rate: 15 mL/min) to afford 323 mg of a yellowish oil. LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 295.93.
Tert-butyl 2-((6-iodo-2-methoxypyridin-3-yl)oxy)acetate
(284) This compound has been prepared from 6-iodo-2-methoxy-3-(methoxymethoxy)pyridine according to procedures described for acid 2 (steps 2-3). LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 366.01.
Tert-butyl 2-((2-methoxy-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate
(285) This compound has been prepared from tert-butyl 2-((6-iodo-2-methoxypyridin-3-yl)oxy)acetate according to the procedure described for acid 9 (2. step). LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 333.05.
2-((2-Methoxy-6-(methylsulfonamido)pyridin-3-yl)oxy)acetic acid
(286) This compound has been prepared from tert-butyl 2-((2-methoxy-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.49 min; [M+H].sup.+: 277.04.
Acid 64: 2-((2-Chloro-6-((N-methylsulfamoyl)amino)pyridin-3-yl)oxy)acetic acid
(287) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate according to the procedure described for acid 52 (steps 1-2) using N-methylsulfamide instead of N,N-dimethylsulfamide in the Ullmann coupling. LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: 295.95.
Acid 65: 2-((6-(1,1-Dioxidoisothiazolidin-2-yl)-2-ethylpyridin-3-yl)oxy)acetic acid
(288) This compound has been prepared from acid 51 according to the procedure described for acid 50 (1. step). LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 301.26.
Acid 66: 2-((6-(Cyclopropylcarbamoyl)-2-ethylpyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetate
(289) This compound has been prepared from 6-chloro-5-(methoxymethoxy)picolinic acid according to the procedure described for acid 48 (steps 1-3) using cyclopropylamine instead of N-methylcyclopropylamine in the amide coupling. LC-MS (A): t.sub.R=0.87 min; [M+H].sup.+: 327.05.
2-((6-(Cyclopropylcarbamoyl)-2-ethylpyridin-3-yl)oxy)acetic acid
(290) This compound has been prepared from tert-butyl 2-((2-chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetate according to procedures described for acid 50. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 265.14.
Acid 67: 3-(Carboxymethoxy)-2-chloropyridine 1-oxide
2-Chloro-3-(2-methoxy-2-oxoethoxy)pyridine 1-oxide
(291) This compound has been prepared from methyl 2-((2-chloropyridin-3-yl)oxy)acetate (for the synthesis see acid 20) according to procedures described for acid 55 (1. step). LC-MS (A): t.sub.R=0.45 min; [M+H].sup.+: 218.27.
3-(Carboxymethoxy)-2-chloropyridine 1-oxide
(292) This compound has been prepared from 2-chloro-3-(2-methoxy-2-oxoethoxy)pyridine 1-oxide according to procedures described for acid 17 (3. step). LC-MS (A): t.sub.R=0.32 min; [M+H].sup.+: 204.30.
Acid 68: 2-((2-Chloro-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetic acid
(293) This compound has been prepared from 6-chloro-5-(methoxymethoxy)picolinic acid according to procedures described for acid 15 using cyclopropylamine instead of dimethylamine in the amide coupling. LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 271.16.
Acid 69: 2-((2-Cyclopropyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetic acid 3-(Benzyloxy)-2-chloro-6-iodopyridine
(294) A mixture of 2-chloro-6-iodopyridin-3-ol (40.4 g), K.sub.2CO.sub.3 (33 g) and benzyl bromide (20 mL) in DMF (320 mL) was stirred at 60° C. for 2 h. The mixture was diluted at rt with EA and aq. sat. NH.sub.4Cl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was stirred with mixture of heptane/EA (95/5) at rt for 10 min and filtrated off to afford 43.2 g of a colourless solid. LC-MS (A): t.sub.R=0.97 min; [M+H].sup.+: 345.79.
5-(Benzyloxy)-6-chloropicolinic acid
(295) This compound has been prepared from 3-(benzyloxy)-2-chloro-6-iodopyridine according to the procedure described for acid 11 (1. step). LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 263.99.
5-(Benzyloxy)-6-chloro-N-cyclopropylpicolinamide
(296) This compound has been prepared from 5-(benzyloxy)-6-chloropicolinic acid according to procedures described for acid 15 (1. step) using cyclopropylamine instead of dimethylamine in the amide coupling. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 302.99.
6-Chloro-N-cyclopropyl-5-hydroxypicolinamide
(297) This compound has been prepared from 3-(benzyloxy)-2-chloro-6-iodopyridine according to the procedure described for acid 54 (3. step). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 213.07.
N, 6-Dicyclopropyl-5-hydroxypicolinamide
(298) A mixture of 6-chloro-N-cyclopropyl-5-hydroxypicolinamide (100 mg), cyclopropylboronic acid (175 mg), tetrakis(triphenylphosphine)palladium (102 mg) and K.sub.2CO.sub.3 (62 mg) in dioxane (6 mL) was stirred at 120° C. for 3 days. The mixture was filtrated off and the solvent was evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 50 mg of a yellowish solid. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 219.13.
2-((2-Cyclopropyl-6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)acetic acid
(299) This compound has been prepared from N,6-Dicyclopropyl-5-hydroxypicolinamide according to the procedures described for acid 1. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 277.13.
Acid 70: 2-((2-Cyclopropyl-6-(methylsulfonamido)pyridin-3-yl)oxy)acetic acid
(300) This compound has been prepared from tert-butyl 2-((2-chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetate (acid 9) according to the procedures described for acid 69 (step 5 and 7). LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 287.10.
Acid 71: 2-((2-Chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)acetic acid
Tert-butyl 2-((2-chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)acetate
(301) A mixture of tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate (see synthesis of acid 9, 1. step) (100 mg), sodium methanesulfinate (33 mg) and CuI (155 mg) in DMSO (5 mL) was stirred at 100° C. for 30 min. The mixture was diluted at rt with EA and aq. sat. NH.sub.4Cl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was with column chromatography (solvent A: Heptane, solvent B: EA, gradient in % B: 5 to 100) to afford 70 mg of a colourless solid. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 322.05.
2-((2-Chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)acetic acid
(302) This compound has been prepared from tert-butyl 2-((2-chloro-6-(methylsulfonyl)pyridin-3-yl)oxy)acetate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 265.39.
