QUINOLINE cGAS ANTAGONIST COMPOUNDS

Abstract

The present disclosure provides compounds that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

Claims

1-82. (canceled)

83. A compound, wherein the compound is of formula I-a-3: ##STR04577## or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is —NR.sup.aR.sup.5, ##STR04578## each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; Ring B1 is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.5 is —(CR.sub.2).sub.0-4OR, —(CR.sub.2).sub.0-5CO.sub.2R, —(CR.sub.2).sub.0-5CONR.sub.2, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CONR.sub.2, —(CR.sub.2).sub.0-4NRC(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, or R.sup.B; each R.sup.6 is independently halogen, —COR, —(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4CONR.sub.2, —OR, —(CR.sub.2).sub.1-4OR, —NR.sub.2, —(CR.sub.2).sub.1-4NR.sub.2, —NRC(O)OR, —NRC(O)R, —NRC(O)NR.sub.2, —SR, —SO.sub.2R, —S(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, —B(OR).sub.2, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; each m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and q is 0, 1, or 2.

84. A compound, wherein the compound is of formula I-a-4: ##STR04579## or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted 4- to 7-membered saturated or partially unsaturated heterocyclic ring or heteroaryl ring, having 0 to 3 heteroatoms (in addition to the nitrogen already depicted in Ring A) independently selected from nitrogen, oxygen, phosphorus, and sulfur; R.sup.2 is —NR.sup.aR.sup.5, ##STR04580## each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; Ring B1 is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.5 is —(CR.sub.2).sub.0-4OR, —(CR.sub.2).sub.0-5CO.sub.2R, —(CR.sub.2).sub.0-5CONR.sub.2, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CONR.sub.2, —(CR.sub.2).sub.0-4NRC(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, or R.sup.B; each R.sup.6 is independently halogen, —COR, —(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4CONR.sub.2, —OR, —(CR.sub.2).sub.1-4OR, —NR.sub.2, —(CR.sub.2).sub.1-4NR.sub.2, —NRC(O)OR, —NRC(O)R, —NRC(O)NR.sub.2, —SR, —SO.sub.2R, —S(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, —B(OR).sub.2, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; each m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and q is 0, 1, or 2.

85. A compound, wherein the compound is of formula I-a-5: ##STR04581## or a pharmaceutically acceptable salt thereof, wherein: R.sup.2 is —NR.sup.aR.sup.5, ##STR04582## each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; Ring B1 is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.4 is hydrogen or an optionally substituted C.sub.1-6 aliphatic; R.sup.5 is —(CR.sub.2).sub.0-4OR, —(CR.sub.2).sub.0-5CO.sub.2R, —(CR.sub.2).sub.0-5CONR.sub.2, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CONR.sub.2, —(CR.sub.2).sub.0-4NRC(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, or R.sup.B; each R.sup.6 is independently halogen, —COR, —(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4CONR.sub.2, —OR, —(CR.sub.2).sub.1-4OR, —NR.sub.2, —(CR.sub.2).sub.1-4NR.sub.2, —NRC(O)OR, —NRC(O)R, —NRC(O)NR.sub.2, —SR, —SO.sub.2R, —S(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR,—(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, —B(OR).sub.2, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; each m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and q is 0, 1, or 2.

86. A compound, wherein the compound is of formula I-b-1: ##STR04583## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is ##STR04584## or an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.4 is hydrogen or an optionally substituted C.sub.1-6 aliphatic; R.sup.C is an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; and each n is 1, 2, 3, or 4.

87. A compound, wherein the compound is of formula I-b-2: ##STR04585## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is ##STR04586## or an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.4 is hydrogen or an optionally substituted C.sub.1-6 aliphatic; R.sup.5 is —(CR.sub.2).sub.0-4OR, —(CR.sub.2).sub.0-5CO.sub.2R, —(CR.sub.2).sub.0-5CONR.sub.2, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4C(O)NR(CR.sub.2).sub.0-4CONR.sub.2, —(CR.sub.2).sub.0-4NRC(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; and each n is 1, 2, 3, or 4.

88. A compound, wherein the compound is of formula I-b-3: ##STR04587## or a pharmaceutically acceptable salt thereof, wherein: Ring B1 is phenyl, preferably substituted phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; R.sup.1 is ##STR04588## or an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.4 is hydrogen or an optionally substituted C.sub.1-6 aliphatic; each R.sup.6 is independently halogen, —COR, —(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4CONR.sub.2, —OR, —(CR.sub.2).sub.1-4OR, —NR.sub.2, —(CR.sub.2).sub.1-4NR.sub.2, —NRC(O)OR, —NRC(O)R, —NRC(O)NR.sub.2, —SR, —SO.sub.2R, —S(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2).sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, —B(OR).sub.2, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; each m is 0, 1, 2, 3, or 4; and n is 1, 2, 3, or 4.

89. A compound, wherein the compound is of formula I-b-7: ##STR04589## or a pharmaceutically acceptable salt thereof, wherein: Ring B2 is phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur; R.sup.1 is ##STR04590## or an optionally substituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.3 is independently halogen, —OR, —NR.sub.2, —SR, or R.sup.C; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-6 aliphatic; benzyl; phenyl; a 4- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R.sup.4 is hydrogen or an optionally substituted C.sub.1-6 aliphatic; each R.sup.6 is independently halogen, —COR, —(CR.sub.2).sub.0-4CO.sub.2R, —(CR.sub.2).sub.0-4CONR.sub.2, —OR, —(CR.sub.2).sub.1-4OR, —NR.sub.2, —(CR.sub.2).sub.1-4NR.sub.2, —NRC(O)OR, —NRC(O)R, —NRC(O)NR.sub.2, —SR, —SO.sub.2R, —S(O)R, —(CR.sub.2).sub.0-4SO.sub.3R, —(CR.sub.2).sub.0-4SO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4OSO.sub.2NR.sub.2, —(CR.sub.2).sub.0-4NRSO.sub.2R, —(CR.sub.2).sub.0-4NRSO.sub.2OR, —(CR.sub.2).sub.0-4OP(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(OR).sub.2, —(CR.sub.2.sub.0-4P(O)(OR).sub.2, —(CR.sub.2).sub.0-4OP(O)(H)OR, —B(OR).sub.2, or R.sup.B; R.sup.B and R.sup.C, independently, are an optionally substituted group selected from C.sub.1-6 aliphatic; phenyl; a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carboxylic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R.sup.a is independently H or C.sub.1-6alkyl; each m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; and q is 0, 1, or 2.

90. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 83.

91. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 84.

92. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 85.

93. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 86.

94. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 87.

95. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 88.

96. A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 89.

97. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 83.

98. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 84.

99. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 85.

100. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 86.

101. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 87.

102. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 88.

103. A method of treating an inflammatory, allergic, autoimmune, or neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 89.

Description

4. EXAMPLES

[0904] The following Examples provide syntheses of the provided compounds and their in vitro activity.

Intermediates

Preparation of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (Intermediate 1)

[0905] ##STR02158##

[0906] Step 1: Preparation of ethyl 3-((2,3-dichlorophenyl)amino)-3-oxopropanoate. 2,3-dichloroaniline (10.33 g, 64 mmol, 1.0 eq) was mixed with diethyl malonate 1-2 (24 mL, 24.3 g, 158 mmol) and heated at 180° C. for 16 hours until product formation ceased (confirmed by LC-MS). The resulting oil mixture was used in the next step. MS (ES): [M+1].sup.+276.

[0907] Step 2: Preparation of 3-((2,3-dichlorophenyl)amino)-3-oxopropanoic acid. The mixture of the first step was diluted with MeOH (80 mL) and water (80 mL) and chilled with an ice-water bath. To the above solution was added a solution of NaOH (12 g, ˜2 eq to the amount of diethyl malonate) in 50 mL water slowly. After stirring 30 to 60 min, solids precipitated. Water was added to help stirring. After stirring for 3 to 4 hours at room temperature, starting material was consumed (confirmed by LC-MS), the reaction mixture was acidified with conc. HCl to pH 1 to form a precipitate. After filtration, rinsing with water, and drying under vacuum, the titled compound (10.57 g) was used in the next step without further purification. MS (ES): [M+1].sup.+248.

[0908] Step 3: Preparation of 7,8-dichloroquinoline-2,4(1H,3H)-dione. The product of step 2 (10.57 g) was suspended and stirred with PPA (55 g) at 140° C. for 3 hours until all solids were dissolved. After starting material was consumed (confirmed by LC-MS), the reaction mixture was quenched with ice. The formed solids were collected by filtration and rinsed with water. After drying under vacuum, the titled compound (17 g) was used in the next step without further purification. MS (ES): [M+1].sup.+230

[0909] Step 4: Preparation of 2,4,7,8-tetrachloroquinoline (1.6). The product of step 3 was suspended in POCl.sub.3 (45 g) and heated at 130° C. until all solids were dissolved. After starting material was consumed (confirmed by LC-MS), excess POCl.sub.3 was removed by under vacuum. The residue was treated with ice-water (exothermic) to afford solids and the suspended solids were stirred for 4 hours. Filtration, rinsing with water, and drying under vacuum afforded the crude product as a brown solid (9.25 g) that was suspended in hexane (400 mL) and heated at reflux. After hot filtration to remove residual solids and cooling slowly to room temperature, 5.73 g of the titled compound was obtained as a light brown solid. The solids concentrated from the filtrate and undissolved solids from the above recrystallization were purified by a flash silica column to afford additional product (1.7 g). MS (ES): [M+1].sup.+266.0. .sup.1H NMR (400 Hz, CDCl.sub.3): δ 8.074-8.046 (dd, J=9.2 and 2.4 Hz, 1H), 7.705-7.677 (dd, J=9.2 and 2.4 Hz, 1H), 7.571 (s, 1H) ppm.

[0910] Step 5: Preparation of 4,7,8-trichloroquinolin-2(1H)-one. The product of step 4 (4.93 g) was suspended in dioxane (80 mL), conc. H.sub.2SO.sub.4 (16 mL), water (24 mL), and heated to reflux for 12 to 16 hours. A clear solution was initially formed followed by the precipitation of solids. After starting material was consumed (confirmed by LC-MS) and the reaction mixture was cooled, 100 mL of ACN was added to form a precipitate. Filtration, rinsing with CAN, and drying under vacuum afforded the titled compound (4.12 g) as colorless powder. MS (ES): [M+1].sup.+248.0.

[0911] Step 6: Preparation of 7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2(1H)-one (I-8). The product of step 5 (4.12 g) was suspended in DMF (20 mL) with imidazole (4 g) and heated to 130° C. until starting material was consumed (confirmed by LC-MS). Additional imidazole can be added to push the reaction to the completion. After cooling, ACN (150 mL) was added to form a precipitate which was collected by filtration and rinsing with CAN afforded the titled compound (1.8, 3.90 g). MS (ES): [M+1].sup.+280.0. .sup.1H NMR (400 Hz, DMSO-d6): δ 8.089 (s, 1H), 7.650 (s, 1H), 7.494-7.516 (d, J=8.8 Hz, 1H), 7.316-7.338 (d, J=8.8 Hz, 1H), 7.225 (s. 1H), 6.795 (s, 1H) ppm.

[0912] Step 7: 2,7,8-trichloro-4-(1H-imidazol-1-yl) quinoline (Intermediate 1). The product of step 6 (3.90 g) was suspended in ACN (100 mL) and POCl.sub.3 (8 mL) and heated to reflux until all solids were dissolved and starting material was consumed (confirmed by LC-MS). After concentrating under vacuum, the residue was cooled in an ice bath and carefully neutralized by 5% NaOH to pH 7 to precipitate Intermediate 1. Filtration, rinsing with water, and drying under vacuum afforded Intermediate 1 (3.8 g) as light tan solid. MS (ES): [M+1].sup.+298. .sup.1H NMR (400 Hz, DMSO-d6): δ 8.200 (s, 1H), 8.005 (s, 1H), 7.925-7.948 (d, J=9.2 Hz, 1H), 7.785-7.808 (d, J=9.2 Hz, 1H), 7.772 (s. 1H), 7.286 (s, 1H) ppm.

Preparation of 2,7,8-trichloro-4-(1H-pyrazol-4-yl)quinoline (Intermediate 2)

[0913] ##STR02159##

[0914] Step 1: Preparation of 7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2(1H)-one. 4,7,8-trichloroquinolin-2(1H)-one (300 mg, 1.21 mmol), Na.sub.2CO.sub.3 (321 mg, 3.03 mmol), and Pd(PPh.sub.3).sub.4 (140 mg, 0.121 mmol) were added to a round-bottom flask and diluted with dioxane (10 mL) and water (5 mL). The mixture was cooled in an ice-bath, and vacuumed and purged with N.sub.2 three times. A solution of boron ester 2.1 (703 mg, 3.62 mmol) in dioxane (3 mL) was prepared and degassed. Under N.sub.2, a portion of the boron ester 2.1 (1 mL, 1.0 eq) in dioxane was added to the reaction mixture via a syringe. The reaction mixture was heated at 110° C. for 2 hwhile LC-MS showed that around 50% of 1.7 was consumed. The rest of the boron ester 2.1 in dioxane was added under N.sub.2. After heating and stirring for an additional 3 h, compound 1.7 was consumed (confirmed by LC-MS). After cooling to room temperature, the reaction mixture was further diluted with water (20 mL). The precipitated solids were collected by centrifuge or filtration and washed with DCM (5 mL×3). After drying under the vacuum, the titled compound was afforded (2.2, 315 mg). MS: [M+1].sup.+280.

[0915] Step 2: Preparation of 2,7,8-trichloro-4-(1H-pyrazol-4-yl)quinoline (Intermediate 2). The product of step 1 (208 mg, 0.743 mmol) was suspended in ACN (2.5 mL) and POCl.sub.3 (0.42 mL). The resultant mixture was heated at 80° C. for 3 hor until less than 10% of compound 2.2 remained (confirmed by LC-MS). After the concentrating under vacuum, the residue was cooled in an ice bath and carefully neutralized by 5% NaOH to pH 7 to precipitate Intermediate 2 as a yellow solid. The solids were collected by centrifuge or filtration and washed with water (15 mL×3). After drying in vacuo, Intermediate 2 was afforded (180 mg). MS: [M+1].sup.+298. .sup.1HNMR (400 MHz, DMSO-D6) δ: 8.8.25-8.30 (m, 3H), 7.84 (d, J=9.2 Hz, 1H) and 7.72 (s, 1H) ppm.

Preparation of 2,7-dichloro-4-(1H-imidazol-1-yl) quinoline (Intermediate 3).

[0916] ##STR02160##

[0917] Step 1: Preparation of 4,7-dichloroquinoline 1-oxide. To a solution of 4,7-dichloroquinoline (20.0 g, 101.5 mmol) in DCM (400 mL) at room temperature was added 3-chloroperoxybenzoic acid (mCPBA) (28.8 g, 85% purity, 142.1 mmol) in portions and the resulting solution was stirred at 40° C. for 2 hrs. The solution was then washed with aqueous NaHCO.sub.3 (2×50 mL), aqueous Na.sub.2S.sub.2O.sub.3 (100 mL×2), dried over anhydrous Mg2SO.sub.4, filtered, concentrated under reduced pressure, and dried under high vacuum to yield the titled product (21 g) as a white solid. MS: [M+1].sup.+214.1.

[0918] Step 2: Preparation of 2,4,7-trichloroquinoline. The product of step 1 (20.0 g, 1.0 eq) was dissolved in POCl.sub.3(74 mL) at rt and the resulting solution was stirred at 110° C. for 2 hrs. The mixture was concentrated under reduced pressure and adjusted to pH 9 with a 10% NaOH solution. The precipitate was collected, washed with water, and dried to afford the titled compound (18 g, yield 83%) as an off-white solid. MS: [M+1].sup.+234.0. NMR (400 Hz, CDCl.sub.3): δ 8.148-8.126 (d, J=8.8 Hz, 1H), 8.033 (s, 1H), 7.622-7.596 (dd, J=1.4 Hz, 1H), 7.510 (s, 1H) ppm.

[0919] Step 3: Preparation of 4,7-dichloroquinolin-2(1H)-one. To a solution of the product of step 2 (5.0 g ,1.0 eq) in 1,4-diaoxane (125 mL) was added 15% H.sub.2SO.sub.4 (250 mL) at 25° C. The resulting mixture was stirred at 140° C. for 12 hrs. The precipitated solids were collected by filtration, washed with water, and dried to afford the titled compound (3.9 g) as a gray solid. MS: [M+1].sup.+214.1. .sup.1H NMR (400 Hz, CDCl.sub.3): δ 12.122 (s, 1H), 7.880-7.859 (d, J=8.4 Hz, 1H), 7.406 (s, 1H), 7.368-7.343 (dd, J=1.4 Hz, 1H), 6.865 (s, 1H) ppm.

[0920] Step 4: Preparation of 7-chloro-4-(1H-imidazol-1-yl)quinolin-2(1H)-one. To a solution of 4,7-dichloroquinolin-2(1H)-one (9.0 g, 1.0 eq) in DMF (18 mL) was added imidazole (48.8 g, 17 eq). After stirring at 120° C. for 21 hrs, the reaction mixture was diluted with ACN (100 mL) and stirred for 0.5 hrs. The precipitated solid was collected, washed with ACN, and dried in vacuo to afford the crude titled compound (6.7 g) as a gray solid. MS: [M+1].sup.+246.1. .sup.1H NMR (400 MHz, DMSO): δ 12.19 (s, 1H), 8.09 (s, 1H), 7.65 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.0 Hz, 1H), 7.21 (s, 1H), 6.66 (s, 1H) ppm.

[0921] Step 5: Preparation of 2,7-dichloro-4-(1H-imidazol-1-yl) quinolone (Intermediate 3). To a solution of compound 3.5 (5.0 g, 1.0 eq) in ACN (50 mL) was added POCl.sub.3 (10 mL) and the resulting mixture was stirred at 80° C. for 0.5 hrs. The mixture was concentrated in vacuo and the residue was carefully quenched with 5-10% NaOH solution to pH 7 in an ice-bath. The precipitated solid was collected, washed with water, and dried in vacuo to yield Intermediate 3 (4.1 g) as a white solid. MS (ES): [M+1].sup.+264. .sup.1H NMR (400 Hz, CDCl.sub.3): δ 8.164 (s, 1H), 7.970 (s, 1H) ,7.786-7.763(d, J=9.2 Hz, 1H), 7.631-7.608 (d, J=9.2 Hz, 1H), 7.422 (s, 1H), 7.357 (s, 1H) ppm.

Preparation of 2,4-dichloro-7-(trifluoromethyl)quinoline (Intermediate 4A) and 2,4-dichloro-5-(trifluoromethyl)quinoline (Intermediate 4B)

[0922] ##STR02161##

[0923] Step 1: 3-Oxo-3-((3-(trifluoromethyl) phenyl) amino) propanoic acid. A mixture of 3-(trifluoromethyl) aniline (5.74 g) and diethyl malonate (14.9 g) was stirred and heated at 180° C. over 4 hours. The resultant mixture was dissolved in MeOH (30 mL) and water (10 mL). The solution was cooled in an ice-bath and treated with NaOH (7.1 g). After stirring at room temperature over 2 hours and removal of MeOH under vacuum, the resultant mixture was further diluted with water (60 mL) and acidified to pH 1 to 2 with conc. HCl. After extraction with EtOAc (30 mL×4), the combined organic layers were washed by brine and dried over Na.sub.2SO.sub.4. Evaporation of EtOAc under reduced pressure afforded 4.3 (8.76 g) as oil. MS: [M+1].sup.+276.

[0924] Step 2: 7-(Trifluoromethyl) quinoline-2,4(1H,3H)-dione 4-4 and 5-(trifluoromethyl) quinoline-2,4 (1H,3H)-dione. Neat 4.3 (8.76 g) was suspended in PPA (42 g) and heated at 130° C. over 4 hours. The resultant mixture was further diluted with water (120 mL) and the aqueous layer was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. Evaporation under reduced pressure afforded a mixture of two titled regioisomers (5.99 g) as sticky solids. MS: [M+1].sup.+230.

[0925] Step 3: 2,4-Dichloro-7-(trifluoromethyl)quinoline (Intermediate 4A) and 2,4-dichloro-5-(trifluoromethyl)quinoline (Intermediate 4B). The mixture of 4.4 and 4.5 (5.99 g) from the previous step were suspended in POCl.sub.3, stirred, and heated at reflux over 3 h. POCl.sub.3was removed under reduced pressure and the resultant mixtures were carefully quenched with ice. The aqueous layer was extracted with EtOAc (30 mL×3) and the combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. Column chromatography, eluting with a gradient of DCM/Hexane from 0 to 50%, afforded Intermediate 4A (3.1 g) and Intermediate 4B (0.59 g). 4A: MS [M+1].sup.+: 266.1. .sup.1HNMR (400 MHz, CD3Cl) δ: 8.38 (s, 1H), 8.37 (d, J=8 Hz, 1H), 7.86 (dd, J=8 and 4 Hz) and 7.66 (s, 1H) ppm. 4B: MS [M+1].sup.+: 266.1. .sup.1HNMR (400 MHz, CD.sub.3Cl) δ: 8.29 (d, J=8 Hz, 1H), 8.18 (d, J=8 Hz, 1H), 7.85 (t, J=8 Hz) and 7.72 (s, 1H) ppm.

[0926] Following the above procedures to prepare Intermediates 1 and 4, the following intermediates were prepared.

TABLE-US-00002 Starting Inter- MS: Inter- MS: Material mediate # Structure [M + 1].sup.+ mediate # Structure [M + 1].sup.+ [02162] 5A [02163] 228 5B [02164] 260 [02165] 6A [02166] 240 6B [02167] 272 [02168] 7A [02169] 254 7B [02170] 286 [02171] 8A [02172] 212 8B [02173] 244 [02174] 9A [02175] 212 9B [02176] 244 [02177] 10A [02178] 250 10B [02179] 282 [02180] 11A [02181] 266 11B [02182] 298 [02183] 12A [02184] 266 12B [02185] 298 [02186] 13A [02187] 266 13B [02188] 298 [02189] 14A [02190] 266 14B [02191] 298 [02192] 15A [02193] 262 15B [02194] 294 [02195] — — — 16 [02196] 298 [02197] 17 [02198] 306 — — — [02199] 18 [02200] 266 — — —

Example 1: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-N-(pyridin-4-ylmethyl)quinolin-2-amine (I-353)

[0927] ##STR02201##

[0928] To a solution of 2,7-dichloro-4-(1H-imidazol-1-yl) quinoline (132 mg, 0.5 mmol) in DMF (2 mL) was added pyridin-4-ylmethanamine (0.15 mL, 1.5 mmol). The solution was vigorously stirred at 120° C. for 3 h. After cooling down to room temperature, the solvent was removed by evaporation to give a crude. The crude was purified directly by column chromatography on silica gel to give the title product as a solid (115 mg, 68% yield). MS: [M+1].sup.+336.1.

[0929] The following compounds are prepared essentially by the same method described above to prepare I-353.

TABLE-US-00003 MS I-# Starting Material Structure [M + 1]+ I-354 [02202] [02203] [02204] 358 I-126 [02205] [02206] [02207] 371 I-131 [02208] [02209] [02210] 371 I-355 [02211] [02212] [02213] 321 I-447 [02214] [02215] [02216] 371 I-356 [02217] [02218] [02219] 371 I-357 [02220] [02221] [02222] 357 I-115 [02223] [02224] [02225] 427 I-121 [02226] [02227] [02228] 347 I-95  [02229] [02230] [02231] 349 I-87  [02232] [02233] [02234] 397 I-91  [02235] [02236] [02237] 393 I-211 [02238] [02239] [02240] 406 I-212 [02241] [02242] [02243] 420 I-213 [02244] [02245] [02246] 392 I-214 [02247] [02248] [02249] 406 I-215 [02250] [02251] [02252] 392 I-216 [02253] [02254] [02255] 482 I-358 [02256] [02257] [02258] 434 I-218 [02259] [02260] [02261] 436 I-434 [02262] [02263] [02264] 407 I-433 [02265] [02266] [02267] 393 I-437 [02268] [02269] [02270] 449 I-438 [02271] [02272] [02273] 483 I-352 [02274] [02275] [02276] 363 I-432 [02277] [02278] [02279] 407 I-359 [02280] [02281] [02282] 363 I-431 [02283] [02284] [02285] 393 I-360 [02286] [02287] [02288] 469 I-361 [02289] [02290] [02291] 469 I-362 [02292] [02293] [02294] 469 I-444 [02295] [02296] [02297] 391 I-244 [02298] [02299] [02300] 351 I-92  [02301] [02302] [02303] 393 I-241 [02304] [02305] [02306] 351 I-242 [02307] [02308] [02309] 351 I-93  [02310] [02311] [02312] 393 I-94  [02313] [02314] [02315] 407 I-85  [02316] [02317] [02318] 328 I-138 [02319] [02320] [02321] 363 I-139 [02322] [02323] [02324] 363 I-240 [02325] [02326] [02327] 337 I-239 [02328] [02329] [02330] 323 I-249 [02331] [02332] [02333] 353 I-245 [02334] [02335] [02336] 349 I-141 [02337] [02338] [02339] 363 I-243 [02340] [02341] [02342] 351 I-86  [02343] [02344] [02345] 376 I-246 [02346] [02347] [02348] 399 I-247 [02349] [02350] [02351] 399 I-155 [02352] [02353] [02354] 367 I-128 [02355] [02356] [02357] 391 I-152 [02358] [02359] [02360] 462 I-363 [02361] [02362] [02363] 371 I-140 [02364] [02365] [02366] 343 I-99  [02367] [02368] [02369] 359 I-97  [02370] [02371] [02372] 379 I-88  [02373] [02374] [02375] 342 I-446 [02376] [02377] [02378] 357 I-364 [02379] [02380] [02381] 381 I-117 [02382] [02383] [02384] 391 I-365 [02385] [02386] [02387] 342 I-366 [02388] [02389] 371 I-367 [02390] [02391] [02392] 328 I-116 [02393] [02394] [02395] 426 I-89  [02396] [02397] [02398] 375 I-158 [02399] [02400] [02401] 387 I-160 [02402] [02403] [02404] 401 I-200 [02405] [02406] [02407] 386 I-201 [02408] [02409] [02410] 400 I-202 [02411] [02412] [02413] 414 I-178 [02414] [02415] [02416] 336 I-179 [02417] [02418] [02419] 350 I-204 [02420] [02421] [02422] 400 I-159 [02423] [02424] [02425] 401 I-205 [02426] [02427] [02428] 414 I-148 [02429] [02430] [02431] 426 I-149 [02432] [02433] [02434] 426 I-150 [02435] [02436] [02437] 412 I-368 [02438] [02439] [02440] 440 I-206 [02441] [02442] [02443] 400 I-207 [02444] [02445] [02446] 400 I-210 [02447] [02448] [02449] 400 I-190 [02450] [02451] [02452] 350 I-191 [02453] [02454] [02455] 364 I-192 [02456] [02457] [02458] 378 I-428 [02459] [02460] [02461] 377 I-327 [02462] [02463] [02464] 393 I-369 [02465] [02466] [02467] 393 I-370 [02468] [02469] [02470] 417 I-328 [02471] [02472] [02473] 393 I-238 [02474] [02475] [02476] 337 I-145 [02477] [02478] [02479] 349 I-203 [02480] [02481] [02482] 386 I-144 [02483] [02484] [02485] 349 I-371 [02486] [02487] [02488] 392 I-372 [02489] [02490] [02491] 379 I-373 [02492] [02493] [02494] 426 I-250 [02495] [02496] [02497] 387 I-248 [02498] [02499] [02500] 351 I-374 [02501] [02502] [02503] 377 I-375 [02504] [02505] [02506] 391 I-157 [02507] [02508] [02509] 373 I-98  [02510] [02511] [02512] 379 I-443 [02513] [02514] [02515] 391 I-142 [02516] [02517] [02518] 379 I-435 [02519] [02520] [02521] 377 I-143 [02522] [02523] [02524] 377 I-436 [02525] [02526] [02527] 391 I-448 [02528] [02529] [02530] 376 I-451 [02531] [02532] [02533] 404 I-348 [02534] [02535] [02536] 452 I-429 [02537] [02538] [02539] 393 I-453 [02540] [02541] [02542] 404 I-449 [02543] [02544] [02545] 392 I-450 [02546] [02547] [02548] 390 I-147 [02549] [02550] [02551] 377 I-345 [02552] [02553] [02554] 393 I-376 [02555] [02556] [02557] 377 I-430 [02558] [02559] [02560] 395 I-439 [02561] [02562] [02563] 459 I-322 [02564] [02565] [02566] 395 I-377 [02567] [02568] [02569] 285 I-269 [02570] [02571] [02572] 360 I-268 [02573] [02574] [02575] 374 I-267 [02576] [02577] [02578] 332 I-266 [02579] [02580] [02581] 332 I-264 [02582] [02583] [02584] 386 I-263 [02585] [02586] [02587] 386 I-262 [02588] [02589] [02590] 370 I-261 [02591] [02592] [02593] 386 I-260 [02594] [02595] [02596] 386 I-259 [02597] [02598] [02599] 353 I-132 [02600] [02601] [02602] 363 I-133 [02603] [02604] [02605] 363 I-134 [02606] [02607] [02608] 363 I-455 [02609] [02610] [02611] 393 I-456 [02612] [02613] [02614] 391 I-457 [02615] [02616] [02617] 453 I-458 [02618] [02619] [02620] 387 I-459 [02621] [02622] [02623] 407 I-460 [02624] [02625] [02626] 419 I-461 [02627] [02628] [02629] 377 I-462 [02630] [02631] [02632] 459 I-463 [02633] [02634] [02635] 421 I-464 [02636] [02637] [02638] 401 I-465 [02639] [02640] [02641] 401 I-466 [02642] [02643] [02644] 395 I-467 [02645] [02646] [02647] 399 I-468 [02648] [02649] [02650] 459 I-469 [02651] [02652] [02653] 389 I-470 [02654] [02655] [02656] 389 I-471 [02657] [02658] [02659] 431 I-472 [02660] [02661] [02662] 407 I-473 [02663] [02664] [02665] 391 I-474 [02666] [02667] [02668] 389 I-475 [02669] [02670] [02671] 403 I-476 [02672] [02673] [02674] 425 I-477 [02675] [02676] [02677] 391 I-478 [02678] [02679] [02680] 403 I-479 [02681] [02682] [02683] 405 I-480 [02684] [02685] [02686] 389 I-481 [02687] [02688] [02689] 391 I-482 [02690] [02691] [02692] 391 I-483 [02693] [02694] [02695] 405 I-484 [02696] [02697] [02698] 391 I-485 [02699] [02700] [02701] 395 I-486 [02702] [02703] [02704] 395 I-487 [02705] [02706] [02707] 453 I-488 [02708] [02709] [02710] 387 I-489 [02711] [02712] [02713] 389 I-490 [02714] [02715] [02716] 389 I-491 [02717] [02718] [02719] 401 I-492 [02720] [02721] [02722] 403 I-493 [02723] [02724] [02725] 417 I-494 [02726] [02727] [02728] 403 I-495 [02729] [02730] [02731] 358 I-496 [02732] [02733] [02734] 401 I-497 [02735] [02736] [02737] 407 I-498 [02738] [02739] [02740] 393 I-499 [02741] [02742] [02743] 393 I-500 [02744] [02745] [02746] 407 I-501 [02747] [02748] [02749] 365 I-502 [02750] [02751] [02752] 392 I-503 [02753] [02754] [02755] 388 I-504 [02756] [02757] [02758] 399 I-659 [02759] [02760] [02761] 349 I-644 [02762] [02763] [02764] 433 I-660 [02765] [02766] [02767] 439 I-835 [02768] [02769] [02770] 379 I-888 [02771] [02772] [02773] 427 I-881 [02774] [02775] [02776] 434 I-883 [02777] [02778] [02779] 427 I-872 [02780] [02781] [02782] 451

Example 2: Synthesis of 2-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)acetic acid (I-123)

[0930] ##STR02783##

[0931] Step 1: Ethyl 2-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)acetate . To a solution of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (38 mg, 0.144 mmol) in DMF (1 mL) was added ethyl 2-(piperidin-3-yl)acetate (50 mg, 0.3 mmol). The solution was vigorously stirred at 140° C. for 3 h. After cooling down to room temperature, the solvent was removed by evaporation and the residue was purified by column chromatography on silica gel to give the titled product as an oil (MS: [M+1].sup.+399.1).

[0932] Step 2: 2-(1-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pipe ridin-3-yl)acetic acid. To a solution of ethyl 2-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)acetate (20 mg, 0.05 mmol) in MeOH (2 mL) was added 10% NaOH (aq., 0.5 mL). The mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the crude was acidified by 1 N HCl (2.5 mL). The titled compound was collected as a solid by filtration (MS: [M+1].sup.+371.1).

