CA2743534A1 - Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor - Google Patents

Abstract

Compounds of formula (I) (see formula (I)) are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity.

Description

FUSED AZABICYCLIC COMPOUNDS THAT INHIBIT VANILLOID RECEPTOR
SUBTYPE 1 (VRi) RECEPTOR

TECHNICAL BACKGROUND
The present invention relates to compounds of formula (1), which are useful for treating disorders caused by or exacerbated by vanilloid receptor activity, pharmaceutical compositions containing compounds of formula (I) and are useful in treating pain, bladder overactivity, and urinary incontinence.

BACKGROUND OF INVENTION
Nociceptors are primary sensory afferent (C and A6 fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH
< 6) modalities. The lipophillic vanilloid, capsaicin., activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as VR1. The intradehrial administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of VR.1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal.
Thus, the long lasting anti-nociceptive effects of capsaicin has prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepinc, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. VR1 receptors are also localized on sensory afferents which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.
The VRl receptor has been called a "polymodal detector" of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vatulloids and thus is classified as a ligand-gated ion channel. VR1 receptor activation by capsaicin can be blocked by the competitive VRl receptor antagonist, capsazepine. The channel can also be activated by protons. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH <6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43 C, the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.
The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization.
This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.
Recently, two groups have reported the generation of a "knock-out" mouse lacking the VRl receptor. Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The VR1 (-/-) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociception.
However, the VRl knock-out mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55 C), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.
The compounds of the present invention are novel VR1 antagonists and have utility in treating pain, bladder overactivity, and urinary incontinence.

SUMMARY OF THE PRESENT INVENTION
The present invention discloses fused azabicyclic compounds, a method for inhibiting the VRl receptor in mammals using these compounds, a method for controlling pain in mammals, and pharmaceutical compositions including those compounds. More particularly, the present invention is directed to compounds of formula (I) IR&a Rsb-~ x5 Zz t X2 X, R7 I
X3~, X4 Y ~ R6 or a pharmaceutically acceptable salt or prodrug thereof, wherein --- is absent or a single bond;
X1 is selected from the group consisting of N and CRS;
X2 is selected from the group consisting of N and CR_,;
X3 is selected from the group consisting of N, NR3, and CR3;
X4 is a bond or selected from the group consisting of N and CR4;
X5 is selected from the group consisting of N and C;
provided that at least one of X1, X2, X3, and X4 is N;
ZI is selected from the group consisting of 0, NH, and S;
Z2 is a bond or selected from the group consisting of NH and 0;
L is selected from the group consisting of alkenylene, alkylene, alkynylene, Ry cycloalkylene, - --~N- , -(CH2)mO(CH2)õ, and N(Ry), wherein the left end of -(CH2)mO(CH2)n- is attached to Z2 and the right end is attached to R9;
in and n are each independently 0-6;
Ry is selected from the group consisting of hydrogen and alkyl;
R1, R3, R5, R6, and R7 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylatkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NRAS(0)2RB, -S(O)2ORA, -S(O)2RB, -NZAZB, (NZAZB)alkyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl and (NZAZB)sulfonyl, wherein ZA
and ZB are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, formyl, aryl, and arylalkyl;
R2 and R4 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, allcoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoallyl, nitro, (CF3)2(HO)C-, -NRAS(O)2RB, -S(O)2ORA, -S(O)2RB, -NZAZB, (NZAZB)alkyl, (NZAZB)alkylcarbonyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl, (NZAZB)sulfonyl, (NZAZB)C(=NH)-, (NZAZB)C(=NCN)NH-, and (NZAZB)C(=NH)NH-;
RA is selected from the group consisting of hydrogen and alkyl;
RB is selected from the group consisting of alkyl, aryl, and arylalkyl;
Rga is selected from the group consisting of hydrogen and alkyl;
R8b is absent when X5 is N or Rnb is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy when X5 is C; and R9 is selected from the group consisting of hydrogen, aryl, cycloalkyl, and heterocycle.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
In the principle embodiment, compounds of formula (I) are disclosed Z, R8a R8b-_ I5 z2 X~ Rr \4#R6 m, or a pharmaceutically acceptable salt or prodrug thereof, wherein --- is absent or a single bond;

X, is selected from the group consisting of N and CR,;
X2 is selected from the group consisting of N and CR2;
X3 is selected 1 from the group consisting of N, NR3, and CR3;
X4 is a bond or selected from the group consisting of N and CR4;
X5 is selected from the group consisting of N and C;
provided that at least one of X,, X2, X3, and X4 is N;
Z, is selected from the group consisting of 0, N1=1, and S;
Z2 is a bond or selected from the group consisting of NH and 0;
L is selected from the group consisting of alkenylene, alkylene, allcynylene, Ry --N IAN-cycloalkylene, "--" , -(CH2),,,0(CH2)n-, and N(Ry), wherein the left end of -(CH2)mO(CH2)õ- is attached to Z2 and the right end is attached to R9i m and a are each independently 0-6;
Ry is selected from the group consisting of hydrogen and alkyl;
R,, R3, R5, R6, and R7 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkenyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NRAS(O)2RB, -S(0)20RA, -S(0)2RB, -NZAZB, (NZAZB)alkyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl and (NZAZB)sulfonyl, wherein ZA and ZB are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, formyl, aryl, and arylalkyl;
R2 and R4 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyearbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylallcyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NRAS(0)2RB, -S(O)2ORA, -S(0)2RB, -NZAZB, (NTZAZB)alkyl, (NZAZB)alkylcarbonyl, (NZAZB)carbonyl, (NZAZB)carbonylalkyl, (NZAZB)sulfonyl, (NZAZB)C(=NH)-, (NZAZB)C(=NCN)NH-, and (NZAZB)C(=NH)NH-;

RA is selected from the group consisting of hydrogen and alkyl;
RB is selected from the group consisting of alkyl, aryl, and arylalkyl;
RSa is selected from the group consisting of hydrogen and alkyl;
R8b is absent when X5 is N or R8b is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy when X5 is C; and R9 is selected from the group consisting of hydrogen, aryl, cycloallcyl, and heterocycle.
. in another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is CR4; and R,, R2, R4, R5, R6, R7, R8a, Rgb, R9, X5, Z1, Z2, and L are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is a single bond; Xi is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R.ab is absent; ZI is 0; Z2 is NH; L is alkylene; R9 is aryl; and RI, R2, R4, R5, R6, R7, and R8a are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein -- is a single bond; XI is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; R8a is hydrogen; R8b is absent; ZI is 0; Z2 is NH; L
is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, ZB, ZC, and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; Xi is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5, R6 and R7 are each hydrogen; Rab is absent; ZI is 0; Z2 is NH; L
is alkylene; R9 is aryl wherein said aryl is substituted with aryloxy; and R8,, is as defined in formula (1).

In another embodiment of the present invention, compounds of formula (I) are disclosed wherein,--- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R2, R1, R5, R6, R7, and R.g, are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene;
R9 is aryl wherein said aryl is phenyl substituted with aryloxy wherein said aryloxy is phenoxy optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.I]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, I-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, I-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R2, R4, R5, R6, R7, and R8a are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene;
and R9 is aryl wherein said aryl is napthyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is cycloalkyl; R1, R2, R4, R5, R6, R7, and R8a is as defined in formula (1).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1i X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Rga is hydrogen;R8b is absent; Z1 is 0; Z2 is NH; L
is alkylene; R9 is cycloalkyl wherein said cyloalkyl is selected from the group consisting of adamantanyl, bicyclo[3.1.1jheptane, and cyclohexyl, wherein the cycloalkyl is optionally substituted with 1 or 2 alkyl substituents; and ZA and ZB are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; Rgb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is heterocycle; and R1, R2, R4, R5, R6, R7, and R8a are as defined in formula (1).