Acid 72: 2-((2-Chloro-6-(N-methylsulfamoyl)pyridin-3-yl)oxy)acetic acid
Methyl 3-((5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropyridin-2-yl)sulfonyl)propanoate
(303) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)acetate (see synthesis of acid 9) and sodium 3-methoxy-3-oxopropane-1-sulfinate according to the procedure described for acid 71 (1. step). LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 394.12.
2-((2-Chloro-6-(N-methylsulfamoyl)pyridin-3-yl)oxy)acetic acid
(304) A mixture of methyl 3-((5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropyridin-2-yl)sulfonyl) propanoate (100 mg) and 0.5 M sodium methanolate in MeOH (0.5 mL) was stirred at rt for 15 min. the solvent was evaporated in vacuo and the crude was dissolved in THF (4 mL). ChloraminT trihydrate (120 mg) was added and the mixture was stirred at rt for 15 min. Methylamine in methanol (33%-solution, 0.254 mL) was added and the mixture was stirred at rt for 19 h. The mixture was diluted at rt with EA and aq. sat. NH.sub.4Cl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 55 mg of a yellowish oil. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 336.99.
2-((2-Chloro-6-(N-methylsulfamoyl)pyridin-3-yl)oxy)acetic acid
(305) This compound has been prepared from 2-((2-chloro-6-(N-methylsulfamoyl)pyridin-3-yl)oxy)acetic acid according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.52 min; [M+H].sup.+: 281.03.
Acid 73: 2-((2-Chloro-6-(N,N-dimethylsulfamoyl)pyridin-3-yl)oxy)acetic acid
(306) This compound has been prepared from methyl 3-((5-(2-(tert-butoxy)-2-oxoethoxy)-6-chloropyridin-2-yl)sulfonyl)propanoate (see synthesis of acid 72, 1. step) according to the procedures described for acid 72 (step 2 and 3) using dimethylamine instead of methylamine in the amination step. LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 295.04.
Acid 74: 2-((1-Methyl-1H-indol-4-yl)oxy)acetic acid
(307) This compound has been prepared from 1-methyl-1H-indol-4-ol according to the procedures described for acid 4 (step 4 and 5). LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: 206.11.
Acid 75: 2-((7-Methoxy-2-methylquinolin-4-yl)oxy)acetic acid
(308) This compound has been prepared from 7-methoxy-2-methylquinolin-4-ol according to the procedures described for acid 4 (step 4 and 5). LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 248.18.
Acid 76: 2-((7-Chloro-8-methylquinolin-4-yl)oxy)acetic acid
(309) This compound has been prepared from 7-chloro-8-methylquinolin-4-ol according to the procedures described for acid 4 (step 4 and 5). LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 252.06.
Acid 77: 2-((5,8-Difluoroquinolin-4-yl)oxy)acetic acid
(310) This compound has been prepared from 5,8-difluoroquinolin-4-ol according to the procedures described for acid 4 (step 4 and 5). LC-MS (A): t.sub.R=0.44 min; [M+H].sup.+: 240.10.
Acid 78: 1-((2-Ethyl-6-methylpyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
Methyl 4-bromo-2-((2-ethyl-6-methylpyridin-3-yl)oxy)butanoate
(311) A mixture of 2-ethyl-6-methylpyridin-3-ol (500 mg), methyl 2,4-dibromobutanoate (0.670 mL) and K.sub.2CO.sub.3 (655 mg) in DMF (5 mL) was stirred at rt for 4 h. The mixture was diluted with EA and aq. 1N HCl. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 15, flow rate: 20 mL/min) to afford 748 mg of a colourless oil. LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 315.93.
Methyl 1-((2-ethyl-6-methylpyridin-3-yl)oxy)cyclopropane-1-carboxylate
(312) To a solution of methyl 4-bromo-2-((2-ethyl-6-methylpyridin-3-yl)oxy)butanoate (740 mg) in THF (10 mL) was added at −20° C. potassium tert-butoxide (276 mg) and the mixture was stirred for 5 min. The mixture was diluted with EA and water. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 2 to 15, flow rate: 20 mL/min) to afford 239 mg of a colourless oil. LC-MS (A): t.sub.R=0.54 min; [M+H].sup.+: 236.06.
1-((2-Ethyl-6-methylpyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
(313) This compound has been prepared from methyl 1-((2-ethyl-6-methylpyridin-3-yl)oxy)cyclopropane-1-carboxylate according to the procedure described for acid 17 (3. step). LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 252.06.
Acid 79: 1-((2-Chloro-6-(((methylthio)peroxy)amino)pyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
Tert-butyl 4-bromo-2-((2-chloro-6-iodopyridin-3-yl)oxy)butanoate
(314) To a solution of 2-chloro-6-iodopyridin-3-ol (500 mg) in DMF (10 mL) was added at 0° C. NaH (115 mg, 60% dispersion in mineral oil) and the mixture was stirred at this temperature for 30 min. Methyl 2,4-dibromobutanoate (0.400 mL) was added and the mixture was stirred at rt for 6 h. The mixture was diluted with heptane and aq. sat. NaHCO.sub.3. The layers were separated and the aq. phase was washed twice with heptane. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 5, flow rate: 20 mL/min) to afford 417 mg of a colourless oil. LC-MS (A): t.sub.R=1.02 min; [M+H].sup.+: 475.82.
Tert-butyl 1-((2-chloro-6-iodopyridin-3-yl)oxy)cyclopropane-1-carboxylate
(315) This compound has been prepared from tert-butyl 4-bromo-2-((2-chloro-6-iodopyridin-3-yl)oxy)butanoate according to the procedure described for acid 78 (2. step). LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 396.02.
Tert-butyl 1-((2-chloro-6-(((methylthio)peroxy)amino)pyridin-3-yl)oxy)cyclopropane-1-carboxylate
(316) This compound has been prepared from tert-butyl 1-((2-chloro-6-iodopyridin-3-yl)oxy)cyclopropane-1-carboxylate according to the procedure described for acid 9 (2. step). LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 363.11.
1-((2-Chloro-6-(((methylthio)peroxy)amino)pyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
(317) This compound has been prepared from tert-butyl 1-((2-chloro-6-(((methylthio)peroxy)amino)pyridin-3-yl)oxy)cyclopropane-1-carboxylate according to the procedure described for acid 1 (2. step). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 306.89.