[0933] The following compounds were prepared essentially by the same method as described above for I-123.

TABLE-US-00004 MS I-# Starting Material Structure [M + 1].sup.+ I-84 [02784] [02785] [02786] 372 I-122 [02787] [02788] [02789] 357.1 I-127 [02790] [02791] [02792] 357.1 I-445 [02793] [02794] [02795] 343.0 I-331 [02796] [02797] [02798] 357.1 I-135 [02799] [02800] [02801] 373.1 I-332 [02802] [02803] [02804] 373 I-334 [02805] [02806] [02807] 406 I-130 [02808] [02809] [02810] 373.1 I-136 [02811] 373.1 I-124 [02812] [02813] [02814] 407 I-333 [02815] [02816] [02817] 371 I-505 [02818] [02819] [02820] 389 I-506 [02821] [02822] [02823] 373 I-507 [02824] [02825] [02826] 391 I-508 [02827] [02828] [02829] 445 I-509 [02830] [02831] [02832] 576 I-510 [02833] [02834] [02835] 576 I-511 [02836] [02837] [02838] 576 I-512 [02839] [02840] [02841] 528 I-513 [02842] [02843] [02844] 389 I-514 [02845] [02846] [02847] 393 I-515 [02848] [02849] [02850] 417 I-516 [02851] [02852] [02853] 403 I-517 [02854] [02855] [02856] 417 I-518 [02857] [02858] [02859] 462 I-519 [02860] [02861] [02862] 392 I-520 [02863] [02864] [02865] 413 I-521 [02866] [02867] [02868] 393 I-844 [02869] [02870] [02871] 427 I-845 [02872] [02873] [02874] 441 I-831 [02875] [02876] [02877] 407 I-887 [02878] [02879] [02880] 413 I-854 [02881] [02882] [02883] 393 I-830 [02884] [02885] [02886] 393 I-882 [02887] [02888] [02889] 419

Example 3: Synthesis of (7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycine (I-166)

[0934] ##STR02890##

[0935] Step 1: tert-Butyl (7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycinate. A mixture of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.114 mmol), tert-butyl glycinate (38 mg, 0.228 mmol), triethylamine (0.2 mL) and dioxane (2 mL) was heated at 100° C. for 16 h. After cooling to room temperature, the crude was diluted with water (5 mL) and extracted by EtOAc (2×5 mL). The combined organics were dried and concentrated. The residue was purified by column chromatography on silica gel (25-100% EtOAc/Hexanes) to give tert-butyl (7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycinate as a solid (MS: [M+1].sup.+359.1).

[0936] Step 2: (7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycine. Tert-butyl (7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycinate (20 mg, 0.056 mmol) was placed in a vial with dichloromethane (3 mL). Hydrochloric acid (2.0 M in diethyl ether) was added and the reaction was stirred at r.t. for 16 h. The volatiles were concentrated off and the resulting solid was triturated with dichloromethane, then dried in vacuo to afford (7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)glycine as a solid (MS: [M+1].sup.+303.1).

[0937] The following compounds were prepared essentially by the same method as described above to prepare I-166:

TABLE-US-00005 MS I-# Starting Material Structure [M + 1].sup.+ I-182 [02891] [02892] [02893] 317.1 I-167 [02894] [02895] [02896] 317.1

Example 4: Synthesis of 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxynicotinic acid (I-57)

[0938] ##STR02897##

[0939] 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-methoxynicotinic acid (I-33, 15 mg, 0.04 mmol) was placed in a vial with acetic acid (1 mL). Hydrobromic acid (33% in acetic acid, 0.2 mL) was added and the reaction was stirred at r.t. for 16 h. The volatiles were concentrated off and the resulting residue was purified on a silica prep plate to afford the title compound (MS: [M+1].sup.+367.0).

Example 5: Synthesis of (7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)serine (I-168)

[0940] ##STR02898##

[0941] Step 1: Methyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)serinate. To a solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) was added DL-Serine methyl ester HCl (39 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.1 mL) and the solution was stirred at 95° C. for 16 h. After cooling to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 0-15% MeOH/dichloromethane to afford methyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)serinate (MS: [M+1].sup.+381.0).

[0942] Step 2: (7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)serine. Methyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)serinate (12 mg, 0.031 mmol) was placed in a vial with THF (0.6 mL), methanol (0.2 mL), and water (0.2 mL). Lithium hydroxide monohydrate (4 mg, 0.09 mmol) was added and the reaction was allowed to stir at r.t. for 16 h. The volatiles were concentrated off and the resulting residue neutralized by the addition of 1 N hydrochloric acid. The resulting solution was lyophilized to afford the titled compound (MS: [M+1].sup.+367.0).

[0943] The following compounds were prepared essentially by the same method described above to prepare I-168:

TABLE-US-00006 MS I-# Starting Material Structure [M + 1].sup.+ I-169 [02899] [02900] [02901] 443.0 I-185 [02902] [02903] [02904] 365.0 I-186 [02905] [02906] [02907] 365.0 I-189 [02908] [02909] [02910] 427.0 I-187 [02911] [02912] [02913] 393.0 I-184 [02914] [02915] [02916] 365.0 I-183 [02917] [02918] [02919] 365.1 I-188 [02920] [02921] [02922] 393.0

Example 6: Synthesis of N-(7,8-dichloro-4-(1H-imidazol-1-yl)quinoline-2-yl)-N-(2-morpholinoethyl)glycine (I-172)

[0944] ##STR02923##

[0945] Step 1: tert-Butyl (2-morpholinoethyl)glycinate. To a solution of 2-morpholinoethan-1-amine (260 mg, 2.0 mmol) in acetonitrile (5 mL) was added K.sub.2CO.sub.3 (1.38 g, 10 mmol). The reaction was cooled to 0° C. and tert-butyl 2-bromoacetate (390 mg, 2.0 mmol) in acetonitrile (5 mL) was added dropwise. The reaction was stirred at 0° C. for 1 hthen filtered through Celite and concentrated. The residue was purified by column chromatography to afford tert-butyl (2-morpholinoethyl)glycinate as an oil (200 mg) (MS: [M+1].sup.+245.2).

[0946] Step 2: tert-Butyl N-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N-(2-morpholinoethyl)glycinate. To a solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) was added tert-butyl (2-morpholinoethyl)glycinate (200 mg) and N,N-diisopropylethylamine (0.1 mL). The solution was stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 0-15% MeOH/dichloromethane to afford tert-butyl N-(7,8-dichloro-4-(1H-imidazol-1-yl)294uinoline-2-yl)-N-(2-morpholinoethypglycinate (10 mg) (MS: [M+1].sup.+506.1).

[0947] Step 3: N-(7,8-dichloro-4-(1H-imidazol-1-yl)quinoline-2-yl)-N-(2-morpholinoethyl)glycine. tert-Butyl N-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N-(2-morpholinoethyl)glycinate (10 mg, 0.02 mmol) was placed in a vial with dichloromethane (1 mL). Trifluoroacetic acid (0.1 mL) was added and the reaction stirred at r.t. for 16 h. The volatiles were removed by rotary evaporation and the residue was dried under vacuum to afford N-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N-(2-morpholinoethyl)glycine (MS: [M+1].sup.+450.1).

[0948] The following compounds were prepared essentially by the same methods described above to prepare I-172:

TABLE-US-00007 MS I-# Starting Material Structure [M + 1].sup.+ I-173 [02924] [02925] [02926] 395.0 I-174 [02927] [02928] [02929] 395.1 I-175 [02930] [02931] [02932] 409.1 I-176 [02933] [02934] [02935] 428.0

Example 7: Synthesis of 2-((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoic acid (I-170)

[0949] ##STR02936##

[0950] Step 1: Ethyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methioninate. To a solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) was added ethyl methioninate (47 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.1 mL). The solution was stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 0-100% EtOAc/hexanes to afford ethyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yOmethioninate (20 mg) (MS: [M+1].sup.+439.0).

[0951] Step 2: Ethyl 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoate. Ethyl (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methioninate (20 mg, 0.045 mmol) was placed in a vial with dichloromethane (2 mL). m-CPBA (20 mg, 0.09 mmol) was added and the reaction was allowed to stir at r.t. for 16 h. Sodium sulfite (2 mL, 10% aq.) was added and the organics were dried (Na.sub.2SO.sub.4) and purified by silica chromatography using 0-10% MeOH/CH.sub.2Cl.sub.2 to afford ethyl 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoate (10 mg) (MS: [M+1].sup.+471.1).

[0952] Step 3: 2-((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoic acid. Ethyl 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoate (20 mg, 0.042 mmol) was placed in a vial with THF (1 mL) and water (0.25 mL). Lithium hydroxide monohydrate (5 mg, 0.13 mmol) was added and the reaction mixture was stirred at r.t. for 3 h. The volatiles were removed by rotary evaporation and the residue was neutralized by the addition of 1N HCl (aq.). The resulting solution was lyophilized to afford 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-4-(methylsulfonyl)butanoic acid (12 mg) (MS: [M+1].sup.+443.0).

Example 8: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)quinoline (I-2)

[0953] ##STR02937##

[0954] A mixture of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (132 mg, 0.5 mmol), (4-methoxyphenyl)boronic acid (114 mg, 0.75 mmol), Na.sub.2CO.sub.3 (265 mg, 2.5 mmol), 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was purged by N.sub.2 for 30 min. Tetrakis(triphenylphosphine)palladium (55 mg, 0.05 mmol) was added to the mixture above under N.sub.2. The mixture was vigorously stirred at 100° C. for 3 h. After cooling down to room temperature, the crude was diluted by EtOAc (20 mL) and washed by water (5 mL×2) and brine (5 mL×2). The organic phase was concentrated and purified by column chromatography on silica gel to give the titled product I-2 as a solid (MS: [M+1].sup.+336.1).

[0955] The following compounds were prepared essentially by the same methods described above to prepare I-2.

TABLE-US-00008 MS I-# Starting Material Structure [M + 1].sup.+ I-5 [02938] [02939] [02940] 364.1 I-12 [02941] [02942] [02943] 378.1 I-3 [02944] [02945] [02946] 364.1 I-35 [02947] [02948] [02949] 347 I-36 [02950] [02951] [02952] 363 I-25 [02953] [02954] [02955] 406.1 I-31 [02956] [02957] [02958] 384.0 I-18 [02959] [02960] [02961] 434 I-45 [02962] [02963] [02964] 414 I-40 [02965] [02966] [02967] 395 I-46 [02968] [02969] [02970] 419 I-41 [02971] [02972] [02973] 386 I-43 [02974] [02975] [02976] 356 I-44 [02977] [02978] [02979] 440 I-47 [02980] [02981] [02982] 356 I-20 [02983] [02984] [02985] 365 I-28 [02986] [02987] [02988] 394 I-378 [02989] [02990] [02991] 330.0

Example 9: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)quinoline (I-6)

[0956] ##STR02992##

[0957] Step 1: Methyl 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoate. A mixture of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (132 mg, 0.5 mmol), (3-(methoxycarbonyl)phenyl)boronic acid (136 mg, 0.75 mmol), Na.sub.2CO.sub.3 (265 mg, 2.5 mmol), 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was purged by N.sub.2 for 30 min. Tetrakis(triphenylphosphine) palladium (55 mg, 0.05 mmol) was added to the mixture above under N.sub.2. The mixture was vigorously stirred at 100° C. for 2 h. After cooling down to room temperature, the crude was diluted by EtOAc (20 mL) and washed by water (5 mL×2) and brine (5 mL×2). The organic phase was concentrated and purified by column chromatography on silica gel to give the titled product as a solid (MS: [M+1].sup.+364.1).

[0958] Step 2: 3-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid. To a solution of methyl 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoate (80 mg, 0.22 mmol) in MeOH (4 mL) was added 10% NaOH (aq., 1 mL). The mixture was stirred at 50° C. for 1 h. After cooling down to room temperature, the crude was acidified by 1 N HCl (5 mL). The titled compound was collected as a solid by filtration (MS: [M+1].sup.+350.1).

[0959] The following compounds are prepared essentially by the same method described above to prepare 1-6:

TABLE-US-00009 MS I-# Starting Material Structure [M + 1].sup.+ I-13 [02993] [02994] [02995] 350.1 I-4 [02996] [02997] [02998] 350.1 I-15 [02999] [03000] [03001] 380 I-30 [03002] [03003] [03004] 380 I-55 [03005] [03006] [03007] 356 I-37 [03008] [03009] [03010] 394.0 I-38 [03011] 430.0 I-27 [03012] [03013] [03014] 428.0 I-17 [03015] [03016] [03017] 368.0 I-14 [03018] [03019] [03020] 364.1 I-9 [03021] [03022] [03023] 364.1 I-32 [03024] [03025] [03026] 351.0 I-33 [03027] [03028] [03029] 381.1

Example 10: Synthesis of 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzamide (I-7)

[0960] ##STR03030##

[0961] To a solution of 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid (25 mg, 0.07 mmol) in THF (1 mL) was added SOCl.sub.2 (0.015 mL, 0.2 mmol). After 1 h, NH.sub.4OH (aq., 0.5 mL) was added. After 3 h, the solvent was removed by evaporation to give a crude. The crude was purified directly by column chromatography on silica gel to give the titled product as a solid (MS: [M+1].sup.+349.1).

Example 11: Synthesis of 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-methoxybenzoic acid (I-24) and 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-hydroxybenzoic acid (I-26)

[0962] ##STR03031##

[0963] Step 1: 3-(4,7-dichloroquinolin-2-yl)-5-methoxybenzoic acid was prepared essentially by the same methods described above to prepare 1-2.

[0964] Step 2: 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-methoxybenzoic acid. To a vial were added 3-(4,7-dichloroquinolin-2-yl)-5-methoxybenzoic acid (50 mg, 0.144 mmol), imidazole (49 mg, 0.718 mmol), Cs.sub.2CO.sub.3 (70 mg, 0.216 mmol) and DMF (1.0 mL). The resulting reaction mixture was stirred at 110° C. overnight. At room temperature the reaction mixture was diluted by H.sub.2O (4 mL) and acidified by HCl (1 N) to pH about 3. A lot of white solid precipitated, centrifuged and washed by H.sub.2O (2×4 mL). The residue was dried in vacuo to afford the titled compound as white solid (30 mg). MS: [M+1].sup.+380.

[0965] Step 3: 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-hydroxybenzoic acid. To a vial were added 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-methoxybenzoic acid (7.9 mg, 0.0208 mmol), NaI (20 mg, 0.133 mmol) and HBr in HOAc (33%, 1.0 mL). The resulting mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and diluted by H.sub.2O (10 mL), centrifuged, and washed with H.sub.2O (4 mL). The residue was dried under high vacuum to afford the title product as off-white solid (18 mg) (MS: [M+1].sup.+366).

Example 12: Synthesis of 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoic acid (I-16) and 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-ethoxybenzoic acid (I-19)

[0966] ##STR03032##

[0967] Step 1: Methyl 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-methoxybenzoate was prepared according to the procedure above to prepare compound I-2.

[0968] Step 2: 5-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoic acid (I-16) was prepared according to the procedure above to prepare compound I-26. (MS: [M+1].sup.+366).

[0969] Step 3: Ethyl 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-ethoxybenzoate. To a vial were added 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoic acid (14 mg, 0.0383 mmol), ethyl iodide (22 μl, 0.274 mmol), Cs.sub.2CO.sub.3 (62 mg, 0.191 mmol) and DMF (1.0 mL). The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (40 mL), washed by H.sub.2O (4×20 mL) and brine (15 mL). After concentration, the crude was used in next step.

[0970] Step 4: 5-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-ethoxybenzoic acid. To the crude product above were added MeOH (0.6 mL), THF (0.4 mL) and a solution of NaOH in H.sub.2O (7.66 mg/0.2 mL). The resulting reaction mixture was stirred at room temperature overnight. Then the mixture was diluted by H.sub.2O (3 mL) and acidified by HOAc to pH 4. The cloudy mixture was centrifuged and the residue was washed by H.sub.2O (2×1.5 mL), dried over high vacuum to afford the title product as off-white solid (6 mg) (MS: [M+1].sup.+394).

Example 13: Synthesis of 3-amino-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid (I-22)

[0971] ##STR03033##

[0972] Step 1: methyl 3-amino-5-(4,7-dichloroquinolin-2-yl)benzoate was prepared according to the procedure above to prepare compound I-2.

[0973] Step 2: 3-amino-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid was prepared according to the procedure above to prepare compound I-24 (MS: [M+1].sup.+365).

Example 14: Synthesis of 4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1H-pyrrole-2-carboxylic acid (I-56)

[0974] ##STR03034##

[0975] Step 1: 1-(tert-Butyl) 2-methyl 4-(4,7-dichloroquinolin-2-yl)-1H-pyrrole-1,2-dicarboxylate was prepared according to the procedure described above to prepare compound I-2.

[0976] Step 2: Methyl 4-(4,7-dichloroquinolin-2-yl)-1H-pyrrole-2-carboxylate was prepared according to the procedure described above to prepare compound I-172 (step 3).

[0977] Step 3: 4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1H-pyrrole -2-carboxylic acid was prepared according to the procedure described above to prepare compound I-24 (step 2). (MS: [M+1].sup.+339).

Example 15: Synthesis of 3-(7-Chloro-4-(1H-pyrazol-5-yl)quinolin-2-yl)benzoic acid (I-74)

[0978] ##STR03035##

[0979] Step 1: Methyl 3-(4,7-dichloroquinolin-2-yl)benzoate was prepared according to the procedure described above to prepare compound I-2.

[0980] Step 2: Methyl 3-(7-chloro-4-(1H-pyrazol-5-yl)quinolin-2-yl)benzoate was prepared according to the procedure described above to prepare compound I-2.

[0981] Step 3: 3-(7-Chloro-4-(1H-pyrazol-5-yl)quinolin-2-yl)benzoic acid was prepared according to the procedure described above to prepare compound I-24 (step 2). (MS: [M+1].sup.+350).

Example 16: Synthesis of 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-hydroxyacetamido)benzoic acid (I-23)

[0982] ##STR03036##

[0983] Step 1: 3-(2-Acetoxyacetamido)-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid. To a vial were added 3-amino-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid (9.3 mg, 0.0255 mmol), DCM (0.5 mL) and TEA (8.9 μl, 0.0637 mmol). A solution of 2-chloro-2-oxoethyl acetate in DCM (4.18 mg/0.1 mL, 0.0306 mmol) was added and the resulting reaction mixture was stirred at room temperature for 1 h. H.sub.2O (0.5 mL) was added to quench the reaction. Most of DCM was removed under reduced pressure and the crude was used in next step.

[0984] Step 2: 3-(7-Chloro -4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-hydroxyacetamido)benzoic acid. To the crude product above (3-(2-acetoxyacetami do)-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoic acid) were added MeOH (0.5 mL), THF (1.0 mL) and a solution of LiOH—H.sub.2O in H.sub.2O (5.36 mg/0.2 mL, 0.127 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. All volatiles were removed and the mixture was diluted by H.sub.2O (2.5 mL). After centrifugation, the residue was washed by H.sub.2O (2×3 mL), dried under high vacuum to afford the title product as white solid (MS: [M+1].sup.+423).

Example 17: Synthesis of 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-(2-hydroxyethoxy)benzoic acid (I-21)

[0985] ##STR03037##

[0986] Step 1: Methyl 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoate was prepared according to the procedure described above to prepare compound I-2.

[0987] Step 2: Methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzoate. To a vial were added methyl 5-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoate (10 mg, 0.0263 mmol), Cs.sub.2CO.sub.3 (10.3 mg, 0.0316 mmol) and a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane in DMF (6.8 μl/0.5 mL, 0.0316 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. Then the mixture was diluted by ethyl acetate (30 mL), washed by H.sub.2O (4×10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4After concentration, the crude was used in next step.

[0988] Step 3: 5-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-(2-hydroxyethoxy)benzoic acid. To the crude step 2 were added MeOH (0.5 mL), THF (1.0 mL) and a solution of LiOH—H.sub.2O in H.sub.2O (5.5 mg/0.5 mL, 0.132 mmol). The resulting reaction mixture was stirred at room temperature for 48 h. The mixture was acidized by acetic acid to pH 5. Most of volatiles were removed and the residue was diluted with H.sub.2O (1.5 mL), centrifuged, washed by H.sub.2O (2×1.5 mL), dried under high vacuum to afford the title product as off-white solid (MS: [M+1].sup.+410).

[0989] The following compounds are prepared essentially by the same method described above to prepare I-21.

TABLE-US-00010 MS I-# Starting Material Structure [M + 1].sup.+ I-29 [03038] [03039] [03040] 410

Example 18: Synthesis of 5-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoic acid (I-42)

[0990] ##STR03041##

[0991] Step 1: Methyl 2-methoxy-5-(4,7,8-trichloroquinolin-2-yl)benzoate. To a suspension of 2,4,7,8-tetrachloroquinoline (200 mg, 0.75 mmol) with (4-methoxy-3-(methoxycarbonyl)phenyl) boronic acid (205.3 mg, 0.98 mmol) and Na.sub.2CO.sub.3 (178 mg, 1.68 mmol) in dioxane (8.0 mL) and water (2.0 mL) was added Pd(PPh.sub.3).sub.4 (79.2 mg). The resultant mixture was vacuumed and purged with N.sub.2 for three cycles, then stirred and heated at 80° C. over two hours. After cooling to room temperature, the reaction mixture was dissolved in DCM (50 mL) and washed with water and brine. The resultant organic layer was separated and dried over anhydrous Na.sub.2SO.sub.4. A silica gel flash column chromatography eluting with DCM/Hexane afforded the desired colorless product (MS: [M+1].sup.+396).

[0992] Step 2: 2-Hydroxy-5-(4,7,8-trichloroquinolin-2-yl)benzoic acid (I-75). Methyl 2-methoxy-5-(4,7,8-trichloroquinolin-2-yl) benzoate (17 mg) in DCM (1.5 mL) was treated with 1M BBr.sub.3 in DCM (0.1 mL) at room temperature over 8 hours. The resulting mixture was diluted with EtOAc (25 mL), washed with water (10 mL) and dried over Na.sub.2SO.sub.4. Concentration under vacuum afforded the desired light brown solid (11 mg), 2-hydroxy-5-(4,7,8-trichloroquinolin-2-yl) benzoic acid (MS: [M+1].sup.+368).

[0993] Step 3: 5-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-hydroxybenzoic acid. To a solution of 2-hydroxy-5-(4,7,8-trichloroquinolin-2-yl) benzoic acid (11 mg) in DMF (0.5 mL) was added imidazole (55 mg) and K.sub.2CO.sub.3 (50 mg). The resultant solution was stirred and heated at 120° C. over 5 hours until the starting material was completely consumed. The reaction mixture was diluted with water (3 mL) and treated with Dowex resin until the pH to 3. The resultant colorless solid was isolated by filtration and washed with water (3 mL). After drying under vacuum, the desired product was obtained (MS: [M+1].sup.+400).

Example 19: Synthesis of 3-(4-(1H-imidazol-1-yl)-7-(trifluoromethyl)quinolin-2-yl)benzoic acid (I-49)

[0994] ##STR03042##

[0995] Step 1: Methyl 3-(4-chloro-7-(trifluoromethyl)quinolin-2-yl)benzoate. To a mixture of 2,4-dichloro-7-(trifluoromethyl)quinoline (217 mg, 0.82 mmol) with (3-(methoxycarbonyl)phenyl)boronic acid (190.9 mg, 1.06 mmol) in dioxane (7 mL) and water (3 mL) were added Na.sub.2CO.sub.3 (191 mg, 1.804 mmol) and Pd(PPh.sub.3).sub.4 (95 mg, 0.082 mmol). The resultant mixture was placed under vacuum and purged with nitrogen repeatedly three times, then was stirred and heated at 90° C. over 3 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (20 mL). After isolation of the organic layer and a column chromatography eluting with a gradient of DCM/Hexane from 0 to 60%), the desired product (254 mg) methyl 3-(4-chloro-7-(trifluoromethyl)quinolin-2-yl)benzoate (MS: [M+1].sup.+366).

[0996] Step 2: 3-(4-(1H-Imidazol-1-yl)-7-(trifluoromethyl)quinolin-2-yl)benzoic acid. A mixture of methyl 3-(4-chloro-7-(trifluoromethyl)quinolin-2-yl)benzoate (42 mg, 0.12 mmol), imidazole (40 mg) and Cs.sub.2CO.sub.3 was added DMF (0.6 mL). The suspended solution was stirred and heated at 100° C. over 6 hours. The reaction mixture was diluted with water (2 mL) and acidified with HOAc to pH 3 to precipitate the product. The product was isolated by centrifuge and rinsed with water and 50% acetonitrile/water. The wet solid was dried in vacuo to afford the title compound (30 mg) ([M+1].sup.+: 384).

Example 20: Synthesis of 3-(7-Bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl)benzoic acid (I-48)

[0997] ##STR03043##

[0998] Following step 1 in the preparation of I-49, tert-butyl 3-(7-bromo-4-chloro-8-methoxyquinolin-2-yl) benzoate was prepared from Intermediate 17.

[0999] Step 1: tert-Butyl 3-(7-bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl)benzoate. To a mixture of tert-butyl 3-(7-bromo-4-chloro-8-methoxyquinolin-2-yl) benzoate (125 mg) and Cs.sub.2CO.sub.3 (136.8 mg) in DMF (2 mL) was added imidazole (96 mg). The suspended solution was stirred and heated at 130° C. over 2 h. Aqueous work-up with EtOAc and a column chromatography eluting with EtOAc/Hexane afforded the desired product tert-butyl 3-(7-bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl) benzoate (120 mg) (MS: [M+1].sup.+480).

[1000] Step 2: 3-(7-Bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl)benzoic acid. To a solution of tert-butyl 3-(7-bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl)benzoate (65 mg) in DCM (0.2 mL) and MeOH (0.2 mL) was added TFA (0.4 mL). The resultant solution was stirred over 5 h and concentrated to dryness. The resultant oily residue was suspended in water (0.5 mL) and lyophilized to afford the title compound 3-(7-bromo-4-(1H-imidazol-1-yl)-8-methoxyquinolin-2-yl) benzoic acid (60 mg) as light brown powder (MS: [M+1].sup.+424).

Example 21: Synthesis of 7-bromo-4-(1H-imidazol-1-yl)-8-methoxy-2-phenylquinoline (I-54)

[1001] ##STR03044##

[1002] 7-Bromo-4-chloro-8-methoxy-2-phenylquinoline was prepared following step 1 in the preparation procedure of methyl 3-(4-chloro-7-(trifluoromethyl)quinolin-2-yl)benzoate.

[1003] To a solution of 7-bromo-4-chloro-8-methoxy-2-phenylquinoline (63 mg) in DMF (2.0 mL) were added imidazole (129 mg) and Cs.sub.2CO.sub.3 (62 mg). The resultant mixture was heated at 80° C. overnight. The reaction mixture was diluted with water (4 mL) to precipitate the desired product. Isolation of the product and rinsing with water (2 mL) afforded the title compound (55 mg) 7-bromo-4-(1H-imidazol-1-yl)-8-methoxy-2-phenylquinoline (MS:[M+1].sup.+380).

Example 22: Synthesis of 7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-ol (I-53)

[1004] ##STR03045##

[1005] To a solution of 7-bromo-4-chloro-8-methoxy-2-phenylquinoline (20 mg) in DMF (0.5 mL) were added imidazole (50 mg) and Cs.sub.2CO.sub.3 (50 mg). The resultant mixture was stirred at 120° C. overnight. The reaction mixture was diluted with water (3 mL) to precipitate the desired product. Isolation of the product and rinsing with water (1 mL) afforded the title compound (MS: [M+1].sup.+366).

Example 23: Synthesis of 2-((7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-yl)oxy)acetic acid (I-379)

[1006] ##STR03046##

[1007] Step 1: tert-Butyl 2-((7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-yl)oxy)acetate. To a solution of 7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-ol (10 mg) in DMSO (2 mL) were added tert-butyl 2-bromoacetate (40 mg) and K.sub.2CO.sub.3 (40 mg). The resultant solution was stirred at room temperature for 3 hrs and diluted with water/EtOAc (20 mL). The organic layer was separated, washed with brine, and dried over Na.sub.2SO.sub.4, then a column chromatography eluting with hexane/EtOAc afforded the desired product (9 mg). MS:[M+1].sup.+480.

[1008] Step 2: 2-((7-Bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-yl)oxy)acetic acid. To a solution of tert-butyl 2-((7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinolin-8-yl)oxy)acetate (9 mg) in DCM (0.8 mL) was added TFA (0.2 mL). The resultant solution was stirred overnight and concentrated to dryness. Lyophilization afforded the desired product (6.6 mg) (MS: [M+1].sup.+424).

Example 24: Synthesis of 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-ypaniline (I-8)

[1009] ##STR03047##

[1010] 2,7-Dichloro-4-(1H-imidazol-1-yl)quinoline (26 mg, 0.10 mmol) was placed in a vial with dioxane 2.3 mL) and water (0.5 mL) under N.sub.2. (3-Aminophenyl)boronic acid (21 mg, 0.15 mmol) and potassium carbonate (70 mg, 0.50 mmol) were added followed by tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The mixture was stirred at 100° C. for 16 h. Water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. Purification by silica chromatography afforded 3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)aniline (MS: [M+1].sup.+321.1).

[1011] The following compounds are prepared essentially by the same method described above to prepare I-8.

TABLE-US-00011 MS I-# Starting Material Structure [M + 1].sup.+ I-34 [03048] [03049] [03050] 365.0 I-58 [03051] [03052] [03053] 323.1 I-59 [03054] [03055] [03056] 323.0

Example 25: Synthesis of N-(3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)phenyl)methanesulfonamide (I-10)

[1012] ##STR03057##

[1013] 3-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)aniline (12 mg, 0.04 mmol) was placed in a vial with dichloromethane (2 mL) and TEA (0.1 mL) and cooled to 0° C. Methanesulfonyl chloride (6 mg, 0.06 mmol) was added and the solution was stirred at rt for 16 h. Water (3 mL) was added and the aqueous extracted with ethyl acetate (2×5 mL). The combined organics were dried and concentrated and the residue purified by silica chromatography to afford N-(3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)phenyl)methanesulfonamide (MS: [M+1].sup.+399.0).

Example 26: Synthesis of 1-(3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)phenyl)urea (I-11)

[1014] ##STR03058##

[1015] 3-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)aniline (10 mg, 0.03 mmol) was placed in a vial with acetic acid (0.2 mL). Potassium cyanate (25 mg, 0.31 mmol) in water was then added dropwise to the vial and the solution was stirred at rt for 1.5 h. Water (3 mL) was added and the aqueous extracted with 10% methanol/dichloromethane (2×5 mL). The combined organics were dried and concentrated and the residue was purified by silica chromatography to afford 1-(3-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)phenyl)urea (MS: [M+1].sup.+364.1).

Example 27: Synthesis of 7-bromo-4-(1H-imidazol-1-yl)-2-(thiophen-2-yl)quinoline (I-380)

[1016] ##STR03059##

[1017] Step 1: N-(2-Acetyl-5-bromophenyl)thiophene-2-carboxamide. 1-(2-Amino-4-bromophenypethan-1-one (214 mg, 1.00 mmol) was placed in a flask with dichloromethane (5 mL) and triethylamine (0.15 mL, 1.10 mmol) then cooled to 0° C. Thiophene-2-carbonyl chloride (147 mg, 1.10 mmol) was added dropwise. The reaction was warmed to r.t. and stirred for 16 h. The volatiles were removed and the resulting solids were triturated with dichloromethane, filtered and vacuum dried to afford N-(2-acetyl-5-bromophenyl)thiophene-2-carboxamide as a solid (MS: [M+1].sup.+323.9).

[1018] Step 2: 7-Bromo-2-(thiophen-2-yl)quinolin-4-ol. N-(2-acetyl-5-bromophenyl)thiophene-2-carboxamide (250 mg, 0.77 mmol) was placed in a flask with dioxane (10 mL). Sodium hydroxide (108 mg, 2.7 mmol) was added and the mixture heated to 110° C. for 2 h. Ethanol (2 mL) was added and the resulting solids filtered off. The filtrate was concentrated to dryness. Water (4 mL) and hexanes (1 mL) were added and the mixture was stirred for 5 minutes. The solution was acidified with HCl (1.0 N aq.) and the resulting solids filtered and vacuum dried to afford 7-bromo-2-(thiophen-2-yl)quinolin-4-ol as a solid (MS: [M+1].sup.+306.0).