In another embodiment of the present invention, compounds of fonnula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; Xs is N; RI, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; R8a is hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L
is alkylene; R9 is heterocycle wherein said heterocycle is pyridinyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-I-piperidinyl, pyridinyl, 1 -pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, ZB, Zc, and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) arc disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; Z1 is 0; Z2 is NH; R8b is absent; R9 is hydrogen; and L, RI, R2, R4, R5, R6, R7, and R8a are as defined in formula (1).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5, R6, R7, and R8a are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene;
and R9 is hydrogen.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; Z1 is 0; Z2 is NH; L is cycloalkylene; R8b is absent; R9 is aryl; and RI, R2, R4, R5, R6, R7, and R8a are as defined in formula (1).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CRI; X2, is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5, R6, R7, and R8a are each hydrogen; Rsb is absent; Z1 is 0; Z2 is NH; L is cycloalkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2. 1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZn; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; Z, is 0; Z2 is a bond; L is cycloalkylene; Rsb is absent; R9 is aryl; and RI, R2, R4, R5, JZ6, R-1, and R8a are as defined in formula (1).
In another embodiment of the present invention, compounds of fonnula (I) are disclosed wherein --- is a single bond; Xi is CR1; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R2, R4, R5, R6, R7, and R8a are each hydrogen; R8b is absent; Z1 is 0; Z2 is a bond; L is cycloalkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-diunethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZn; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X, is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; ZI is 0; Z2 is NH; L is -(CH2)mO(CH2)r,- wherein the left end is attached to Z2 and the right end is attached to R9i Rsb is absent; R9 is aryl; and in, n, RI, R2, R4, R5, R6, R7, and R8a are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5, R6, R7, and R8a are each hydrogen; R8b is absent; ZI is 0; Z2 is NH; L is -(C12)mO(CH2)n wherein the left end is attached to Z2 and the right end is attached to R9; m is 0-2; n is 0-2; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting-of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.I]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, I-azepanyl, 1-azocanyl, cyan, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X-, is CR2; X3 is N; X4 is CR4; X5 is N; Z1 is 0; Z2 is NH; L is N(Ry); R8b is absent; R9 is aryl; and Ry, R1, R2, R4, R5, R6, R7, and R8a are as defined in formula (1).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; Ry, R1, R2, R4, R5, R6, R7, and Rs, are each hydrogen; Rsv is absent; ZI is 0; Z2 is NH; L is N(Ry); Rq is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, I -azepanyl, 1-azocanyl, cyan, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, I -piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4;:X5 is N; Z1 is 0; Z2 is a bond;
Ry +N I-`N-j-L is \--J ; R8b is absent; R9 is aryl; and Ry, RI, R2, R4, R5, R6, R7, and R8a are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R5, R6, R7, and R8a are each hydrogen; R8b is absent; R2 is selected from the group consisting of hydrogen and alkyl; ZI is 0; Z2 is a bond;
Ry --N r k N-L is \-J ; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl- I -piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and Ry, Zc, and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; Xi is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5 and R6 are each hydrogen; R7 is (CF3)2(HO)C-; Rgb is absent; ZI is 0; Z2 is NH; L
is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dunethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-pip eridinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and R8a, Zc, and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; XI is CRI; X2 is CR2i X3 is N; X4 is CR4; X5 is N; ZI is 0; Z2 is 0; L is allcylene; R8b is absent; R9 is aryl; RI, R2i R4, R5, R6, R7, and Rga are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R2, R4, R5, R6, R7, and Rsa are each hydrogen; R81, is absent; ZI is 0; Z2 is 0; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; and Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; RI, R2, R4, R5, R6 and R7 are each hydrogen; ZI is 0; Z2 is 0; L is alkylene; R8b is absent; R9 is aryl wherein said aryl is naphthyl; and Rsa is as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X, is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R8b is absent; ZI is 0; Z2 is a bond; L is alkenylene; R9 is aryl; and R1, R2, R4, R5, R6, R7, and R8a are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is N; R1, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Rsa is hydrogen; Rgb is absent; Z1 is 0; Z2 is a bond; L is alkenylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabieyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyan, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, ZB, Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; ZI is 0; Z2 is NH; L is alkylene; R9 is heterocycle; and RI, R2, R4, R5, R6, R7, R3a, and Rsb are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; XI is CRi; X2 is CR2; X3 is N; X4 is CR4; X5 is C; R1, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; RSa and Rab are hydrogen; Z1 is 0; Z2 is NH; L is alkylene; R9 is heterocycle wherein said heterocycle is selected from the group consisting of imidazolyl, pyridinyl, pyrrolidinyl, and thienyl, wherein the heterocycle is optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyan, haloalkoxy, haloalkyl, haloalkylthio, halogen, oxo, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, I -pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, ZB, Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; Z1 is 0; Z2 is NH; L is -(CH2),,,O(CH2)õ wherein the left end is attached to Z2 and the right end is attached to R9i R9 is hydrogen; and in, n, R1, R2, R4, R5, R6, R7, Rg, and Rsb are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; R1, R6 and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Rga and Rsb are hydrogen; Z1 is 0; Z2 is NH; L is -(CH2),,O(CH2)n-wherein the left end is attached to Z2 and the right end is attached to R9; m is 0-4; n is 0-4; R9 is hydrogen; and ZA and ZB are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl; and R1, R2, R4, R5, R6, R7, Rga, and Rsb are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is a single bond; X1 is CR1 i X2 is CR2; X3 is N; X4 is CR4; X5 is C; R1, R6, R7, Rga and Rib are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Zi is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1 -azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1 -piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-fliiomorpholinyl, and -NZCZD; and ZA, Z3, Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; RI, R6, and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Rga is selected from the group consisting of hydrogen and alkyl; P1-8b is alkyl; ZI is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.I Ihept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, I-piperidinyl, 4-methyl-l-pip eridinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, Zf3, Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
in another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; R1, R6, and R7 and are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; R8a is hydrogen; R.gb is selected from the group consisting of alkoxy, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, halogen, and hydroxy; ZI is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, l-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, I-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and ZA, ZB, Zc and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CRI; X2 is CR2; X3 is N; X4 is CR4; X5 is C; R1, R6, R7, and R7 are each hydrogen; R2 and R4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and -NZAZB; R5 is selected from the group consisting of hydrogen and halogen; Rga is selected from the group consisting of hydrogen and alkyl; Rgb is selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxy; Z1 is 0; Z2 is 0; L is alkylene; R9 is hydrogen; and ZA and ZB
are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is N; and R1, R2, R5, R6, R7, Rsa, R8b, R9, X5, Z1, Z2, and L are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; XI is CRI; X2 is CR2; X3 is N; X4 is N; X5 is N; Rsb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl; and R1, R2, R5, R6, R7, Rsa, and Rsb are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR1; X2 is CR2; X3 is N; X4 is N; X5 is N; R1, R5, R6 and R7 are each hydrogen; Rsb is absent; R2 is selected from the group consisting of alkyl and halogen; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, t-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, I-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; and Rga, Zc, and ZD
are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CR2; X2 is N; X3 is CR3; X4 is CR4; and R1, R3, R5, R6, R7, Rsa, Rsb, R9, Xs, Z1, Z2, and L are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is a single bond; X1 is CRI; X2 is N; X3 is CR3; X4 is CR4; X5 is N; Rsb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl; and R1, R3, R5, R6, R7, and Rsa are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is a single bond; X1 is CRI; X2 is N; X3 is CR3; X4 is CR4; X5 is N; R1, R3, R4, R5, R6 and R7 are each hydrogen; Rsb is absent; Z1 is 0; Z2 is NH; L
is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkyltbio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-pipetdinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and Rga, ZC, and ZD are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CR1i X2 is CR2; X3 is NR3; X1 is a bond; and R1, R2, R3, R5, R6, R7, Rga, R8b, R9, X5, Z1, Z2, and L are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CR1; X2 is CR2; X3 is NR3; X4 is a bond; Xs is N; Rgb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl; and R1, R2, R3, R5, R6, R7, and Rga are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is absent; X1 is CR1 i X2 is CR2; X3 is N; X4 is a bond;
X5 is N; R1, R2, R5, R6 and R7 are each hydrogen; Rgb is absent; Zl, is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; Rga, ZC, and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is absent; X1 is CR1; X2 is CR2; X3 is NR3; X4 is a bond;
X5 is N; R1 and R2 are each independently alkyl; R5, R6 and R7 are each hydrogen; Rgb is absent; Zl is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; Rga, Zc, and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.