Acid 80: 1-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
5-(1-Tert-butoxycarbonyl)cyclopropoxy)-6-chloropicolinic acid
(318) This compound has been prepared from tert-butyl 1-((2-chloro-6-iodopyridin-3-yl)oxy)cyclopropane-1-carboxylate (for the synthesis see acid 79, 2. step) according to the procedure described for acid 11 (1. step). LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 314.02.
1-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)cyclopropane-1-carboxylic acid
(319) This compound has been prepared from 5-(1-tert-butoxycarbonyl)cyclopropoxy)-6-chloropicolinic acid according to the procedures described for acid 15 (step 1 and 4). LC-MS (A): t.sub.R=0.61 min; [M+H].sup.+: 285.07.
Acid 81: 2-((2-Chloro-6-(((methylthio)peroxy)amino)pyridin-3-yl)oxy)-2-methyl propanoic acid
(320) This compound has been prepared from 2-chloro-6-iodopyridin-3-ol and tert-butyl 2-bromo-2-methylpropanoate according to the synthetic route described for acid 9 (step 1-3). LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 308.96.
Acid 82: 2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)-2-methylpropanoic acid 5-((1-(Tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-chloropicolinic acid
(321) This compound has been prepared from tert-butyl 2-((2-chloro-6-iodopyridin-3-yl)oxy)-2-methylpropanoate (for the synthesis see acid 81, 1. step) according to the procedure described for acid 11 (1. step). LC-MS (A): t.sub.R=0.83 min; [M+H].sup.+: 316.03.
2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)-2-methylpropanoic acid
(322) This compound has been prepared from 5-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-6-chloropicolinic acid according to the procedures described for acid 15 (step 1 and 4). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 287.08.
(323) Following compounds were prepared by modified synthetic routes. If not explicitly indicated otherwise, the LC-MS conditions used were LC-MS (A).
Example 1.4.11
Methyl 3-((6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)sulfonyl)propanoate
(324) A solution of 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone (150 mg), CuI (135 mg) and sodium 3-methoxy-3-oxopropane-1-sulfinate (124 mg) in DMSO (1.5 mL) was stirred at 130° C. for 2.5 h. Sat. aq. NH.sub.4Cl (5 mL) was added at rt and the mixture was stirred for 1 h. The mixture was diluted with EA and sat. aq. NaHCO.sub.3. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by FC (solvent: DCM/MeOH, 95/5) to afford 107 mg of a beige solid. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 642.49.
Example 1.4.12
6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridine-2-sulfonamide
(325) A 5M solution of sodium methoxide in MeOH (0.3 mL) was added at rt to the solution of methyl 3-((6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)sulfonyl)propanoate (95 mg) in DMSO (1.5 mL). After 15 min, a solution of hydroxylamine-sulfonic acid (307 mg) and sodium acetate (187 mg) in water was added at 0° C. and the mixture was stirred at rt for 60 h. EA was added, the org. layer was washed with water, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to afford 16 mg of a beige solid. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 571.31.
Example 1.4.13
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((2-hydroxyethyl)-(methyl)amino)pyridin-3-yl)oxy)ethanone
(326) This compound has been prepared according to the Ullmann procedure from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using 2-(methylamino)ethanol instead of morpholine. LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 565.40.
Example 1.4.14
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((2-methoxyethyl)(methyl)-amino)pyridin-3-yl)oxy)ethanone
(327) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using 2-methoxy-N-methylethanamine instead of morpholine. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 579.44.
Example 1.4.15
1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone
(328) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazo-o[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using 2,5-dimethylpyrrolidine instead of morpholine. LC-MS (A): t.sub.R=1.04 min; [M+H].sup.+: 589.49.
Example 1.4.16
N-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-cyclopropanesulfonamide
(329) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using cyclopropanesulfonamide instead of morpholine. LC-MS (A): t.sub.R=0.87 min; [M+H].sup.+: 612.99.
Example 1.4.17
1-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)pyrrolidin-2-one
(330) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using pyrrolidin-2-one instead of morpholine. LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: 574.99.
Example 1.4.18
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)-pyridin-3-yl)oxy)ethanone
(331) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using 3,3-difluoroazetidine instead of morpholine. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 583.42.
Example 1.4.20
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-((3S,5S)-3,5-dimethylpipe-ridin-1-yl)pyridin-3-yl)oxy)ethanone
(332) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using (3S,5S)-3,5-dimethylpiperidine instead of morpholine. LC-MS (A): t.sub.R=0.97 min; [M+H].sup.+: 605.14.
Example 1.4.22
2-((6-amino-2-chloropyridin-3-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone
(333) This compound has been prepared according to the Ullmann procedure (see synthesis of the acid 4, 2. step) from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone using tert-butyl carbamate instead of morpholine. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 507.02.
Example 1.4.23
6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-(cyano-methyl)picolinamide
6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinic acid
(334) This acid has been prepared according to the procedure described for example 1.46.1 from methyl 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxo-ethoxy)picolinate. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: 535.85. 6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-(cyano-methyl)picolinamide
(335) This compound has been prepared according to the amide coupling procedure 2 from 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinic acid and cyanamid. LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 561.73.
Example 1.4.25
6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-hydroxy-picolinamide
(336) To a solution of 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinic acid (33 mg) in toluene (1 mL) was added at rt oxalyl chloride (5.8 μl) and DMF (2 drops). The mixture was stirred for 1 h. A solution of DIPEA (15.6 μl) and hydroxylamine hydrochloride (2.2 mg) in DMF (1 mL) was added and the mixture was stirred overnight. The suspension was filtrated off and the crude was purified by preparative LC-MS (I) to afford 9 mg of a colourless solid. LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 550.98.
Example 1.4.26
3-Chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzamide
(337) To a solution of 3-chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)benzonitrile (81 mg) and K.sub.2CO.sub.3 (26 mg) in DMSO (4 mL) was added dropwise H.sub.2O.sub.2 at rt and the mixture was stirred overnight. The mixture was diluted at 5° C. with EA and 10% aq. Na.sub.2S.sub.2O.sub.3. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was dissolved in MeCN and the white precipitate was filtered off to afford 45 mg of colourless powder. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 533.98.