[1019] Step 3: 7-Bromo-4-chloro-2-(thiophen-2-yl)quinoline. 7-Bromo-2-(thiophen-2-yl)quinolin-4-ol (180 mg, 0.59 mmol) was placed in a flask with phosphorus oxychloride (3 mL). The reaction was heated to 110° C. for 3 h. After cooling to r.t., ice was added. The aqueous portion was extracted with ethyl acetate (2×5 mL) and the combined organics dried (Na.sub.2SO.sub.4) then concentrated to afford 7-bromo-4-chloro-2-(thiophen-2-yl)quinoline (MS: [M+1].sup.+323.9).

[1020] Step 4: 7-bromo-4-(1H-imidazol-1-yl)-2-(thiophen-2-yl)quinoline. 7-Bromo-4-chloro-2-(thiophen-2-yl)quinoline (65 mg, 0.2 mmol) was placed in a flask with imidazole (34 mg, 0.50 mmol), potassium t-butoxide (34 mg, 0.30 mmol), Bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) and DMA (3 mL) under N.sub.2. The mixture was heated at 110° C. for 2 h. After cooling down to room temperature, the crude was diluted by EtOAc (20 mL) and washed by water (5 mL×2) and brine (5 mL×2). The organic phase was concentrated and purified by column chromatography on silica gel to give 7-bromo-4-(1H-imidazol-1-yl)-2-(thiophen-2-yl)quinoline as a solid (MS: [M+1].sup.+356.0).

[1021] The following compounds are prepared essentially by the same method described above to prepare I-380.

TABLE-US-00012 MS I-# Starting Material Structure [M + 1].sup.+ I-381 [03060] [03061] [03062] 380.0 I-382 [03063] [03064] [03065] 380.0 I-1 [03066] [03067] [03068] 306.1 I-275 [03069] [03070] [03071] 382.1 I-383 [03072] [03073] [03074] 351.0 I-384 [03075] [03076] [03077] 351.0 I-385 [03078] [03079] [03080] 364.0 I-50 [03081] [03082] [03083] 340.0

Example 28: Synthesis of (S)-(2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetyl)glycine (I-156)

[1022] ##STR03084##

[1023] Step 1: tert-Butyl (S)-(2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetyl)glycinate To a mixture of (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetic acid (9.4 mg), tert-butyl glycinate (8.05 mg), EDC HCl (9.2 mg), HOBt (6.5 mg) and DMAP (8.7 mg) was added DMF (0.2 mL) and TEA (0.05 mL). The resulting mixture was stirred overnight at room temperature and diluted with EtOAc (20 mL). The organic solution was washed with water, brine and dried over anhy. Na.sub.2SO.sub.4. A column chromatography eluting with a gradient of hexanes and EtOAc afforded the desired product (9.0 mg) as yellow solids (MS: [M+1].sup.+544.2).

[1024] Step 2: (S)-(2-(1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetyl)glycine. To a solution of tert-butyl (S)-(2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetyl)glycinate (9.0 mg) in DCM (0.4 mL) was added TFA (0.1 mL). After stirring over 4 hours, the reaction mixture was concentrated to dryness under reduced pressure and diluted with water for lyophilization. A total of 9.2 mg of the title compound, (S)-(2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)acetyl)glycine, was afforded (MS [M+1].sup.+448).

[1025] The following compounds are prepared essentially by the same method described above to prepare I-156.

TABLE-US-00013 MS I-# Starting Materials Structure [M + 1].sup.+ I-325 [03085] [03086] [03087] 488 I-326 [03088] [03089] [03090] 448 I-454 [03091] [03092] [03093] 474 I-386 [03094] [03095] [03096] 488 I-339 [03097] [03098] [03099] 488 I-340 [03100] [03101] [03102] 476 I-338 [03103] [03104] [03105] 490 I-387 [03106] [03107] [03108] 476 I-388 [03109] [03110] [03111]   524.1 I-196 [03112] [03113] [03114] 422 I-389 [03115] [03116] [03117] 462 I-321 [03118] [03119] [03120] 422 I-320 [03121] [03122] [03123] 436 I-323 [03124] [03125] [03126] 434 I-324 [03127] [03128] [03129] 448 I-341 [03130] [03131] [03132] 450 I-342 [03133] [03134] [03135] 464 I-343 [03136] [03137] [03138] 450 I-344 [03139] [03140] [03141] 464 I-522 [03142] [03143] [03144] 544 I-524 [03145] [03146] [03147] 488 I-525 [03148] [03149] [03150] 476 I-526 [03151] [03152] [03153] 490 I-527 [03154] [03155] [03156] 476 I-528 [03157] [03158] [03159] 524 I-529 [03160] [03161] [03162] 502 I-530 [03163] [03164] [03165] 502 I-531 [03166] [03167] [03168] 462 I-532 [03169] [03170] [03171] 502 I-533 [03172] [03173] [03174] 502 I-534 [03175] [03176] [03177] 537 I-535 [03178] [03179] [03180] 516 I-536 [03181] [03182] [03183] 512 I-537 [03184] [03185] [03186] 523 I-538 [03187] [03188] [03189] 504 I-539 [03190] [03191] [03192] 477 I-540 [03193] [03194] [03195] 504 I-541 [03196] [03197] [03198] 473 I-542 [03199] [03200] [03201] 420 I-543 [03202] [03203] [03204] 584 I-544 [03205] [03206] [03207] 487 I-452 [03208] [03209] [03210] 420 I-545 [03211] [03212] [03213] 490 I-546 [03214] [03215] [03216] 488 I-547 [03217] [03218] [03219] 488 I-548 [03220] [03221] [03222] 488 I-549 [03223] [03224] [03225] 490 I-550 [03226] [03227] [03228] 476 I-551 [03229] [03230] [03231] 486 I-552 [03232] [03233] [03234] 474 I-553 [03235] [03236] [03237] 488 I-554 [03238] [03239] [03240] 448 I-555 [03241] [03242] [03243] 464 I-608 [03244] [03245] [03246] 433 I-562 [03247] [03248] [03249] 422 I-563 [03250] [03251] [03252] 436 I-564 [03253] [03254] [03255] 450 I-565 [03256] [03257] [03258] 436 I-566 [03259] [03260] [03261] 497 I-567 [03262] [03263] [03264] 471 I-568 [03265] [03266] [03267] 421

[1026] The following compounds were prepared essentially by the same method as step 1 described above for I-156.

TABLE-US-00014 MS I-# Starting Material Structure [M + 1].sup.+ I-556 [03268] [03269] [03270] 475 I-557 [03271] NH.sub.4Cl [03272] 392 I-558 [03273] NH.sub.2OH [03274] 408 I-603 [03275] NH.sub.3 [03276] 390

[1027] The following compounds were prepared essentially by the same method as step 2 described above for I-156.

TABLE-US-00015 MS I-# Starting Material Structure [M + 1].sup.+ I-559 [03277] LiOH [03278] 407 I-560 [03279] LiOH [03280] 407 I-561 [03281] LiOH [03282] 451

Example 29: Synthesis of N-benzyl-3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propenamide (I-193)

[1028] ##STR03283##

[1029] Step 1: tert-Butyl 3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propanoate. To a solution of 2,7,8-trichloro-4-(1H-pyrazol-4-yl)quinoline (125 mg, 0.42 mmol) in DMSO (0.5 mL) was added tert-butyl 3-(methylamino)propanoate (133 mg, 0.84 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.26 mmol). The solution is stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics are dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 20-80% EtOAc/hexanes to afford tert-butyl 3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propanoate (120 mg) (MS: [M+1].sup.+421).

[1030] Step 2: 3-((7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propanoic acid. To a solution of tert-butyl 3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propanoate (100 mg, 0.24 mmol) in dichloromethane (3 mL) was added hydrochloric acid (0.5 mL, 4.0 M in dioxane). The reaction is stirred at rt for 16 h. The volatiles are removed by rotary evaporation and the resulting solids were used without further purification (MS: [M+1].sup.+365).

[1031] Step 3: N-Benzyl-3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propenamide. To a solution of 3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)(methyl)amino)propanoic acid (20 mg, 0.055 mmol) in dimethylformamide (0.3 mL) was added HATU (31 mg, 0.082 mmol), N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) and benzylamine (9 mg, 0.082 mmol). The reaction is stirred at rt for 16 hrs. Water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 0-15% MeOH/CH.sub.2Cl.sub.2 to afford the titled compound (MS: [M+1].sup.+454).

[1032] The following compounds are prepared essentially by the same method described above to prepare I-193.

TABLE-US-00016 MS I-# Starting Material Structure [M + 1]+ I-194 [03284] [03285] [03286] 408 I-195 [03287] [03288] [03289] 421 I-197 [03290] [03291] [03292] 392 I-198 [03293] [03294] [03295] 448 I-199 [03296] [03297] [03298] 462

Example 30: Synthesis of (S)-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)carbamate (I-153)

[1033] ##STR03299##

[1034] To a solution of tert-butyl (S)-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)carbamate (174 mg) in DCM (2 mL) was added TFA (0.4 mL). After the resultant solution was stirred over 6 hours, evaporation under reduced pressure and lyophilization afforded the title compound (200 mg) as brown powder-tert-butyl (S)-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)carbamate (MS: [M+1].sup.+362).

Example 31: Synthesis of (S)—N-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)-2-hydroxyacetamide (I-154)

[1035] ##STR03300##

[1036] To a solution of (S)-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methanamine TFA salt (50 mg) in DCM (0.4 mL) and TEA (0.05 mL) was added 2-chloro-2-oxoethyl acetate (17 mg). After stirred over 4 hours, the reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with NaHCO.sub.3 and brine. A column chromatography with a gradient of hexane and 5% MeOH in EtOAc afforded the desired intermediate 13.4 mg (MS: [M+1].sup.+462.). The intermediate (13.4 mg) was dissolved in MeOH (0.4 mL) and water (0.1 mL) and treated with LiOH H.sub.2O (4 mg) over 2 hours. The reaction mixture was diluted with water (1 mL) and acidified with HOAc (0.02 mL) to precipitate out the product which was further lyophilized to the final product 2260 (7.8 mg) as a powder (MS: [M+1].sup.+420).

[1037] The following compounds are prepared essentially by the same method described above to prepare I-154.

TABLE-US-00017 MS I-# Starting Materials Structure [M + 1].sup.+ I-151 [03301] [03302] [03303] 440 I-390 [03304] [03305] [03306] 512 I-335 [03307] [03308] [03309] 498 I-391 [03310] [03311] [03312] 546 I-392 [03313] [03314] [03315] 586 I-393 [03316] [03317] [03318] 573 I-637 [03319] [03320] [03321] 538 I-638 [03322] [03323] [03324] 546 I-639 [03325] [03326] [03327] 484 I-640 [03328] [03329] [03330] 546 I-641 [03331] [03332] [03333] 473

Example 32: Synthesis of N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)aminosulfonamide (I-223)

[1038] ##STR03334##

[1039] Step 1: tert-Butyl 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethylcarbamate. To a vial were added 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (100 mg, 0.335 mmol), tert-butyl 2-(methylamino)ethylcarbamate (175 mg, 1.01 mmol), DMF (2.0 mL), and TEA (187 μl, 1.34 mmol). The resulting reaction mixture was stirred at 70° C. for 3 h and cooled to room temperature, followed by adding H.sub.2O (20 mL). The cloud mixture was centrifuged and the residue was extracted by DCM (2×10 mL). The organic phase was washed by H.sub.2O (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4, concentrated to afford an off-white solid (132 mg) (MS: [M+1].sup.+436).

[1040] Step 2: N-(2-aminoethyl)-7,8-dichloro-4-(1H-imidazol-1-yl)-N-methylquinolin-2-amine. To a vial were added tert-butyl 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethylcarbamate (131 mg, 0.300 mmol), DCM (1.5 mL) and TFA (1.5 mL). The resulting mixture was stirred at room temperature for 2 hrs. Then all volatile solvents were removed under reduced pressure and the residue was dried under high vacuum to afford the title product. The crude was used in next step.

[1041] Step 3: N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)aminosulfonamide . To a vial were added N-(2-aminoethyl)-7,8-dichloro-4-(1H-imidazol-1-yl)-N-methylquinolin-2-amine (12.5 mg, 0.0373 mmol), DMF (0.5 mL), sulfamoyl chloride (26 mg, 0.224 mmol) and DIPEA (52 μl, 0.296 mmol). The resulting reaction mixture was stirred at 50° C. overnight. The reaction mixture was diluted by ethyl acetate (15 mL). The organic phase was washed by H.sub.2O (3×5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4. After concentration, 30% of the crude was purified by PTLC to afford the title product as an off-white solid (1.3 mg) (MS: [M+1].sup.+415).

[1042] The following compounds are prepared essentially by the same method described above to prepare I-223.

TABLE-US-00018 MS I-# Starting Material Structure [M + 1]+ I-224 [03335] [03336] [03337] 429 I-346 [03338] [03339] [03340] 450 I-347 [03341] [03342] [03343] 434 I-349 [03344] [03345] [03346] 532 I-350 [03347] [03348] [03349] 496 I-351 [03350] [03351] [03352] 470

[1043] The following compounds were prepared essentially by the same method to prepare I-223. Some analogues were prepared from a general amide formation and a following hydrolysis of an ester to form the corresponding acid.

TABLE-US-00019 MS I-# Starting Material Structure [M + 1]+ I-609 [03353] [03354] [03355] 534 I-610 [03356] [03357] [03358] 458 I-611 [03359] [03360] [03361] 534 I-612 [03362] [03363] [03364] 520 I-613 [03365] [03366] [03367] 394 I-614 [03368] [03369] [03370] 408 I-615 [03371] [03372] [03373] 476 I-616 [03374] [03375] [03376] 436 I-617 [03377] [03378] [03379] 472 I-618 [03380] [03381] [03382] 458 I-619 [03383] [03384] [03385] 456 I-620 [03386] [03387] [03388] 484 I-621 [03389] [03390] [03391] 502 I-622 [03392] [03393] [03394] 476 I-623 [03395] [03396] [03397] 520

Example 33: Synthesis of (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-ol (I-119)

[1044] ##STR03398##

[1045] Step 1: 1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-ol was the same as that for compound I-353 (MS: [M+1].sup.+263).

[1046] Step 2: (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl sulfamate. To a vial were added 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-ol (20 mg, 0.0551 mmol), DMF (0.3 mL) and TEA (50 μl, 0.364 mmol). A stock solution of sulfamoyl chloride in DMF (38 mg/100 μl, 0.33 mmol) was added. The resulting reaction mixture was stirred at 100° C. for 6 hrs and cooled to room temperature followed by adding 4 mL of water. The mixture was centrifuged and the residue was purified by PTLC (30% MeOH/DCM) to afford the desired product as white solid (1 mg) (MS: [M+1].sup.+442).

[1047] The following compounds are prepared essentially by the same methods as for I-223.

TABLE-US-00020 MS I-# Starting Material Structure [M + 1]+ I-118 [03399] [03400] [03401] 456 I-96 [03402] [03403] [03404] 458

Example 34: Synthesis of N-(2-47-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)cyclopropanesulfonamide (I-226)

[1048] ##STR03405##

[1049] Step 1: tert-Butyl (2-((7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)carbamate. To a solution of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (528 mg, 2.0 mmol) in DMF (2 mL) was added tert-butyl (2-(methylamino)ethyl)carbamate (871 mg, mmol) and Hunig's base (0.5 mL). The solution was stirred at 95° C. for 16 h. After cooling down to room temperature, water (10 mL) was added and the organics were extracted into 10% Methanol/dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica column chromatography using 50-100% EtOAc/Hex to afford tert-butyl (2-((7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)carbamate as a solid (MS: [M+1].sup.+-Boc 302).

[1050] Step 2: N1-(7-Chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N1-methylethane-1,2-diamine. To a vial was added tert-butyl (2-((7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)carbamate (120 mg, 0.30 mmol). Hydrochloric acid (4.0M in dioxane (1.0 mL) was added and the reaction allowed to stir at rt for 16 h. The resulting solids were filtered off and dried to afford N1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N1-methylethane-1,2-diamine hydrochloride as a solid (MS: [M+1].sup.+302).

[1051] Step 3: N-(2-((7-Chloro-4-(1H-imidazol-1-yl) quinolin-2-yl) (methyl) amino)ethyl) cyclopropanesulfonamide. To a vial was added N1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N1-methylethane-1,2-diamine hydrochloride (20 mg, 0.06 mmol) in DMF (0.5 mL) and Hunig's base (0.1 mL). Cyclopropanesulfonyl chloride (17 mg, 0.12 mmol) was added and the reaction allowed to stir at rt for 16h. Water (5 mL) was added and the aqueous extracted with ethyl acetate (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) then purified by silica chromatography using 0-10% MeOH/CH.sub.2Cl.sub.2 to afford 12 mg N-(2-((7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)cyclopropanesulfonamide (MS: [M+1].sup.+406).

[1052] The following compounds are prepared essentially by the same method described above to prepare I-226.

TABLE-US-00021 MS I-# Starting Material Structure [M + 1].sup.+ I-227 [03406] [03407] [03408] 442 I-228 [03409] [03410] [03411] 510 I-394 [03412] [03413] [03414] 510 I-232 [03415] [03416] [03417] 446 I-229 [03418] [03419] [03420] 476 I-230 [03421] [03422] [03423] 432 I-231 [03424] [03425] [03426] 443 I-236 [03427] [03428] [03429] 344 I-237 [03430] [03431] [03432] 406 I-234 [03433] [03434] [03435] 380 I-235 [03436] [03437] [03438] 414 I-225 [03439] [03440] [03441] 414

Example 35: Synthesis of (1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-amine) (I-108)

[1053] ##STR03442##

[1054] To a vial was added tert-butyl (1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)carbamate (90 mg, 0.21 mmol) with dichloromethane (5 mL). Trifluoromethanesulfonic acid (0.5 mL) was added and the reaction was stirred at rt for 16 h. The volatiles were removed by rotary evaporation and the crude product (1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-amine) (di-TFA salt) was used directly in the next step (MS: [M+1].sup.+328).

Example 36: Synthesis of N-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methanesulfonamide (I-105)

[1055] ##STR03443##

[1056] To a solution of 1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-amine (di TFA salt) (55 mg, 0.10 mmol) in dichloromethane (3 mL) and DMF (0.3 mL) was added triethylamine (0.3 mL) followed by methanesulfonyl chloride (23 mg, 0.20 mmol). The mixture is stirred at rt for 3 h. Water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. Purification by silica chromatography afforded N-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methanesulfonamide (33 mg) (MS: [M+1].sup.+406).

[1057] The following compounds are prepared essentially by the same method described above to prepare I-105.

TABLE-US-00022 MS I-# Starting Material Structure [M + 1]+ I-395 [03444] [03445] [03446] 428 I-100 [03447] [03448] [03449] 432 I-103 [03450] [03451] [03452] 472 I-107 [03453] [03454] [03455] 468 I-102 [03456] [03457] [03458] 469 I-109 [03459] [03460] [03461] 472 I-101 [03462] [03463] [03464] 458

Example 37: Synthesis of 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl hydrogen phosphonate (I-111)

[1058] ##STR03465##

[1059] Step 1: 1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-ol was prepared according to the procedure described above to prepare compound I-353.

[1060] Step 2: 2-Cyanoethyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl phosphonate. To a vial were added 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-ol (20 mg, 0.0551 mmol), DCM (1.0 mL), pyridinium trifluoroacetate (10.6 mg, 0.0551 mmol). Then 3-(bis(diisopropylamino)phosphinooxy) propanenitrile (26 0.0826 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS. H.sub.2O (0.1 mL) was added and the reaction mixture was stirred for 1 hr. All volatiles were removed under reduced pressure. The crude was used in next step.

[1061] Step 3: 1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl hydrogen phosphonate. To a vial containing crude product 2-cyanoethyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)345uinoline-2-yl)piperidin-3-yl phosphonate in step 2 were added MeOH (0.5 mL), THF (1.0 mL) and a solution of LiOH H.sub.2O in H.sub.2O (4.63 mg/0.5 mL, 0.110 mmol). The resulting reaction mixture was stirred overnight, acidified to pH 5, and concentrated. The crude was purified by HPLC to afford the title product as a white solid (8 mg) (MS: [M+1].sup.+427).

[1062] The following compounds are prepared essentially by the same method described above to prepare I-111.

TABLE-US-00023 MS I-# Starting Material Structure [M + 1]+ I-110 [03466] [03467] [03468] 441 I-255 [03469] [03470] [03471] 401 I-396 [03472] [03473] [03474] 494 I-329 [03475] [03476] [03477] 441 I-257 [03478] [03479] [03480] 468 I-256 [03481] [03482] [03483] 415 I-330 [03484] [03485] [03486] 455 I-258 [03487] [03488] [03489] 415

Example 38: Synthesis of 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl dihydrogen phosphate (I-112)

[1063] ##STR03490##

[1064] To a vial were added product I-111 (6.2 mg, 0.0145 mmol) and pyridine (0.3 mL). Trimethylsilyl 2,2,2-trifluoro-N-(trimethylsilyl)acetimidate (0.019 mL, 0.0726 mmol) was then added. The resulting reaction mixture was stirred for 5 min. A solution of I.sub.2 in pyridine (4.4 mg/0.1 mL) was then added dropwise and the reaction mixture was stirred for 5 min. The volatiles were removed under reduced pressure. The crude was purified by prep HPLC to afford the title product as a white solid (2.6 mg) (MS: [M+1].sup.+443).

Example 39: Synthesis of (1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methyl dihydrogen phosphate (I-113)

[1065] ##STR03491##

[1066] (1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methyl dihydrogen phosphate was prepared according to the procedure described above to prepare compound I-112 (MS: [M+1].sup.+457).

Example 40: Synthesis of Ethyl hydrogen (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)methylphosphonate (I-253) and (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)methylphosphonic acid (I-254)

[1067] ##STR03492##

[1068] Step 1: Ethyl hydrogen (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)methylphosphonate. To a vial were added 2,7,8-trichloro-4-(1H-pyrazol-4-yl)quinoline (30 mg, 0.10 mmol), DMSO (0.3 mL), diethyl aminomethylphosphonate (50 mg, 0.3 mmol), and DIPEA (52 μl, 0.3 mmol). The resulting reaction mixture was stirred at 130° C. for 20 hrs. The crude was purified by prep HPLC to afford product 2157 as a white solid (5.2 mg) (MS: [M+1].sup.+401).

[1069] Step 2: (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)methylphosphonic acid. To a vial were added ethyl hydrogen (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)methylphosphonate (3.7 mg, 0.0092 mmol) and hydrochloric acid (37%, 0.5 mL). The resulting reaction mixture was stirred at 70° C. overnight. All starting material was converted to desired product. After concentration, the title product was obtained as a white solid (3.5 mg) (MS: [M+1].sup.+373).

Example 41: Synthesis of (3-((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)amino)propyl)phosphonic acid (I-397)

[1070] ##STR03493##

[1071] Step 1: Diethyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)propylphosphonate. To a vial were added 2,7,8-trichloro-4-(1H-pyrazol-4-yl)quinoline (30 mg, 0.10 mmol), DMSO (0.3 mL), diethyl 3-aminopropylphosphonate (58.6 mg, 0.30 mmol) and DIPEA (52 μl, 0.30 mmol). The resulting reaction mixture was stirred at 110° C. for 5 hrs followed by addition of H.sub.2O (4 mL). The precipitated white solid was collected by a centrifuge, and the crude was purified by silica gel chromatography (eluted by 5% MeOH/DCM) to afford the desired product as a white solid (9 mg) (MS: [M+1].sup.+457).

[1072] Step 2: 3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)propylphosphonic acid. To a vial were added diethyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ylamino)propylphosphonate (4.5mg, 0.0098 mmol) and hydrochloric acid (37%, 0.5 mL). The resulting reaction mixture was stirred at 70° C. overnight. All starting material was converted to desired product. After concentration, the title product was obtained as a white solid (4.0 mg) (MS: [M+1].sup.+401).

Example 42: Synthesis of diethyl (1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methylphosphonate (I-114)

[1073] ##STR03494##

[1074] Step 1: (1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methanol was prepared according to the procedure described above to prepare compound I-353. (MS: [M+1].sup.+377).

[1075] Step 2: 2-(3-(Bromomethyl)piperidin-1-yl)-7,8-dichloro-4-(1H-imidazol-1-yl)quinoline. To a vial were added (1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methanol (100 mg, 0.265 mmol), CBr.sub.4 (176 mg, 0.53 mmol), and DCM (5 mL). The mixture was cooled in ice-water bath for 20 min followed by addition of a solution of Ph.sub.3P in DCM (105 mg/1 mL, 0.398 mmol). The resulting mixture was stirred at 0° C. for 1 hr. The mixture was concentrated, purified by silica gel chromatography eluting by 50% to 60% of ethyl acetate in hexanes to afford desired product as an off-white solid (85 mg) (MS: [M+1].sup.+439).

[1076] Step 3: Diethyl (1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pipe ridin-3-yl)methylphosphonate. To a vial were added 2-(3-(bromomethyl)piperidin-1-yl)-7,8-dichloro-4-(1H-imidazol-1-yl)quinoline (20 mg, 0.0455 mmol) and triethyl phosphate (0.5 mL). The resulting mixture was stirred at 150° C. for 10 hrs. The reaction mixture (30%) was purified by PTLC to afford the desired product as a white solid (2.0 mg) (MS: [M+1].sup.+497).

[1077] Step 4: (1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)methylphosphonic acid was prepared according to the procedure described above to prepare compound I-397 (step 2) (MS: [M+1].sup.+441).

Example 43: Synthesis of Ethyl hydrogen (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methylphosphonate (I-252)

[1078] ##STR03495##

[1079] Step 1: 2-(Bromomethyl)-4,7,8-trichloroquinoline. To a flask were added 4,7,8-trichloro-2-methylquinoline (493 mg, 2.0 mmol), NBS (356 mg, 2.0 mmol), AIBN (66 mg, 0.40 mmol) and CCl.sub.4 (6 mL). The reaction mixture was degassed by bubbling N.sub.2 flow for 20 min and stirred at 65° C. for 16 hrs. under N.sub.2. After being cooled to room temperature, the mixture was diluted by ethyl acetate (50 mL), washed by H.sub.2O (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4. After concentration, the crude was used in next step.

[1080] Step 2: Diethyl (4,7,8-trichloroquinolin-2-yl)methylphosphonate was prepared according to the procedure described above to prepare compound 2060 step 3 (MS: [M+1].sup.+382).

[1081] Step 3: Ethyl hydrogen (7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methylphosphonate was prepared according to the procedure described above to prepare compound I-56 (step 3) (MS: [M+1].sup.+386).

Example 44: Synthesis of 47,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methyl)phosphonic acid (I-251)

[1082] ##STR03496##

[1083] ((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methyl)phosphonic acid was prepared according to the procedure described above to prepare compound I-397 (step 2) (MS: [M+1].sup.+358).

Example 45: Synthesis of 2-(benzyloxy)-7-chloro-4-(1H-imidazol-1-yl)quinoline (I-277)

[1084] ##STR03497##

[1085] To a vial were added 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (132 mg, 0.5 mmol), DMSO (1 mL), benzyl alcohol (62 μl, 0.6 mmol) and NaOH (24 mg, 0.6 mmol). The mixture was stirred at 100° C. overnight. The 10% of the reaction mixture was purified by PTLC, eluted by 7.5% MeOH/DCM to afford the title product as white solid (4.5 mg, 27% yield) (MS: [M+1].sup.+336.1).

[1086] The following compounds are prepared essentially by the same method described above to prepare I-277.

TABLE-US-00024 MS I-# Starting Material Structure [M + 1]+ I-278 [03498] [03499] [03500] 322 I-282 [03501] [03502] [03503] 366 I-281 [03504] [03505] [03506] 380 I-284 [03507] [03508] [03509] 373 I-283 [03510] [03511] [03512] 366 I-280 [03513] [03514] [03515] 274 I-279 [03516] [03517] [03518] 359

Example 46: Synthesis of (7,8-Dichloro-2-(1H-pyrazol-3-yl)quinolin-4-yl)glycine (I-287)

[1087] ##STR03519##

[1088] Step 1: tert-Butyl (4,7,8-trichloroquinolin-2-yl)glycinate and tert-butyl (2,7,8-trichloroquinolin-4-yl)glycinate. To a solution of 2,4,7,8-tetrachloroquinoline (270 mg) and tert-butyl glycinate HCl (270 mg) in DMSO (0.8 mL) was added K.sub.2CO.sub.3 (276 mg). The resultant reaction mixture was heated at 85° C. over 4 h. Aqueous work up with EtOAc (30 mL) and a column chromatography eluting with a gradient of DCM/Hexane from 0 to 50% afforded two colorless compounds. The earlier eluted fraction is 4-substituted product (120 mg) (MS: [M+1].sup.+361) and the later fraction with 2-substituted product (62 mg) (MS: [M+1].sup.+361).

[1089] Step 2: tert-Butyl (7,8-dichloro-2-(1H-pyrazol-4-yl)quinolin-4-yl)glycinate. To a mixture of tert-butyl (2,7,8-trichloroquinolin-4-yl)glycinate (52 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg), K.sub.2CO.sub.3 (48 mg) and Pd(PPh.sub.3).sub.4 (16 mg) were added dioxane (2 mL) and water (0.5 mL). The resultant suspended solution was vacuumed and purged with nitrogen repeatedly three time, then stirred and heated at 85° C. under nitrogen over 4 hours. An aqueous work-up with EtOAc and a column chromatography gave the desired colorless product (27 mg) (MS: [M+1].sup.+393).

[1090] Step 3: (7,8-Dichloro-2-(1H-pyrazol-3-yl)quinolin-4-yl)glycine. To a solution of tert-butyl (7,8-dichloro-2-(1H-pyrazol-3-yl) quinolin-4-yl) glycinate (27 mg) in DCM (0.5 mL) was added TFA (0.2 mL). The resultant solution was stirred overnight. After removal of DCM and TFA under reduced pressure, the resultant was mixed with 0.4 mL water and lyophilized to afford the title product (MS: [M+1].sup.+337).

[1091] The following compounds are prepared essentially by the same method described above to prepare I-287 and some analogues are prepared from intermediates by additional deprotection.

TABLE-US-00025 MS I-# Starting Material Structure [M + 1].sup.+ I-285 [03520] [03521] [03522] 351 I-290 [03523] [03524] [03525] 407 I-286 [03526] [03527] [03528] 351 I-300 [03529] [03530] [03531] 337 I-288 [03532] [03533] [03534] 337 I-301 [03535] [03536] [03537] 386 I-401 [03538] [03539] [03540] 319 I-295 [03541] [03542] [03543] 354 I-296 [03544] [03545] [03546] 320 I-161 [03547] [03548] [03549] 334 I-306 [03550] [03551] [03552] 305 I-294 [03553] [03554] [03555] 305 I-171 [03556] [03557] [03558] 305 I-307 [03559] [03560] [03561] 330 I-312 [03562] [03563] [03564] 316

Example 47: Synthesis of (7,8-dichloro-4-((2-sulfamoylethyl)amino)quinolin-2-yl)glycine (I-319)

[1092] ##STR03565##

[1093] Step 1: tert-Butyl (7,8-dichloro-4-((2-sulfamoylethyl)amino)quinolin-2-yl)glycinate. To a mixture of tert-butyl (4,7,8-trichloroquinolin-2-yl) glycinate (28 mg), 2-aminoethane-1-sulfonamide (20 mg) and K.sub.2CO.sub.3 (22 mg) was added DMSO (0.4 mL). After stirring at 130° C. overnight, the reaction mixture was diluted with water and extracted with EtOAc (15 mL). A column chromatography afforded the desired product (6 mg) (MS: [M+1].sup.+449).

[1094] Step 2: (7,8-Dichloro-4-((2-sulfamoylethyl)amino)quinolin-2-yl)glycine. The acidic deprotection of tert-butyl (7,8-dichloro-4-((2-sulfamoylethyl) amino) quinolin-2-yl) glycinate (6 mg) in DCM (0.4 mL) with TFA (0.1 mL) afforded the desired product (5 mg) (MS: [M+1].sup.+393).

Example 48: Synthesis of (7,8-dichloro-2-((2-sulfamoylethyl)amino)quinolin-4-yl)glycine (I-318)

[1095] ##STR03566##

[1096] Following the similar preparation procedure of I-319, tert-butyl (4,7,8-trichloroquinolin-2-yl)glycinate (27.8 mg) was treated with 2-aminoethane-1-sulfonamide (18.5 mg) in DMSO and the following deprotection afforded the desired product (5.9 mg) (MS: [M+1].sup.+393).

Example 49: Synthesis of (7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)glycine (I-177)

[1097] ##STR03567##

[1098] (7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)glycine was prepared essentially by the same method described above to prepare I-287.

[1099] The following compounds are prepared essentially by the same method described above to prepare I-177.