In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CRI; X2 is CR2; X3 is NR3; X4 is a bond; Xs is N; Rsb is absent; Z1 is 0; Z2 is 0; L is alkylene; R9 is aryl; and RI, R2, R3, R5, R6, R7, R8a, and R9 are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CRI; X2 is CR2; X3 is NR3; X4 is a bond; X5 is N; R8a, RI, R2, R5, R6 and R7 are each hydrogen; Rgb is absent; Z1 is 0; Z2 is 0; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of allkoxy, alkyl, alkylsulfonyl, 2-azabieyclo[2.2.1]hept-2-yl, 8-azabieyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, I -pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; Ria, Zc, and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
and RI, R3, R5, R6, R7, R8a, R.gb, R9, X5, ZI, Z2. and L are as defined in formula (1).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; XI is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; Rib is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl; and RI, R3, R5, R6, R7, and Rsa are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein -- is absent; XI is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RI, R5, R6 and R7 are each hydrogen;=Rib is absent; Z1 is 0; Z2 is NH; L is alkylene;
R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2. I ]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; R8a, ZC, and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; Xl is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RBa, R1, R5, R6 and R7 are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene wherein the alkylene is -CH2-; R9 is aryl wherein said aryl is phenyl optionally substituted with 2 substituents independently selected from the group consisting of 8-azabicyclo[3.2.1]oct-8-yl, trifluoromethyl, and -Cl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; R8a, R1, R5, R6 and R7 are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene wherein the alkylene is -CH2-; R9 is aryl wherein said aryl is 4-(8-azabicyclo[3.2.1]oct-8-yl)-'3-(trifluoromethyl)phenyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; XI is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; Rsa, R1, R5, R6 and R7 are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene wherein the alkylene is -CH2-; R9 is aryl wherein said aryl is 4-(8-azabicyclo[3.2.1 ]oct-8-yl)-2-chlorophenyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is absent; XI is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RI, R6 and R7 are each hydrogen; R5 is alkyl wherein a preferred alkyl is methyl or ethyl; Rsb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.l]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-I-piperidinyl, pyridinyl, I -pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; Zc and ZD are independently selected from the group consisting of hydrogen and alkyl; and R8a and R3 are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; Rga, RI, R6 and R7 are each hydrogen; R5 is alkyl wherein a preferred alkyl is methyl or ethyl; Rnb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1Jhept-2-yl, 8-azabicyclo[32.1Joct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; Zc and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (1) aie disclosed wherein --- is absent; XI is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RI, R5, R6 and R7 are each hydrogen; Rnb is absent; Z1 is 0; Z2 is NH; L is alkylene;
R9 is aryl wherein said aryl is selected from the group consisting of naphthyl and phenyl; and Rga and R3 are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; Rna, RI, R5, R6 and R7 are each hydrogen; Rnb is absent; Z1 is 0; Z2 is NH; L is alkylene; R9 is aryl wherein said aryl is selected from the group consisting of naphthyl and phenyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein -- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RI, R5, R6 and R7 are each hydrogen; R8b is absent; Z1 is 0; Z2 is NH; L is alkylene;
R9 is heterocycle wherein said heterocycle is pyridinyl substituted with alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-diniethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; and Zc, ZD, Rga, and R3 are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; X1 is CRI; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; X5 is N;
Rga, R1, R5, R6 and R7 are each hydrogen; R8b is absent; Z, is 0; Z2 is NH; L
is alkylene; R9 is heterocycle wherein said heterocycle is pyridinyl substituted with alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-moipholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZCZD; Zo and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is absent; Xi is CR1; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; REb is absent; Z1 is 0; Z2 is NH; L is Ry \-/ ; R9 is heterocycle; and RBa, R1, R3, R5, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (I) are disclosed wherein --- is absent; Xi is CRi; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; R1, R5, R6 and R7 are each hydrogen; RBb is absent; Zi is 0; Z2 is NH; L is Ry rI1 --N -~N-.
R9 is heterocycle wherein said heterocycle is pyridinyl optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyclo[3.2.1]oct-8-yl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-l-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; Zc and ZD are independently selected from the group consisting of hydrogen and alkyl; and RBa and R3 are as defined in formula (I).
In another embodiment of the present invention, compounds of formula (1) are disclosed wherein --- is absent; Xi is CR1; X2 is N; X3 is NR3; X4 is a bond;
X5 is N; RBa, R1, R5, R6 and R7 are each hydrogen; RSb is absent; Zi is 0; Z2 is NH; L is Ry -- rk N- .
N
R9 is heterocycle wherein said heterocycle is pyridinyl optionally substituted with 1 or 2 substituents selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 2-azabicyclo[2.2.1]hept-2-yl, 8-azabicyelo[3.2.1]oct-8-yl, I-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloallcyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, I-piperidi_nyl, 4-methyl-l-piperidinyl, pyridinyl, I-pyrrolidinyl, 4-thiomorpholinyl, and -NZcZD; ZC and ZD are independently selected from the group consisting of hydrogen and alkyl; and R3 is selected from the group consisting of hydrogen and alkoxycarbonyl.

Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VRI.) receptor in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method for controlling pain in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a method of treating inflammatory thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Definition of Terms As used throughout this specification and the appended claims, the following terms have the following meanings:
The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
The term "alkenylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond.
Representative examples of alkenylene include, but are not limited to, -CH=CH-, -CH=CH2CH2-, and -CH=C(CH3)CH2-.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkoxyalkoxy" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
Representative examples of alkoxyalkoxy include, but are not limited to, methoxymethoxy, ethoxymethoxy and 2-ethoxyethoxy.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term. "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl" as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.