Example 1.4.27
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(methylamino)pyridin-3-yl)oxy)ethanone
(338) This compound has been prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone according to the procedure described for acid 5 (2. step). LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 521.01.
Example 1.4.28
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-cyclopropylpyridin-3-yl)oxy)-ethanone
(339) A solution of 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone (50 mg), cyclopropylboronic acid (7 mg), palladium(II)acetate (1.3 mg), tricyclohexylphosphine (3 mg) and potassium phosphate tribasic monohydrate (28 mg) in toluene (3 mL) was stirred in sealed vial at 100° C. for 3 days and additional cyclo-propylboronic acid (7 mg), palladium(II)acetate (1.3 mg), tricyclohexylphosphine (3 mg) was added on the first and second day respectively.
(340) The reaction mixture was filtrated off, evaporated in vacuo and the crude was purified by preparative LC-MS (I) to afford 7 mg of a colourless solid. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 531.78.
Example 1.4.29
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-(3,3-difluoroazetidin-1-yl)phe-noxy)ethanone
2-(2-Chloro-4-iodophenoxy)acetic acid
(341) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 2-(2-chloro-4-iodophenoxy)acetate. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: not visible.
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-iodophenoxy)ethanone
(342) This compound has been prepared according to the method C from 5-(4-chloro-2-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine and 2-(2-chloro-4-iodophenoxy)acetic acid. LC-MS (A): t.sub.R=1.00 min; [M+H].sup.+: 616.99.
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-(3,3-difluoroazetidin-1-yl)phenoxy)ethanone
(343) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-iodophenoxy)etha-none according to the procedures described for acid 4 (2. step) using 3,3-difluoroazetidine instead of morholine. LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 582.07.
Example 1.4.30
N-(3-Chloro-4-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)phenyl)cyclo-propanesulfonamide
(344) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-iodophenoxy)etha-none according to the procedures described for acid 4 (2. step) using cyclopropanesulfonamide instead of morholine. LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 611.85.
Example 1.4.32
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)oxy)ethanone
(345) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone according to the procedures described for acid 4 (2. step) using 4,4-difluoropiperidine instead of morholine. LC-MS (A): t.sub.R=1.00 min; [M+H].sup.+: 613.11.
Example 1.4.33
2-((6-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-chloropyridin-3-yl)oxy)-1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(346) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone according to the procedures described for acid 4 (2. step) using 2-oxa-5-azabicyclo[2.2.1]heptane instead of morholine. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 589.10.
Example 1.4.34
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-cyclopropylphenoxy)-ethanone
(347) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-(2-chloro-4-iodophenoxy)-ethanone according to the procedures described for example 1.4.28. LC-MS (A): t.sub.R=1.00 min; [M+H].sup.+: 532.80.
Example 1.4.35
1-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)piperazin-2-one
Tert-butyl 4-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-3-oxopiperazine-1-carboxylate
(348) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy) ethanone according to the procedures described for acid 4 (2. step) using tert-butyl 3-oxopiperazine-1-carboxylate instead of morpholine. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 690.07.
1-(6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)piperazin-2-one
(349) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 4-(6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)-3-oxopiperazine-1-carboxylate. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 589.75.
Example 1.4.37
1-(5-(4-Chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)oxy)ethanone
(350) This compound was prepared from 1-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-iodopyridin-3-yl)oxy)ethanone according to the procedures described for acid 4 (2. step) using 3,3-difluoropyrrolidine instead of morholine. LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 597.43.
Example 1.4.41
6-Chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methoxypicolinamide
(351) This compound has been prepared according to the method C from 6-chloro-5-(2-(5-(4-chloro-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinic acid and O-methylhydroxylamine. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 564.86.
Example 1.9.1
5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyl-thiophene-3-carboxamide
(352) This amide has been prepared according to the method C from 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid (example 1.46.1) and dimethylamine. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 602.49.
Example 1.9.2
5-(6-(2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide
Methyl 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiophene-3-carboxylate
(353) This compound has been prepared according to the method A from the aldehyde 7. LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 335.87.
Tert-butyl 5-(4-(methoxycarbonyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(354) This compound has been prepared according to the procedure described for aldehyde 22 (2. step) from methyl 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylate. LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 435.85.
5-(6-(Tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid
(355) This compound has been prepared according to the procedure described for acid 17 (3. step) from tert-butyl 5-(4-(methoxycarbonyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 420.83.
Tert-butyl 5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(356) This compound has been prepared according to the procedure described for aldehyde 26 (1. step) from 5-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid using dimethylamine instead of diethylamine. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 448.05.
N,N-Dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide
(357) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.47 min; [M+H].sup.+: 348.00.
5-(6-(2-((2-chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide
(358) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide and acid 21. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 607.82.
Example 1.9.3
5-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide
(359) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide and acid 19. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 583.72.
Example 1.9.4
5-(6-(2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetra-hydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiophene-3-carboxamide
(360) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide and acid 9. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 609.64.
Example 1.9.5
6-Chloro-5-(2-(5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethyl-picolinamide
(361) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide and acid 15. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 587.92.
Example 1.9.6
6-Chloro-5-(2-(5-(4-(dimethylcarbamoyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N-methyl-picolinamide
(362) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxamide and acid 22. LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 575.89.
Example 1.22.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)-thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
5-(2-Bromothiazol-5-yl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine
(363) This compound has been prepared according to the method A from 2-bromothiazole-5-carbaldehyde. LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 357.84.
Tert-butyl 5-(2-bromothiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridine-6(5H)-carboxylate
(364) This compound has been prepared according to the procedure described for aldehyde 22 (2. step) from 5-(2-bromothiazol-5-yl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridine. LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 457.96.
Tert-butyl 5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridine-6(5H)-carboxylate
(365) To a solution of tert-butyl 5-(2-bromothiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo-[4,5-c]pyridine-6(5H)-carboxylate (300 mg) in DMF (6 mL) was added 2M Me.sub.2NH in THF (1.0 mL) and K.sub.2CO.sub.3 (273 mg) and the mixture was stirred at 60° C. for 3 days. The mixture was diluted with sat. aq. NH.sub.4Cl and EA. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent: DCM, flow rate: 10 mL/min) to afford 145 mg of a colourless solid. LC-MS (A): t.sub.R=0.68 min; [M+H].sup.+: 420.93.