TABLE-US-00026 MS I-# Starting Material Structure [M + 1].sup.+ I-402 [03568] [03569] [03570] 407 I-180 [03571] [03572] [03573] 351 I-181 [03574] [03575] [03576] 351 I-265 [03577] [03578] [03579] 386 I-403 [03580] [03581] [03582] 319

Example 50: Synthesis of 4,7,8-trichloro-2-(1H-pyrazol-4-yl)quinoline (I-404) and 2-((7,8-dichloro-2-(1H-pyrazol-4-yl)quinolin-4-yl)amino)ethan-1-ol (I-289)

[1100] ##STR03583##

[1101] Step 1: 4,7,8-Trichloro-2-(1H-pyrazol-4-yl)quinoline. To a mixture of 2,4,7,8-tetrachloroquinoline (430 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (345 mg), Na.sub.2CO.sub.3 (513 mg) and Pd(PPh.sub.3).sub.4 (186 mg) were added dioxane (6 mL) and water (3 mL). The resultant mixture was vacuumed and purged with N.sub.2 repeatedly three time, then stirred and heated at 90° C. over 2 hours. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg) in dioxane (2 mL) was added to the reaction mixture. After 1.5 h, the second portion of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg) in dioxane (2 mL) was added. After 1.5 hour, the starting material-2,4,7,8-tetrachloroquinoline was completely consumed and only one major product was observed by LC-MS. The reaction mixture was diluted with water (4 mL) to precipitate out the desired product. After isolation by a filtration, the isolated solid was washed with water (4 mL) and EtOAc/Hexane (1:1, 6 mL) to afford the desired product I-404 (350 mg) (MS: [M+1].sup.+298).

[1102] Step 2: 2-((7,8-Dichloro-2-(1H-pyrazol-4-yl)quinolin-4-yl)amino)ethan-1-ol. To a mixture of 4,7,8-trichloro-2-(1H-pyrazol-4-yl) quinoline (45 mg) and 2-aminoethan-1-ol (46 mg) were added Na.sub.2CO.sub.3 (32 mg) and DMSO (0.4 mL). The resultant suspension was stirred at 110° C. overnight until the starting material was consumed. Dilution with water (3 mL) precipitated the desired product. Isolation by centrifuge, rinsing with water and drying under vacuum afforded the title product (27.2 mg) (MS: [M+1].sup.+323).

[1103] The following compounds are prepared essentially by the same method described above to prepare I-289.

TABLE-US-00027 MS I-# Starting Materials Structure [M + 1].sup.+ I-297 [03584] [03585] [03586] 337 I-292 [03587] [03588] [03589] 377 I-291 [03590] [03591] [03592] 377 I-298 [03593] [03594] [03595] 363 I-299 [03596] [03597] [03598] 362

[1104] The following compounds are prepared essentially by the same method described above to prepare I-289 (Suzuki coupling, nucleophilic substitution, and deprotection).

TABLE-US-00028 MS Example Starting Materials Structure [M + 1]+ I-425 [03599] [03600] [03601] [03602] 351 I-426 [03603] [03604] [03605] [03606] 337

Example 51: Synthesis of 2-(benzyloxy)-7-chloro-4-(1H-imidazol-1-yl)quinoline (I-405)

[1105] ##STR03607##

[1106] To a solution of 4,7,8-trichloro-2-methylquinoline (0.5 g) in DMF (4 mL) were added K.sub.2CO.sub.3 (0.2 g) and imidizaole (0.54g). The resultant suspension was heated at 120° C. over 2 h. The reaction mixture was diluted with water (8 mL) to precipitate out the title compound. Filtration and rinsing with water afforded the title compound (0.55 g)- 7,8-dichloro-4-(1H-imidazol-1-yl)-2-methylquinoline (MS: [M+1].sup.+278).

[1107] The following compounds are prepared essentially by the same method described above to prepare I-405. Some analogues were isolated in pure form by precipitation from water and others were purified by column chromatography.

TABLE-US-00029 MS I-# Starting Materials Structure [M + 1].sup.+ I-316 [03608] [03609] [03610] 353 I-315 [03611] [03612] [03613] 310 I-313 [03614] [03615] [03616] 284 I-314 [03617] [03618] [03619] 298 I-305 [03620] [03621] [03622] 324 I-310 [03623] [03624] [03625] 324 I-302 [03626] [03627] [03628] 310 I-311 [03629] [03630] [03631] 325 I-317 [03632] [03633] [03634] 374.0 I-308 [03635] [03636] [03637] 334.0 I-303 [03638] [03639] [03640] 345.0 I-293 [03641] [03642] [03643] 285.0 I-304 [03644] [03645] [03646] 271.0 I-309 [03647] [03648] [03649] 299.0 I-66 [03650] [03651] [03652] 348 I-65 [03653] [03654] [03655] 346 I-64 [03656] [03657] [03658] 345 I-62 [03659] [03660] [03661] 331 I-61 [03662] [03663] [03664] 334 I-63 [03665] [03666] [03667] 336 I-60 [03668] [03669] [03670] 320 I-52 [03671] [03672] [03673] 406 I-39 [03674] [03675] [03676] 414

Example 52: Synthesis of 7,8-dichloro-2-methyl-4-(1H-pyrazol-4-yl)quinoline (I-406)

[1108] ##STR03677##

[1109] To a mixture of 4,7,8-trichloro-2-methylquinoline (0.2 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (281 mg), K.sub.2CO.sub.3 (278 mg) and Pd(PPh.sub.3).sub.4 (85 mg) were added dioxane (4 mL) and water (2 mL). The resultant mixture was vacuumed and purged with N.sub.2 repeatedly three time, then stirred and heated at 90° C. over 2 hours. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150 mg) in dioxane (2 mL) was degassed and added to the reaction mixture. After 2 hours, the second portion of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150 mg) in dioxane (2 mL) was added. After stirring overnight, 2,4,7,8-tetrachloroquinoline was completely consumed. Aqueous work-up and column purification eluting with hexane/EtOAc afforded the title compound (108 mg)-7,8-dichloro-2-methyl-4-(1H-pyrazol-4-yl) quinoline-MS: [M+1].sup.+278.

[1110] The following compounds are prepared essentially by the same method described above to prepare I-406 and the Suzuki coupling in I-42.

TABLE-US-00030 MS I-# Starting Materials Structure [M + 1].sup.+ I-407 [03678] [03679] [03680] 278 I-67 [03681] [03682] [03683] 306 I-68 [03684] [03685] [03686] 306 I-73 [03687] [03688] [03689] 333 I-72 [03690] [03691] [03692] 305 I-70 [03693] [03694] [03695] 317 I-69 [03696] [03697] [03698] 317 I-71 [03699] [03700] [03701] 318

pExample 53: Synthesis of 8-chloro-4-(1H-imidazol-1-yl)quinoline (I-408)

[1111] ##STR03702##

[1112] 4,8-Dichloroquinoline (50 mg, 0.25 mmol) was placed in a vial with dioxane (2 mL). Imidazole (68 mg, 1.0 mmol) was added and the reaction was heated to 130° C. for 16 h. Water (10 mL) was added to the reaction and then the organics were extracted into ethyl acetate (2×5 mL). The organic phase was dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica chromatography using 30-100% (EtOAc/Hexanes) to afford 8-chloro-4-(1H-imidazol-1-yl)quinoline as a solid (MS: [M+1].sup.+230).

[1113] The following compounds are prepared essentially by the same method described above to prepare I-408.

TABLE-US-00031 MS I-# Starting Material Structure [M + 1].sup.+ I-409 [03703] [03704] [03705] 274 I-410 [03706] [03707] [03708] 196 I-411 [03709] [03710] [03711] 210 I-412 [03712] [03713] [03714] 274 I-413 [03715] [03716] [03717] 196 I-414 [03718] [03719] [03720] 274 I-415 [03721] [03722] [03723] 274 I-416 [03724] [03725] [03726] 214 I-417 [03727] [03728] [03729] 226.1 I-418 [03730] [03731] [03732] 275.0 I-419 [03733] [03734] [03735] 2 I-420 [03736] [03737] [03738] 74.9

Example 54: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-8-methylquinoline (I-421)

[1114] ##STR03739##

[1115] 4,7-Dichloro-8-methylquinoline (53 mg, 0.25 mmol), imidazole (43 mg, 0.63 mmol), potassium t-butoxide (42 mg, 0.38 mmol), Bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.013 mmol) and DMF (3 mL) were placed in a vial under N.sub.2. The mixture was heated at 110° C. for 2 h. After cooling down to room temperature, the crude is diluted by EtOAc (20 mL) and washed by water (5 mL×2) and brine (5 mL×2). The organic phase is concentrated and purified by column chromatography on silica gel to give 7-chloro-4-(1H-imidazol-1-yl)-8-methylquinoline as a solid. (MS: [M+1].sup.+244.0)

[1116] The following compounds are prepared essentially by the same method described above to prepare I-421.

TABLE-US-00032 MS I-# Starting Material Structure [M + 1].sup.+ I-422 [03740] [03741] [03742] 298

Example 55: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-8-methylquinoline (I-82)

[1117] ##STR03743##

[1118] Step 1: 1-tert-Butyl 2-methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-1,2-dicarboxylate was prepared essentially by the same method described above to prepare I-79.

[1119] Step 2: Methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylate. To a vial were added 1-tert-butyl 2-methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-1,2-dicarboxylate (276 mg), DCM (1.0 mL) and TFA (1.0 mL). The resulting reaction mixture was stirred at room temperature for 2 hrs. All solvents were removed under reduced pressure. The residue was dried under high vacuum and the crude was used in next step (MS: [M+1].sup.+506).

[1120] Step 3: Methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-methylpiperazine-2-carboxylate. To a vial were added methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylate (0.025 mmol), DMF (0.5 mL), Cs.sub.2CO.sub.3 (16 mg, 0.05 mmol), a solution of CH.sub.3I in DMF (1.87 μl/0.5 mL, 0.03 mmol). The resulting reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), washed by water (5 mL×2) and brine (5 mL), and dried over Na.sub.2SO.sub.4. The crude was purified by silica gel chromatography to afford 4 mg of the title compound (MS: [M+1].sup.+420).

[1121] Step 4: 4-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-methylpiperazine-2-carboxylic acid. To a vial were added methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-methylpiperazine-2-carboxylate (4.4 mg, 0.0105 mmol), MeOH (0.25 mL), THF (0.5 mL), a solution of LiOH—H.sub.2O in H.sub.2O (2.2 mg/0.25 mL, 0.0523 mmol). The resulting reaction mixture was stirred at room temperature overnight, acidified to pH 4. The cloudy mixture was centrifuged and the residue was dried under high vacuum to afford 4 mg the titled product as a white solid (MS: [M+1].sup.+406).

[1122] The following compounds were prepared essentially by the same method described above to prepare I-82.

TABLE-US-00033 MS I-# Starting Material Structure [M + 1]+ I-80 [03744] [03745] [03746] 420 I-81 [03747] [03748] [03749] 436

Example 56: Synthesis of 4-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylic acid (I-79)

[1123] ##STR03750##

[1124] Step 1: 1-(tert-Butyl) 2-methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-1,2-dicarboxylate. A solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl) quinoline (120 mg), 1-(tert-butyl) 2-methyl piperazine-1,2-dicarboxylate (230 mg), and DIPEA (0.1 mL) in DMF (0.6 mL) was heated at 90 ° C. overnight until the starting material was consumed. Aqueous work-up with EtOAc (25 mL)/water (10 mL) and a column chromatography eluting with a gradient of hexanes and EtOAc afforded the title compound (85 mg) (MS: [M+1].sup.+506).

[1125] Step 2: 4-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylic acid. To a solution of 1-(tert-butyl) 2-methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-1,2-dicarboxylate (85 mg) in dioxane (2 mL) was added 2 N HCl (2 mL). The resultant mixture was heated at 80° C. over 4 hours until the Boc protecting group and the methyl ester were removed. Evaporation under reduced pressure and lyophilization afforded the title compound (80 mg) as a di-HCl salt (MS: [M+1].sup.+392).

Example 57: Synthesis of 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-(2-hydroxyacetyl)piperazine-2-carboxylic acid (I-83)

[1126] ##STR03751##

[1127] Step 1: Methyl 1-(2-acetoxyacetyl)-4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylate. Methyl 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylate TFA salt (20 mg) in DMF (0.5 mL) and TEA (0.1 mL) was treated with 2-chloro-2-oxoethyl acetate (20 mg) over 4 hours. Aqueous work up with EtOAc/water/sat NaHCO.sub.3/brine and purification by column chromatography afforded methyl 1-(2-acetoxyacetyl)-4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-2-carboxylate (12 mg) (MS: [M+1].sup.+506).

[1128] Step 2: 4-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-(2-hydroxyacetyl)piperazine-2-carboxylic acid. The intermediate was dissolved in MeOH (0.8 mL) and water (0.2 mL) and treated with LiOH—H.sub.2O (20 mg) overnight. The reaction mixture was diluted with water (2 mL) and acidified with HOAc (0.02 mL) to precipitate 4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1-(2-hydroxyacetyl)piperazine-2-carboxylic acid (7 mg) (MS: [M+1].sup.+450).

Example 58: Synthesis of 1-(7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2-yl)-3-(2-hydroxyacetamido) piperidine-3-carboxylic acid (I-125)

[1129] ##STR03752##

[1130] Step 1: 3-Amino-1-(7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2-yl)piperidine-3-carboxylic acid. A solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl) quinoline (30 mg) with 3-aminopiperidine-3-carboxylic acid (65 mg) and triethylamine (0.2 mL) in DMF (0.5 mL) was heated at 90° C. over 5 hours until the starting material was consumed. The resultant mixture was diluted with water (2 mL), frozen and lyophilized to afford a mixture containing the title compound, which was used in the next step directly (MS: [M+1].sup.+406).

[1131] Step 2: Methyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-(2-hydroxyacetamido)piperidine-3-carboxylate. The mixture from the above step was suspended in anhydrous DCM (2 mL) and mixed with 2-chloro-2-oxoethyl acetate (0.06 mL) and TEA (0.1 mL). The resultant mixture was stirred at room temperature over 3 hours until the starting was completely consumed. The reaction mixture was concentrated to dryness under reduced pressure. The resultant mixture was dissolved in anhydrous MeOH (5 mL) and treated with a couple of drops of SOCl.sub.2. After stirring overnight, the acid was converted to the methyl ester. After solvent evaporation under reduced pressure and aqueous work up with EtOAc, column chromatography afforded the desired methyl ester (12 mg). (MS: [M+1].sup.+478)

[1132] Step 3: 1-(7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2-yl)-3-(2-hydroxyacetamido) piperidine-3-carboxylic acid. Methyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-(2-hydroxyacetamido)piperidine-3-carboxylate (12 mg) was treated with LiOH—H.sub.2O (8 mg) in MeOH (2 mL) and water (0.5 mL) over 4 hours. After evaporation of the organic solvents under reduced pressure, the resultant solid mixtures were carefully suspended in water (1 mL) and neutralized with HOAc (0.020 mL). The solid was isolated by centrifuge and rinsed with water (1 mL). The resultant wet cake was lyophilized to afford the title compound (7 mg) as a colorless powder (MS: [M+1].sup.+464).

Example 59: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-2-(piperazin-1-yl)quinoline (I-76)

[1133] ##STR03753##

[1134] A solution of 2,7-dichloro-4-(1H-imidazol-1-yl)quinoline (46 mg) in EtOH (5 mL) was treated with tert-butyl piperazine-1-carboxylate (60 mg) in the presence of K.sub.2CO.sub.3 (48 mg) overnight at 80° C. Aqueous work-up with EtOAc and water removed inorganic bases. The separation of the organic layer and evaporation of organic solvents afforded the desired tert-butyl 4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate intermediate. Deprotection with DCM (3 mL) and TFA (1 mL) in 4 hours at room temperature gave the TFA salt of the desired product. The TFA salt were dissolved in DMF (1 mL) and precipitated out as neutral product (40 mg) after adding an aqueous solution of NaHCO.sub.3 to afford the title compound (30 mg) (MS: [M+1].sup.+314).

Example 60: Synthesis of 1-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazin-1-yl)-2-hydroxyethan-1-one (I-77)

[1135] ##STR03754##

[1136] A solution of 7-chloro-4-(1H-imidazol-1-yl)-2-(piperazin-1-yl)quinoline (10 mg, 1981) in DMF (1 mL) was added to a mixture of 2-chloro-2-oxoethyl acetate (56 mg) and TEA (0.1 mL). After stirring over 2 hours, aqueous work-up with EtOAc (10 mL) and evaporation under reduced pressure afforded a residue with the desired intermediate 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperazin-1-yl)-2-oxoethyl acetate (20 mg). (MS: [M+1].sup.+414). This residue was treated with LiOH (60 mg) in MeOH (4 mL) and water (1 mL) over 4 hours. Aqueous work-up with EtOAc and a column chromatography afforded the desired product (7 mg) (MS: [M+1].sup.+372).

Example 61: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-2-(4-(methylsulfonyl) piperazin-1-yl) quinoline (I-78)

[1137] ##STR03755##

[1138] To a solution of 7-chloro-4-(1H-imidazol-1-yl)-2-(piperazin-1-yl) quinoline (10 mg) in DMF (1 mL) were added methanesulfonyl chloride (30 mg) and TEA (0.1 mL). After stirring overnight, aqueous work-up with EtOAc/water and a column chromatography afforded the titled product (8 mg) (MS: [M+1].sup.+392).

Example 62: Synthesis of 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetic acid (I-90)

[1139] ##STR03756##

[1140] Step 1: tert-butyl 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetate. To a solution of 4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-1,4-diazepan-2-one (20 mg) and tert-butyl 2-bromoacetate (30 mg) in anhydrous DMF was added NaH (10 mg, 65% in mineral oil). After stirring 3 hours, the reaction mixture was diluted with EtOAc (10 mL) and carefully quenched with water (5 mL). Isolation of the organic layer and a column chromatography eluting with a gradient of hexanes and EtOAc afforded the desired intermediate tert-butyl 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetate (20 mg) (MS: [M+1].sup.+456).

[1141] Step 2: 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetic acid. tert-butyl 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetate was further treated with TFA (0.4 mL) in DCM (0.8 mL). Removal of DCM and TFA under reduced pressure and lyophilization afforded the desired product (10 mg)- 2-(4-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-oxo-1,4-diazepan-1-yl)acetic acid (MS: [M+1].sup.+400).

Example 63: Synthesis of (R)-1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N-hydroxypiperidine-3-carboxamide (I-137)

[1142] ##STR03757##

[1143] To a solution of (R)-1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidine-3-carboxylic acid (25 mg, 0.05 mmol, TEA salt) in DMF (2 mL) was added (COCl).sub.2 (0.017 mL, 0.2 mmol) at 0° C. The solution was stirred at rt for 1 h. The mixture was evaporated to give a crude as white solid.

[1144] Hydroxylamine hydrochloride (35 mg, 0.5 mmol) and TEA (0.1 mL) was dissolved in THF (0.5 mL) and water (0.1 mL) at 0° C. A solution of the crude from the first step in DCM (1 mL) was added. The mixture was stirred at rt overnight. The crude was purified directly by column chromatography on silica gel to give (R)-1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N-hydroxypiperidine-3-carboxamide as a solid. (11 mg, 59% yield) (MS: [M+1].sup.+372).

Example 64: Synthesis of (1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)boronic acid (I-120)

[1145] ##STR03758##

[1146] Step 1: 7,8-Dichloro-4-(1H-imidazol-1-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-yl)quinoline. To a solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine (38 mg, 0.15 mmol) in DMF (1 mL) was added NaHCO.sub.3 (42 mg, 0.5 mmol). The solution was vigorously stirred at 100° C. for 2 h. After cooling down to room temperature, water (2 mL) was added. The crude was collected by filtration (50 mg) which is used for next step without purification (MS: [M+1].sup.+472).

[1147] Step 2: (1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)boronic acid. To a mixture of 7,8-dichloro-4-(1H-imidazol-1-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-1-yl)quinoline (50 mg, 0.1 mmol), NaIO.sub.4 (43 mg, 0.2 mmol) and NH.sub.4OAc (15 mg, 0.2 mmol) was added water (1 mL) and acetone (1 mL). The mixture was stirred at rt overnight. After evaporation, the crude was purified directly by column chromatography on silica gel to give the titled product as a solid (35 mg) (MS: [M+1].sup.+391).

Example 65: Synthesis of tert-butyl ((2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholino)sulfonyl)carbamate (I-398) and 2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholine-4-sulfonamide (I-219)

[1148] ##STR03759##

[1149] Step 1: tert-Butyl 2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholine-4-carboxylate. To a solution of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (300 mg, 1 mmol) in DMF (2 mL) was added tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (320 mg, 1.5 mmol) and NaHCO.sub.3 (336 mg, 4 mmol). The mixture was vigorously stirred at 120° C. for 2 h. After cooling down to rt, DMF was removed by evaporation. The residue was dissolved in DCM (20 mL) and washed by H.sub.2O (10 mL) and brine (10 mL×2). The organic phase was collected and concentrated to give white solid (500 mg) which was used directly without purification (MS: [M+1].sup.+478).

[1150] Step 2: 7,8-Dichloro-4-(1H-imidazol-1-yl)-N-(morpholin-2-ylmethyl)quinolin-2-amine . A solution of tert-butyl 2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholine-4-carboxylate (500 mg crude from step 1) in 50% TFA in DCM (5 mL) was stirred at rt for 1 h. After evaporation, the crude was purified directly by column chromatography on silica gel to give the titled product as a solid. (110 mg) (MS: [M+1].sup.+378).

[1151] Step 3: tert-Butyl ((2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholino)sulfonyl)carbamate.

[1152] To a solution of chlorosulfonyl isocyanate (0.1 mL, 1.15 mmol) in DCM (1 mL) was added t-BuOH (0.085 mL, 1.15 mmol) at 0° C. for 30 min. To a solution of 7,8-dichloro-4-(1H-imidazol-1-yl)-N-(morpholin-2-ylmethyl)quinolin-2-amine (48 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol) in DCM (1 mL) was added the N-chlorosulfonyl carbamate solution above (0.1 mL, 0.115 mmol) at 0° C. After 2 h, the mixture was evaporated and purified by column chromatography on silica gel to give the titled product as a solid (25 mg) (MS: [M+1].sup.+557).

[1153] Step 4: 2-(((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholine-4-sulfonamide. A solution of tert-butyl ((2-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)morpholino)sulfonyl)carbamate (11 mg, 0.02 mmol) in 50% TFA in DCM (1 mL) was stirred at rt for 1 h. After evaporation, the crude was purified directly by column chromatography on silica gel to give the titled product as a solid (3 mg) (MS: [M+1].sup.+457.0).

[1154] The following compounds are prepared essentially by the same method described above to prepare I-398 and I-219.

TABLE-US-00034 MS I-# Starting Material Structure [M + 1]+ I-399 [03760] [03761] [03762] 478.2 I-220 [03763] [03764] [03765] 378.1 I-217 [03766] [03767] [03768] 378.1

Example 66: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-8-methylquinoline (I-221)

[1155] ##STR03769##

[1156] To a solution of 7,8-dichloro-N-(morpholin-2-ylmethyl)-4-(1H-pyrazol-4-yl)quinolin-2-amine (20 mg, 0.053 mmol) in THF (1 mL) was added triethylamine (0.074 mL, 0.53 mmol) and acetyl chloride (0.0057 mL, 0.08 mmol) at 0° C. After 1 h at rt, the reaction was quenched by MeOH (0.1 mL). After evaporation, the crude was purified directly by column chromatography on silica gel to give 1-(2-(((7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)amino)methyl)morpholino)ethan-1-one as a solid (7 mg) (MS: [M+1].sup.+420.0).

[1157] The following compounds are prepared essentially by the same method described above to prepare I-221.

TABLE-US-00035 MS I-# Starting Material Structure [M + 1]+ I-400 [03770] [03771] 478.1 I-222 [03772] [03773] 436.1

Example 67: Synthesis of 7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinoline (I-424)

[1158] ##STR03774##

[1159] Step 1: 7-Bromo-2-phenylquinolin-4-ol (250 mg, 0.83 mmol) was placed in a flask with phosphorus oxychloride (8 mL) and heated to 100° C. for 4 h. After removal of the volatiles under reduced pressure, the residue was dried in vacuo. The crude 7-bromo-4-chloro-2-phenylquinoline was taken onward without further purification.

[1160] Step 2: 7-Bromo-4-chloro-2-phenylquinoline (50 mg, 0.16 mmol), imidazole (27 mg, 0.39 mmol), potassium t-butoxide (26 mg, 0.23 mmol), Bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.008 mmol) and DMA (5 mL) were placed in a vial under N.sub.2. The mixture was heated at 110° C. for 2 h. After cooling down to room temperature, ice was added and then the aqueous was extracted with EtOAc (2×10 mL) and washed by water (5 mL×2) and brine (5 mL×2). The organic phase was concentrated and purified by column chromatography on silica gel to give 7-bromo-4-(1H-imidazol-1-yl)-2-phenylquinoline as a solid (37 mg) (MS: [M+1].sup.+350).

Example 68: Synthesis of 1-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)urea (I-104)

[1161] ##STR03775##

[1162] To a solution of 1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-amine (di TFA salt) (I-108, 23 mg, 0.041 mmol) in THF (3 mL) and triethylamine (0.03 mL, 0.212 mmol) was added (trimethylsilyl) isocyanate (8 mg, 0.071 mmol). The solution was stirred at rt for 3 h. Methanol (1 mL) was added and then the volatiles were removed by rotary evaporation. Water (3 mL) was added to the residue and the resulting solids were filtered and dried to afford 1-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)urea (12 mg) (MS: [M+1].sup.+371).

Example 69: Synthesis of 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonic acid (I-162)

[1163] ##STR03776##

[1164] Step 1: 2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate. A solution of tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (1.25 g, 5.0 mmol) in pyridine (2 mL) was cooled to −10° C. Tosyl chloride (0.95 g, 5.0 mmol) in pyridine (2 mL) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to rt and stirred for 16 h. The reaction was poured over ice, then extracted with (4:1) hexanes/Ethyl acetate (2×10 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The crude 2-((tert-butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate (MS: [M+1-Boc].sup.+306) was taken onward directly.

[1165] Step 2: S-(2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate. 2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate (1.6 g, 3.95 mmol) was placed in a flask with DMF (10 mL). Potassium thioacetate (677 mg, 5.93 mmol) in DMF (5 mL) was added to the flask then allowed to stir at rt for 16 h. Water (25 mL) was added and the organics were extracted into (4:1) hexanes/EtOAc (2×20 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated to afford S-(2-((tert-butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate (MS: [M+1-Boc].sup.+210).

[1166] Step 3: 2-Amino-3-phenylpropane-1-sulfonic acid hydrochloride. S-(2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate (309 mg, 1.0 mmol) was dissolved in formic acid (1.0 mL) and added dropwise at 0° C. to a solution of hydrogen peroxide (1 mL, 30% aq) in formic acid. The reaction was stirred at rt for 16 h. The volatiles were concentrated off to afford 2-amino-3-phenylpropane-1-sulfonic acid hydrochloride (MS: [M+1].sup.+216).

[1167] Step 4: 2-((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonic acid. 2-amino-3-phenylpropane-1-sulfonic acid hydrochloride (62 mg, 0.25 mmol) was placed in a vial with 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) and N,N-diisopropylethylamine (0.1 mL). The solution is stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by silica chromatography using 0-25% methanol/dichloromethane to afford 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonic acid (MS: [M+1].sup.+477).

[1168] The following compounds are prepared essentially by the same method described above to prepare I-162:

TABLE-US-00036 MS I-# Starting Material Structure [M + 1]+ I-163 [03777] [03778] [03779] 395

Example 70: Synthesis of 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonamide (I-208)

[1169] ##STR03780##

[1170] Step 1: 2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate. A solution of tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (1.25 g, 5.0 mmol) in pyridine (2 mL) was cooled to −10° C. Tosyl chloride (0.95 g, 5.0 mmol) in pyridine (2 mL) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to rt and stirred for 16 h. The reaction was poured over ice, then extracted with (4:1) hexanes/Ethyl acetate (2×10 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated. The crude 2-((tert-butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate (MS: [M+1-Boc].sup.+306) was taken onward directly.

[1171] Step 2: S-(2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate. 2-((tert-butoxycarbonyl)amino)-3-phenylpropyl 4-methylbenzenesulfonate (1.6 g, 3.95 mmol) was placed in a flask with DMF (10 mL). Potassium thioacetate (677 mg, 5.93 mmol) in DMF (5 mL) was added to the flask then allowed to stir at rt for 16 h. Water (25 mL) was added and the organics were extracted into (4:1) hexanes/EtOAc (2×20 mL). The combined organics were dried (Na.sub.2SO.sub.4) and concentrated to afford S-(2-((tert-butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate (MS: [M+1-Boc].sup.+210).

[1172] Step 3: tert-Butyl (1-(chlorosulfonyl)-3-phenylpropan-2-yl)carbamate. S-(2-((tert-Butoxycarbonyl)amino)-3-phenylpropyl) ethanethioate (300 mg, 0.97 mmol) was placed in a vial with acetonitrile (3 mL) and water (52 μL) then cooled to 0° C. tert-butyl hypochlorite (0.33 mL, 2.9 mmol) was added and the reaction allowed to stir at 0° C. for 20 mins. The volatiles were removed by rotary evaporation and the crude tert-butyl (1-(chlorosulfonyl)-3-phenylpropan-2-yl)carbamate taken onward without further purification.

[1173] Step 4: tert-Butyl (1-phenyl-3-sulfamoylpropan-2-yl)carbamate. Tert-butyl (1-(chlorosulfonyl)-3-phenylpropan-2-yl)carbamate was placed in a vial with acetonitrile (5 mL) and cooled to 0° C. Ammonium hydroxide (2 mL) was added and the reaction was stirred at 0° C. for 10 minutes then warmed to rt and stirred for 1 h. Dichloromethane (25 mL) was added followed by water (10 mL) and the mixture stirred vigorously for 5 mins. The organics were separated, dried (Na.sub.2SO.sub.4) and concentrated to afford tert-butyl (1-phenyl-3-sulfamoylpropan-2-yl)carbamate (MS: [M+1-Boc].sup.+215).

[1174] Step 5: 2-amino-3-phenylpropane-1-sulfonamide hydrochloride. tert-butyl (1-phenyl-3-sulfamoylpropan-2-yl)carbamate (100 mg, 0.32 mmol) was placed in a vial with dichloromethane (2 mL). Hydrochloric acid (4.0M in dioxane) (0.5 mL) was added and the reaction allowed to stir at rt for 1 h. Acetonitrile was added and the resulting solids were filtered off and vacuum dried to afford 2-amino-3-phenylpropane-1-sulfonamide hydrochloride (MS: [M+1].sup.+215).

[1175] Step 6: 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonamide. 2-amino-3-phenylpropane-1-sulfonamide hydrochloride (55 mg, 0.23 mmol) was placed in a vial with 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) and N,N-diisopropylethylamine (0.1 mL). The solution is stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics are dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by Combiflash using 0-10% Methanol/Dichloromethane to afford 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)-3-phenylpropane-1-sulfonamide (MS: [M+1].sup.+476)

[1176] The following compounds are prepared essentially by the same method described above to prepare I-208:

TABLE-US-00037 MS I-# Starting Material Structure [M + 1]+ I-209 [03781] [03782] [03783] 428.0

Example 71: Synthesis of 2-(benzyl(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethane-1-sulfonic acid (I-164)

[1177] ##STR03784##

[1178] Step 1: Isopropyl ethenesulfonate. 2-Chloroethane-1-sulfonyl chloride (0.65 mL, 6.1 mmol) was placed in a flask with dichloromethane (3.0 mL) and isopropanol (0.47 mL, 6.1 mmol) and cooled to −10° C. A solution of pyridine (0.98 mL, 6.1 mmol) in dichloromethane (1.4 mL) was added dropwise and the reaction was allowed to stir at −10° C. for 2 h and warmed to rt over 30 mins. The mixture was quenched by the addition of 1M HCl (20 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined extracts were dried (Na.sub.2SO.sub.4) and concentrated to afford isopropyl ethenesulfonate as an oil and was taken onward without further purification.

[1179] Step 2: 2-(Benzylamino)ethane-1-sulfonic acid hydrochloride. A solution of isopropyl ethenesulfonate (440 mg, 0.2 mmol) in methanol (1.5 mL) was added to a solution of benzyl amine (0.31 g, 2.9 mmol) in methanol (1.0 mL) at 0° C. The reaction was stirred at 0° C. for 1.5 hthen warmed to rt. The solution was acidified by the addition of HCl (1.0M in MeOH) then heated at 90° C. for 16 h. The resulting precipitate was filtered off and dried to afford 2-(benzylamino)ethane-1-sulfonic acid hydrochloride (MS: [M+1].sup.+216).