The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl. ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-diniethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and I-oxopentyl.
The term "alkylcarbonylalkyl" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, etylcarbonyloxy, and tert-butylcarbonyloxy.
The term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from I to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CII(CH3)CH2-, and -(CH2)pCH(Rz)(CH2)q-, wherein p and q are independently 0-4 and Rz is selected from the group consisting of aryl, cycloalkyl, and hydroxy. A preferred aryl group is phenyl.
The term "alkylsulfonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
The term "alkynyl" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "alkynylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one triple bond.
Representative examples of alkynylene include, but are not limited to, -C=C-, -CH2C=C-, -CH(CH3)CH2C=C-, -C=CCH2-, and -C---CCH(CH3)CH2-.
The term "aryl" as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group.
Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
The aryl groups of this invention can be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, -NZcZD, (NZcZD)alkyl, (NZCZD)carbonyl, (NZcZD)carbonylalkyl, (NZCZD)sulfonyl, -NRAS(O)2RB, -S(O)2ORA and -S(O)2RA wherein RA and RB are as defined herein. The aryl groups of this invention can be further substituted with any one of an additional aryl, arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, or heterocyclethio group, as defined herein, wherein the additional aryl, arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, and heterocyclethio group can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, allcynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, -NZCZD, (NZcZD)alkyl, (NZcZD)carbonyl, (NZCZD)carbonylalkyl, (NZcZD)sulfonyl, -NRAS(O)2RB, -S(O)2ORA and -S(O)2RA
wherein RA and RB are as defined herein. Representative examples include, but are not limited to, 4-(2-azabicyclo[2.2.1 ]hept-2-yl)-2-(trifluoromethyl)phenyl, 4-(8-azabicyelo[3.2.1 ]oct-8-yl)-2-chlorophenyl, 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-chlorophenyl, 4-(8-azabicyclo[3.2.1]oct-8-yl)phenyl, 4-(S-azabicyclo[3.2.1 ]oct-8-yl)-3-(trifluoromethyl)phenyl, 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-(trifluoromethyl)phenyl, 4-(8-azabicyclo[3.2.I]oct-8-yl)-3-fluorophenyl, 3-chloro-4-azepan-1-ylphenyl, 2-chloro-4-azepan-1-ylphenyl, 3,5-difluoro-4-azepan-1-ylphenyl, 4-(8-azabicyclo[3.2.1]oct-8-yl)-3,5-difluorophenyl, 4-bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 4-bromo-2-fluorophenyl, 4-chloro-2-fluorophenyl, 4-(tert-butyl)phenyl), 4-cyanophenyl, 4-etylphenyl, 3-fluorophenyl, 2,4-difluorophenyl, 4-bromo-3-fluorophenyl, 2,3-difluoro-4-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 4-[(trifluoromethyl)thio]phenyl, 4-azepan-1-yl-3-(trifluoromethyl)phenyl, 4-azepan-l-yl-2-(trifluoromethyl)phenyl, 3-methylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 4-isopropylphenyl, 4-methylphenyl, 4-bromo-3-methylphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 3-chloro-4-fluorophenyl, 4-(1-pyrrolidinyl)phenyl, 4-(1-azepanyl)phenyl, 3-fluoro-4-(1-pyrrolidinyl)phenyl, 3-fluoro-4-(1-azepanyl)phenyl, 4-(1-azocanyl)phenyl, 4-(I-piperidinyl)phenyl, 3-fluoro-4-(l.-piperidinyl)phenyl, 4-(2-pyridinyl)phenyl, 1,1'-biphenyl, 3-fluoro-4-(4 methyl-l piperidinyl)phenyl, 4 (4 methyl 1 piperidinyl)phenyl, 4-(4-morpholinyl)phenyl, 4-(2,6-dimethyI-4-morpholinyl)phenyl, 4-(4-thiomorpholinyl)phenyl, 3,5-difluoro-4-(4-morpholinyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, and 2,5-bis(trifluoromethyl)phenyl.
The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
The term "arylthio" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of arylthio include, but are not limited to, phenylsulfanyl, naphth-2-ylsulfanyl, and 5-phenyihexylsulfanyl.
The term "carbonyl" as used herein, means a -C(O)- group.
The term "carboxy" as used herein, means a -CO2H group.
The term "carboxyalkyl" as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
The term "cyan.o" as used herein, means a -CN group.
The term "cyanoalkyl" as used herein, means a cyano group, as defined herein,, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoyethyl, and 3-cyanopropyl.
The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyelo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03'7]nonane and tricyclo[3.3.1.13'7]decane (adamantyl).
The cycloalkyl groups of this invention can be substituted with 1, 2, 3, 4 or substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, -NZCZD, (NZcZD)alkyl, (NZcZD)carbonyl, (NZcZD)carbonylalkyl, (NZcZn)sulfonyl, -NRAS(O)2RB, -S(O)20RA, and -S(O)2RA
wherein RA and RB are as defined herein. Representative examples include, but are not limited to, 6,6-dinethylbicyclo[3.1.1]heptyl, 6,6-dimethylbieyclo[3.1.1]hept-2-yl, 4-tcrt-butylcyclohexyl, and 4-(trifluoromethyl)cyclohexyl.
The term "cycloalkylalkyl" as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexyhnethyl, and 4-cycloheptylbutyl.
The term "cycloalkylene" as used herein, means a divalent group derived from a cycloalkyl group, as defined herein. Representative examples of cycloalkylene include, but are not limited to and The term "ethylenedioxy" as used herein, means a -O(CH2)20- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
The term "formyl" as used herein, means a -C(O)H group.
The term "formylalkyl" as used herein, means a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. .
Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl.
The term "halo" or "halogen" as used herein, means -Cl, -Br, -I or -F.
The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "haloalkylthio" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkylthio group, as defined herein. Representative examples of haloalkylthio include, but are not limited to, trifluoromethylthio.
The term "heterocycle" or "heterocyclic" as used herein, means a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds.
Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system. Additionally, bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring system are linked by an alkylene group. Representative examples of bicyclic ring systems include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, benzimidazolyl, benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl, indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridinyl. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl, carbolinyl, dibenzo[b,d]furanyl, dibenzo[b,d]tluenyl, naphtho[2,3-b]furan, naphtho[2,3-bjthienyl, phenazinyl, phenothiazinyl, phenoxazinyl, thianthrenyl, thioxanthenyl and xanthenyl.
The heterocycles of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, a.lkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkenyl, arylalkyl, aryloxy, arylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, oxo, -NZCZD, (NZCZD)alkyl, (NZcZD)carbonyl, (NZcZD)carbonylalkyl, (NZcZD)sulfonyl, -NRAS(0)2RB, -S(O)20RA and -S(O)2RA wherein RA and RB are as defined herein. The heterocycles of this invention can be further substituted with any one of an additional aryl, arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, or heterocyclethio group, as defined herein, wherein the additional aryl, arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, and heterocyclethio group can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, allcylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, h.aloalkyl, haloalkylthio, halogen., hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, -NZCZD, (NZCZD)alkyl, (NZCZD)carbonyl, (NZCZD)carbonylalkyl, (NZCZD)sulfonyl, -NRAS(O)2RB, -S(O)20RA
and -S(O)2RA wherein RA and RB are as defined herein. Representative examples include, but are not limited to, 2,6-dimethylmorpholinyl, 4-(3-chlorophenyl)-1-pip erazinyl, 4-(3,4-dimethylphenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl, 4-(4-methylphenyl)-3-methyl-l-piperazinyl, 4-(2,3-dimethylphenyl)-1-piperazinyl, 4-(2,3-dichlorophenyl)-1-piperazinyl, 4-(3,4-dichlorophenyl)-1-pip erazinyl, 4-[3-(trifluoromethyl)phenyl]-l-piperazinyl, 4-(4-bromophenyl)-1-piperazinyl, 4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinyl, 2-oxo-l-pyrrolidinyl, 5-(trifluoromethyl)-2-pyridinyl, 6-(trifluoromethyl)-3-pyridinyl.

The term "heterocyclealkyl" as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl.
The term "heterocycleoxy" as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
Representative examples of heterocycleoxy include, but are not limited to, pyridin-3-yloxy and quinolin-3-yloxy.
The term "heterocyclethio" as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
Representative examples of heterocyclethio include, but are not limited to, pyridin-3-ylsulfanyl and quinolin-3-ylsulfanyl.
The teen "hydroxy" as used herein, means an -OH group.
The term "hydroxyalkyl" as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
The term "mercapto" as used herein, means a -SH group.
The term "mercaptoalkyl" as used herein, means a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein, Representative examples of mercaptoalkyl include, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.
The term "methylenedioxy" as used herein, means a -OCHZO- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
The term "nitro" as used herein, means a -NO2 group.
The term "-NZAZB" as used herein, means two groups, ZA and ZB, which are appended to the parent molecular moiety through a nitrogen atom. ZA and ZB are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.
Representative examples of -NZAZB include, but are not limited to, amino, methylamino, acetylamino, benzylamino, phenylamino, and acetylmethylamino.

The teen "(NZAZB)alkyl" as used herein, means a -NZAZB group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of (NZAZB)alkyl include, but are not limited to, anninomethyI, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl and (ethylmethylarnino)methyl.
The term "(NZAZB)alkylcarbonyl" as used herein, means a (NZAZB)alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NZAZB)alkylearbonyl include, but are not limited to, d.imethylaminomethylcarbonyl, 2-(dimethylamino)ethylcarbonyl, and (ethylmethylamino)methylcarbonyl.
The term "(NZAZB)carbonyl" as used herein, means a -NZAZB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NZAZB)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dim ethylam no)carbonyl and (ethylmethyl amino)carbonyl.
The tern "(NZAZB)carbonylalkyl " as used herein, means a (NZAZB)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NZAZB)carbonylalkyl include, but are not limited to, (aminocarbonyl)methyl, 2-((methylan-tino)carbonyI) ethyl and ((dimethylamino)carbonyl)methyl.
The term "( NZAZB)sulfonyl" as used herein, means a -NZAZB group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NZAZB)sulfonyl include, but are not limited to, aminosulfonyl, (methylainino)sulfonyl, (dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
The term "-NZAZB" as used herein, means two groups, ZA and ZB, which are appended to the parent molecular moiety through a nitrogen atom. ZA and ZB are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.
Representative examples of -NZAZB include, but are not limited to, amino, methylamino, acetylamino, benzylainino, phenylamino, and acetylmethylamino.
The term "-NZCZD" as used herein, means two groups, ZC and ZD, which are appended to the parent molecular moiety through a nitrogen atom. Zc and ZD are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.
Representative examples of-NZcZD include, but are not limited to, amino, methylamino, acetylamino, benzylamino, phenylamino, and acetylmethylamino.

The term " (NZCZD)alkyl" as used herein, means a -NZcZD group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of (NZcZD)alkyl include, but are not limited to, aminomethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl and (ethylmethylamino)methyl.
The term "(NZcZD)carbonyl" as used herein, means a -NZcZD group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of (NZcZD)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl and (ethylmethylamino)carbonyl.
The term "(NZcZD)carbonylalkyl " as used herein, means a (NZcZD)carbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NZcZD)carbonylalkyl include, but are not limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl.)ethyl and ((dimethylaniino)carbonyl)methyl.
The term "(NZcZD)sulfonyl" as used herein, means a -NZcZD group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NZcZD)sulfonyl include, but are not limited to, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
The term "oxo" as used herein, means =O.
The term "sulfonyl" as used herein, means a -S(O)2- group.
In Vitro Data Determination of Inhibition Potencies Dulbecco's modified Eagle medium (D-MEM)(with 4.5 mg/mL glucose) and fetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan, Utah).
Dulbecco's phosphate-buffered saline (D-PBS)(with 1 mg/mL glucose and 3.6 mg/l Na pyruvate)(without phenol red), L-glutamine, hygromycin B, and LipofectamineTM
were obtained from Life Technologies (Grand Island, NY). G418 sulfate was obtained from Calbiochem-Novabiochem Corp. (San Diego, CA)_ Capsaicin (8-methyl-N-vanillyl-6-nonenamide) was obtained from Sigma-Aldrich, Co. (St. Louis, MO). Fluo-4 AM (N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine, (acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene, OR).