N,N-Dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine
(366) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3-]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.42 min; [M+H].sup.+: 321.26.
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(367) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 4. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 574.96.
Example 1.22.2
2-((2-Chloro-6-(dimethylamino)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(368) This compound has been prepared according to the amide coupling procedure 2 from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 16. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 532.88.
Example 1.22.3
2-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(369) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 10. LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: 557.83.
Example 1.22.4
2-((2-Chloro-5-fluoropyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(370) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 1. LC-MS (A): t.sub.R=0.65 min; [M+H].sup.+: 507.96
Example 1.22.5
2-(2-Chloro-4-(trifluoromethyl)phenoxy)-1-(5-(2-(dimethylamino) thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(371) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 19. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 556.78.
Example 1.22.6
N-(6-Chloro-5-(2-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methane-sulfonamide
(372) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 9. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 582.81.
Example 1.22.7
2-((2-Chloropyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(373) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 20. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 489.81.
Example 1.22.8
2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)-1-(5-(2-(dimethylamino)-thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(374) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 21. LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 580.85.
Example 1.22.9
6-Chloro-5-(2-(5-(2-(dimethylamino)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide
(375) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-amine and acid acid 15. LC-MS (A): t.sub.R=0.60 min; [M+H].sup.+: 560.77.
Example 1.36.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-((dimethylamino)-methyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone
Thiophene-2-carbaldehyde
(376) This compound has been prepared according to the procedure described for aldehyde 1 (2. step) from thiophen-2-ylmethanol. LC-MS (A): t.sub.R=0.56 min; [M+H].sup.+: not visible.
2-(Thiophen-2-yl)-1,3-dioxolane
(377) This compound has been prepared according to the procedure described for aldehyde 15 (1. step) from thiophene-2-carbaldehyde. LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: not visible.
5-(1,3-Dioxolan-2-yl)thiophene-2-carbaldehyde
(378) This compound has been prepared according to the procedure described for aldehyde 22 (3. step) from 2-(thiophen-2-yl)-1,3-dioxolane. LC-MS (A): t.sub.R=0.64 min; [M+MeCN].sup.+: 226.28.
5-(2-Methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde
(379) This compound has been prepared according to the method A from 5-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde. LC-MS (A): t.sub.R=0.47 min; [M+H].sup.+: 305.23.
5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde
(380) This amide has been prepared according to the method C from 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde and acid 4. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: not visible
2-((2-chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-((dimethylamino)methyl)thiophen-2-3/1)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(381) This compound has been prepared from 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde and dimethylamine according to the procedure described for aldehyde 5 (3. step). LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 588.52
Example 1.37.1
2-(6-(2-((2-Chloro-6-(methylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetra-hydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
Methyl 2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiazole-5-carboxylate
(382) This compound has been prepared according to the according to the method A from the aldehyde 13. LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 336.04.
Tert-butyl 5-(5-(methoxycarbonyl)thiazol-2-3/1)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(383) This compound has been prepared according to the procedure described for aldehyde 22 (2. step) from methyl 2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiazole-5-carboxylate LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 436.00.
2-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-5-yl)thiazole-5-carboxylic acid
(384) This compound has been prepared according to the procedure described for acid 17 (3. step) from tert-butyl 5-(5-(methoxycarbonyl)thiazol-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thia-diazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 421.98.
Tert-butyl 5-(5-(dimethylcarbamoyl)thiazol-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(385) This amide has been prepared according to the method C from 2-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-5-yl)thiazole-5-carboxylic acid and dimethylamine. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: 449.07.
N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-5-carboxamide
(386) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(5-(dimethylcarbamoyl)thiazol-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.45 min; [M+H].sup.+: 348.83.
2-(6-(2-((2-chloro-6-(methylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
(387) This compound has been prepared according to the method C from N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazole-5-carboxamide and acid 22. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 574.92.
Example 1.37.2
2-(6-(2-((2-Chloro-6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
(388) This compound has been prepared according to the method C from N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazole-5-carboxamide and acid 21. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 608.08.
Example 1.37.3
2-(6-(2-((2-Chloro-6-(methylsulfonamido)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
(389) This compound has been prepared according to the method C from N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazole-5-carboxamide and acid 9. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 610.90.
Example 1.37.4
2-(6-(2-((2-Chloro-6-(dimethylcarbamoyl)pyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
(390) This compound has been prepared according to the method C from N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazole-5-carboxamide and acid 15. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 588.92.
Example 1.37.5
2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylthiazole-5-carboxamide
(391) This compound has been prepared according to the method C from N,N-dimethyl-2-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazole-5-carboxamide and acid 4. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 602.98.
Example 1.38.1
4-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carboxylic acid
5-(5-(1,3-Dioxolan-2-yl)thiophen-3-yl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo-[2′,3′:2,3]-imidazo[4,5-c]pyridine
(392) This compound has been prepared to the method A from 5-(1,3-dioxolan-2-yl)thiophene-3-carbaldehyde. LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 348.87.
1-(5-(5-(1,3-Dioxolan-2-yl)thiophen-3-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone
(393) This compound has been prepared according to the method C from 5-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridine and acid 4. LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 603.50.
4-(6-(2-(2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde
(394) This compound has been prepared according to the procedure described for aldehyde 5 (4. step) from 1-(5-(5-(1,3-dioxolan-2-yl)thiophen-3-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 559.38.
4-(6-(2-(2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carboxylic acid
(395) To a solution of 4-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde (70 mg) in tBuOH (0.5 mL) and 2-methylbut-2-ene (0.05 mL) was added at 0° C. sodium chlorite (17 mg) and sodium phosphate (0.15 mL) and the mixture was stirred overnight at rt. The mixture was diluted with 1N NaOH and TBME. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to) to afford 35 mg of a yellow solid. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 575.41.
Example 1.40.1
6-Chloro-5-(2-(5-(5-(dimethylcarbamoyl)furan-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,4]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide
5-(2-Methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylic acid
(396) This compound has been prepared according to the method A from 5-formylfuran-2-carboxylic acid. LC-MS (A): t.sub.R=0.41 min; [M+H].sup.+: 304.96.
5-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylic acid
(397) This compound has been prepared according to the procedure described for aldehyde 22 (2. step) from 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylic acid. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 404.96.