[1180] Step 3: 2-(benzyl(7,8-dichloro-4-(1H-imidazol-1-ypquinolin-2-yl)amino)ethane-1-sulfonic acid. 2-(Benzylamino)ethane-1-sulfonic acid hydrochloride (50 mg, 0.2 mmol) was placed in a vial with 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) in DMSO (0.2 mL) and N,N-diisopropylethylamine (0.1 mL). The solution is stirred at 95° C. for 16 h. After cooling down to room temperature, water (5 mL) was added and the organics were extracted into 10% methanol in dichloromethane (2×5 mL). The combined organics are dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue was purified by Combiflash using 0-10% methanol/dichloromethane to afford 2-(benzyl(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethane-1-sulfonic acid (33 mg) (MS: [M+1].sup.+477).

[1181] The following compounds are prepared essentially by the same method described above to prepare I-164:

TABLE-US-00038 MS I-# Starting Material Structure [M + 1]+ I-165 [03785] [03786] [03787] 429

Example 72: Synthesis of N-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)-2-hydroxyacetamide (I-106)

[1182] ##STR03788##

[1183] To a solution of 2-((1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)amino)-2-oxoethyl acetate (I-395) (17 mg, 0.04 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (5 mg, 0.12 mmol). The solution was stirred at rt for 16 h. The volatiles were removed, and the residue was neutralized with 1M HCl (aq) to pH ˜7. The organics were extracted into ethyl acetate (2×5 mL). The combined organics were dried and concentrated to afford N-(1-(7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)piperidin-3-yl)-2-hydroxyacetamide (9 mg) (MS: [M+1].sup.+386).

Example 73: Synthesis of (E)-5-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methylene)thiazolidine-2,4-dione (I-276)

[1184] ##STR03789##

[1185] Step 1: 7,8-Dichloro-4-(1H-imidazol-1-yl)quinoline-2-carbaldehyde. To a solution of 7,8-dichloro-4-(1H-imidazol-1-yl)-2-methylquinoline (104 mg) in dioxane (5 mL) was added selenium dioxide (82 mg). After the reaction mixture was stirred at 85° C. over 2 hours, a filtration through a Celite pad and evaporation under reduced pressure afforded the desired 7,8-dichloro-4-(1H-imidazol-1-yl)quinoline-2-carbaldehyde (90 mg) as a brown solid.

[1186] Step 2: (E)-5-((7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methylene)thiazolidine-2,4-dione. The aldehyde (20 mg) was suspended in HOAc (1 mL) and treated with thiazolidine-2,4-dione (65 mg) and beta-analine (33 mg) at 100° C. over 4 hours. After removal of HOAc under reduced pressure, the residue was diluted with water (1 mL) and saturated NaHCO.sub.3 solution (1 mL). The solid was isolated by centrifuge and rinsed with water and 50% acetonitrile/water. Drying in vacuo afforded the desired product (24 mg), (E)-5-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)methylene)thiazolidine-2,4-dione, as a brown color solid (MS: [M+1].sup.+391).

Example 74: Synthesis of 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)acrylic acid (I-423)

[1187] ##STR03790##

[1188] Step 1: tert-Butyl 3-(4,7,8-trichloroquinolin-2-yl)acrylate. To a solution of 2,4,7,8-tetrachloroquinoline (1.3 g) in dry DMF (1 mL) were added tert-butyl acrylate (3.4 g), TEA (1.96 g) and PdCl.sub.2(PPh.sub.3).sub.4 (0.34 g). The resultant mixture was stirred at 110° C. overnight and diluted with water. The aqueous layer was extracted with EtOAc (80 mL), and the isolated organic layer was rinsed with sat NH.sub.4Cl and dried over anhydrous Na.sub.2SO.sub.4. Silica gel column chromatography (eluting with a gradient of petroleum ether and EtOAc) afforded the desired product (1.4 g) (MS: [M+1].sup.+358).

[1189] Step 2: tert-Butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ypacrylate. To a solution of tert-butyl 3-(4,7,8-trichloroquinolin-2-yl)acrylate (358 mg) in dioxane (5 mL) and water (2 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (580 mg), Na.sub.2CO.sub.3 (650 mg) and Pd(PPh.sub.3).sub.4 (115 mg). The resultant mixture was purged with N.sub.2 via 3 cycles of vacuum and purging) and stirred at 120° C. over 4 hours under N.sub.2. After dilution with water (20 mL), the aqueous layer was extracted with EtOAc (30 mL). The isolated organic layer was washed with brine and dried over anhy. Na.sub.2SO.sub.4. A column chromatography gave the desired product (130 mg) (MS: [M+1].sup.+390).

[1190] Step 3: 3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)acrylic acid. To a solution of tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)acrylate (15 mg) in DCM (0.4 mL) was added TFA (0.2 mL). The resultant solution was stirred over 1 hour and concentrated to dryness. The residue was purified by a preparative thin layer chromatography to afford the title compound (1.4 mg) (MS: [M+1].sup.+334).

Example 75: Synthesis of 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoic acid (I-270)

[1191] ##STR03791##

[1192] Step 1: tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate. To a solution of tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-ypacrylate (60 mg) in EtOH (5 mL) were added LiCl (23 mg) and NaBH.sub.4 (9 mg) at 0° C. After stirring at 0° C. over 1 hour, the reaction mixture was quenched with 0.5 N HCl (0.5 mL). The mixture was concentrated to dryness to afford the crude of tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate.

[1193] Step 2: 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoic acid. To a solution of tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoateresidue in DCM (2 mL) was added TFA (0.8 mL) and the reaction stirred at rt over 4 hours. The crude product was purified by preparative HPLC to afford the desired 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoic acid (19 mg). MS: [M+1].sup.+336. .sup.1H NMR (400 MHz, DMSO-D6): δ 8.193-8.171 (m, 3H), 7.735-7.712 (d, J=8.8 Hz, 1H), 7.626 (s, 1H), 3.216-3.252 (t, J=7.2 Hz, 2H), 2.863-2.899 (t, J=7.2 Hz, 2H) ppm.

Example 76: Synthesis of 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propan-1-ol (I-271)

[1194] ##STR03792##

[1195] Step 1: Methyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate. To a solution of tert-butyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate (235 mg) in MeOH HCl (5 mL). The resultant solution was stirred at rt overnight. After concentration under reduced pressure, the residue was purified by preparative thin layer chromatography to afford the title compound (150 mg) as a powder (MS: [M+1].sup.+322).

[1196] Step 2: 3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propan-1-ol. To a solution of methyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate (100 mg) in anhydrous THF (4 mL) was added DIABL-H (1.1 mL, 1M in THF) at −60° C. After stirring over one hour at 60° C., the reaction mixture was slowly warmed up to room temperature, quenched by adding MeOH (1 mL) and diluted with EtOAc (25 mL). The combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure and purification by preparative HPLC afforded the title compound (6 mg). MS: [M+1].sup.+322. .sup.1H NMR (400 MHz, DMSO-D6): δ 8.195-8.173 (m, 3H), 7.735-7.712 (d, J=8.8 Hz, 1H), 7.594 (s, 1H), 3.520-3.536 (m, 2H), 2.996-3.034 (t, J=7.6 Hz, 2H), 1.965-2.002 (m, 2H) ppm.

Example 77: Synthesis of 7-chloro-4-(1H-imidazol-1-yl)-8-methylquinoline (I-274)

[1197] ##STR03793##

[1198] Step 1: tert-Butyl 4-(7,8-dichloro-2-(3-methoxy-3-oxopropyl)quinolin-4-yl)-1H-pyrazole-1-carboxylate. To a solution of methyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propanoate (30 mg) in DMF (1 mL) were added DMAP (12 mg), (BOC).sub.2O (28 mg) and TEA (35 mg) under N.sub.2. After stirring over 2 hat room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL). The separated organic layer was washed with saturated NH.sub.4Cl and concentrated to dryness. The residual was purified by preparative thin layer chromatography to afford the title compound (33 mg) as a solid. (MS: [M+1].sup.+450)

[1199] Step 2: tert-Butyl 4-(7,8-dichloro-2-(3-oxopropyl)quinolin-4-yl)-1H-pyrazole-1-carboxylate. To a solution of tert-butyl 4-(7,8-dichloro-2-(3-methoxy-3-oxopropyl)quinolin-4-yl)-1H-pyrazole-1-carboxylate (190 mg) in DCM (2 mL) was added DIBAL-H (0.56 mL) at −60° C. The reaction mixture was stirred and slowly warmed to room temperature in 2 hours. The reaction was quenched with MeOH (1 mL) and water (100 mL). Extraction with EtOAc, washing with brine and purification by preparative thin layer chromatography afforded the title compound (57 mg) as a solid. (MS: [M+1].sup.+420)

[1200] Step 3 and Step 4: (E)-5-(3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propylidene)thiazolidine-2,4-dione. To a solution of tert-butyl 4-(7,8-dichloro-2-(3-oxopropyl)quinolin-4-yl)-1H-pyrazole-1-carboxylate (30 mg) in EtOH was added thiazolidine-2,4-dione (18 mg) and piperidine (8 mg). The reaction mixture was stirred at 85° C. for 1 hour. After concentration under reduced pressure, the residue was diluted EtOAc (10 mL) and washed with water (10 mL). After removal of organic solvents, the crude intermediate was treated with TFA (0.3 mL) in DCM (0.9 mL) over 2 hour. After concentrated under reduced pressure, the crude product was purified by preparative HPLC to afford the title compound (7.3 mg) as a powder. MS: [M+1].sup.+419.1. .sup.1H NMR (400 MHz, DMSO-D6): δ 8.186-8.209 (d, J=9.2 Hz, 1H), 8.168 (s, 1H), 7.733-7.756 (d, J=9.2 Hz, 1H), 7.636 (s, 1H), 7.073-7.111 (t, J=7.6 Hz, 1H), 3.3 (m, 2H), 2.768-2.822 (dd, J=14.4 and 7.2 Hz, 2H) ppm.

Example 78: Synthesis of 5-(3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)thiazolidine-2,4-dione (I-272)

[1201] ##STR03794##

[1202] Crude (E)-5-(3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propylidene)thiazolidine-2,4-dione (40 mg) in DMF (1 mL) was treated with NaBH.sub.4 (7 mg) and LiCl (5 mg) at 0° C. for 3 hours. The product was purified by preparative HPLC to afford the title product (4.5 mg). MS: [M+1].sup.+421.0. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.202-8.224 (d, J=9.2 Hz, 1H), 8.143 (s, 1H), 7.733-7.710 (d, J=9.2 Hz, 1H), 7.643-7.650 (d, J=2.8 Hz, 1H), 4.532-7.552 (d, J=8 Hz, 1H), 3.154-3.171 (m, 2H), 2.259-2.291 (m, 2H) and 2.014-2.062 (m, 2H) ppm.

Example 79: Synthesis of 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylic acid (I-273)

[1203] ##STR03795##

[1204] Step 1: Ethyl 3-(4,7,8-trichloroquinolin-2-yl)cyclohex-3-ene-1-carboxylate. Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was synthesized according to WO2020/112706. To a mixture of 2,4,7,8-tetrachloroquinoline, ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(50 mg, 0.19mmol), Na.sub.2CO.sub.3 (53 mg, 0.38 mmol), Pd(Ph.sub.3P).sub.4 (23 mg, 0.02 mmol) in dioxane/H.sub.2O (5/1, 5 mL) was purged with N.sub.2 via 3 cycles of vacuum/purging. Then the reaction mixture was stirred at 100° C. overnight. After cooling to rt, the reaction mixture was taken up with EtOAc, washed with brine, and concentrated under reduced pressure. The crude was purified by prep-TLC with pet. ether/DCM (1/1) to afford the desired product of ethyl 3-(4,7,8-trichloroquinolin-2-yl)cyclohex-3-ene-1-carboxylate (36 mg) as light brown semi-solid. MS (ES±): [M+1].sup.+, m/z 384.1, 386.1

[1205] Step 2: Ethyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylate. To a mixture of ethyl 3-(4,7,8-trichloroquinolin-2-yl)cyclohex-3-ene-1-carboxylate, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36 mg, 0.093 mmol), Na.sub.2CO.sub.3 (38.6 mg, 0.28 mmol), Pd(Ph.sub.3P).sub.4 (10.7 mg, 0.009 mmol) dioxane/H.sub.2O (2/1, 15 mL) was purged with N.sub.2 via 3 cycles of vacuum/purging. Then the reaction was stirred at 100° C. overnight. After cooling to rt, it was taken up with EtOAc, washed with brine, concentrated. The crude was purified by prep-TLC with pet. ether/DCM (1/1) to afford the desired product of ethyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylate (5.1 mg) as an off-white solid. MS: (ES±): [M+1].sup.+m/z 416.1, 418.1

[1206] Step 3: 3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylic acid. To a mixture of ethyl 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylate (10 mg, 0.024 mmol) in CH.sub.3OH/H.sub.2O/THF (1/1/1, 3 mL) was LiOH (6 mg). The reaction mixture was stirred at rt overnight. After quenched with aq. HCl, it was taken up with DCM/iPrOH, washed with brine, and concentrated. The crude was purified by prep-HPLC to afford the desired product of 3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)cyclohex-3-ene-1-carboxylic acid (3.4 mg) as an off-white solid (MS: (ES.sup.+): m/z 388.1 [M+1].sup.+). .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): δ 8.38 (s, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.70 (s, 1H), 7.56 (d, J=9.2 Hz, 1H), 5.89 (s, 1H), 2.90 (s, 1H), 2.71-2.63 (m, 2H), 2.42 (s, 2H), 2.01-1.94(s, 2H).

Example 80: Synthesis of (3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)glycine (I-336)

[1207] ##STR03796##

[1208] Step 1: tert-Butyl 4-(2-(3-((2-(tert-butoxy)-2-oxoethypamino)propyl)-7,8-dichloroquinolin-4-yl)-1H-pyrazole-1-carboxylate. To a solution of tert-butyl 4-(7,8-dichloro-2-(3-oxopropyl)quinolin-4-yl)-1H-pyrazole-1-carboxylate (100 mg) and tert-butyl glycinate (62 mg) in DCM (0.5 mL) and EtOH (2.5 mL) were added NaBH3CN(100 mg) and acetic acid (1 drop). After stirring overnight, quenching with water, extraction with DCM, and concentration under reduced pressure, the residue was purified by a preparative thin layer chromatography (eluting with 15% MeOH in DCM) to afford the title compound (58 mg). MS: [M+1].sup.+479.

[1209] Step 2: (3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)glycine. To a solution of tert-butyl 4-(2-(3-((2-(tert-butoxy)-2-oxoethypamino)propyl)-7,8-dichloroquinolin-4-yl)-1H-pyrazole-1-carboxylate (15 mg) in DCM (3 mL) was added TFA (0.5 mL). The resultant solution was stirred over 6 hours at room temperature. After evaporation under reduced pressure, the residue was purified by preparative HPLC to afford the tile compound (6.4 mg) (MS: [M+1].sup.+379.1). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.179-8.202 (d, J=9.2 Hz, 1H), 8.140 (s, 1H), 7.690-7.713 (d, J=9.2 Hz, 1H), 7.596 (s, 1H), 4.019 (S, 2H), 3.324-3.365 (m, 4H), 2.338-2.391 (m, 2H) ppm

Example 81: Synthesis of N-(3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)-N-(methylsulfonyl) glycine (I-337)

[1210] ##STR03797##

[1211] Step 1: tert-Butyl 4-(2-(3-(N-(2-(tert-butoxy)-2-oxoethyl)methylsulfonamido)propyl)-7,8-dichloroquinolin-4-yl)-1H-pyrazole-1-carboxylate. A solution of tert-butyl 4-(2-(3-42-(tert-butoxy)-2-oxoethyDamino)propyl)-7,8-dichloroquinolin-4-yl)-1H-pyrazole-1-carboxylate (15 mg) in DCM (0.5 mL) were added MsCl (6.4 mg) and TEA (14.8 mg). After stirring at room temperature over 1 hour, aqueous work up with DCM, washing with brine, condensation under reduced pressure, and purification by preparative thin layer chromatography afforded the title compound (8 mg). MS: [M+1].sup.+613.

[1212] Step 2: N-(3-(7,8-Dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)-N-(methylsulfonyl) glycine. To a solution of N-(3-(7,8-dichloro-4-(1H-pyrazol-4-yl)quinolin-2-yl)propyl)-N-(methylsulfonyl) glycine (8 mg) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred over 5 hours at room temperature. Evaporation under reduced pressure and purification by preparative HPLC afforded the title compound (3 mg) as a powder (MS: [M+1].sup.+457.1). .sup.1H NMR (400 MHz, DMSO-D6): δ 8.192-8.215 (d, J=9.2 Hz, 1H), 8.140 (s, 1H), 7.697-7.720 (d, J=9.2 Hz, 1H), 7.664 (s, 1H), 4.149 (S, 2H), 3.468-3.503 (t, J=7.2 Hz, 2H), 3.160-3.196 (t, J=7.2 Hz, 2H), 3.011 (S, 3H), 2.202-2.237 (m, 2H) ppm.

Example 82: Synthesis of (2S,4S)-4-(carboxymethoxy)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid (I-569)

[1213] ##STR03798##

[1214] Step 1: To a mixture of NaH (6 mg, 0.15 mmol), tert-butyl 2-bromoacetate (80 uL, 0.4 mmol) and TBAI (5 mg, 0.01 mmol) and THF (1 mL) was added a solution of methyl (2S,4S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)-4-hydroxypyrrolidine-2-carboxylate (41 mg, 0.1 mmol) in THF (1 mL) at 0° C. The resulting mixture was stirred 2 hat room temperature and quenched by NH.sub.4Cl (aq, sat., 1 mL). The crude was diluted by EtOAc and the organic phase was washed with water, brine and dried over anhy. Na.sub.2SO.sub.4. A column chromatography eluting with a gradient of hexanes and EtOAc afforded the desired product (25 mg) as white solids (MS: [M+1].sup.+520.1).

[1215] Step 2: methyl (2S,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)pyrrolidine-2-carboxylate (25 mg, 0.05 mmol) was placed in a vial with THF (1.2 mL), methanol (0.4 mL), and water (0.4 mL). Lithium hydroxide monohydrate (8 mg, 0.18 mmol) was added and the reaction was allowed to stir at r.t. for 16 h. The volatiles were concentrated off and the resulting residue neutralized by the addition of 1 N hydrochloric acid. The resulting solution was lyophilized to afford the titled compound (MS: [M+1].sup.+450.1).

Synthesis of (2S,4S)-4-(((carboxymethyl)carbamoyl)oxy)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)pyrrolidine-2-carboxylic acid (I-570)

[1216] ##STR03799##

[1217] Step 1: To a solution of methyl (2S,4S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)-4-hydroxypyrrolidine-2-carboxylate (40 mg, 0.1 mmol) in THF (1 mL) was added CDI (32 mg, 0.2 mmol). After 1 h, a solution of tert-butyl glycinate (25 mg, 0.15 mmol) and DIPEA (52 μL, 0.3 mmol) in THF (1 mL) was added. The mixture was stirred at 60° C. overnight. After cooling down to r.t., the solvent was evaporated. The crude was dissolved in EtOAc (5 mL) and washed with water, brine and dried over anhy. Na.sub.2SO.sub.4. A column chromatography eluting with a gradient of hexanes and EtOAc afforded the desired product (40 mg) as white solids (MS: [M+1].sup.+563.1).

[1218] Step 2: methyl (2S,5S)-4-(4-(((2-(tert-butoxy)-2-oxoethyl)carbamoyl)oxy)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)pyrrolidine-2-carboxylate (40 mg, 0.07 mmol) was placed in a vial with THF (1.2 mL), methanol (0.4 mL), and water (0.4 mL). Lithium hydroxide monohydrate (8 mg, 0.18 mmol) was added, and the reaction was allowed to stir at r.t. for 16 h. The volatiles were concentrated off and the resulting residue neutralized by the addition of 1 N hydrochloric acid. The resulting solution was lyophilized to afford the titled compound (MS: [M+1].sup.+493.1).

[1219] The following compounds were prepared essentially by the same method described above to prepare I-570.

TABLE-US-00039 MS I-# Starting Material Structure [M + 1]+ I-571 [03800] [03801] [03802] 506

Example 83: Synthesis of methyl (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yppyrrolidin-2-yl)acetate (I-572)

[1220] ##STR03803##

[1221] At 0° C., oxalyl chloride (60 uL, 0.5 mmol) or thionyl chloride was added dropwise to MeOH (1 mL). After 30 min, a solution of (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)pyrrolidin-2-yl)acetic acid (40 mg, 0.1 mmol) in MeOH (0.1 mL) was added. The solution was stirred at r.t. overnight. After evaporation, the crude was dissolved in EtOAc (5 mL) and washed with saturated NaHCO.sub.3 (aq.), water, brine and dried over anhy. Na.sub.2SO.sub.4. A column chromatography eluting with a gradient of hexanes and EtOAc afforded the desired product (40 mg) as white solids (MS: [M+1].sup.+404.1).

[1222] The following compounds were prepared essentially by the same method described above to prepare I-572.

TABLE-US-00040 MS I-# Starting Material Structure [M + 1]+ I-573 [03804] [03805] [03806] 447 I-574 [03807] MeOH [03808] 405 I-575 [03809] MeOH [03810] 409 I-576 [03811] MeOH [03812] 403 I-577 [03813] MeOH [03814] 403 I-578 [03815] MeOH [03816] 405 I-579 [03817] MeOH [03818] 403 I-580 [03819] MeOH [03820] 417 I-581 [03821] MeOH [03822] 439 I-582 [03823] MeOH [03824] 417 I-583 [03825] MeOH [03826] 419 I-584 [03827] MeOH [03828] 403 I-585 [03829] MeOH [03830] 405 I-586 [03831] MeOH [03832] 405 I-587 [03833] MeOH [03834] 419 I-588 [03835] MeOH [03836] 439 I-589 [03837] MeOH [03838] 406 I-590 [03839] MeOH [03840] 405 I-591 [03841] MeOH [03842] 403 I-592 [03843] MeOH [03844] 409 I-593 [03845] MeOH [03846] 391 I-594 [03847] CH.sub.3CH.sub.2OH [03848] 405 I-595 [03849] [03850] [03851] 419 I-596 [03852] CH.sub.3OH [03853] 407 I-597 [03854] CH.sub.3OH [03855] 407 I-598 [03856] CH.sub.3OH [03857] 407 I-599 [03858] CH.sub.3CH.sub.2OH [03859] 421 I-600 [03860] [03861] [03862] 435 I-601 [03863] [03864] [03865] 449 I-602 [03866] [03867] [03868] 449 I-662 [03869] MeOH [03870] 421 I-663 [03871] [03872] [03873]1 543

Example 84: Synthesis of methyl (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)naphthalen-2-yl)azetidin-2-yl)acetate (I-604)

[1223] ##STR03874##

[1224] Step 1: At 0° C., oxalyl chloride (0.1 mL) was added dropwise to MeOH (1 mL). After 30 min, a solution of (S)-2-(1-(tert-butoxycarbonyl)azetidin-2-yl)acetic acid (43 mg, 0.2 mmol) in MeOH (0.1 mL) was added. The solution was stirred at r.t. overnight. After evaporation, the crude was dissolved in EtOAc (5 mL) and washed with saturated NaHCO.sub.3 (aq.), water, brine and dried over anhy. Na.sub.2SO.sub.4. The crude was used in the next step without further purification. (MS: [M+1].sup.+230.1).

[1225] Step 2: A solution of tert-butyl (S)-2-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (50 mg crude, 0.2 mmol) in 50% TFA/DCM was stirred at r.t. for 30 min. After evaporation, the crude was dissolved in DCM (2 mL). The solvent was removed by evaporation. The process was repeated twice. The crude was used in the next step without further purification. (MS: [M+1].sup.+130.1).

[1226] Step 3: I-604 was prepared essentially by the same method as I-353. (MS: [M+1].sup.+390.1).

Example 85: Synthesis of (S)-5-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3(2H)-one (I-605)

[1227] ##STR03875##

[1228] To a mixture of (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxamide (100 mg, 0.27 mmol) and DCE (2 mL) was added (COCl).sub.2(35 uL, 0.4 mmol) at r.t. The mixture was stirred at 70° C. overnight and then TMSN3 (1 mL) was added. The solution was stirred at 80° C. for 2 days. After cooling down to r.t., the crude was purified directly by a column chromatography on silica gel to give the titled product as a solid (MS: [M+1].sup.+417.1).

Example 86: Synthesis of (2S,4R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-4-((morpholine-4-carbonyl)oxy)pyrrolidine-2-carboxylic acid (I-606)

[1229] ##STR03876## ##STR03877##

[1230] Step 1: methyl (2S,4R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-4-hydroxypyrrolidine-2-carboxylate. To a vial were added 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (90 mg, 0.302 mmol), methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (146 mg, 0.603 mmol), DMSO (0.20 mL), and N,N-diisopropylethylamine (0.10 mL). The resulting reaction mixture was stirred at 90° C. for 16 h and cooled to room temperature, followed by adding H.sub.2O (20 mL). The cloudy mixture was centrifuged and the residue was extracted with 10% MeOH/DCM (2×10 mL). The organic phase was washed with H.sub.2O (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4, and concentrated. The crude residue was purified by silica chromatography to afford (104 mg) (MS: [M+1].sup.+407).

[1231] Step 2: (3R,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(methoxycarbonyl)pyrrolidin-3-yl 1H-imidazole-1-carboxylate. To a vial were added methyl (2S,4R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-4-hydroxypyrrolidine-2-carboxylate (100 mg, 0.246 mmol), THF (5 mL) and carbonyldiimidazole (CDI) (80 mg, 0.493 mmol). The resulting mixture was stirred at room temperature for 4 hrs. All volatile solvents were then removed under reduced pressure and the residue was dried at high vacuum to afford the titled product. The crude was used in next step.

[1232] Step 3: (3R,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(methoxycarbonyl)pyrrolidin-3-yl morpholine-4-carboxylate. To a vial were added (3R,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(methoxycarbonyl)pyrrolidin-3-yl 1H-imidazole-1-carboxylate (125 mg, 0.250 mmol), THF (2 mL), and morpholine (44 mg, 0.505 mmol). The resulting reaction mixture was stirred at rt for 3h. The volatiles were concentrated off. The reaction mixture was diluted by ethyl acetate (15 mL). The organic phase was washed by H.sub.2O (3×5 mL), brine (5 mL), and dried over Na.sub.2SO.sub.4. After concentration, the crude was purified by silica gel chromatography to afford the titled product as an off-white solid (60 mg) (MS: [M+1].sup.+520).

[1233] Step 4: (2S,4R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-4-((morpholine-4-carbonyl)oxy)pyrrolidine-2-carboxylic acid. To a vial were added (3R,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(methoxycarbonyl)pyrrolidin-3-yl morpholine-4-carboxylate (50 mg, 0.096 mmol), THF (0.8 mL), methanol (0.2 mL), water (0.2 mL) and morpholine. Lithium hydroxide monohydrate (12 mg, 0.288 mmol) was added and the resulting reaction mixture was stirred at rt for 16 h. The volatiles were concentrated off The reaction mixture was diluted by water (2 mL) then acidified with 1M HCl to afford the titled product as an off-white solid (38 mg) (MS: [M+1].sup.+506).

[1234] The following compound was synthesized in a similar manner as I-606:

TABLE-US-00041 MS I-# Starting Material Structure [M + 1]+ I-607 [03878] [03879] [03880] 494

Example 87: Synthesis of 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)-N-(2-hydroxyethypethane-1-sulfonamide (I-624)

[1235] ##STR03881##

[1236] Step 1: I-159 was heated in the excess of thionyl chloride at 60° C. over 4 hours. The resultant solution was concentrated under vacuum to afford 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethane-1-sulfonyl chloride, which was used in the following step without further purification.

[1237] Step 2: 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl) (methyl)amino)ethane-1-sulfonyl chloride was mixed with 2-aminoethan-1-ol in pyridine. Aqueous work-up and purification by prep-HPLC afforded the titled compound (I-624). MS [M+1].sup.+444.

[1238] Following the preparation of I-624 described above, the following compounds were prepared.

TABLE-US-00042 MS I-# Starting Materials Structure [M + 1].sup.+ I-625 [03882] [03883] [03884] 512 I-626 [03885] [03886] [03887] 498 I-627 [03888] [03889] [03890] 498 I-628 [03891] [03892] [03893] 526 I-629 [03894] [03895] [03896] 512 I-630 [03897] [03898] [03899] 472 I-631 [03900] [03901] [03902] 512 I-632 [03903] [03904] [03905] 458 I-633 [03906] [03907] [03908] 458

Example 88: Synthesis of 3-(N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)methylsulfonamido) propanoic acid (I-634)

[1239] ##STR03909##

[1240] A mixture of N-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N1-methylethane-1,2-diamine (100 mg, 0.3 mmol), tert-butyl acrylate (41.9 mg, 0.33 mmol) and DBU (135 mg, 0.9 mmol) in DMF was stirred at 40° C. until completion by LCMS. After cooling to 0° C., MsCl (103 mg, 0.9 mmol) was added and the mixture was stirred for another 3 h, monitored by TLC. The mixture was then quenched with aq.NaHCO.sub.3, taken up with DCM, washed with brine, dried, concentrated, and purified by prep-TLC to afford tert-butyl 3-(N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)methylsulfonamido)propanoate which was dissolved in DCM/TFA (1/1, 2 mL) and stirred for 2 h, monitored by TLC. The solvent was then removed under vacuum and the residue was purified by prep-HPLC to the titled product (I-634) as a light yellow solid. NMR (400 MHz, CD.sub.3OH, ppm): δ 9.22 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.41-7.33 (m, 3H), 4.05(s, 2H), 3.59-3.58(m, 4H), 3.31(s, 3H), 2.92 (s, 3H), 2.65 (s, 2H). LCMS: (ES±): m/z 486.1 [M+1].sup.+.

Example 89: Synthesis of N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)-N-(methylsulfonyl)glycine (I-635)

[1241] ##STR03910##

[1242] To a mixture of N-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-N1-methylethane-1,2-diamine (100 mg, 0.3 mmol) and ethyl 2-oxoacetate (74 mg, 50% in toluene, 0.36 mmol) in DCM/DCM/CH.sub.3OH (2/1, 3 mL) and cat. AcOH (2 drops) was added NaBH.sub.3CN (38 mg, 0.6 mmol) at rt. and stirred for 10 huntil completion by LCMS. The mixture was then quenched with aq. NaHCO.sub.3, taken up with DCM, washed with brine, dried, and concentrated to afford crude desired product of ethyl 2-oxoacetate, which was used into next step without further purification. The residue was dissolved into DCM/TEA (5/1, 5 mL), then MsCl (150 μL) was added into the mixture at rt, and stirred for another 2 h, monitored by TLC. The mixture was then quenched with aq. NH.sub.4Cl, taken up with DCM, washed with brine, dried, and concentrated. The residue was purified by prep-TLC to afford ethyl N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)-N-(methylsulfonyl)glycinate which was dissolved in CH.sub.3OH/H.sub.2O (2/1, 3 mL), added LiOH, and stirred for 1 h, monitored by TLC. The reaction was then quenched with TFA, concentrated, and purified by prep-TLC (DCM/CH.sub.3OH=8/1) to afford the titled product (I-635) as a light yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): δ 8.09 (s, 1H), 7.56 (s, 1H), 7.36-7.20 (m, 4H), 4.02-3.97 (m, 4H), 3.65(br, 2H), 3.31(s, 3H), 3.02 (s, 3H). LCMS: (ES±): m/z 473.1 [M+1].sup.+.

Example 90: Synthesis of 3-((N-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(methyl)amino)ethyl)methylsulfonamido) methyl)benzoic acid (I-636)

[1243] ##STR03911##

[1244] I-636 was prepared according to the same method to prepare I-635. .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): δ 9.20 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.64 (s, 1H), 757-7.47 (m, 2H), 7.34(d, J=8.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 4.33 (s, 2H), 3.84-3.72(m, 4H), 3.06(m, 3H), 3.02(s, 3H). LCMS: (ES±): m/z 548.1 [M+1].sup.+.

Example 91: Synthesis of methyl (2S,3S)-3-acetoxy-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylate (I-642) and (2S,3S)-3-acetoxy-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid (I-643)

[1245] I-642 and I-643 were prepared according to the follow synthetic scheme:

##STR03912##

TABLE-US-00043 MS I-# Starting Material Structure [M + 1]+ I-642 [03913] [03914] [03915] 449 I-643 [03916] [03917] [03918] 435

Example 92: Synthesis of tert-butyl (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (I-645)

[1246] ##STR03919##

[1247] Step 1: (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared similar to the preparation of I-123, step 1.