The cDNAs for the human VRl receptor were isolated by reverse transcriptase-polymerase chain reaction (RT-PCR) from human small intestine poly A+RNA
supplied by Clontech (Palo Alto, CA) using primers designed surrounding the initiation and termination codons identical to the published sequences (Hayes et al. Pain 88: 205-215, 2000). The resulting cDNA PCR products were subcloncd into pCIneo mammalian expression vector (Promega `111) and fully sequenced using fluorescent dye-terminator reagents (Prism, Perkin-Elmer Applied Biosystems Division) and a Perkin-Elmer Applied Biosystems Model DNA sequencer or Model 310 genetic analyzer. Expression plasniids encoding the hVR1 eDNA were transfected individually into 1321N1 human astrocytoma cells using LipofectamnineTM. Forty-eight hours after transfection, the neomycin-resistant cells were selected with growth medium containing 800 rg/ nL GeneucinTM (Gibco BRL).
Surviving individual colonies were isolated. and screened for VR1 receptor activity.
Cells expressing recombinant homomeric VRl receptors were maintained at 37 C in D-MEM
containing 4 mM L-glutamine, 300 g/mL G418 (Cal-biochem) and 10% fetal bovine serum under a humidified 5% CO2 atmosphere.
The functional activity of compounds at the VRI receptor was determined with a Ca2+
influx assay and measurement of intracellular Ca2+ levels ([Ca2+]i). All compounds were tested over an I 1-point half-log concentration range. Compound solutions were prepared in D-PBS (4x final concentration), and diluted serially across 96-well v-bottom tissue culture plates using aBiomek 2000 robotic automation workstation (Beckman-Coulter, Inc., Fullerton, CA). A 0.2 M solution of the VR1 agonist capsaicin was also prepared in D-PBS. The fluorescent Ca2+ chelating dye fluo-4 was used as an indicator of the relative levels of [Caz+]i in a 96-well format using a Fluorescence Imaging Plate Reader (FLIPRINI)(Molecular Devices, Sunnyvale, CA). Cells were grown to confluency in 96-well black-walled tissue culture plates. Then, prior to the assay, the cells were loaded with 100 L
per well of fluo-4 AM (2 M, in D-PBS) for 1-2 hours at 23 C. Washing of the cells was performed to remove extracellular fluo-4 AM (2 x 1 mL D-PBS per well), and afterward, the cells were placed in the reading chamber of the FLIPRTM instrument. 50 gL of the compound solutions were added to the cells at the 10 second time mark of the experimental run. Then, after a 3 minute time delay, 50 L of the capsaicin solution was added at the 190 second time mark (0.05 [.iM final concentration)(final volume = 200 L) to challenge the VRI receptor. Time length of the experimental nun was 240 seconds. Fluorescence readings were made at 1 to 5 second intervals over the course of the experimental run. The peak increase in relative fluorescence units (minus baseline) was calculated from the 190 second time mark to the end of the experimental run, and expressed as a percentage of the 0.05 M capsaicin (control) response.
Curve-fits of the data were solved using a four-parameter logistic Hill equation in GraphPad Prism (GraphPad Software, Inc., San Diego, CA), and IC5o values were calculated.
The compounds of the present invention were found to be antagonists of the vanilloid receptor subtype 1 (VR1) receptor with IC5o, from 1000 nM to 0.1 nM. In a preferred range, compounds tested had IC5o, from 500 nM to 0.1 nM. In a more preferred range, compounds tested had IC5o, from 50 nM to 0.1 nM.
In Vivo Data Determination of Antinociceptive Effect Experiments were performed on 400 adult male 129J mice (Jackson laboratories, Bar Harbor, ME), weighing 20-25 g. Mice were kept in a vivarium, maintained at 22 C, with a 12 hour alternating light-dark cycle with food and water available ad libitum.
All experiments were performed during the light cycle. Animals were randomly divided into separate groups of 10 mice each. Each animal was used in one experiment only and was sacrificed immediately following the completion of the experiment. All animal handling and experimental procedures were approved by an IACUC Committee.
The antinociceptive test used was a modification of the abdominal constriction assay described in Collier, et at., Br. J. Pharmacol. Chemother. 32 (1968) 295-3 10.
Each animal received an intraperitoneal (i.p.) injection of 0.3 mL of 0.6% acetic acid in normal saline to evoke writhing. Animals were placed separately under clear cylinders for the observation and quantification of abdominal constriction. Abdominal constriction was defined as a mild constriction and elongation passing caudally along the abdominal wall, accompanied by a slight twisting of the trunk and followed by bilateral extension of the hind limbs. The total number of abdominal constrictions was recorded from 5 to 20 minutes after acetic acid injection. The ED50, were determined based on the i.p. injection.
The compounds of the present invention tested were found to have antinocieeptive effects with ED505 from 1 mg/kg to 500 mg/kg.
The in vitro and in vivo data demonstrates that compounds of the present invention antagonize the VRI receptor and are useful for treating pain.

Compounds of the present invention, as VRI antagonists, are also useful for ameliorating or preventing additional disorders that are affected by the VRI
receptors such as, but not limited to, infammatory thermal hyperalgesia, bladder overactivity, and urinary incontinence.
Compounds of the present invention, including but not limited to those specified in the examples, can be used to treat pain as demonstrated by Nolano, M. et al., Pain 81 (1999) 135; Caterina, M.J. and Julius, D., Annu. Rev. Neurosci. 24, (2001) 487-517;
Caterina, M.J.
et al., Science 288 (2000) 306-313; Caterina, M.J. et al., Nature 389 (1997) 816-824.
Compounds of the present invention, including but not limited to those specified in the examples, can be used to treat bladder overactivity and/or urinary incontinence as demonstrated by Fowler, C. Urology 55 (2000) 60.
Compounds of the present invention, including but not limited to those specified in the examples, can be used to treat inflammatory thermal hyperalgesia as demonstrated by Davis, J. et al., Nature 405 (2000) 183-187.
The present invention also provides pharmaceutical compositions that comprise compounds of the present invention. The pharmaceutical compositions comprise compounds of the present invention that may be formulated together with one or more non-toxic pharmaceutically acceptable carriers.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally , intraeisternally, iutravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose;
starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin;
f) absorption accelerators such as quaternary armnonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.
33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well-known in the art. For example, S.
M.
Berge et al. describe pharmaceutically acceptable salts in detail in (J.
Pharmaceutical Sciences, 1977, 66: 1 et seq). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;
arylallcyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not Limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethyl amuie, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazii e and the like.
The term "pharmaceutically acceptable prodrug" or "prodrug,"as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
Prodrugs of the present invention may be rapidly transformed in vivo to compounds of formula (I), for example, by hydrolysis in blood. Representative examples include, but are not limited to, methyl 4-{[({[4-(8-azabicyclo[3.2.I)oct-8-yl)-3-(trifluoromethyl)phenyl]methyl} amino)carbonyl]amino } -1 H-indazole- l -carboxylate, ethyl 4-{[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)phenyl]methyl} ami.no)earbonyl]amino }-1 H-indazole- l-carboxylate, tert-butyl 4-[({[4-(8-azabicyclo[3.2.1 ]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-l-carboxylate, tert-butyl 4-[({[4-(8-azabicyclo[3.2.1 ]oct-8-yl)-2-chlorobenzyl]amino} carbonyl)amino]-1 H-indazole-l-carboxylate, ethyl 4-[( {[4-(8-azabicyclo[3.2.1 ]oct-8-yl)-2-chlorobenzyl]amino} carbonyl)amino]-IH-indazole-l -carboxylate, and methyl 4-[({[4-(8-azabicyclo[3.2.1 ]oct-8-yl)-2-chlorobenzyl]amino } carbonyl)amino]-1 H-indazole- l -carboxylate.
The present invention contemplates compounds of formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.01 to about 100 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.1 to about 25 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

Compounds of the present invention were named by ACD/ChemSketch version 5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names which appeared to be consistent with ACD nomenclature.
Abbreviations Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: dba for dibenzylideneacetone; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; BINAP for 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl;
DCC for 1,3-dicyclohexylcarbodiimide; DIEA for diisopropylethylam.ine; DMAP
for 4-di nethylaminopyridine; DMF for N,N-dimethylformani.ide; DMSO for dimethylsulfoxide;
EDCI or EDC for 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; HMPA
for hexamethylphosphoramide; HPLC high pressure liquid chromatography; NBS for N-bromosuccinimide; Pd for palladium; Ph for phenyl; psi for pounds per square inch; and THE
for tetrahydrofuran.
Preparation of Compounds of the Present Invention The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes and Examples which illustrate a means by which the compounds of the present invention can be prepared.