Tert-butyl 5-(5-(dimethylcarbamoyl)furan-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(398) This compound has been prepared according to the method C from 5-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxylic acid. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 431.95.
N,N-Dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxamide
(399) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(5-(dimethylcarbamoyl)furan-2-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.46 min; [M+H].sup.+: 332.10.
6-chloro-5-(2-(5-(5-(dimethylcarbamoyl)furan-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-N,N-dimethylpicolinamide
(400) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxamide and acid 15. LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 571.89.
Example 1.40.2
5-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethylfuran-2-carboxamide
(401) This compound has been prepared according to the method C from N,N-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)furan-2-carboxamide and acid 4. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 585.93.
Example 1.41.1
Ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate
(402) This compound has been prepared according to the procedure described for acid 17 (3. step) from ethyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate (example 1.27.1). LC-MS (A): t.sub.R=0.73 min; [M+H].sup.+: 576.38.
Example 1.43.1
2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyloxazole-4-carboxamide
2-(6-(2-(2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)oxazole-4-carboxylic acid
(403) This compound has been prepared according to the procedure described for acid 17 (3. step) from methyl 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)oxazole-4-carboxylate. LC-MS (A): t.sub.R=0.72 min; [M+H].sup.+: 560.39.
2-(6-(2-(2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyloxazole-4-carboxamide
(404) This compound has been prepared according to the method C) from 2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N,N-dimethyloxazole-4-carboxamide. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 587.52.
Example 1.44.1
2-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylthiazole-4-carboxamide
2-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylic acid
(405) This compound has been prepared according to the procedure described for acid 17 (3. step) from ethyl 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylate (Example 1.27.3). LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 557.95.
2-(6-(2-(2-Chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylthiazole-4-carboxamide
(406) This compound has been prepared according to the method C from 2-(6-(2-(2-chloro-4-(trifluoromethyl)phenoxy)acetyl)-2-methyl-5,6,7,8-tetra-hydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylic acid using methylamine instead of dimethylamine. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 571.02.
Example 1.44.2
2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-N-methylthiazole-4-carboxamide
(407) This compound has been prepared according to the method C from 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo [2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylic acid (Example 1.41.1) using methylamine instead of dimethylamine. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 589.13.
Example 1.45.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-(hydroxymethyl)-thiophen-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(408) This compound was isolated as a side product by the preparation of example 1.69.1. LC-MS (A): t.sub.R=0.77 min; [M+H].sup.+: 561.13.
Example 1.46.1
5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid
(409) To a solution of methyl 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy) acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylate (40 mg) in methanol (1 mL) was added 1N aq. NaOH (0.2 mL). The reaction mixture was stirred at rt for 27 h. The mixture was evaporated in vacuo. The mixture was diluted with DCM and sat. aq. HCl. The layers were separated and the aq. phase was washed twice with DCM. The combined org. layers were washed with aq. sat. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude (38 mg of a white salt) was used in the next step without purification. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: 574.87.
Example 1.48.1
2-(6-(2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxamide
(410) This compound has been prepared according to the to the method C from 2-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazole-4-carboxylic acid (Example 1.41.1) using ammonia instead of dimethylamine. LC-MS (A): t.sub.R=0.74 min; [M+H].sup.+: 575.21.
Example 1.49.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(3,3-difluoro-azetidin-1-yl)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone
Tert-butyl 5-(2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(411) To a solution of tert-butyl 5-(2-bromothiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate (50 mg) in DMF (1 mL) was added 3-3-difluoroazetidine hydrochloride (28 mg) and K.sub.2CO.sub.3 (76 mg) and the reaction mixture was stirred at 60° C. for overnight. Additional 3-3-difluoroazetidine hydrochloride (28 mg) and DIPEA (0.04 mL)) were added and the reaction mixture was stirred at 100° C. for 70 h. The mixture was diluted with sat. aq. NH.sub.4Cl and EA. The layers were separated and the aq. phase was washed twice with EA. The combined org. layers were washed with sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 2 g cartridge, solvent A: heptane, solvent B: EA, gradient in % B: 1 to 26, flow rate: 8 mL/min) to afford 66 mg of an yellow oil. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 469.07.
5-(2-(3, 3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine
(412) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 368.90.
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(2-(3, 3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-ethanone
(413) This compound has been prepared according to the to the method C from 5-(2-(3,3-difluoroazetidin-1-yl)thiazol-5-yl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine and acid 4. LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 622.94.
Example 1.51.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-(ethylamino)-1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
Tert-butyl (1,4-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-5-yl)-1H-pyrazol-3-yl)(ethyl)carbamate
(414) This compound has been prepared according to the to the method A from tert-butyl ethyl(5-formyl-1,4-dimethyl-1H-pyrazol-3-yl)carbamate and aldehyde 22. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 432.44.
Tert-butyl (5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-1,4-dimethyl-1H-pyrazol-3-yl)(ethyl)carbamate
(415) This compound has been prepared according to the to the method C from tert-butyl (1,4-dimethyl-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-1H-pyrazol-3-yl)(ethyl)carbamate and acid 4. LC-MS (A): t.sub.R=0.93 min; [M+H].sup.+: 686.67.
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-(ethylamino)-1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(416) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl (5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-1,4-dimethyl-1H-pyrazol-3-yl)(ethyl)carbamate. LC-MS (A): t.sub.R=0.70 min; [M+H].sup.+: 585.99.
Example 1.52.1
1-(5-(2-Amino-5-fluorothiazol-4-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone
Tert-butyl (5-fluoro-4-((methoxy(methyl)amino)methyl)thiazol-2-yl)carbamate
(417) To a solution of tert-butyl (4-((methoxy(methyl)amino)methyl)thiazol-2-yl)carbamate (1 g) in THF (45 mL) was added at −78° C. nBuLi 1.6M in hexanes (4.9 mL). The mixture was stirred at −78° C. for 3 h. NFSI (1.8 g) was added and the mixture was allowed to warm up to −10° C. The mixture was diluted with 1NHCl, the layers were separated and the aq. phase was extracted with Et.sub.2O. The combined org. layers were washed with sat. aq. NaHCO.sub.3 and sat. aq. NaCl, dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 1 to 6, flow rate: 10 mL/min) to afford 249 mg of a yellow oil. LC-MS (A) t.sub.R=0.55 min; [M+H].sup.+: 188.09.