[1248] Step 2: The mixture of (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylic acid (380 mg, 0.083 mmol) and 1,1-di-tert-butoxy-N,N-dimethylmethanamine (200 mg, 0.983 mmol) was stirred at 80° C. overnight. The crude was purified by silica gel chromatography to afford I-645 (MS: [M+1].sup.+449)

Example 93: Synthesis of methyl (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-methoxypyrrolidine-2-carboxylate (I-646)

[1249] ##STR03920##

[1250] Step 1: (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate HCl salt was prepared similar to the preparation of I-593.

[1251] Step 2: To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid HCl salt (268 mg, 1.47 mmol) in DCN (6 mL) was added Boc.sub.2O (385 mg, 1.76 mmol) and TEA (0.612 mL, 4.39 mmol). The resulting reaction solution was stirred overnight. The mixture was diluted with DCM (20 mL), washed with H.sub.2O (2×10 mL), brine (10 mL), and dried over Na.sub.2SO.sub.4. After concentration, the crude (2S,3S)-1-tert-butyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate was used in next step.

[1252] Step 3: To a solution of (2S,3S)-1-tert-butyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate (0.5 mmol) and iodomethane (0.093 mL, 1.5 mmol) in DCM (1.5 mL) was added 700 mg of Ag.sub.2O (700 mg, 3.02 mmol). After being stirred overnight, the mixture was filtered through a pad of Celite and purified by silica gel chromatography to afford (2S,3S)-1-tert-butyl 2-methyl 3-methoxypyrrolidine-1,2-dicarboxylate as an oil.

[1253] Step 4: To a solution of (2S,3S)-1-tert-butyl 2-methyl 3-methoxypyrrolidine-1,2-dicarboxylate (56.5 mg, 0.218 mmol) in DCM (0.5 mL) was added TFA (0.25 mL). After being stirred for 4 hours, the mixture was concentrated to remove all volatiles. The residue (2S,3S)-methyl 3-methoxypyrrolidine-2-carboxylate was used in next step.

[1254] Step 5: (2S,3S)-methyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-methoxypyrrolidine-2-carboxylate was prepare by a procedure similar to that of I-123, step 1. (MS: [M+1].sup.+421).

[1255] The following compounds were prepared essentially by the same method to prepare I-646.

TABLE-US-00044 MS I-# Starting Material Structure [M + 1].sup.+ I-647 [03921] [03922] [03923] 421 I-648 [03924] [03925] [03926] 465 [03927]

Example 94: Synthesis of methyl (2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-fluoropyrrolidine-2-carboxylate (I-649)

[1256] ##STR03928##

[1257] To a mixture of methyl (2S,3R)-1-(7,8-dichlo ro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (40.7 mg, 0.1 mmol) in DCM (0.5 mL) was added a solution of DAST (0.040 mL, 0.30 mmol) in DCM (0.2 mL) at −10° C. The mixture was stirred at −10° C. for 2 hours. After aqueous work-up, the crude was purified by PTLC to afford the titled product as a white solid (MS: [M+1].sup.+409).

[1258] The following compounds were prepared essentially by the same method to prepare I-649.

TABLE-US-00045 MS I-# Starting Material Structure [M + 1].sup.+ I-650 [03929] DAST [03930] 409 I-651 [03931] DAST [03932] 395

Example 95: Synthesis of methyl 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-4,5-dihydro-1H-pyrrole-2-carboxylate (I-652)

[1259] ##STR03933##

[1260] To the solution of methyl (2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-fluoropyrrolidine-2-carboxylate (10 mg, 0.0244 mmol) in methanol (0.5 mL) was added a solution of LiOH—H.sub.2O (1.57 mg, 0.0366 mmol) in H.sub.2O (0.10 mL) with stirring. After 5 min, the reaction was quenched with HOAc (0.00209 mL, 0.0366 mmol) in H.sub.2O (0.10 mL). The resulting mixture was purified by HPLC to afford the titled product as a white solid. (MS: [M+1].sup.+389).

Example 96: Synthesis of methyl (2S,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-(((2-methoxy-2-oxoethyl)carbamoyl)oxy)pyrrolidine-2-carboxylate (I-653)

[1261] ##STR03934##

[1262] To a solution of methyl (2S,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (30 mg, 0.0737 mmol) in THF (0.5 mL) was added TEA (0.051 mL, 0.369 mmol) and CDI (40 mg, 0.247 mmol). The resulting mixture was stirred for 2 hours. Methyl glycinate HCl salt (18.5 mg, 0.147 mmol) was then added. After 2 hours of stirring, the mixture was diluted with DCM (20 mL), washed with H.sub.2O (2×10 mL), brine (10 mL), and dried over Na.sub.2SO.sub.4. The crude was purified by silica gel chromatography to afford the title product as a white solid. (MS: [M+1].sup.+522).

Example 97: Synthesis of (S)-1-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2,2,2-trifluoroethan-1-ol (I-654) and (R)-1-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2,2,2-trifluoroethan-1-ol (I-655)

[1263] ##STR03935##

[1264] Step 1: To a flask were added tert-butyl (S)-2-formylpyrrolidine-1-carboxylate (1.992 g, 10 mmol) and THF (25 mL). The solution was cooled in ice bath for 20 min. After the slow addition of a solution of trimethyl(trifluoromethyl)silane in THF (2.0 M, 7.5 mL, 15 mmol) at 0° C., a solution of TBAF in THF (1.0 M, 0.5 mL, 0.5 mmol) was added dropwise. The resultant mixture was stirred at the same temperature for 2 hours. More TBAF solution in THF (1.0 M, 2.0 mL, 2.0 mmol) was added and the mixture was stirred at room temperature for another 2 hours. After being quenched by saturated NH.sub.4Cl and concentrated, the resultant mixture was diluted with DCM (150 mL), washed with H.sub.2O, brine, dried over Na.sub.2SO.sub.4 and then concentrated. The crude product was purified by silica gel chromatography to afford tert-butyl (S)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carboxylate.

[1265] Step 2: To a vial were added tert-butyl (S)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carboxylate (50 mg, 0.186 mmol), DCM (0.5 mL) and TFA (0.25 mL). The resulting solution was stirred for 2 hours. After removing all volatiles under vacuo, the crude (S)-2,2,2-trifluoro-14(S)-pyrrolidin-2-ypethan-1-ol was used directly in next step. The same procedure was used to prepare the (R, S)-isomer.

[1266] Step 3: Both of (S)-1-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2,2,2-trifluoroethan-1-ol I-654 (MS: [M+1].sup.+431) and (R)-1-(S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2,2,2-trifluoroethan-1-ol I-655 (MS: [M+1].sup.+431) were prepared following the synthetic procedure to prepare I-123, step 1.

Example 98: Synthesis of (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-42-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-656)

[1267] ##STR03936##

[1268] Step 1: To a vial were added DCM (3 mL) and oxalyl chloride (0.220 mL, 2.6 mmol) followed being cooled in dry ice/acetone bath. A solution of DMSO (0.383 mL, 5.4 mmol) in DCM (2.5 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min. Then a solution of tert-butyl (S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-carboxylate (582 mg, 2.16 mmol) in DCM (2.5 mL) was added dropwise at same temperature. After 30 min, TEA (1.5 mL, 10.8 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min. The resulting mixture was stirred at room temperature for 1 hour, then quenched by adding H.sub.2O (10 mL). The aqueous phase was extracted by DCM (2×15 mL).

[1269] The combined organic phase was concentrated, purified by silica gel chromatography to afforded tert-butyl (S)-2-(2,2,2-trifluoroacetyl)pyrrolidine-1-carboxylate.

[1270] Step 2: tert-butyl (S)-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrrolidine-1-carboxylate was prepared similar to the procedure to prepare I-654, step 1.

[1271] Step 3: (S)-1,1,1,3,3,3-hexafluoro-2-(pyrrolidin-2-yl)propan-2-ol was prepared similar to the procedure to prepare I-654, step 2.

[1272] Step 4: (S)-2-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol was prepared similar to the procedure to prepare I-123, step 1. (MS: [M+1].sup.+499)

Example 99: Synthesis of methyl (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (I-657)

[1273] ##STR03937##

[1274] To a vial were added methyl (2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxylate (20 mg, 0.0491 mmol) THF(0.5 mL) and ethanol (1.0 mL). At 0° C., LiBH.sub.4 (9.5 mg, 0.436 mmol) was added and the resulting mixture was stirred overnight. The mixture was diluted with DCM (20 mL), washed with saturated NH.sub.4Cl (5 mL), H.sub.2O (5 mL), brine (5 mL), and dried over Na.sub.2SO.sub.4. The crude was purified by silica gel chromatography to afford the titled compound as white solid (MS: [M+1].sup.+379).

Example 100: Synthesis of ((5)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl hydrogen phosphonate (I-658)

[1275] I-658 was prepared essentially by the same method to prepare I-111.

TABLE-US-00046 MS I-# Starting Material Structure [M + 1].sup.+ I-658 [03938] [03939] [03940] 427

Example 101: Synthesis of (R)-2-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyacetic acid. hexafluoropropan-2-ol (I-661)

[1276] ##STR03941##

[1277] Step 1: To a vial were added DCM (10 mL), TEA (1 mmol, 0.1 mL) and tert-butyl (S)-2-formylpyrrolidine-1-carboxylate (1 g, 5 mmol) and the mixture was stirred at r.t overnight. After evaporation, the crude tert-butyl (S)-2((R)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate was used in the next step without further purification. (MS: [M+1].sup.+227.1).

[1278] Step 2: A mixture of tert-butyl (S)-2-((R)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate (230 mg, 1 mmol), HCl (con., 1 mL) and 1,4-dioxane (1 mL) was refluxed for 2 h. After evaporation, the crude (R)-2-hydroxy-2-((S)-pyrrolidin-2-yl)acetic acid was used in the next step without further purification. (MS: [M+1].sup.+146.1).

[1279] Step 3: (R)-2-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyacetic acid (I-661) was prepared similar to step 1 for the preparation of I-123. (MS: [M+1].sup.+407.1).

Example 102: Synthesis of methyl (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate (I-665) and (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-664)

[1280] ##STR03942##

[1281] Step 1: tert-Butyl (S)-2-43-(tert-butoxy)-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate. To a vial were added tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (805 mg, 4.1 mmol, 1.0 eq.), Cs.sub.2CO.sub.3 (1.3 g, 4.1 mmol, 1.0 eq.), t-BuOH (5 mL) and tert-butyl acrylate (1.8 mL, 20 mmol, 5 eq.). The resulting reaction mixture was stirred over night. Then the mixture was diluted by ethyl acetate (50 mL), washed by H.sub.2O (3×15 mL), brine (15 mL) and dried over Na.sub.2SO.sub.4. After concentration, the crude was purified by a silica gel chromatography to afford the title product (1.22 g).

[1282] Step 2: (S)-3-(Pyrrolidin-2-ylmethoxy)propanoic acid. The mixture of tert-butyl (S)-2-43-(tert-butoxy)-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate (400 mg, 1.21 mmol), TFA (2 mL) and DCM (2 mL) was stirred overnight at room temperature. The mixture was concentrated to remove all volatiles. The crude was used in the next step.

[1283] Step 3: (S)-3-41-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-664). To a vial were added 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (227 mg, 0.759 mmol, 1.0 eq.), the crude product in step 2 (0.911 mmol), DMSO (4.0 mL), DIPEA (0.66 mL, 3.8 mmol, 5.0 eq.) and NaHCO.sub.3. The reaction mixture was srirred at 90° C. overnight. Then the mixture was diluted by ethyl acetate (30 mL) and acidified by HOAc (1 M, 5 mL), washed by H.sub.2O (3×10 mL), brine (10 mL) and dried over Na.sub.2SO.sub.4. After concentration, the crude was used in the next step. The acid product was purified by silica gel chromatography. MS: [M+1].sup.+435.

[1284] Step 4: Methyl (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate (I-665). To a vial were added the crude product in step 3 (0.345 mmol) and anhydrous methanol (2.0 mL). The reaction solution was cooled to 0° C. and was treated with SOCl.sub.2 (0.100 mL, 1.38 mmol, 4.0 eq.) at 0° C. After being stirred at room temperature for 2 hours, the reaction mixture was diluted by ethyl acetate (30 mL), washed by NaHCO.sub.3/H.sub.2O (5%, 10 mL), H.sub.2O (3×10 mL), brine (10 mL) and dried over Na.sub.2SO.sub.4. After concentration, the crude was purified by a silica gel column to afford the title product (135 mg). MS: [M+1].sup.+449.

[1285] The following compounds are prepared essentially by the same methods as described above for I-664 and 665.

TABLE-US-00047 MS Example Starting Material Structure [M + 1].sup.+ I-670 [03943] [03944] [03945] 435 I-671 [03946] [03947] 449 I-674 [03948] [03949] [03950] 435 [03951] I-688 [03952] [03953] [03954] 421 [03955] I-696 [03956] [03957] [03958] 449 [03959] I-698 [03960] [03961] [03962] 451 I-701 [03963] [03964] 465 I-699 [03965] [03966] [03967] 471 [03968] I-705 [03969] [03970] [03971] 453 [03972] I-708 [03973] [03974] [03975] 449 [03976] I-709 [03977] [03978] [03979] 461 [03980] I-719 [03981] [03982] [03983] 449 I-720 [03984] [03985] 463 I-717 [03986] [03987] [03988] 449 I-718 [03989] [03990] 463 I-741 [03991] [03992] [03993] 451 [03994] I-747 [03995] [03996] [03997] 449 [03998] I-745 [03999] [04000] [04001] 449 [04002] I-750 [04003] [04004] [04005] 449 [04006] I-752 [04007] [04008] [04009] 465 [04010] I-748 [04011] [04012] [04013] 465 [04014] I-749 [04015] [04016] [04017] 467 [04018] I-721 [04019] [04020] [04021] 503 [04022] I-722 [04023] [04024] [04025] 503 [04026] I-711 [04027] [04028] [04029] 465 [04030] I-704 [04031] [04032] [04033] 453 [04034] I-702 [04035] [04036] [04037] 451 [04038] I-703 [04039] [04040] [04041] 451 [04042] I-695 [04043] [04044] [04045] 485 [04046] I-672 [04047] [04048] [04049] 449 [04050] I-673 [04051] [04052] [04053] 463 [04054] I-677 [04055] [04056] [04057] 463 [04058] I-713 [04059] [04060] [04061] 527 [04062] I-712 [04063] [04064] [04065] 541 [04066] I-767 [04067] [04068] [04069] 421 I-769 [04070] [04071] 435 I-771 [04072] [04073] [04074] 421 [04075] I-707 [04076] [04077] [04078] 447 [04079] I-710 [04080] [04081] [04082] 447 [04083] I-689 [04084] [04085] [04086] 421 [04087] I-772 [04088] [04089] [04090] 435 [04091] I-773 [04092] [04093] [04094] 435 [04095] I-789 [04096] [04097] [04098] 449 [04099] I-693 [04100] [04101] [04102] 395 [04103] I-692 [04104] [04105] [04106] 423 [04107] I-694 [04108] [04109] [04110] 409 [04111] I-790 [04112] [04113] [04114] 449 [04115] I-792 [04116] [04117] [04118] 449 [04119] I-804 [04120] [04121] [04122] 447 [04123] I-808 [04124] [04125] [04126] 489 [04127] I-809 [04128] [04129] [04130] 447 [04131] I-806 [04132] [04133] [04134] 483 [04135] I-810 [04136] [04137] [04138] 449 [04139] I-832 [04140] [04141] [04142] 423 [04143] I-833 [04144] [04145] [04146] 437 [04147] I-834 [04148] [04149] [04150] 435 [04151] I-805 [04152] [04153] [04154] 447 [04155] I-836 [04156] [04157] [04158] 477 [04159] I-837 [04160] [04161] [04162] 485 [04163] I-838 [04164] [04165] [04166] 439 [04167] I-839 [04168] [04169] [04170] 511 [04171] I-873 [04172] [04173] [04174] 425 [04175] I-874 [04176] [04177] [04178] 497 [04179] I-816 [04180] [04181] [04182] 475 [04183] I-796 [04184] [04185] [04186] 507 [04187] I-815 [04188] [04189] [04190] 489 [04191] I-818 [04192] [04193] [04194] 479 [04195] I-858 [04196] [04197] [04198] 423 [04199] I-859 [04200] [04201] [04202] 397 [04203] I-860 [04204] [04205] [04206] 431 [04207] I-861 [04208] [04209] [04210] 445 [04211] I-862 [04212] [04213] [04214] 479 [04215] I-856 [04216] [04217] [04218] 431 [04219] I-857 [04220] [04221] [04222] 513 [04223] I-875 [04224] [04225] [04226] 431 [04227] I-876 [04228] [04229] [04230] 469 [04231] I-793 [04232] [04233] [04234] 503 [04235] I-794 [04236] [04237] [04238] 463 [04239] I-795 [04240] [04241] [04242] 449 [04243] I-827 [04244] [04245] [04246] 369 [04247] I-800 [04248] [04249] [04250] 447 [04251] I-801 [04252] [04253] [04254] 447 [04255] I-802 [04256] [04257] [04258] 511 [04259] I-803 [04260] [04261] [04262] 517 [04263] I-797 [04264] [04265] [04266] 465 [04267] I-798 [04268] [04269] [04270] 465 [04271] I-853 [04272] [04273] [04274] 435 [04275] I-855 [04276] [04277] [04278] 435 [04279] I-867 [04280] [04281] [04282] 465 [04283] I-799 [04284] [04285] [04286] 520 [04287] I-865 [04288] [04289] [04290] 463 [04291] I-807 [04292] [04293] [04294] 461 [04295] I-864 [04296] [04297] [04298] 435 [04299] I-866 [04300] [04301] [04302] 463 [04303] I-868 [04304] [04305] [04306] 465 [04307] I-811 [04308] [04309] [04310] 461 [04311] I-829 [04312] [04313] [04314] 435 [04315] I-869 [04316] [04317] [04318] 479 [04319] I-870 [04320] [04321] [04322] 479 [04323] I-871 [04324] [04325] [04326] 479 [04327] I-814 [04328] [04329] [04330] 449 [04331]

Example 103: Synthesis of methyl (S)-2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)acetate (I-667) and (S)-2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)acetic acid (I-666)

[1286] ##STR04332##

[1287] Step 1: tert-Butyl (S)-2-((2-(tert-butoxy)-2-oxoethoxy)methyl)pyrrolidine-1-carboxylate. To a flask were added tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 g, 4.98 mmol, 1.0 eq.), Bu.sub.4NI (920 mg, 2.49 mmol, 0.50 eq.), toluene (20 mL) and tert-butyl 2-bromoacetate (1.94 g, 9.95 mmol, 2.0 eq.). The reaction mixture was cooled in an ice bath. A solution of NaOH/H2O (30%, 12 mL) was added slowly at 0° C. The resulting reaction mixture was stirred at 0° C. for 3 hours. Then the mixture was diluted by ethyl acetate (50 mL), washed by H.sub.2O (3×15 mL), brine (15 mL), and dried over Na.sub.2SO.sub.4. After concentration, the crude was purified by silica gel chromatography to afford the title product (1.14 g).

[1288] Step 2: (S)-2-(Pyrrolidin-2-ylmethoxy)acetic acid. The mixture of tert-butyl (S)-2-42-(tert-butoxy)-2-oxoethoxy)methyl)pyrrolidine-1-carboxylate (300 mg, 0.951 mmol), TFA (1.5 mL) and DCM (1.5 mL) was stirred overnight at room temperature. The mixture was concentrated to remove all volatiles. The crude was used in the next step.

[1289] Step 3: (S)-2-((1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yppyrrolidin-2-yl)methoxy)acetic acid (I-666). The procedure was the same as that in the synthesis of I-665. MS: [M+1].sup.+421.

[1290] Step 4: Methyl (S)-2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)acetate. The procedure was the same as that in the synthesis of I-665. MS: [M+1].sup.+435.

[1291] The following compounds are prepared essentially by the same methods described above for I-666.

TABLE-US-00048 MS Example Starting Material Structure [M + 1].sup.+ I-697 [04333] [04334] [04335] 437 I-706 [04336] [04337] [04338] 439 I-740 [04339] [04340] [04341] 437 I-743 [04342] [04343] [04344] 435 I-744 [04345] [04346] [04347] 435 I-751 [04348] [04349] [04350] 451 I-746 [04351] [04352] [04353] 435 I-742 [04354] [04355] [04356] 437 I-669 [04357] [04358] [04359] 449 I-668 [04360] [04361] 435 I-766 [04362] [04363] [04364] 407 I-768 [04365] 421 I-770 [04366] [04367] [04368] 407 I-820 [04369] [04370] [04371] 449

Example 104: Synthesis of 3-(((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)-2-fluoropropanoic acid (I-716) and methyl 3-4(5)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)-2-fluoropropanoate (I-700)

[1292] ##STR04372## ##STR04373##

[1293] Step 1: tert-Butyl (2S)-2-((3-(tert-butoxy)-2-fluoro-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate and tert-butyl (2S)-2-((2-fluoro-3-methoxy-3-oxop ropoxy)methyl)pyrrolidine -1-carboxylate . The procedure was the same as that in the synthesis of I-665. The two title compounds were obtained.

[1294] Step 2: 2-Fluoro-3-(((S)-pyrrolidin-2-yl)methoxy)propanoic acid. The procedure was the same as that in the synthesis of I-665.

[1295] Step 3: 3-(((S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)-2-fluoropropanoic acid. The procedure was the same as that in the synthesis of I-665. (MS: [M+1].sup.+453)

[1296] Step 4: Methyl 2-fluoro-3-4(S)-pyrrolidin-2-yl)methoxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1297] Step 5: Methyl 3-4(S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)-2-fluoropropanoate. The procedure was the same as that in the synthesis of I-665. MS: [M+1].sup.+467.

Example 105: Synthesis of (2S,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-hydroxyethyl)pyrrolidine-2-carboxylic acid (I-783)

[1298] ##STR04374##

[1299] Step 1: di-tert-Butyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate. To a vial were added di-tert-butyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (1.14 g, 4.0 mmol, 1.0 eq.) and anhydrous THF (20 mL). The solution was cooled in a dry ice/acetone bath for 20 min. Then a solution of LiEt.sub.3BH (1 M, 4.8 mL, 4.8 mmol) was added at −78° C. dropwise. After addition, the resulting reaction mixture was stirred at −78° C. for 30 min. A saturated NaHCO.sub.3 in H.sub.2O (6 mL) was added to quench the reaction and the reaction mixture was warmed to 0° C. slowly followed by addition of H.sub.2O.sub.2/H.sub.2O (30%, 0.050 mL). After being stirred at room temperature for 20 min, the raction mixture was concentrated, diluted by H.sub.2O (20 mL), extracted by DCM (3×20 mL), and dried over Na.sub.2SO.sub.4. After concentration, the crude was used in the next step.

[1300] Step 2: di-tert-Butyl (2S,5S)-5-(2-methoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate. To a stirred suspension of sodium hydride (60%, 100 mg, 2.5 mmol, 1.2 eq.) in anhydrous DMF (5 mL) was added methyl 2-(diethoxyphosphoryl)acetate (529 mg, 2.5 mmol, 1.2 eq.). The mixture was stirred at room temperature for 1 hour and then a solution of the crude in step 1 (602 mg, 2.09 mmol) in DMF (5 mL) was added. The reaction was stirred overnight at room temperature, quenched with saturated aqueous NH.sub.4Cl solution, extracted with ethyl acetate (3×25 mL), and dried over Na.sub.2SO.sub.4. After concentration, the residue was purified by silica gel chromatography to afford the title product (150 mg).

[1301] Step 3: di-tert-Butyl (2S,5S)-5-(2-hydroxyethyl)pyrrolidine-1,2-dicarboxylate. To a vial were added di-tert-butyl (2S,5S)-5-(2-methoxy-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (150 mg, 0.437 mmol, 1.0 eq.) and diethyl ether (2.5 mL). Then LiBH.sub.4 (19 mg, 0.874 mmol, 2 eq.) was added and the resulting reaction mixture was stirred overnight at room temperature. After addition of HOAc/H.sub.2O (1 M, 2 mL) and H.sub.2O (10 mL), the reaction mixture was extracted with ethyl acetate (2×20 mL) and dried over Na.sub.2SO.sub.4. After concentration, the residue was purified by silica gel chromatography to afford the title product (103 mg).

[1302] Step 4: (2S,5S)-5-(2-Hydroxyethyl)pyrrolidine-2-carboxylic acid. The procedure was the same as that in the synthesis of I-665.

[1303] Step 5: (2S,5S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-hydroxyethyl)pyrrolidine-2-carboxylic acid. The procedure was the same as that in the synthesis decribed above for I-665. MS: [M+1].sup.+421.

Example 106: Synthesis of (2S,5S)-5-(2-(2-carboxyethoxy)ethyl)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid (I-714)

[1304] ##STR04375## ##STR04376##

[1305] Step 1: di-tert-Butyl (2S,5S)-5-(2-(3-(tert-butoxy)-3-oxopropoxy)ethyl)pyrrolidine-1,2-dicarboxylate. The procedure was the same as that in the synthesis described above for I-665.

[1306] Step 2: (2S,5S)-5-(2-(2-Carboxyethoxy)ethyl)pyrrolidine-2-carboxylic acid. The procedure was the same as that in the synthesis of I-665.

[1307] Step 3: Methyl (2S,5S)-5-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-2-carboxylate. The procedure was the same as that in the synthesis described above for I-665.

[1308] Step 4: Methyl (2S,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-2-carboxylate. The procedure was the same as that in the synthesis described above for I-665.

[1309] Step 5: (2S,5S)-5-(2-(2-Carboxyethoxy)ethyl)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid (I-714). To a vial were added methyl (2S,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-(3-methoxy-3-oxopropoxy)ethyl)pyrrolidine-2-carboxylate (3.7 mg, 0.0071 mmol, 1.0 eq.), THF (0.5 mL), MeOH (0.3 mL), and a solution of LiOH.H.sub.2O (1.5 mg, 0.0355 mmol, 5.0 eq.)/H.sub.2O (0.1 mL). The resulting solution was stirred at 40° C. for 6 h and acidized by aqueous HOAc (1 M, 0.040 mL). After concentration, the title product was obtained. MS: [M+1].sup.+493.

Example 107: Synthesis of (2S,5S)-5-(2-(carboxymethoxy)ethyl)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid (I-715)

[1310] ##STR04377## ##STR04378##

[1311] Step 1: di-tert-Butyl (2S,5S)-5-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)pyrrolidine-1,2-dicarboxylate. The procedure was the same as that in the synthesis described above for I-667.

[1312] Step 2: (2S,5S)-5-(2-(Carboxymethoxy)ethyl)pyrrolidine-2-carboxylic acid. The procedure was the same as that in the synthesis described above for I-665.

[1313] Step 3: Methyl (2S,5S)-5-(2-(2-methoxy-2-oxoethoxy)ethyl)pyrrolidine-2-carboxylate. The procedure was the same as that in the synthesis described above for I-665.

[1314] Step 4: Methyl (2S,5S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(2-(2-methoxy-2-oxoethoxy)ethyl)pyrrolidine-2-carboxylate. The procedure was the same as that in the synthesis described above for I-665.

[1315] Step 5: (2S,5S)-5-(2-(Carboxymethoxy)ethyl)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylic acid. The procedure was the same as that in the synthesis described above for I-714. MS: [M+1].sup.+479.

Example 108: Synthesis of (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-3-amine (I-765)

[1316] ##STR04379##

[1317] Step 1: tert-Butyl (S)-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-3-yl)carbamate. The procedure was the same as that in the synthesis of I-665.

[1318] Step 2: (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-3-amine. The procedure was the same as that in the synthesis described above for I-665. MS: [M+1].sup.+348.

Example 109: Synthesis of (S)—N-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-3-yl)acetamide (I-764)

[1319] ##STR04380##

[1320] The procedure used to prepare I-764 was the same as that described above to prepare I-665. MS: [M+1].sup.+390.

Example 110: Synthesis of (S)-2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)acetamide (I-760)

[1321] ##STR04381##

[1322] To a vial were added (S)-2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)acetic acid (30 mg, 0.0712 mmol, 1.0 eq.), NH.sub.4Cl (19 mg, 0.356 mmol, 5.0 eq.), EDCHCl (27 mg, 0.142 mmol, 2.0 eq.), HOBt (9.6 mg, 0.0712 mmol, 1.0 eq), DMF (0.5 mL). With stirring, DIPEA (0.062 mL, 0.356 mmol, 5.0 eq.) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 mL), washed with H.sub.2O (3×10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4. After concentration, the residue was purified by silica gel chromatography to afford the title product. MS: [M+1].sup.+420.

[1323] The following compounds are prepared essentially by the same methods as described above for I-760.

TABLE-US-00049 MS Example Starting Material Structure [M + 1].sup.+ I-761 [04382] NH.sub.2OH.Math.HC1 [04383] 436 I-762 [04384] NH.sub.2CN [04385] 445

Example 111: Synthesis of (S)-(2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)ethyl)phosphonic acid (I-763)

[1324] ##STR04386##

[1325] Step 1: tert-Butyl (S)-2-((2-(diethoxyphosphoryl)ethoxy)methyl)pyrrolidine-1-carboxylate. To a vial were added t-BuOK (247 mg, 2.2 mmol, 2.2 eq.) and anhydrous DCM (2.0 mL). The mixture was cooled in an ice bath for 20 min, followed by addition of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.0 mmol, 1.0 eq.). After the mixture was stirred at 0° C. for 30 min, diethyl (2-bromoethyl)phosphonate (294 mg, 1.2 mmol, 1.2 eq.) was added and the resultant reaction mixture was stirred at room temperature overnight. After being quenched by addition of ice (5 g), the mixture was diluted with ethyl acetate (30 mL), washed with H.sub.2O (2×10 mL), brine (10 mL), and dried over Na.sub.2SO.sub.4. After concentration, the residue was purified by silica gel chromatography to afford the title product (155 mg).

[1326] Step 2: Diethyl (S)-(2-(pyrrolidin-2-ylmethoxy)ethyl)phosphonate. The procedure was the same as that in the synthesis described above for I-665.

[1327] Step 3: Diethyl (S)-(2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)ethyl)phosphonate. The procedure was the same as that in the synthesis described above for I-665.

[1328] Step 4: (S)-(2-((1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)ethyl)phosphonic acid. The mixture of diethyl (S)-(2-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)ethyl)phosphonate (9.5 mg, 0.018 mmol) and a solution of HCl/H.sub.2O (37%, 1.0 mL) was stirred at 75° C. over two days. The mixture was concentrated to give the title product. (MS: [M+1].sup.+471)

Example 112: Synthesis of 3-((2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxamido)propanoic acid (I-784) and methyl 3-((2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxamido)propanoate (I-791)

[1329] ##STR04387##

[1330] Step 1: tert-Butyl 3-((2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxamido)propanoate. The procedure was the same as that in the synthesis described above for I-760.

[1331] Step 2: 3-((2S,3S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxamido)propanoic acid. The procedure was the same as that in the synthesis described above for I-665. MS: [M+1].sup.+464.

[1332] Step 3: Methyl 3-((2S,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidine-2-carboxamido)propanoate . The procedure was the same as that in the synthesis described above for I-665. MS: [M+1].sup.+478.

Example 113: Synthesis of 2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetic acid (I-785) and methyl 2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetate (I-786)

[1333] ##STR04388##

[1334] Step 1: (S)-4-((tert-Butyldimethylsilyl)oxy)-3,4-dihydro-2H-pyrrole 1-oxide. (S)-Pyrrolidin-3-ol (1.5 g, 17.2 mmol) was treated with TBSCl (3.37 g, 22.3 mol) and imidazole (3.51 g) in DCM (25 mL) overnight. After dilution with DCM (50 mL), the organic layer was washed with water (15 mL), saturated NaHCO.sub.3 (15 mL) and brine. The isolated organic layer was dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure afforded the desired crude (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (4.3 g), which was used in the following step without further purification. To an ice-water chilled solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (3.5 g) in MeOH (40 mL) was added urea hydrogen peroxide (4.94 g). Then a solution of CH.sub.3ReO.sub.3 (21.8 mg) in MeOH (3 mL) was stepwise added to the above reaction mixture over 3 hours. After being stirred at room temperature over 4 h, the reaction mixture was quenched with Na.sub.2S.sub.2O.sub.3 (4 g, 27 mmol) cautiously. After aqueous work up with EtOAc (80 mL), the reaction mixture was purified by silica gel column chromatography to afford two products, the less polar fraction is the title product (0.72 g), eluting with a gradient between DCM and EtOAc. MASS: m/z: [M+1].sup.+: 216.