Scheme I

RI NH2 R, HNA,CC13 R2 R7= O R2 R7 N, / *R6 + CV CC13 base Rs (1) (2) O H

R1 HNAN"L-R9 (2) + H2N=L.R9 DBU R2 -I Rr (3) R6 (4) O
R1 HN0 L,R9 O + HO-L.Rs DBU- R2 I R7 2 -^-N
(5) R6 (6) Ureas of general formula (4), wherein RI, R2, R4, R5, R6, R7, R0, and L are as defined in formula (I), may be prepared as described in Scheme 1. 5-Aminoisoquinolines of general formula (1), purchased commercially or prepared using standard chemistry known to those in the art, can be treated with trichloroacetyl chloride and a base such as, but not limited to, triethylamine in a solvent such as dichloromethane to provide trichloroacetamides of general formula (2). TrichloroacetanZides of general formula (2) can be treated with amines of general formula (3) and a non-nucleophilic base such as, but not limited to, DBU in a solvent such as, but not limited to, acetonitrile to provide ureas of general formula (4).
Carbamates of general formula (6), wherein RI, R2, R4, R5, R6, R7, R9 and L
are as defined in formula (I), may also be prepared as described in Scheme 1.
Trichioroacetamides of general forniula (2) can be treated with alcohols of general formula (5) and a non-nucleophilic base such as, but not limited to, DBU in a solvent such as, but not limited to, acetonitrile to provide carbamates of general formula (6).

Scheme 2 H2N'L`R9 CIC(O)CI OCN R9 O
H

R2 R7 L` I
I
N + OCN' R9 N
Rs Rs R4 R5 (g) R4 R5 (1) (4) Ureas of general formula (4), wherein R1, R2, R4, R5, R6, R7, R9, and L are as defined in formula (I), may be prepared as described in Scheme 2. Amines of general formula (3) can be treated with phosgene or triphosgene and DMAP in a solvent such as, but not limited to, dichloromethane to provide isocyanates of general formula (8). 5-Aminoisoquinolines of general formula (1) can be treated with isocyanates of general formula (8) in a solvent such as, but not limited to, toluene or YElP or a combination thereof to provide ureas of general formula (4).

Scheme 3 R2 R7 CIC(O)CI R2 R7 N N
Rs R6 (1) (10) O
~ L`
R1 HN N' R9 (10) + H2N.L,R9 R2 \ *R7 (3) Rs (4) Ureas of general formula (4), wherein R1, R2, R4, R5, R6, R7, R9, and L are as defined in formula (I), may be prepared as described in Scheme 3. 5-Aminoisoquinolines of general formula (1) can be treated with phosgene or triphosgene and DMAP in a solvent such as, but not limited to, dichloromethane to provide isocyanates of general formula (10). Isocyanates of general formula (10) can be treated with amines of general formula (3) in a solvent such as, but not limited to, toluene or THE or a combination thereof to provide ureas of general formula (4).

Scheme 4 O O

I Schemes 1-3 I 1 NN Rs N N Rs N,N Rs (12) (13) (14) O H O

R1 NH2 R1 HNAN L R9 R1 HNAO'L,R9 R7 R7 \ \ R~
N Schemes 1-3 N N

(15) (16) (17) Ureas of general formula (13), wherein R1, R2, R5, R6, R7, R9, and L are as defined in formula (I), and carbamates of general formula (14), wherein R1, R2i R5, R6, R7, R9 and L are as defined in formula (1), may be prepared as described in Scheme 4. 5-Aminocinnolines of general formula (12), purchased commercially or prepared using standard chemistry known to those in the art, may be processed as described in Schemes 1-3 to provide ureas of general formula (13) and carbamates of general formula (14).
Ureas of general formula (16), wherein R1, R3, R4, R5, R6, R7, R9 and L are as defined in formula (1), and carbamates of general formula (17), wherein R1, R3, R4, R5, R6, R7, R9 and L are as defined in formula (1), may be prepared as described in Scheme 4.
8-Aminoisoquinolines of general formula (15), purchased commercially or prepared using standard chemistry known to those in the art, may be processed as described in Schemes 1-3 to provide ureas of general formula (16) and carbamates of general formula (17).

Scheme 5 I0' 0 R NH2 )H L, R7 R, HN N~ R9 RZ HN~0R9 R Schemes 1-3 R7 R7 R3 R5 , R6 I R6 (19) R3 R5 R3 R5 (20) (21) NH2 ~H, Ri HN N L, R9 R1 HN R9 N ~OrL N \ R7 Schemes 1-3 N R, R7 N R7 R6 N 'N
R3 R5 , R6 Rs (22) R3 R5 R3 R5.
(23) (24) Ureas of general formula (20), wherein R1, R2, R3, R5, R6, R7, R9, and L are as defined in formula (I), and carbamates of general formula (21), wherein R1, R2, R3, R5, R6, R7, R9, and L are as defined in formula (I), maybe prepared as described in Scheme 5.
4-Aminoindoles of general formula (19), purchased commercially or prepared using standard chemistry known to those in the art, may be processed as described in Schemes 1-3 to provide ureas of general formula (20) and carbamates of general formula (21).
Ureas of general formula (23), wherein R1, R3, R5, R6, R7, R9 and L are as defined in formula (1), and carbamates of general formula (24), wherein R1, R3, R5, R6, R7, R9, and L are as defined in formula (I), may be prepared as described in Scheme 5. 4-Aminoindazoles of general formula (22), purchased commercially or prepared using standard chemistry known to those in the art, may be processed as described in Schemes 1-3 to provide areas of general formula (23) and carbamates of general formula (24).

Scheme 6 R1 NH2 R1 Br R1O OEt N NBS (C(O)OEt)2 R6 R6 Rs (1) (27) (28) ZRjOEt R10 OEt Reducing R2 R7 R2 R7 Agent N CIC(O)CH3 N
(28) Rs R6 (29) (30) O O
H
R1 oEt R1 N L'R9 10% PD/C R2 R7 H2N R9 R2 R7 TEA, H2 (3) N N
(30) / R6 R6 (31) (32) O

HO~L'R9 R2 R7 (5) i (31) N R6 (33) Amides of general formula (32), wherein Rl, R2, R4, R5, R6, R7, R9, and L are as defined in formula (1), can be prepared as described in Scheme 6. Amines of general formula (1) can be treated with an acid such as, but not limited to, concentrated sulfuric acid and N-bromosuccinimide to provide bromides of general formula (27). Bromides of general formula (27) can be treated with an organolithium reagent such as, but not limited to, n-butyllithiurn and diethyl oxalate in a solvent such as, but not limited to, THE to provide keto esters of general formula (28). Keto esters of general formula (28) can be treated with a reducing agent such as, but not limited to, 10% Pd/C under a hydrogen atmosphere (50 psi) in a solvent such as, but not limited to, ethanol to provide hydroxy esters of general formula (29). Hydroxy esters of general formula (29) can be treated with an acid chloride such as, but not limited to, acetyl chloride in a solvent such as, but not limited to, pyridine to provide desters of general formula (30). Diesters of general formula (30) can be treated with 10%
Pd/C and a base such as, but not limited to, triethylamine tinder a hydrogen atmosphere (60 psi) in a solvent such as, but not limited to, ethanol to provide esters of general formula (31).
Esters of general formula (31) can be treated with amines of general formula (3) to provide amides of general formula (32). Alternatively, esters of general formula (31) can be treated with aqueous base such as, but not limited to, aqueous sodium hydroxide or aqueous potassium hydroxide to provide the acids which can then be converted into amides of general formula (32) by treatment with amines of general formula (3) under standard DCC or EDCI
coupling procedures that are well known in the art.
Esters of general formula (33), wherein RI, R2, R4, R5, R6, R7, R9 and L are as defined in formula (I), can be prepared as described in Scheme 6. Esters of general formula (31) can be treated with alcohols of general formula (5) under standard transesterification conditions well known to those of skill in the art to provide esters of general formula (33).