Tert-butyl (5-fluoro-4-formylthiazol-2-yl)carbamate
(418) A mixture of tert-butyl (4-((methoxy(methyl)amino)methyl)thiazol-2-yl)carbamate (125 mg) in THF (6 mL) and NaClO (0.86 mL) in water (0.6 mL) was stirred at rt for 16 h. The solvent was evaporated in vacuo. The mixture was diluted with DCM and sat. aq NaHCO.sub.3, the layers were separated and the aq. phase was extracted with DCM. The combined org. layers were washed filtrated off over phase separator and evaporated in vacuo. The crude (135 mg, yellow oil) was used in the next step without purification. LC-MS (A): t.sub.R=0.78 min; [M+H].sup.+: not visible.
Tert-butyl (5-fluoro-4-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]-pyridin-5-yl)thiazol-2-yl)carbamate
(419) This compound has been prepared according to the method A from tert-butyl (5-fluoro-4-formylthiazol-2-yl)carbamate. LC-MS (A): t.sub.R=0.64 min; [M+H].sup.+: 410.92.
Tert-butyl (4-(6-(2-(2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-5-fluorothiazol-2-yl)carbamate
(420) This compound has been prepared according to the method C from tert-butyl (5-fluoro-4-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiazol-2-yl)carbamate and acid 4. LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 665.15.
1-(5-(2-Amino-5-fluorothiazol-4-yl)-2-methyl-7,8-dihydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone
(421) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl (4-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-5-fluorothiazol-2-yl)carbamate. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 564.93.
Example 1.63.1
1-(5-(4-(2H-Tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone
Methyl 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiophene-3-carboxylate
(422) This compound has been prepared according to method A from methyl 5-formylthiophene-3-carboxylate (aldehyde 7). LC-MS (A): t.sub.R=0.51 min; [M+H].sup.+: 334.96.
Tert-butyl 5-(4-(methoxycarbonyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate
(423) This compound has been prepared according to the procedure described for aldehyde 22 (2. step) from methyl 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiophene-3-carboxylate. LC-MS (A): t.sub.R=0.93 min; [M+H].sup.+: 434.90.
5-(6-(Tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid
(424) This compound has been prepared according to the procedure described for acid 17 (3. step) from tert-butyl 5-(4-(methoxycarbonyl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.80 min; [M+H].sup.+: 420.81.
Tert-butyl 5-(4-carbamoylthiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridine-6(5H)-carboxylate
(425) This compound has been prepared according to the method C from 5-(6-(tert-butoxycarbonyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo-[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carboxylic acid and ammonia. LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 419.98.
Tert-butyl 5-(4-cyanothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridine-6(5H)-carboxylate
(426) A solution of tert-butyl 5-(4-carbamoylthiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridine-6(5H)-carboxylate 270 mg) and Burgess reagent (176 mg) was stirred at rt for 3 h. The mixture was diluted with sat. aq. NaHCO.sub.3, the layers were separated and the aq. layer was washed with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 5 g cartridge, solvent A: heptane, solvent B: EA, gradient in % B: 5 to 55, flow rate: 10 mL/min) to afford 206 mg of a colourless solid. LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 401.99.
5-(2-Methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-thiophene-3-carbonitrile
(427) This compound has been prepared according to the procedure described for acid 1 (2. step) from tert-butyl 5-(4-cyanothiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo-[4,5-c]pyridine-6(5H)-carboxylate. LC-MS (A): t.sub.R=0.47 min; [M+H].sup.+: 302.00.
5-(6-(2-(2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carbonitrile
(428) This compound has been prepared according to the method C from 5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carbonitrile and acid 4. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 555.90.
1-(5-(4-(2H-Tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]-imidazo[4,5-c]pyridin-6(5H)-yl)-2-((2-chloro-6-morpholinopyridin-3-yl)oxy)ethanone
(429) A solution of 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetra-hydro[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-3-carbonitrile (44 mg), NaN.sub.3 (8 mg) and NH.sub.4Cl (7 mg) in DMF (2 mL) was stirred at 110° C. for 36 h. Additionally NaN.sub.3 (16 mg) were added and the mixture was stirred at 150° C. for 36 h. The mixture was diluted with water and EA, the layers were separated and the aq. layer was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo The crude was purified by preparative LC-MS (I) to) to afford 10 mg of an orange oil. LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 599.15.
Example 1.69.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(5-((dimethylamino)-methyl)thiophen-3-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(430) To a solution of 4-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbaldehyde (35 mg) in MeOH (1 mL) was added dimethylamine in ethanol (0.012 mL). The reaction mixture was stirred at rt overnight. Sodium borohydride (4 mg) was added and the resulting mixture was stirred at rt overnight. The mixture was diluted with 1N aq. NaOH and EA, the layers were separated and the aq. layer was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to) to afford 12 mg of a colourless solid. LC-MS (A): t.sub.R=0.66 min; [M+H].sup.+: 588.44.
Example 1.70.1
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5-(1H-tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo-[4,5-c]pyridin-6(5H)-yl)ethanone
4-Fluoro-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbonitrile
(431) This compound has been prepared according to the method A from 4-fluoro-5-formylthiophene-2-carbonitrile (aldehyde 28). LC-MS (A): t.sub.R=0.50 min; [M+H].sup.+: 320.10.
5-(6-(2-(2-Chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluorothiophene-2-carbonitrile
(432) This compound has been prepared according to the method C from 4-fluoro-5-(2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)thiophene-2-carbonitrile and acid 4. LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: 573.97.
2-((2-Chloro-6-morpholinopyridin-3-yl)oxy)-1-(5-(3-fluoro-5-(1H-tetrazol-5-yl)thiophen-2-yl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)ethanone
(433) This compound has been prepared according to the procedure described for example 1.63.1 (8. step) from 5-(6-(2-((2-chloro-6-morpholinopyridin-3-yl)oxy)acetyl)-2-methyl-5,6,7,8-tetrahydro[1,3,4]-thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-5-yl)-4-fluorothiophene-2-carbonitrile. LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 616.85.