[1335] Step 2: Methyl 2-((2R,3S)-1,3-bis((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)acetate. To a solution of (S)-4-((tert-butyldimethylsilyl)oxy)-3,4-dihydro-2H-pyrrole 1-oxide (0.72 g) in DCM were added 4 A sieves (1.1 g) and ZnI.sub.2 (0.26 g). After the suspended solution was chilled with a bath of dry ice-acetone under N.sub.2, tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (640 mg) was added stepwise via a syringe. The reaction mixture was stirred overnight as the temperature slowly rose back to room temperature. After aqueous work-up with DCM and concentration under reduced pressure, the resultant mixture was purified by silica gel column chromatography, eluting with 5% EtOAc in Hexane, to afford the title product (245 mg) as colorless solids. MASS: m/z: [M+1].sup.+: 404.

[1336] Step 3: Methyl 2-((2R,3S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)acetate. A solution of methyl 2-((2R,3S)-1,3-bis((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)acetate (109 mg) with 5% Pd/C in AcOH (3.5 mL) was degassed (vacuum/purge) three times with hydrogen and stirred under hydrogen overnight. After filtration, rinsing with EtOAc, and concentration under reduced pressure, the resultant mixture was dissolved in EtOAc (15 mL). The organic layer was washed with sat. NaHCO.sub.3, brine, and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure afforded the title product (I-786-4, 76.8 mg). MASS: m/z: [M+1].sup.+: 274.

[1337] Step 4: 2-((2R,3S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetate (I-786). To a solution of methyl 2-((2R,35)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)acetate (76.8 mg) and DIPEA (0.12 mL) in DMSO (0.4 mL) was added 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (50 mg). The resultant mixture was stirred at 90° C. over 3 h and diluted with EtOAc (15 mL). The organic solution was treated with 1 M TBAF in THF (0.4 mL) over 30 min. The organic solution was washed with water and brine, then dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure and purification by silica gel column chromatography afforded the title product (I-786, 18 mg) as light tan solids. MASS: m/z: [M+1].sup.+: 421.

[1338] Step 5: 2-((2R,3S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetic acid (I-785). To a solution of I-786 (44.8 mg) in MeOH (0.8 mL), THF (0.6 mL) and water (0.2 mL) was added LiOH.H.sub.2O (18 mg). The solution was stirred at room temperature over 3 h. After removal of the organic solvents under reduced pressure, the resultant slurry was mixed with AcOH (0.025 mL) and water (1.5 mL) to afford a suspended solution. The solid was isolated via a centrifuge and rinsed with water (0.5 mL×2). The wet cake was lyophilized to afford the title product (30 mg) as tan solids. MASS: m/z: [M+1].sup.+: 407.

Example 114: Synthesis of ethyl (2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetyl)glycinate (I-787) and (2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetyl)glycine (I-788)

[1339] ##STR04389##

[1340] Step 1: Ethyl (2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetyl)glycinate (I-787). To a solution of 2-((2R,3S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetic acid (I-785, 20 mg) in DMF (0.7 mL) were added EDC HCl (19 mg), HOBt (13 mg) and TEA (20 mg). The resultant solution was stirred at room temperature over 24 h. After the dilution with EtOAc (15 mL), the organic layer was washed with sat. NaHCO.sub.3, brine and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure and silica gel column chromatography, eluting with a gradient between hexane and EtOAc, afforded the title product (16 mg). MASS: m/z: [M+1].sup.+: 492.

[1341] Step 2: (2-((2R,3S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetyl)glycine (I-788). To a solution of I-787 (8 mg) in MeOH (0.6 mL) and water (0.2 mL) was added LiOH.H.sub.2O (8 mg). The resultant solution was stirred at room temperature over 2h. After removal of MeOH and acidification of aqueous part with 1M HOAc (0.08 mL), the formed solids were isolated via a centrifuge and lyophilized to afford the titled product (6 mg) as tan solids. MASS: m/z: [M+1].sup.+: 464.

Example 115: Synthesis of (3aR,6aR)-4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)hexahydro-2H-furo[3,2-b]pyrrol-2-one (I-774) and 2-((2R,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetic acid (I-781)

[1342] ##STR04390##

[1343] Step 1: Benzyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate. To a solution of methyl 2-((2R,3S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)acetate (280 mg) in EtOAc (8 mL) and water (3 mL) were added benzyl carbonochloridate (CBZ-Cl, 0.2 mL) and K.sub.2CO.sub.3 (200 mg). The reaction mixture was stirred at room temperature over 4 h. After the reaction mixture was diluted with EtOAc (25 mL), the organic layer was washed with water and brine, then dried over anhydrous Na.sub.2SO.sub.4. Removal of the organic solvents afforded the title product (300 mg) as oil. MASS: m/z: [M+1].sup.+: 408.

[1344] Step 2: Benzyl (2R,3S)-3-hydroxy-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate. To a solution of benzyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (300 mg) in MeOH (5 mL) were added water (0.2 mL) and conc. HCl (0.2 mL). After the resultant solution was stirred overnight, it was diluted with EtOAc (40 mL). The organic layer was washed with water and brine, then dried over anhydrous Na.sub.2SO.sub.4. Removal of the organic solvent and purification by a silica gel column afforded the title product (143 mg) as oil. MASS: m/z: [M+1].sup.+294.

[1345] Step 3: 2-((2R,3S)-1-((Benzyloxy)carbonyl)-3-hydroxypyrrolidin-2-yl)acetic acid. To a solution of benzyl (2R,3S)-3-hydroxy-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (143 mg) in MeOH (5 mL) and water (2 mL) was added LiOH.H.sub.2O (62 mg). After the resultant solution was stirred over 3 h, 12 M HCl (0.014 mL) was added to adjust the pH to 2. After the reaction mixture was extracted with EtOAc (15 mL×3), the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. Removal of the organic solvents afforded the title product (98 mg) as colorless solids. MASS: m/z: [M+1].sup.+280.

[1346] Step 4: Benzyl (3aR,6aR)-2-oxohexahydro-4H-furo[3,2-b]pyrrole-4-carboxylate. To a solution of 2-((2R,3S)-1-((benzyloxy)carbonyl)-3-hydroxypyrrolidin-2-yl)acetic acid (97 mg) in THF (8 mL) were added PPh.sub.3 (137 mg) and DEAD (0.24 mL, 40wt% in toluene). After being stirred over 4 h, the reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, then dried over anhydrous Na.sub.2SO.sub.4. After removal of the organic solvents, the residuals were purified by a silica gel column, eluting with EtOAc/Hex, to afford the title product (75 mg).

[1347] Step 5: (3aR,6aR)-Hexahydro-2H-furo[3,2-b]pyrrol-2-one. To a solution of benzyl (3aR,6aR)-2-oxohexahydro-4H-furo[3,2-b]pyrrole-4-carboxylate (75 mg) in MeOH (4 mL) were added AcOH (0.1 mL) and 5% Pd/C (20 mg). The resultant suspension was degassed (vacuum-purge) with hydrogen three times and stirred under hydrogen overnight. Filtration and concentration afforded the title product. MASS: m/z: [M+1].sup.+128.

[1348] Step 6: (3aR,6aR)-4-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)hexahydro-2H-furo[3,2-b]pyrrol-2-one (I-774) and 2-((2R,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-hydroxypyrrolidin-2-yl)acetic acid (I-781). Following the last two steps of the preparation procedures for I-786 and I-785, both title compounds were prepared. I-774, MASS: m/z: [M+1].sup.+389. I-781, MASS: m/z: [M+1].sup.+407.

Example 116: Synthesis of 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yphexahydro-6H-furo[3,4-b]pyrrol-6-one (I-775) and 1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-(hydroxymethyl)pyrrolidine-2-carboxylic acid (I-782)

[1349] ##STR04391##

[1350] Following the last two steps of the preparation procedures of I-786 and I-785, I-775 was prepared from hexahydro-6H-furo[3,4-b]pyrrol-6-one and following hydrolysis afforded I-782. I-775, MASS: m/z: [M+1].sup.+389. I-782, MASS: m/z: [M+1].sup.+407.

Example 117: Synthesis of (S)-1-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)-1H-pyrazole-5-carboxylic acid (I-727)

[1351] ##STR04392##

[1352] Step 1: Methyl (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-1H-pyrazole-5-carboxylate. To a solution tert-butyl (S)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (274 mg) in DMF (1.5 mL) were added methyl 1H-pyrazole-3-carboxylate (145.8 mg) and Cs.sub.2CO.sub.3 (377 mg). After the resultant mixture was stirred overnight, it was diluted with EtOAC. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4. Removal of solvents under reduced pressure and a silica gel column purification, eluting with a gradient between hexane and EtOAc/DCM (1:3), afforded the title product.

[1353] Step 2: (S)-1-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)-1H-pyrazole-5-carboxylic acid (I-727). The title product was prepared by the deprotection of methyl (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-1H-pyrazole-5-carboxylate with TFA/DCM, coupling with 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline, and hydrolysis with LiOH which were identical to the last three steps described above to prepare I-664. MASS: m/z: [M+1].sup.+457.

[1354] The following compounds are prepared essentially by the same methods described above for I-727.

TABLE-US-00050 MS Example Starting Material Structure [M + 1].sup.+ I-728 [04393] [04394] [04395] 457 [04396] I-732 [04397] [04398] [04399] 456 [04400] I-731 [04401] [04402] [04403] 471 I-729 [04404] [04405] 471 I-730 [04406] [04407] [04408] 471 [04409]

Example 118: Synthesis of 2-((R)-2-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyethoxy)acetic acid (I-726)

[1355] ##STR04410## ##STR04411##

[1356] Step 1: tert-Butyl (S)-2((R)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate and tert-butyl (S)-2-((S)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-formylpyrrolidine-1-carboxylate (1.92 g) in DCM (20 mL) was added TEA (2 mL) and acetone cyanohydrin (0.98 g). The resultant solution was stirred at room temperature over 40 h. After removal of DCM under reduced pressure, the residue was diluted with EtOAc (30 mL). The organic layer was washed with diluted HCl (0.5 N) and brine, then dried over anhydrous Na.sub.2SO.sub.4. The reaction mixture was purified with a silica gel column, eluting with a gradient of hexane and Hex/EtOAc/DCM (3/1/6), to afford tert-butyl (S)-2-((R)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate (1.4 g) as oil and tert-butyl (S)-2((S)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate (0.98 g) as solids.

[1357] Step 2-4: tert-Butyl (S)-2-((R)-1-hydroxy-2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-((R)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate (0.68 g) in dioxane (8 mL) was added conc. HCl (8 mL). The resultant solution was heated at reflux over 4 h. The solution was concentrated under reduced pressure to dryness. The residuals were dissolved in MeOH (10 mL) and treated with SOCl.sub.2 (0.1 mL) overnight. After removal of MeOH under reduced pressure, the residuals were suspended in DCM (10 mL) and water (4 mL) in the presence of (Boc).sub.2O (1.29 g) and Na.sub.2CO.sub.3 (954 mg) overnight. After adding DCM (15 mL), the combined DCM layers were isolated and washed with brine, then dried over anhydrous Na.sub.2SO.sub.4. A silica gel column purification afforded the title compound (0.64 g) as oil. MASS: m/z: [M+Na].sup.+282.

[1358] Step 5-6: tert-Butyl (2S)-2-((1R)-2-hydroxy-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-((R)-1-hydroxy-2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (440 mg) in DCM (6 mL) were added 3,4-dihydro-2H-pyran (336 mg) and PPTS (100 mg). The solution was stirred over 6h. After the removal of the solvents under reduced pressure, the residuals were suspended in THF (6 mL) and treated with LiBH4 (96 mg). After the resultant suspension was stirred overnight, it was slowly quenched by adding water. After the aqueous work-up with EtOAc (25 mL), the isolated organic layer was washed with brine and dried over anhydrous Na.sub.2SO.sub.4. A silica gel column purification afforded the title product (224 mg). MASS: m/z: [M+Na].sup.+338.

[1359] Step 7: tert-Butyl (2S)-2-((1R)-2-(2-(tert-butoxy)-2-oxoethoxy)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrrolidine-1-carboxylate. To an ice-chilled solution of tert-butyl (2S)-2-((1R)-2-hydroxy-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrrolidine-1-carboxylate (101 mg) in DMF (3 mL) was slowly added NaH (40 mg, 60% wt suspension in mineral oil). After the resultant solution was stirred over 20 min at 0° C., tert-butyl 2-bromoacetate (187 mg) was added. The reaction mixture was stirred at room temperature overnight and then quenched with water (0.5 mL). Aqueous workup with EtOAc and a silica gel column purification gave the title product (86 mg) as oil. MASS: m/z: [M+Na].sup.+452.

[1360] Step 8-9: 2-((R)-2-((S)-1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyethoxy)acetic acid (I-726). After tert-butyl (2S)-2-((1R)-2-(2-(tert-butoxy)-2-oxoethoxy)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrrolidine-1-carboxylate(86 mg) in DCM (0.2 mL) was treated with TFA (0.2 mL) overnight, the organic solvents were removed under reduced pressure. Additional co-evaporation with toluene/ACN helped the removal of excess of TFA. The residuals in DMSO (0.4 mL) were mixed with 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (48 mg) and Na.sub.2CO.sub.3 (32 mg). The resultant suspension was heated at 90° C. for 5 h. The reaction mixture was treated with AcOH (0.03 mL) and suspended in water. Aqueous work-up with EtOAc and a silica gel column purification with a gradient eluting between EtOAc and DCM/MeOH/AcOH (9/1/0.1) afforded the desired product (14.2 mg) as tan solids. MASS: m/z: [M+1].sup.+: 451.

Example 119: Synthesis of 2-((S)-2-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyethoxy)acetic acid (I-725)

[1361] ##STR04412##

[1362] Following the same methods described above to prepare I-726, I-725 was prepared from tert-butyl (S)-2-((S)-cyano(hydroxy)methyl)pyrrolidine-1-carboxylate. I-725: MASS: m/z: [M+1].sup.+: 451.

Example 120: Synthesis of 3-((R)-2-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxyethoxy)propanoic acid (I-724)

[1363] ##STR04413##

[1364] Following the same methods described above to prepare I-664, I-724 was prepared from tert-butyl (2S)-2-((1R)-2-hydroxy-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyrrolidine-1-carboxylate. I-724: MASS: m/z: [M+1].sup.+: 465.

Example 121: Synthesis of (S)-6-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)hexanoic acid (I-675)

[1365] ##STR04414##

[1366] Step 1: tert-Butyl (S)-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate. At 0° C., NaH (80 mg, 60% in mineral oil, 2.0 mmol) was added to a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1 mmol) in THF (5 mL). After stirring for 30 min at r.t., a solution of methyl 6-bromohexanoate (0.6 mL) in THF (1 mL) was added at 0° C. The mixture was stirred for 2 h at r.t. before quenching by H.sub.2O (1 mL) at 0° C. The organic phase was concentrated and purified by silica gel column to afford the title product (75 mg) as colorless oil. MS: [M+1].sup.+330.

[1367] Step 2: Methyl (S)-6-(pyrrolidin-2-ylmethoxy)hexanoate. To a solution of tert-butyl (S)-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate (75 mg, 0.23 mmol) in DCM (0.8 mL) was added TFA (0.8 mL) at 0° C. After stirring 1 hat r.t., the reaction mixture was concentrated to colorless oil (75 mg) under reduced pressure. The crude was used for the next step without further purification. MS: [M+1].sup.+: 230.

[1368] Step 3: Methyl (S)-6-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)hexanoate. To a solution of methyl (S)-6-(pyrrolidin-2-ylmethoxy)hexanoate (75 mg, crude from last step, about 0.2 mmol) and 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (100 mg, 0.33 mmol) in DMSO (1 mL) was added DIPEA (0.1 mL). The mixture was stirred at 80° C. overnight. After cooling to r.t., H.sub.2O (10 mL) was added. The mixture was acidified to pH.=1 by 1 N HCl and the precipitate was collected by filtration. Purification by silica gel column afforded the title product (100 mg) as colorless oil. MS: [M+1].sup.+491.

[1369] Step 4: (S)-6-((1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)hexanoic acid. To a solution of methyl (S)-6-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)hexanoate (100 mg, 0.2 mmol) in THF (2 mL) was added LiOH (aq., 1 M. 0.4 mL) at 0° C. The mixture was stirred at 50° C. overnight. After cooling to r.t., H.sub.2O (3 mL) and 1 N HCl (0.35 mL) was added. The precipitate was collected by filtration to afford the title product (80 mg) as white solid. MS: [M+1].sup.+477.

[1370] The following compounds are prepared essentially by the same method described above to prepare I-675.

TABLE-US-00051 MS Example Starting Material Structure [M + 1].sup.+ I-676 [04415] [04416] [04417] 463 [04418] I-723 [04419] [04420] [04421] 461 [04422]

Example 122: Synthesis of tert-Butyl (S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate

[1371] ##STR04423##

[1372] At 0° C., LAH (1.2 eq.) was added to a solution of (5)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (4 g, 17 mmol) in THF (75 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched by H.sub.2O (3 mL), 15% NaOH (3 mL) and H.sub.2O (9 mL) respectively at 0° C. After filtration, the filtrate was purified by silica gel column to afford the title product (2.3 g) as colorless oil. MS: [M+1].sup.+216.

Example 123: Synthesis of tert-Butyl (S)-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate

[1373] ##STR04424##

[1374] Step 1: tert-Butyl (S,E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (398 mg, 2 mmol) in THF (8 mL) was added Ph.sub.3P═CHCOOMe (700 mg, 2.2 mmol). The mixture was stirred at 50° C. overnight. After cooling to r.t., the mixture was concentrated by vacuum and purified by silica gel chromatography to afford the title product (430 mg) as colorless oil. MS: [M+1].sup.+256.

[1375] Step 2: tert-Butyl (S)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S,E)-2-(3-methoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (800 mg, 3.1 mmol) in MeOH (10 mL) was added Pd/C (10%, 40 mg). The mixture was stirred under H.sub.2 (1 atm) over night. After filtration, the filtrate was concentrated and afford the title product (800 mg) as colorless oil which was used directly without purification. MS: [M+1].sup.+258.

[1376] Step 3: tert-Butyl (S)-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate. The procedure was essentially the same as described above for the preparation of tert-butyl (S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate. MS: [M+1].sup.+230.

Example 124: Synthesis of tert-Butyl (R)-2-(4-methoxy-4-oxobutyl)pyrrolidine-1-carboxylate

[1377] ##STR04425##

[1378] Step 1: tert-Butyl (S)-2-(2-oxoethyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (340 mg, 1.5 mmol) in DCM (6 mL) and pyridine (1 mL) was added DMP (800 mg) at 0° C. The mixture was stirred at r.t. for 2 h and quenched by Na.sub.2S.sub.2O.sub.3/NaHCO.sub.3 (sat., 10 mL). The organic phase was concentrated by vacuum and purified by silica gel chromatography to afford the title product (280 mg) as colorless oil. MS: [M+1].sup.+214.

[1379] Step 2 and step 3 were essentially the same procedure as described above to prepare tert-butyl (S)-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate preparation (Step 1 and Step 2).

Example 125: Synthesis of tert-Butyl (R)-2-(5-methoxy-5-oxopentyl)pyrrolidine-1-carboxylate

[1380] ##STR04426##

[1381] tert-butyl (R)-2-(5-methoxy-5-oxopentyl)pyrrolidine-1-carboxylate was prepared essentially by the same method described above to prepare tert-butyl (R)-2-(4-methoxy-4-oxobutyl)pyrrolidine-1-carboxylate.

Example 126: Synthesis of Ethyl (2S,3S,4R)-3-hydroxy-4-methylpyrrolidine-2-carboxylate and ethyl (2S,3S,4R)-4-hydroxy-3-methylpyrrolidine-2-carboxylate

[1382] ##STR04427##

[1383] The two intermediates were prepared according the method described in WO 2011/091407, the content of which in herein incorporated by reference.

Example 127: Synthesis of methyl (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)amino)propanoate (I-753) and dimethyl 3,3′-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)azanediyl)(S)-dipropionate (I-757)

[1384] ##STR04428## ##STR04429##

[1385] Step 1: tert-Butyl (S)-2-(azidomethyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg, 2 mmol), Ph.sub.3P (800 mg, 3 mmol) and NaN.sub.3 (200 mg, 3 mmol) in THF (10 mL) was added DEAD (0.47 mL, 3 mmol). The reaction was stirred over night at r.t. After evaporation, the crude was purified by silica gel chromatography to afford the title product (280 mg) as colorless oil. MS: [M+1].sup.+227.

[1386] Step 2 and step 3 were essentially the same as the procedure described above to prepare I-675 (Step 2 and Step 3).

[1387] Step 4: (S)-(1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methanamine To a solution of (S)-2-(2-(azidomethyl)pyrrolidin-1-yl)-7,8-dichloro-4-(1H-imidazol-1-yl)quinoline (190 mg, 0.5 mmol) in THF (3 mL) and H.sub.2O (1 mL) was added Ph.sub.3P (262 mg, 1 mmol). The mixture was stirred over night at r.t. After evaporation, the crude was purified by silica gel chromatography to afford the title product (160 mg) as white solid. MS: [M+1].sup.+362.

[1388] Step 5: Methyl (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)amino)propanoate (I-753) and dimethyl 3,3′-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)azanediyl)(S)-dipropionate (I-757). To a solution of (S)-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methanamine (160 mg) and methyl 3-bromopropanolate (50 mg, 0.44 mmol) was added K.sub.2CO.sub.3 (60 mg). The mixture was stirred at 50° C. overnight. After filtration, the crude was purified by silica gel chromatography to afford the titled compounds I-753 (45 mg, MS: [M+1].sup.+448) and I-757 (2.5 mg, MS: [M+1].sup.+534) as white solid.

Example 128: Synthesis of (5)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)amino)propanoic acid (I-756)

[1389] ##STR04430##

[1390] The procedure was essentially the same as the preparation described above for I-675 (Step 4). MS: [M+1].sup.+434.

Example 129: Synthesis of methyl (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)(methyl)amino)propanoate (I-755) and (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)(methyl)amino)propanoic acid (I-754)

[1391] ##STR04431##

[1392] Step 1: Methyl (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)(methyl)amino)propanoate (I-755). To a solution of methyl (S)-3-(((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)amino)propanoate (19 mg, 0.05 mmol), paraformaldehyde (6 mg, 0.2 mmol), HOAc (0.025 mL) in MeOH (1 mL) was added NaBH.sub.3CN (13 mg, 0.2 mmol). The mixture was stirred at r.t. over night. After evaporation, the crude was purified by silica gel chromatography to afford the title product (15 mg). MS: [M+1].sup.+462.

[1393] Step 2: (S)-3-(((1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methyl)(methyl)amino)propanoic acid (I-754). The procedure was essentially the same that described above for the preparation of I-675 (Step 4). MS: [M+1].sup.+448.

[1394] The following compounds are prepared essentially by the same method described above to prepare I-123.

TABLE-US-00052 MS Example Starting Material Structure [M + 1].sup.+ I-776 [04432] [04433] [04434] 391 I-687 [04435] [04436] [04437] 417 I-680 [04438] [04439] [04440] 419 I-679 [04441] [04442] [04443] 405 I-682 [04444] [04445] [04446] 419 I-685 [04447] [04448] [04449] 417 I-686 [04450] [04451] [04452] 431 I-681 [04453] [04454] [04455] 433 I-683 [04456] [04457] [04458] 433 I-684 [04459] [04460] [04461] 433 I-678 [04462] [04463] [04464] 435 I-779 [04465] [04466] [04467] 435 I-780 [04468] [04469] [04470] 407 I-778 [04471] [04472] [04473] 407 I-690 [04474] [04475] [04476] 393 I-739 [04477] [04478] [04479] 433 I-691 [04480] [04481] [04482] 407 I-758 [04483] [04484] [04485] 408 I-759 [04486] 394

Example 130: Synthesis of (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)benzoic acid (I-735)

[1395] ##STR04487##

[1396] Step 1: tert-Butyl (S)-2-((3-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate. To a stirred mixture of Boc-prolinol (300 mg, 1.49 mmol), methyl-3-hydroxybenzoate (240 mg, 1.45 mmol) and triphenylphosphine (391 mg, 1.49 mmol) in THF (10 mL) was added dropwise diethyl azodicarboxylate (261 mg, 0.65 mL, 1.49 mmol (40% in toluene)). The resulting mixture was heated at 75° C. for 3 h. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed successively with 1N NaOH, water and then brine. The organics were dried (Na.sub.2SO.sub.4) then concentrated. The residue was purified by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent to afford the title compound. MS: [M+1].sup.+280.1 (-t-Bu).

[1397] Step 2: Methyl (S)-3-(pyrrolidin-2-ylmethoxy)benzoate. To a flask containing tert-butyl (S)-2-((3-(methoxycarbonyl)phenoxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.546 mmol) was added dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the reaction allowed to stir at rt for 16 h. The volatiles were removed to afford the title compound which was taken onward without further purification. MS: [M+1].sup.+236.1.

[1398] Step 3: Methyl (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)benzoate. To a vial containing methyl (S)-3-(pyrrolidin-2-ylmethoxy)benzoate (70 mg, 0.3 mmol) was added DMSO (0.15 mL) and DIPEA (0.10 mL). Next 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) was added and the mixture heated to 90° C. for 16 h. The reaction was cooled to rt, then water was added and the organics extracted into 10% MeOH/CH.sub.2Cl.sub.2. The combined organic layers were dried (Na.sub.2SO.sub.4) then concentrated. The residue was purified by silica gel chromatography using 0-5% MeOH/CH.sub.2Cl.sub.2 with 0.5% HOAc as eluent to afford the title compound. MS: [M+1].sup.+497.1.

[1399] Step 4: (S)-3-((1-(7,8-Dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)benzoic acid. To a vial containing methyl (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)benzoate (20 mg, 0.040 mmol) THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (5 mg, 0.12 mmol) and the reaction allowed to stir at rt for 16 h. The volatiles were removed and the residue taken up in water then acidified with 1M HCl until pH˜7. The resulting solids were filtered off and vac-dried to afford the title compound. MS: [M+1].sup.+483.1.

[1400] The following compounds were prepared essentially by the same methods described above to prepare I-735:

TABLE-US-00053 MS Example Starting Material Structure [M + 1].sup.+ I-733 [04488] [04489] [04490] 483.1 I-737 [04491] [04492] [04493] 483.1 I-736 [04494] [04495] [04496] 497.1 I-738 [04497] [04498] [04499] 497.1 I-734 [04500] [04501] [04502] 497.1 I-842 [04503] [04504] [04505] 457 I-843 [04506] [04507] [04508] 471 I-846 [04509] [04510] [04511] 471

Example 131: Synthesis of methyl (S)-2-(2-(pyrrolidin-2-ylmethoxy)phenyl)acetate

[1401] ##STR04512##

[1402] Step 1: tert-Butyl (S)-2-((2-(2-methoxy-2-oxoethyl)phenoxy)methyl)pyrrolidine-1-carboxylate. To a flask containing tert-butyl (S)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (355 mg, 1.00 mmol), methyl 2-(2-hydroxyphenyl)acetate (166 mg, 1.00 mmol) and DMF (10 mL) was added potassium tert-butoxide (112 mg, 1.00 mmol) and the reaction was heated at 55° C. for 16 h. The reaction was cooled to rt, quenched by the slow addition of water then diluted with ethyl acetate. The organic layer was separated and washed further with 5% NaOH, water, and brine then dried (Na.sub.2SO.sub.4) and concentrated. The resulting residue purified by silica gel chromatography using 0-35% EtOAc/hexanes as eluent to afford to title compound. (MS: [M+1].sup.+250.1 (-Boc).

[1403] Step 2: Methyl (S)-2-(2-(pyrrolidin-2-ylmethoxy)phenyl)acetate. To a vial containing tert-butyl (S)-2-((2-(2-methoxy-2-oxoethyl)phenoxy)methyl)pyrrolidine-1-carboxylate (25 mg, 0.061 mmol) was added dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction allowed to stir at rt for 16 h. The volatiles were removed to afford the title compound used to prepare I-735. MS: [M+1].sup.+250.1.

Example 132: Synthesis of 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethoxy)benzoic acid (I-885)

[1404] ##STR04513##

[1405] Step 1: Methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate: To a flask containing methyl 3-hydroxybenzoate (152 mg, 1.0 mmol) and DMF (5 mL) was added potassium carbonate (152 mg, 1.1 mol). The contents were stirred at rt for 10 min then tert-butyl (2-bromoethyl)carbamate (246 mg, 1.1 mmol) was added. The reaction was heated to 65° C. for 16h. Upon cooling, water (10 mL) was added and the organics were extracted into ethyl acetate (2×10 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography to afford 175 mg of the titled compound.

[1406] Step 2: Methyl 3-(2-aminoethoxy)benzoate TFA salt: To a flask containing methyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (120 mg, 0.4 mmol) and dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction was allowed to stir at rt for 16h. The volatiles were concentrated off to afford crude titled compound which was taken on directly to the next step.

[1407] Step 3: Methyl 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethoxy)benzoate: To a vial containing 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (30 mg, 0.1 mmol) and DMSO was added methyl 3-(2-aminoethoxy)benzoate TFA salt (0.4 mmol) and DIPEA. The reaction was heated to 90° C. for 16 h then cooled to rt. Water (5 mL) was added and the organics extracted into ethyl acetate (2×5 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by silica gel chromatography to afford 27 mg of the titled compound.

[1408] Step 4: 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethoxy)benzoic acid: To a vial containing methyl 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)ethoxy)benzoate (20 mg, 0.44 mmol) in THF/H.sub.2O (4 mL/1 mL) was added lithium hydroxide monohydrate (7 mg, 0.175 mmol) and the reaction allowed to stir at rt for 16 h. The volatiles were removed and then residue acidified with 1M HCl. The resulting solids were filtered and dried to afford the titled compound.

[1409] The following compounds are prepared essentially by the same method described above to prepare I-885.

TABLE-US-00054 MS Example Starting Material Structure [M + 1].sup.+ I-886 [04514] [04515] [04516] 443 [04517] I-889 [04518] [04519] [04520] 417 [04521]

Example 133: Synthesis of 4-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxybutanoic acid (I-817)

[1410] ##STR04522##

[1411] Step 1: tert-butyl (2S)-2-(3-cyano-3-hydroxypropyl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-(3-oxopropyl)pyrrolidine-1-carboxylate (114 mg, 0.5 mmol) in DCM (1 mL) was added Et.sub.3N (0.1 mL) and acetone cyanohydrin (0.1 mL, 1.2 mmol). The mixture was stirred at r.t. over night. The solution was concentrated by vacuum and purified by silica gel column to afford the title product (120 mg) as colorless oil. MS: [M+1].sup.+255.

[1412] Step 2: 2-hydroxy-4-((S)-pyrrolidin-2-yl)butanoic acid. To a solution of tert-butyl (2S)-2-(3-cyano-3-hydroxypropyl)pyrrolidine-1-carboxylate (60 mg, 0.23 mmol) in dioxane (0.8 mL) was added HCl (con., 0.8 mL). The mixture was stirred at 100° C. overnight. After cooling to r.t., dioxane was removed by evaporation. The residue was washed by EtOAc (0.5 mL×2). The aqueous phase was collected and evaporated to give a crude product which was used directly in the next step without purification. MS: [M+1].sup.+174.

[1413] Step 3: 4-((S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)-2-hydroxybutanoic acid (I-817). The title compound was prepared essentially by the same methods as for I-664. MS: [M+1].sup.+435.

[1414] Synthesis of (S)-4-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)but-2-ynoic acid (I-819)

##STR04523##

[1415] Step 1: tert-butyl (S)-2-(prop-2-yn-1-yl)pyrrolidine-1-carboxylate.To a solution of tert-butyl (S)-2-(2-oxoethyl)pyrrolidine-1-carboxylate (457 mg, 2.15 mmol) in MeOH (4.5 mL) was added K.sub.2CO.sub.3 (594 mg, 4.3 mmol) and diazole (480 mg, 3.22 mmol). The mixture was stirred at r.t. over night. The mixture was concentrated by vacuum and purified by silica gel column to afford the title product (330 mg) as colorless oil. MS: [M+1].sup.+210.