Scheme 7 R7 NaNO 2 N~ R7 ROC(O)CI Nom` R7 H2N _R6 - - / .Ro fl R6 R5 H R R=alkyl R

(35) (36) 1 R (37) NH2 HN-~-N L^R9 PdIC R7 H
H N I 1) CIC(O)CI R7 N

R
(37) O/~O R5 2) H2N.L R9 6 R (38) (3) R O 5 (39) O
HN,JI-N -L 'R9 H
MeOH/NaOH / R7 (39) N

(40) Indazoles of general formula (39) and indazoles of general formula (40), wherein L, R5, R6, R7, and R9 are as defined in formula (1) and R is alkyl as defined herein, can be prepared as described in Scheme 7. Nitro anilines of general formula (35) can be treated with sodium nitrite and an acid including, but not limited to, acetic acid in water to provide indazoles of general formula (36). Indazoles of general formula (36) can be treated with chloroformates to provide indazoles of general formula (37). Indazoles of general formula (37) can be treated with a transition metal catalyst including, but not limited to, palladium on carbon under a hydrogen atmosphere (about I atm to about 60 atm) to provide indazoles of general formula (38). Indazoles of general formula (38) can be processed as described in Scheme 1-3 to provide indazoles of general formula (39). Indazoles of general formula (39) can be treated with a base including, but not limited to, sodium hydroxide or potassium hydroxide to provide indazoles of general formula (40).

Scheme 8 Pd/C
N, R7 ROCOCI N I R7 H2 Nr R7 N - R6 DBU N - R6 'N R6 (42) (43) 'R (44) N
O
O
O O
HN~O
(44) + N"OYO,N R7 O~O R5 (45) \--0 (45) (3) Ni I R7 OH- Ni I R7 H

R (46) (47) Indazoles of general formula (46) and indazoles of general formula (47), wherein L, R5, R6, R7, and R9 are as defined in formula (1) and R is alkyl as defined herein, can be prepared as described in Scheme 8. Nitro indazoles of general formula (42), purchased or prepared using chemistry known in the art, can be treated with chloroformates and a non-nucleophilic base such as, but not limited to, DBU in a solvent such as, but not limited to, N,N-dimethylformamide to provide nitro indazoles of general formula (43).
Nitro indazoles of general formula (43) can be treated with a transition metal catalyst including but not limited to, palladium on carbon under a hydrogen atmosphere (about 1 atm to about 60 atm) in a solvent including, but not limited to, methanol, ethanol, or ethyl acetate to provide amino indazoles of general formula (44). Amino indazoles of general formula (44) can be treated with N,N'-disuccinimidyl carbonate in a solvent including, but not limited to, acetonitrile to provide indazoles of general formula (45). Indazoles of general formula (45) can be treated with an amine of general formula (3) and a base including, but not limited to, diisopropylethylamine or triethylamine in a solvent including, but not limited to, N,N-dimethylfonmainide to provide indazoles of general formula (46). hndazoles of general formula (46) can be treated with a hydroxide anion source including, but not limited to, sodium hydroxide or potassium hydroxide in a solvent including, but not limited to, acetonitrile, methanol, ethanol, aqueous acetonitrile, aqueous methanol, or aqueous ethanol to provide indazoles of general formula (47).
Amino indazoles of general formula (44) can be processed with phosgene as described in Scheme 2 or Scheme 3 to provide indazoles of general formula (46). Indazoles of general formula (46) can then be treated with hydroxide anion to provide indazoles of general formula (47).

The following Examples are intended. as an illustration of and not a limitation upon the scope of the invention as defined in the appended claims.

Example 1 N-(2-(3 -fluorophenyl )ethyll-N'-iso g uinolin-5-ylurea Example 1A
2,2,2-tri.chloro-N-isoguinolin-5-ylacetamide A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (lmL) at 5 C was treated with tiichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise.
The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with IN HCI. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 'H NMR (300 MHz, d6-DMSO) 6 11.20 (broad s, 1H), 9.41, (s, 11-1), 8.60 (d, IH), 8.18 (ni, 1H), 7.77 (m, 2H), 7.66 (d, 1H); MS
(DCUNH3) m/z 289 (M+H)+.

Example lB
N-(2-(3 -fluorophenyl)ethyl -N-iso guinolin-5 -ylurea The product from Example IA (0.65 g, 2.25 mmol), DBU (0.85 g, 5.6 mmol) and 2-(3-fluorophenyl)ethylamine (0.35 g, 2.5 iumol) in acetonitrile (50 mL) were refluxed for 10 hours. The mixture was cooled, concentrated, diluted with ethyl acetate, washed twice with aqueous ammonium chloride and concentrated to dryness. The solid obtained was suspended in ethyl acetate and filtered to obtain 0.45 g (65%) of the title compound as a tan solid. 1H
NMR (300 MHz, d6-DMSO) S 9.27 (s, 1H), 8.63 (s, 1H), 8.51 (d, 1H), 8.26 (d, 1H), 7.89 (d, 1H), 7.71 (d, 1H), 7.59 (m, 1H), 7.35 (m, 1H), 7.18-7.0 (m, 3H), 6.60 (t, 11-1), 3.42 (m, 2H), 2.72 (m, 2H); MS (DCI NH3) m/z 310 (M+11)'; Anal. Calcd. For C18H,6N3F0.
0.1H20: C
69.48; H 5.25; N 13.51. Found: C 69.31; 1- 15.25; N 13.46.

Example 2 N-f 2-(3-bromophenyl)ethyll-N-isoguinolin-5-ylurea The title compound was prepared using 2-(3-bromophenyl)ethylamine, DBU, the product from Example IA and the procedure described in Example I.B. 1H NMR
(300 MHz, d6-DMSO) S 9.26 (s, 11-1), 8.63 (s, 1H), 8.51 (d, 11-1), 8.23 (d, 1H), 7.90 (d, 1H), 7.71 (d, 1H), 7.59 (m, 1I-1), 7.40 (m, 2H), 7.29 (m, 2H), 6.60 (t, I H), 3.42 (m, 2H), 2.80 (m, 2H); MS
(DCUNH3) m/z 370 (M+H)+; Anal. Calcd. For C,SHt6N3BrO: C 58.39; H 4.36; N
11.35.
Found: C 58.17; H 4.46; N 11.28.

Example 3 N-isoguinolin-5-yl-IN1'-14-(trifluoromethyl)benzyl)urea The title compound was prepared using 4-(trifluorometlryl)benzylarnine, DBU, the product from Example IA and the procedure described in Example 1B. 'H NMR (300 MHz, d6-DMSO) 9.26 (s, 1H), 8.82 (s, 1H), 8.52 (d, 1H), 8.26 (d, 1H), 7.94 (d, 1H), 7.71 (m, 3H), 7.58 (m, 3H), 7.20 (t, 1H), 4.48 (d, 2H); MS (DCI/NH3) m/z 346 (M+H)+; Anal.
Calcd. For C1sH,4N3F30. 0.05H20: C 62.63; H 4.19; N 12.04. Found: C 62.41; H 4.58; N
11.44.