Example 1.84.1
6-chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide
4-(2-(Benzyloxy) ethoxy)-2-fluorobenzaldehyde
(434) A mixture of 2-fluoro-4-hydroxybenzaldehyde (400 mg) and benzyl 2-bromoethyl ether (0.677 mL) in DMF (10 mL) was stirred at 60° C. for 2 h. The mixture was diluted at rt with water and DCM, the layers were separated and the aq. layer was washed with DCM. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by CC (Büchi Sepacore, 20 g cartridge, solvent A: Heptane, solvent B: EA, gradient in % B: 5 to 10, flow rate: 8 mL/min) to afford 760 mg of a colourless oil. LC-MS (A) t.sub.R=0.91 min; [M+H].sup.+: 275.13.
5-(4-(2-(Benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine
(435) This compound has been prepared according to the method A from 4-(2-(benzyloxy)ethoxy)-2-fluorobenzaldehyde. LC-MS (A): t.sub.R=0.67 min; [M+H].sup.+: 439.12.
5-(2-(5-(4-(2-(Benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloro-N-cyclopropylpicolinamide
(436) This compound has been prepared according to the method C from 5-(4-(2-(benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine and acid 68. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 691.33.
6-Chloro-N-cyclopropyl-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)picolinamide
(437) A mixture of 5-(2-(5-(4-(2-(Benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloro-N-cyclopropylpicolinamide (34 mg) and iodotrimethylsilane (0.18 mL) in CHCl3 (0.8 mL) was stirred at rt for 20 h. MeOH (0.1 mL) was added and the solvent was evaporated in vacuo. The mixture was diluted with aq. sat. sodium bisulfide and EA, the layers were separated and the aq. layer was washed with EA. The combined org. layers were dried over MgSO.sub.4, filtrated off and evaporated in vacuo. The crude was purified by preparative LC-MS (I) to) to afford 14 mg of a colourless solid. LC-MS (A): t.sub.R=0.76 min; [M+H].sup.+: 601.16.
Example 1.84.2
N-(6-Chloro-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide
(438) N-(5-(2-(5-(4-(2-(Benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloropyridin-2-yl)methanesulfonamide
(439) This compound has been prepared according to the method C from 5-(4-(2-(benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridine and acid 9. LC-MS (A): t.sub.R=0.90 min; [M+H].sup.+: 701.31.
N-(6-Chloro-5-(2-(5-(2-fluoro-4-(2-hydroxyethoxy)phenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)pyridin-2-yl)methanesulfonamide
(440) This compound has been prepared from N-(5-(2-(5-(4-(2-(benzyloxy)ethoxy)-2-fluorophenyl)-2-methyl-7,8-dihydro-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-c]pyridin-6(5H)-yl)-2-oxoethoxy)-6-chloropyridin-2-yl)methanesulfonamide according to the procedure described for example 1.84.1 (4. step). LC-MS (A): t.sub.R=0.71 min; [M+H].sup.+: 611.17.
(441) TABLE-US-00005 TABLE 2 Example No IC.sub.50 [nM] 1.4.11 57 1.4.12 57 1.4.13 5 1.4.14 3 1.4.15 6 1.4.16 7 1.4.17 2 1.4.18 3 1.4.20 3 1.4.22 10 1.4.23 247 1.4.25 14 1.4.26 10 1.4.27 6 1.4.28 6 1.4.29 6 1.4.30 10 1.4.32 3 1.4.33 2 1.4.34 4 1.4.35 6 1.4.37 3 1.4.41 6 1.9.1 5 1.9.2 32 1.9.3 77 1.9.4 32 1.9.5 22 1.9.6 99 1.22.1 7 1.22.2 25 1.22.3 136 1.22.4 79 1.22.5 130 1.22.6 39 1.22.7 81 1.22.8 19 1.22.9 9 1.36.1 384 1.37.1 176 1.37.2 51 1.37.3 40 1.37.4 40 1.37.5 9 1.38.1 113 1.40.1 90 1.40.2 12 1.41.1 65 1.43.1 26 1.44.1 311 1.44.2 5 1.45.1 33 1.46.1 18 1.48.1 5 1.49.1 15 1.51.1 58 1.52.1 6 1.63.1 23 1.69.1 51 1.70.1 13 1.84.1 14 1.84.2 16
(442) II. Biological Assays
(443) Inhibitory activities on tryptophan hydroxylase 1 have been measured for each example compound using the following procedure:
(444) Biochemical In Vitro Assay Using Fluorescence Readout
(445) To generate the enzyme, full length human TPH1 is cloned into the plasmid pET20b(+) (Novagen) and expressed in E. coli. The bacterial cells are ruptured by sonication on ice and the lysate is cleared by centrifugation. The resulting protein in the pellet is re-extracted and TPH1 is purified from the obtained lysate by affinity chromatography using a pterin cosubstrate analog immobilized to the resin of the column. The protein is further purified by size exclusion chromatography to remove protein aggregates. The activity of TPH1 is determined by using a fluorescence assay. The enzyme activity assay is carried out at 15° C. with atmosphere oxygen for the duration of 60 minutes in a volume of 64 μl. The reaction is carried out in a 0.1 M Tris-HCl buffer, adjusted to pH 7.6, containing 1 mM DTT, 0.2 mg/mL catalase, 100 μM (±)-6-methyl-5,6,7,8-tetrahydropterine dihydrochloride, 40 μM L-tryptophan, and 40-80 nM of TPH1. The reaction is started by bringing together L-tryptophan with all the other reaction substituents and stopped by quenching with perchloric acid (HClO4). The amount of 5-hydroxy-L-tryptophan produced during the enzymatic reaction is determined by fluorescence readout. Fluorescence, as determined at 540 nm when excited at 300 nm wavelength, increases proportionally to the 5-hydroxy-L-tryptophan formed. Compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into the assay plate. Fluorescence is measured for each well and the fluorescence at 540 nm wavelength is compared to the fluorescence of the vehicle in place of compound. Inhibitory activities of example compounds with respect to the TPH1 protein are determined by calculating the IC.sub.50 value (the concentration of compound needed to inhibit 50% of the enzyme activity). The calculated IC.sub.50 values may fluctuate depending on the daily biochemical assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC.sub.50 values have been determined several times for the same compound, the mean is given. IC.sub.50 values of exemplified compounds are displayed in tables 1 and 2.