[1416] Step 2: tert-butyl (S)-2-(4-methoxy-4-oxobut-2-yn-1-yl)pyrrolidine-1-carboxylate. To a solution of tert-butyl (S)-2-(prop-2-yn-1-yl)pyrrolidine-1-carboxylate (330 mg, 1.58 mmol) in THF (3.5 mL) was added n-BuLi (1.1 mL, 1.6 M in hexane) at −78° C. After 30 min, a solution of methyl chloroformate (0.15 mL) in THF (1 mL) was added dropwise. The mixture was warmed to r.t. and stirred over night. The reaction was then quenched by NH.sub.4Cl (sat., 0.5 mL). The mixture was concentrated by vacuum and purified by silica gel column to afford the title product (200 mg) as colorless oil. MS: [M+1].sup.+268.

[1417] (S)-4-(1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)but-2-ynoic acid (I-819) is prepared essentially by the same methods as for I-664 from tert-butyl (S)-2-(4-methoxy-4-oxobut-2-yn-1-yl)pyrrolidine- 1-carboxylate. MS: [M+1].sup.+415.

Example 134: Synthesis of (S)-3-((1-(7-chloro-4-(1H-imidazol-1-yl)-8-phenylquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-863)

[1418] ##STR04524##

[1419] A mixture of (S)-3-((1-(8-bromo-7-chloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (14 mg, 0.03 mmol), Na.sub.2CO.sub.3 (10 mg, 0.14 mmol), dioxane (1 mL) and H.sub.2O (0.5 mL) was purged by N.sub.2 for 10 min. Tetrakis (1 mg, 0.001 mmol) was added. The mixture was stirred at 80° C. for 3 h. The mixture was concentrated by vacuum and purified by silica gel column to afford I-863 (6 mg) as white solid. MS: [M+1].sup.+477.

Example 135: Synthesis of 3-(((S)-1-(7,8-dichloro-4-((R)-3-hydroxypyrrolidin-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-821)

[1420] ##STR04525## ##STR04526##

[1421] Step 1: tert-butyl (S)-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)pyrrolidine-1-carboxylate. The procedure was the same as that in the synthesis of I-665.

[1422] Step 2: (S)-3-(pyrrolidin-2-ylmethoxy)propanoic acid. The procedure was the same as that in the synthesis of I-665.

[1423] Step 3: methyl (S)-3-(pyrrolidin-2-ylmethoxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1424] Step 4: methyl (S)-3-((1-(4,7,8-trichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1425] Step 5: methyl 3-(((S)-1-(7,8-dichloro-4-((R)-3-hydroxypyrrolidin-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate. To a vial were added methyl (S)-3-((1-(4,7,8-trichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate (21 mg, 0.050 mmol), (R)-pyrrolidin-3-ol (22 mg, 0.25 mmol), Na.sub.2CO.sub.3 (5.3 mg, 0.050 mmol) and DMSO (0.5 ml). The reaction mixture was stirred at 60° C. over-night. After simple work-up, the crude was purified by silica gel chromatography to afford the title product (9.2 mg). (MS: [M+1].sup.+454)

[1426] Step 6: 3-(((S)-1-(7,8-dichloro-4-((R)-3-hydroxypyrrolidin-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid. The procedure was the same as that in the synthesis of I-665. (MS: [M+1].sup.+454)

Example 136: Synthesis of (S)-3-((1-(7,8-dichloro-4-(4-methyl-1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-825)

[1427] ##STR04527##

[1428] Step 1: (S)-(1-(4,7,8-trichloroquinolin-2-yl)pyrrolidin-2-yl)methanol. The procedure was the same as that in the synthesis of I-287.

[1429] Step 2: (S)-(1-(7,8-dichloro-4-(4-methyl-1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methanol. The procedure was the same as that in the synthesis of I-821.

[1430] Step 3: tert-butyl (S)-3-((1-(7,8-dichloro-4-(4-methyl-1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1431] Step 4: (S)-3-((1-(7,8-dichloro-4-(4-methyl-1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-825). To a vial were added tert-butyl (S)-3-((1-(7,8-dichloro-4-(4-methyl-1H-imidazol-1-yl)quinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate (13 mg, 0.0257 mmol) and HCl in 1,4-dioxane (4 N, 0.3 ml). The mixture was stirred at room temperature for 3 hours. All volatiles were removed under reduced pressure. After lyophilization, the tilte compound was obtained as HCl salt (11 mg). (MS: [M+1].sup.+449)

Example 137: Synthesis of (±)3-(((2S,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-(methoxycarbonyl)pyrrolidin-3-yl)methoxy)propanoic acid (I-813)

[1432] ##STR04528##

[1433] Step 1: (±)(3aR,6aS)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)hexahydro-6H-furo[3,4-b]pyrrol-6-one. The procedure was the same as that in the synthesis of I-665.

[1434] Step 2: (±)methyl (2S,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-3-(hydroxymethyl)pyrrolidine-2-carboxylate. The crude product in step 1 was treated with TEA (20 μl, 0.143 mmol) and methanol (0.5 ml) for 18 hours. After removing all volatiles, the crude was used in next step.

[1435] Step 3: (±)methyl (2S,3R)-3-((3-(tert-butoxy)-3-oxopropoxy)methyl)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)pyrrolidine-2-carboxylate. The procedure was the same as that in the synthesis of I-665.

[1436] Step 4: (±)3-(((2S,3R)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-2-(methoxycarbonyl)pyrrolidin-3-yl)methoxy)propanoic acid. The procedure was the same as that in the synthesis of I-665. The tilte compound was obtained as TFA salt (17 mg). (MS: [M+1].sup.+493)

Example 138: Synthesis of (S)-3-((1-(4-(6-aminopyridin-3-yl)-7,8-dichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid (I-822)

[1437] ##STR04529##

[1438] Step 1: methyl (S)-3-((1-(4-(6-aminopyridin-3-yl)-7,8-dichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate. To a flask were added methyl (S)-3-((1-(4,7,8-trichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoate (104 mg, 0.25 mmol), 1,4-dioxane (8.0 ml), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (110 mg, 0.50 mmol), NaHCO.sub.3 (62 mg, 0.75 mmol), Pd(dppf)Cl.sub.2—CH.sub.2Cl.sub.2(41 mg, 0.050 mmol) and H.sub.2O (1.0 ml). After degassed with N.sub.2 for 4 times, the reaction mixture was stirred at 100° C. for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with H.sub.2O, brine and dried over Na.sub.2SO.sub.4. After concentration the crude was purified by silica gel column to afford the title product (90 mg).

[1439] Step 2: (S)-3-((1-(4-(6-aminopyridin-3-yl)-7,8-dichloroquinolin-2-yl)pyrrolidin-2-yl)methoxy)propanoic acid. The procedure was the same as that in the synthesis of I-636. The tilte compound was obtained as free acid. (MS: [M+1].sup.+461)

[1440] The following compounds are prepared essentially by the same methods as for I-822.

TABLE-US-00055 MS Example Starting Material Structure [M + 1].sup.+ I-823 [04530] [04531] [04532] 435 I-824 [04533] [04534] [04535] 435 I-826 [04536] [04537] [04538] 449

Example 139: Synthesis of 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)oxy)ethoxy)propanoic acid (I-828)

[1441] ##STR04539##

[1442] Step 1: 2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-ypoxy)ethan-1-ol. The procedure was the same as that in the synthesis of I-277.

[1443] Step 2: tert-butyl 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)oxy)ethoxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1444] Step 3: 3-(2-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)oxy)ethoxy)propanoic acid. The procedure was the same as that in the synthesis of I-825. The title compound was obtained as HCl salt. (MS: [M+1].sup.+396)

Example 140: Synthesis of 3-((3-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzypoxy)propanoic acid (I-840)

[1445] ##STR04540##

[1446] Step 1: (3-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)phenyl)methanol. The procedure was the same as that in the synthesis of I-822.

[1447] Step 2: tert-butyl 3-((3-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzyl)oxy)propanoate. The procedure was the same as that in the synthesis of I-665.

[1448] Step 3: 3-((3-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)benzypoxy)propanoic acid. The procedure was the same as that in the synthesis of I-825. The title compound was obtained as HCl salt. (MS: [M+1].sup.+442)

[1449] The following compounds are prepared essentially by the same methods as for I-840.

TABLE-US-00056 MS Example Starting Material Structure [M + 1].sup.+ I-841 [04541] [04542] [04543] 442 I-877 [04544] [04545] [04546] 456 I-878 [04547] [04548] [04549] 476 I-879 [04550] [04551] [04552] 476 I-880 [04553] [04554] [04555] 456 I-884 [04556] [04557] [04558] 472

Example 141: Synthesis of 5-chloro-2-(3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(isopropyl)amino) propoxy) benzoic acid (I-848)

[1450] ##STR04559##

[1451] Step 1: 3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(isopropyl)amino)propan-1-ol. To a mixture of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (1.074 g), 3-(isopropylamino)propan-1-ol (0.53 g) and Na.sub.2CO.sub.3 (0.96 g) was added DMSO (3.4 mL). The resultant suspended solution was heated at 105° C. overnight. After cooling down to room temperature, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL). The isolated organic layer was washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After concentration under reduced pressure, the residues were purified by silica gel column chromatography, eluting with a gradient of hexane and EtOAc (5% MeOH), to afford the tile compound (654 mg) as light brown solid. MS: [M+1].sup.+379.

[1452] Step 2: 3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl(isopropyl)amino)propyl 4-methylbenzenesulfonate. To a suspension of 3-((7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2-yl) (isopropyl)amino)propan-1-ol (654 mg), DMAP (45 mg) and TsCl (228 mg) in DCM (10 mL) was added TEA (0.3 mL). After the reaction mixture was stirred over 3 hours, it was diluted with DCM (20 mL). The resultant organic solution was washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure afforded the crude title compound (610 mg), which was used in the next step without further purification. MS: [M+1].sup.+533.

[1453] Step 3: methyl 5-chloro-2-(3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(isopropyl)amino)propoxy)benzoate. To a solution of 3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl(isopropyl)amino)propyl 4-methylbenzenesulfonate (32 mg) and methyl 5-chloro-2-hydroxybenzoate (13.5 mg) in anhydrous DMF (0.5 mL) was added anhydrous K.sub.2CO.sub.3 (10 mg). After the reaction mixture was stirred over 3 hat 55° C., it was diluted with water (4 mL) and EtOAc (15 mL). The organic layer was isolated, washed with brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. Concentration under reduced pressure and purification by silica gel column chromatography, eluting with a gradient of hexane and EtOAc (5% MeOH), afforded the tile compound (24 mg). MS: [M+1].sup.+547.

[1454] Step 4: 5-chloro-2-(3-((7,8-dichloro-4-(1H-imidazol-1-yl) quinolin-2-yl) (isopropyl)amino) propoxy) benzoic acid (I-848). To a suspension of methyl 5-chloro-2-(3-((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)(isopropyl)amino)propoxy)benzoate (24 mg) in MeOH (0.4 mL) and water (0.1 mL) was added LiOH.H.sub.2O (10.2 mg). After stirring over 1 h, THF (0.2 mL) was added. A clear solution was afforded after the reaction mixture was stirred overnight. The reaction progress was monitored by LC/MS. After concentration under reduced pressure removed the volatiles, the residues were suspended in water (0.2 mL) and treated with HOAc (0.015 mL). After sonicating over 5 min, the solid was collected by centrifuge and lyophilized to afford the tile compound (13 mg). MS: [M+1].sup.+533.

[1455] The following compounds were prepared essentially by the same methods as described above for I-848.

TABLE-US-00057 MS Example Starting Material Structure [M + 1].sup.+ I-849 [04560] [04561] [04562] 529 I-850 [04563] [04564] [04565] 517 I-851 [04566] [04567] [04568] 500 I-852 [04569] [04570] [04571] 499 I-847 [04572] [04573] [04574] 505

Example 142: Synthesis of (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-oxopyrrolidin-2-yl)methoxy)propanoic acid (I-812)

[1456] ##STR04575##

[1457] Step 1: (S)-1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-(hydroxymethyl)pyrrolidin-2-one. To a mixture of 2,7,8-trichloro-4-(1H-imidazol-1-yl)quinoline (200 mg), bis(dibenzylidenacetone)palladium(0) (20 mg), Rac-BINAP (14 mg), (S)-5-(hydroxymethyl)pyrrolidin-2-one (92 mg) and Cs.sub.2CO.sub.3 (441 mg) were added anhydrous dioxane (6 mL) under N.sub.2. The resultant mixtures were degassed three cycles via vacuum and purging with N.sub.2. The resultant mixture was heated and stirred at 100° C. overnight under N.sub.2. After the aqueous work-up with EtOAc, the isolated organic layer was dried over anhydrous. Na.sub.2SO.sub.4. After concentration under reduced pressure, the residues were purified by silica gel column chromatography, eluting with a gradient of hexane and EtOAc (5% MeOH), to afford the title compound (28 mg). MS: [M+1].sup.+377.

[1458] Step 2: tert-butyl (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-oxopyrrolidin-2-yl)methoxy)propanoate. Following the same preparation procedure as described in step 3 of I-825, the tile compound was prepared. MS: [M+1].sup.+505.

[1459] Step 3: (S)-3-((1-(7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)-5-oxopyrrolidin-2-yl)methoxy)propanoic acid (I-812). Following the same preparation procedure as described in step 4 of I-825, the tile compound was prepared. MS: [M+1].sup.+449.

Example 143: Synthesis of methyl 2-(3-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)-5-fluorophenyl)acetate (I-890) and 2-(3-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)-5-fluorophenyl)acetic acid (I-891)

[1460] ##STR04576##

[1461] Step 1: methyl 2-(3-fluoro-5-methylphenyl)acetate. To a solution of 2-(3-fluoro-5-methylphenyl)acetic acid (336 mg, 2 mmol) in MeOH (4 mL) and DMF (0.01 mL) was added SOCl.sub.2 (0.22 mL, 3 mmol) dropwise at 0° C. The solution was warmed to r.t. and stirred for 2 h. After evaporation, the reaction was quenched by NaHCO.sub.3 (sat., 2 mL) and extracted by EtOAc (5 mL×2). The organic phase was collected and evaporated to give crude product which was used directly for next step without purification.

[1462] Step 2: methyl 2-(3-(bromomethyl)-5-fluorophenyl)acetate. To a solution of crude from step 1 in CCl.sub.4 (5 mL) was added NBS (392 mg, 2.2 mmol) and benzoyl peroxide (10 mg). The mixture was stirred at 75° C. overnight. After cooling down to r.t., the solution was concentrated and purified by silica gel column to afford the title product (150 mg) as colorless oil.

[1463] Step 3: methyl 2-(3-(azidomethyl)-5-fluorophenyl)acetate. To a solution of methyl 2-(3-(bromomethyl)-5-fluorophenyl)acetate (50 mg, 0.19 mmol) in DMF (1 mL) was added NaN.sub.3 (19 mg, 0.29 mmol). The mixture was stirred at 75° C. overnight. After cooling down to r.t., the mixture was diluted by H.sub.2O (2 mL) and extracted by EtOAc (3 mL×2). The organic phase was collected and evaporated to give a crude product which was used directly for next step without purification.

[1464] Step 4: methyl 2-(3-(aminomethyl)-5-fluorophenyl)acetate. The Staudinger reaction is performed essentially the same as for I-757.

[1465] Step 5: methyl 2-(3-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)-5-fluorophenyl)acetate (I-890). I-890 is prepared essentially by the same methods as for I-664. MS: [M−1].sup.−457.

[1466] Step 6: 2-(3-(((7,8-dichloro-4-(1H-imidazol-1-yl)quinolin-2-yl)amino)methyl)-5-fluorophenyl)acetic acid (I-891). I-891 is prepared essentially by the same methods as for I-714. MS: [M−1].sup.−443.

Example 144: Biology

[1467] Expression and Purification of Recombinant cGAS Protein: cDNA encoding full-length or amino acids 147-520 of human cGAS was inserted into a modified pET28a vector containing an in-frame His6-SUMO tag. The E. coli strain BL21/pLys harboring the plasmid was induced with 0.5 mM IPTG at 18° C. overnight. His6-SUMO tag was removed by a SUMO protease digestion following purification of the His6- SUMO-cGAS as described previously (Sun et al, 2013, Science 339, 786).

[1468] In vitro inhibition assay of cGAS activity: A 60 μL mixture containing 20 mM Tirs-Cl, pH 7.5, 5 mM MgCl.sub.2, 0.2 mg/mL BSA, 0.01 mg/mL Herring testis DNA, 6.6 μM ATP, 0.1 mM GTP, 1.5 μg/mL of recombinant human cGAS (aa147-522) and serial dilutions of a test compound in DMSO was added to a 96-well plate and incubated at 37° C. for 20 minutes. At the end of reaction, 40 μL of KinaseGlo Max (Promega) was added and chemiluminescence was measured with a luminometer. Inhibitory effect of a compound is evaluated by plotting percentage of ATP consumption against logarithm of compound concentrations. IC.sub.50 value was calculated using GraphPad Prism 8 (GraphPad Software, Inc.).

[1469] The results of the cGAS inhibition assay for compounds of the disclosure are presented in Table 2 and Table 3. The letter codes for cGAS IC.sub.50 include: A (<2 μM); B (2-30 μM); C (>30 μM).

TABLE-US-00058 TABLE 2 cGAS Inhibition Results I-# IC.sub.50 I-1 B I-2 B I-3 C I-4 B I-5 B I-6 A I-7 B I-8 B I-9 C I-10 B I-11 B I-12 C I-13 C I-14 C I-15 A I-16 C I-17 B I-18 B I-19 A I-20 A I-21 A I-22 A I-23 A I-24 A I-25 C I-26 A I-27 C I-28 A I-29 A I-30 B I-31 C I-32 A I-33 B I-34 C I-35 B I-36 C I-37 C I-38 C I-39 A I-40 C I-41 A I-42 A I-43 A I-44 C I-45 B I-46 A I-47 A I-48 A I-49 C I-50 A I-51 C I-52 C I-53 B I-54 B I-55 A I-56 B I-57 B I-58 C I-59 C I-60 C I-61 C I-62 C I-63 C I-64 C I-65 C I-66 C I-67 B I-68 C I-69 C I-70 C I-71 C I-72 C I-73 C I-74 C I-75 C I-76 B I-77 C I-78 C I-79 A I-80 A I-81 A I-82 A I-83 B I-84 B I-85 A I-86 A I-87 B I-88 B I-89 B I-90 C I-91 A I-92 A I-93 A I-94 A I-95 B I-96 A I-97 B I-98 B I-99 B I-100 A I-101 A I-102 B I-103 B I-104 B I-105 B I-106 B I-107 C I-108 C I-109 C I-110 A I-111 A I-112 A I-113 A I-114 B I-115 A I-116 A I-117 B I-118 A I-119 B I-120 A I-121 B I-122 B I-123 B I-124 A I-125 A I-126 B I-127 B I-128 B I-130 B I-131 B I-132 B I-133 A I-134 B I-135 C I-136 B I-137 B I-138 A I-139 A I-140 B I-141 A I-142 A I-143 A I-144 A I-145 A I-147 A I-148 A I-149 A I-150 A I-151 A I-152 B I-153 B I-154 A I-155 B I-156 A I-157 B I-158 A I-159 A I-160 A I-161 C I-162 C I-163 C I-164 B I-165 A I-166 B I-167 A I-168 A I-169 A I-170 A I-171 C I-172 B I-173 B I-174 A I-175 A I-176 B I-177 B I-178 B I-179 B I-180 B I-181 C I-182 B I-183 A I-184 A I-185 B I-186 A I-187 B I-188 B I-189 B I-190 A I-191 A I-192 A I-193 B I-194 A I-195 A I-196 A I-197 A I-198 A I-199 B I-200 A I-201 A I-202 A I-203 A I-204 A I-205 A I-206 B I-207 A I-208 B I-209 C I-210 B I-211 B I-212 B I-213 B I-214 B I-215 B I-216 B I-217 C I-218 A I-219 A I-220 B I-221 A I-222 A I-223 A I-224 A I-225 A I-226 B I-227 C I-228 C I-229 C I-230 B I-231 B I-232 B I-234 A I-235 A I-236 B I-237 B I-238 A I-239 A I-240 A I-241 A I-242 A I-243 A I-244 A I-245 A I-246 B I-247 B I-248 A I-249 A I-250 A I-251 C I-252 B I-253 A I-254 A I-255 A I-256 A I-257 A I-258 A I-259 C I-260 A I-261 C I-262 A I-263 C I-264 A I-265 C I-266 C I-267 C I-268 C I-269 C I-270 A I-271 B I-272 B I-273 B I-274 B I-275 C I-276 A I-277 B I-278 B I-279 C I-280 C I-281 B I-282 B I-283 C I-284 C I-285 A I-286 A I-287 A I-288 A I-289 B I-290 B I-291 B I-292 B I-293 B I-294 C I-295 C I-296 C I-297 C I-298 C I-299 C I-300 C I-301 C I-302 C I-303 C I-304 C I-305 C I-306 C I-307 C I-308 C I-309 C I-310 C I-311 C I-312 C I-313 C I-314 C I-315 C I-316 C I-317 C I-318 C I-319 C I-320 A I-321 A I-322 A I-323 A I-324 A I-325 A I-326 A I-327 A I-328 A I-329 A I-330 A I-331 B I-332 A I-333 C I-334 C I-335 A I-336 B I-337 A I-338 A I-339 A I-340 A I-341 A I-342 A I-343 B I-344 A I-345 A I-346 A I-347 A I-348 C I-349 A I-350 A I-351 A I-352 B I-353 C I-354 C I-355 B I-356 C I-357 B I-358 B I-359 B I-360 A I-361 B I-362 C I-363 B I-364 B I-365 C I-366 B I-367 C I-368 B I-369 A I-370 A I-371 A I-372 A I-373 A I-374 A I-375 B I-376 C I-377 C I-378 A I-379 B I-380 B I-381 C I-382 B I-383 C I-384 B I-385 B I-386 A I-387 A I-388 B I-389 A I-390 B I-391 A I-392 B I-393 C I-394 C I-395 B I-396 A I-397 A I-398 B I-399 B I-400 B I-401 C I-402 B I-403 C I-404 C I-405 B I-406 B I-407 C I-408 C I-409 C I-410 C I-411 C I-412 B I-413 C I-414 C I-415 C I-416 C I-417 C I-418 C I-419 C I-420 C I-421 B I-422 C I-423 A I-424 B I-425 C I-426 C I-427 A I-428 A I-429 A I-430 A I-431 A I-432 B I-433 A I-434 B I-435 A I-436 B I-437 A I-438 B I-439 B I-443 A I-444 A I-445 B I-446 B I-447 C I-448 A I-449 A I-450 B I-451 B I-452 B I-453 C I-454 A

TABLE-US-00059 TABLE 3 cGAS Inhibition Results I-# IC.sub.50 I-455 A I-456 C I-457 B I-458 B I-459 B I-460 B I-461 A I-462 B I-463 B I-464 A I-465 A I-466 A I-467 B I-468 B I-469 A I-470 A I-471 B I-472 B I-473 A I-474 B I-475 B I-476 B I-477 A I-478 A I-479 A I-480 A I-481 A I-482 A I-483 B I-484 B I-485 A I-486 A I-487 A I-488 A I-489 A I-490 A I-491 A I-492 B I-493 A I-494 A I-495 A I-496 B I-497 B I-498 B I-499 A I-500 B I-501 A I-502 B I-503 A I-504 A I-505 B I-506 B I-507 A I-508 A I-509 A I-510 A I-511 A I-512 A I-513 A I-514 A I-515 A I-516 A I-517 A I-518 A I-519 A I-520 A I-521 A I-522 B I-524 A I-525 A I-526 A I-527 A I-528 C I-529 A I-530 A I-531 A I-532 B I-533 A I-534 B I-535 B I-536 A I-537 B I-538 A I-539 A I-540 A I-541 A I-542 B I-543 B I-544 B I-545 A I-546 B I-547 B I-548 A I-549 A I-550 B I-551 C I-552 A I-553 A I-554 B I-555 A I-556 A I-557 A I-558 A I-559 A I-560 A I-561 A I-562 A I-563 A I-564 A I-565 A I-566 A I-567 A I-568 B I-569 A I-570 B I-571 A I-572 A I-573 B I-574 B I-575 B I-576 A I-577 B I-578 B I-579 C I-580 C I-581 B I-582 A I-583 B I-584 B I-585 B I-586 B I-587 B I-588 A I-589 B I-590 B I-591 B I-592 B I-593 B I-594 B I-595 B I-596 B I-597 B I-598 B I-599 B I-600 B I-601 B I-602 B I-603 A I-604 B I-605 C I-606 B I-607 A I-608 B I-609 C I-610 A I-611 C I-612 B I-613 A I-614 B I-615 B I-616 A I-617 A I-618 A I-619 B I-620 B I-621 B I-622 A I-623 B I-624 A I-625 A I-626 A I-627 A I-628 A I-629 A I-630 A I-631 A I-632 A I-633 A I-634 A I-635 A I-636 A I-637 A I-638 B I-639 A I-640 A I-641 A I-642 B I-643 A I-644 B I-645 B I-646 B I-647 B I-648 B I-649 B I-650 B I-651 A I-652 B I-653 A I-654 A I-655 A I-656 C I-657 A I-658 A I-659 A I-660 B I-661 A I-662 B I-663 A I-664 A I-665 A I-666 A I-667 A I-668 A I-669 B I-670 A I-671 A I-672 A I-673 B I-674 A I-675 A I-676 A I-677 A I-678 A I-679 A I-680 B I-681 B I-682 A I-683 A I-684 A I-685 A I-686 B I-687 B I-688 A I-689 A I-690 A I-691 A I-692 A I-693 A I-694 A I-695 B I-696 A I-697 A I-698 A I-699 A I-700 A I-701 A I-702 A I-703 A I-704 A I-705 A I-706 A I-707 A I-708 A I-709 A I-710 A I-711 A I-712 A I-713 A I-714 A I-715 A I-716 A I-717 A I-718 B I-719 A I-720 B I-721 B I-722 A I-723 A I-724 A I-725 A I-726 A I-727 A I-728 A I-729 A I-730 A I-731 A I-732 A I-733 A I-734 A I-735 A I-736 A I-737 A I-738 A I-739 A I-740 A I-741 A I-742 A I-743 A I-744 A I-745 A I-746 A I-747 A I-748 A I-749 A I-750 A I-751 A I-752 A I-753 C I-754 B I-755 C I-756 B I-757 B I-758 B I-759 A I-760 A I-761 A I-762 A I-763 A I-764 A I-765 B I-766 A I-767 B I-768 B I-769 B I-770 A I-771 B I-772 B I-773 A I-774 A I-775 A I-776 A I-778 B I-779 B I-780 B I-781 A I-782 A I-783 A I-784 A I-785 A I-786 A I-787 A I-788 A I-789 A I-790 B I-791 B I-792 A I-793 A I-794 A I-795 A I-796 A I-797 A I-798 A I-799 A I-800 A I-801 A I-802 A I-803 A I-804 A I-805 A I-806 A I-807 A I-808 A I-809 A I-810 A I-811 A I-812 A I-813 A I-814 A I-815 A I-816 A I-817 A I-818 B I-819 A I-820 A I-821 C I-822 C I-823 C I-824 C I-825 C I-826 C I-827 C I-828 B I-829 A I-830 A I-831 A I-832 A I-833 A I-834 A I-835 A I-836 A I-837 A I-838 A I-839 A I-840 A I-841 A I-842 A I-843 A I-844 A I-845 A I-846 A I-847 B I-848 B I-849 B I-850 B I-851 B I-852 B I-853 A I-854 A I-855 B I-856 A I-857 A I-858 C I-859 B I-860 A I-861 C I-862 A I-863 C I-864 A I-865 A I-866 A I-867 A I-868 A I-869 B I-870 B I-871 B I-872 B I-873 A I-874 A I-875 A I-876 A I-877 A I-878 A I-879 A I-880 A I-881 A I-882 A I-883 A I-884 A I-885 A I-886 A I-887 A I-888 A I-889 A I-890 B I-891 A

[1470] Cellular assay to measure cGAS activity: Reporter THP1 cell line harboring a gene encoding Gaussia Luciferase under the control of 5 tandem repeats of interferon-stimulated response elements (ISRE) fused to an ISG54 minimal promoter was used to test inhibition of cGAS activity by synthetic compounds in human cells. These cells were plated on 96-well plates at 0.3×10.sup.6/well and incubated with serial dilutions of compounds or DMSO for 5 min, followed by transfection of 2 μg/mL of ISD (Interferon Stimulatory DNA, a 45 bp DNA oligo) or mock transfected using lipofectamine 2000 (Life Technology) method, according to manufacturer's instructions. 16 hours later, 15 μL of the media from each well was transferred to a new plate, 50 μL of solution containing 50 mM Hepes-NaOH, pH 6.5, 50 mM NaCl, 10 mM EDTA, 1 μM of coeleanterazine was added to each well and luminescence was measured immediately. Fold increase in luminescence compared to mock transfection was plotted against concentrations of each compound, and IC.sub.50 is calculated using Graphpad. To evaluate the specificity of a compound, the same procedure was performed except that cells were transfected with 2 μg/mL poly(I:C) or infected with Sendai Virus (SeV) at 50 Unit/mL, which are known to activate the RIG-I-MAVS pathway. A specific inhibitory compound should inhibit interferon induction by DNA but have minimal effect on poly(I:C) or Sendai virus induced interferon reporter gene expression.

[1471] The results of the cellular assay for compounds of the disclosure are presented in Table 4. The letter codes for cGAS IC.sub.50 include: A (<2 μM); B (2-10 μM); C (>10 μM).

TABLE-US-00060 TABLE 4 Cellular Assay Results I-# IC.sub.50 I-15 C I-24 B I-39 B I-86 B I-92 C I-116 B I-139 B I-149 C I-200 A I-322 C I-428 B I-429 C I-435 B I-443 B I-448 C I-461 C I-467 B I-469 A I-470 B I-471 B I-473 A I-477 B I-478 B I-487 B I-507 B I-516 C I-532 B I-539 B I-556 A I-575 B I-576 A I-577 B I-578 B I-582 A I-583 A I-584 B I-585 A I-586 A I-591 B I-592 B I-593 B I-594 B I-595 B I-596 A I-597 C I-598 A I-599 A I-600 A I-601 A I-642 A I-645 A I-649 B I-650 B I-663 A I-664 A I-665 A I-666 A I-667 A I-668 A I-669 A I-670 A I-671 A I-672 A I-673 A I-674 B I-676 A I-677 A I-678 B I-679 B I-680 B I-681 A I-682 A I-683 A I-684 A I-685 A I-686 A I-687 C I-688 A I-689 C I-690 A I-691 A I-692 A I-693 C I-694 A I-695 B I-696 A I-698 C I-699 A I-700 B I-701 B I-702 B I-703 C I-704 A I-705 A I-706 A I-707 A I-708 A I-709 A I-710 B I-711 A I-712 A I-713 A I-714 B I-715 C I-716 C I-717 A I-718 A I-719 A I-720 A I-722 B I-723 B I-724 B I-725 C I-726 C I-728 B I-730 B I-732 A I-733 A I-734 A I-735 B I-736 A I-739 A I-740 C I-741 B I-742 C I-743 A I-744 A I-745 A I-747 A I-748 C I-749 A I-750 A I-751 B I-752 C I-753 C

TABLE-US-00061 I-# IC.sub.50 I-755 C I-756 C I-758 C I-759 C I-760 C I-761 C I-762 C I-764 C I-765 B I-773 A I-774 B I-775 B I-776 C I-778 C I-779 C I-780 C I-781 C I-782 C I-784 C I-785 C I-786 B I-787 B I-788 C I-789 A I-791 C I-792 A I-793 A I-794 A I-795 A I-796 A I-797 A I-798 A I-799 C I-800 A I-801 A I-802 A I-803 A I-804 A I-805 A I-806 B I-807 A I-808 A I-809 A I-810 A I-811 A I-813 C I-814 A I-815 B I-816 A I-817 C I-820 A I-828 C I-829 B I-830 A I-831 B I-832 A I-833 A I-834 A I-835 B I-836 A I-837 A I-838 C I-839 C I-840 A I-841 C I-842 B I-843 B I-844 A I-845 A I-846 A I-853 A I-854 C I-855 C I-856 B I-857 A I-860 C I-862 A I-864 C I-865 A I-866 B I-867 A I-868 B I-872 A I-875 A I-876 A I-877 A I-878 A I-879 A I-880 B I-882 C I-883 B I-884 A I-885 B I-886 A I-887 B I-888 B I-889 C I-890 A I-891 A

[1472] All publications, patents, patent applications and other documents cited in this application, including U.S. Provisional Appl. Nos. 63/074,446, 63/124,713, and 63/196,146, are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes.

[1473] While various specific embodiments have been illustrated and described, it will be appreciated that various changes can be made without departing from the spirit and scope of the claimed invention(s).