Example 4 N-i soguinolin-5-yl-N'-(4-phenoxyb enzyl)urea The title compound was prepared using 4-phenoxybenzylamine, DBU, the product from Example IA and the procedure described in Example 1B. 1H NMR (300 MHz, d6-DMSO) 6 9.30 (s, 1H), 8.75 (s, 11-1), 8.58 (d, 1II), 8.31 (d, 111), 7.92 (d, lii), 7.75 (d, IH), 7.60 (t, 1H), 7.40 (m, 4H), 7.18-6.95 (m, 6H), 4.38 (d, 2H); MS (DCUNH3) n3Jz 369 (M+H)+.
Example 5 N-(3-fluoro-5-(trifluoromethy)b 1 -N_isoquinolin-5-ylurea The title compound was prepared using 3-fluoro-5-(trifluoromethyl)benzylimine, DBU, the product from Example 1A and the procedure described in Example IB. 'H
NMR
(300 MHz, d6-DMSO) 6 9.28 (s, 1H), 8.88 (s, 1H), 8.53 (d, 111), 8.22 (d, IH), 7.90 (d, 1H), 7.77 (d, 1H), 7.55 (m, 4H), 7.20 t, 1H), 4.45 (d, 2H); MS (DCI/NH3) m/z 364 (M+H)+

Example 6 N-(2, 5-dichlorob enzyl)-N-i soquinolin-5-ylurea The title compound was prepared using 2,5-dichlorobenzylatnine, DBU, the product from Example IA and the procedure described in Example 113. 'H NMR (300 MTHz, d6-DMSO) 6 9.30 (s, 111), 8.90 (broad s, IH), 8.55 (d, IH), 8.36 (d, 1H), 7.97 (d, 1H), 7.76 (d, IH), 7.61-7.13 (m, 5H), 4.43 (d, 2H); MS (DCUNH3) m/z 345 (M+H)+; Anal. Calcd.
For C17H13N3C120Ø2H20: C 58.07; H 3.90; N 11.95. Found: C 57.76; H 3.84; N
11.64.

Example 7 N-(1,3-benzodioxol-5-ylmethyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 1,3-benzodioxol-5-ylmethylamine, DBU, the product from Example IA and the procedure described in Example 1B. 1H NMR (300 MHz, d6-DMSO) S 9.27 (s, 11-1), 8.85 (broad s, IH), 8.50 (d, 1H), 8.30 (d, 1H), 8.00 (d, 1H), 7.73 (d, 1H), 7.60 t, IIT), 7.15 (m, 2H), 6.89 (m, 2H), 6.00 (s, 2H), 428 (d, 2H);
MS (DCIINH3) m/z 322 (M+H)+; Anal. Calcd. For C H,3N3O. 0.5H2OØ8NH4C1: C 57.94; H 5.19; N
14.26.
Found: C 57.63; H 5.14; N 14.41.

Example 8 N-[2-(4-fluorophenyl)ethyll-N-isoquinolin-5-ylurea The title compound was prepared using 2-(4-fluorophenyl)ethylamine, DBU, the product from Example IA and the procedure described in Example 1B. 'H NMR (300 MHz, d6-DMSO) 6 9.25 (s, 1H), 8.70 (broad s, IH), 8.50 (d, 1H), 8.27 (d, IH), 7.93 (d, 1H), 7.71 (d, 1H), 7.60 (t, 1H), 7.30 (m, 211), 7.13 (m, 2H), 6.70 (t, 111), 3.40 (m, 2H), 2.80 (m, 2H);
MS (DCI/NH3) m/z 310 (M+H)+; Anal. Calcd. For C17H13N3FO. 0.1H20Ø2NH4CI: C
67.18;
H 5.32; N 13.93. Found: C 66.86; H 5.41; N 13.75.

Example 9 N-(3-bromobenzyl)-N' isoquinolin-5-ylurea The title compound was prepared using 3-bromobenzylamine, DBU, the product from Example IA and the procedure described in Example 113. 'H NMR (300 MHz, d6-DMSO) S

9.29 (s, 1H), 8.80 (broad s, 1H), 8.53 (d, 111), 8.25 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.58 (m, 2H), 7.48 (m, 1H), 7.30 (m, 2H), 7.10 (t, 1H), 4.39 (d, 211); MS (DCI/NH3) m/z 356 (M+H)+; Anal. Calcd. For C17H,4N3BrO: C 57.32; H 3.96; N 11.80. Found: C
57.06; H 3.90;
N 11.45.

Example 10 N-(2-(3,4-dimethylphenyl)ethyll-N'-isoquinolin-5-yurea The title compound was prepared using 2-(3,4-dimethylphenyl)ethylamine, DBU, the product from Example IA and the procedure described in Example I B. 'H NMR
(300 MHz, d6-DMSO) S 9.25(s, 1H), 8.68 (broad s, IH), 8.50 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.57 (t, 1H), 7.00 (m, 3H), 6.60 (t, 111), 3.40 in, 2H), 2.71 (m, 2H), 2.19 (s, 311), 2.16 (s, 3H); MS (DCI/NH3) m/z 320 (M+H)}; Anal. Calcd. For C20H21N30Ø3H20: C 73.96;
H
6.70; N 12.94. Found: C 73.80; H 6.32; N 12..98.

Example 11 N-` 1-(4-bromophenyl)ethyll-N'-isoquinolin-5-ylurea 5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) was treated with 1-bromo-4-(I-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) in toluene (10 mL). The mixture was stirred 14 hours at ambient temperature and filtered to obtain 1.2 g (74%) of the product as light grey solid. 'H NMR (300 MHz, d6-DMSO) S 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.72 (d, 111), 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d, 1H), 4.85 (m, IH), 1.40 (d, 3H); MS (DCI/NH3) m/z 370 (M+H)+; Anal. Calcd.
For C18H,6N3BrOØ1H20: C 58.11; H 4.39; N 11.29. Found: C 57.79; H 4.21; N 11.16.

Example 12 4-(trifluoromethyl)benzyl isoguinolin-5-ylcarbamate The title compound was prepared using [4-(trifluoromethyl)phenyl]methanol, DBU, the product from Example IA and the procedure described in Example 113. 'H NMR
(300 Nfz, d6-DMSO) S 9.90 (broad s, 1H), 9.30 (s, 1H), 8.52 (d, 1H), 7.94 (m, 3H), 7.80 d, 2H), 7.70 (m, 3H), 5.30 (s, 2H); MS (DCUNH3) m/z 347 (M-i-H)+; Anal. Calcd. For C18H,3N2O2F3:
C 62.43; H 3.78; N 8.09. Found: C 62.23; H 3.83; N 7.99.

Example 13 2-(3-bromophcnyl)ethyl isoguinolin-5-ylcarbamate The title compound was prepared using 2-(3-bromophenyl)ethanol, DBU, the product from Example IA and the procedure described in Example 1B. 'H NMR (300 MHz, d6-DMSO) S 9.70 (broad s, 1H), 9.30 (s, 1H), 8.50 (d, 1H), 7.88 (m, 3H), 7.64 (t, 1H), 7.56 (s, 1H), 7.45 (m, 1H), 7.30 (m, 2I-I), 4.34 (t, 2H), 3.00 (t, 2H); MS (DCUNH3) m/z 371 (M+H)+;
Anal. Calcd. For C18H15N2O2Br: C 58.24; H 4.07; N 7.55. Found: C 58.35; H
4.07; N 7.51.

Example 14 1-naphthyllmethyl isoguinolin-5-ylcarbamate The title compound was prepared using 1-naphthylmethanol, DBU, the product from Example IA and the procedure described in Example 1B. 'H NMR (DMSO-d6) S 9.85 (s, 1H), 9.31 (s, 1H), 8.48 (d, 111), 8.15 (d, 1H), 8.04-7.91 (m, 5H), 7.72-7.52 (m, 5H), 5.69 (s, 2H); MS (ESI+) mlz 328 (M+H)+; Anal. Calcd. For C21H16N2O2: C 76.81, H 4.91, N
8.53;
Found: C 76.64, H 4.73, N 8.29.

Example 15 N-isoguinolin-5-yl-N'-[4-(trifluoromethoxy)benzyllurea The title compound was prepared using 4-(trifluoromethoxy)benzylamine, DBU, the product from Example 1A and the procedure described in Example I.B. MS (ESI+) mlz 362 (M+H)+; 'H NMR (DMSO-d6) S 4.41 (d, 2H), 7.14 (t, 1H), 7.35 (d, 2H), 7.48 (d, 2H), 7.60 (t, 1H), 7.75 (d, 1H), 7.95 (d, 111), 8.28 (d, 1H), 8.53 (d, IH), 8.79 (s, 1H), 9.27 (s, 1H).

Example 16 N 4-dichlorobenzyl)-N'-(3-methylcinnolin-5-y1)urea Example 16A . .
2,2,2-tricliloro-N-(3-methylcinnolin-5-yl)acetalnide The title compound was prepared using 3-methylcinnolin-5-amine (commercially available, Maybridge), triethylamine, trichloroacetyl chloride and the procedure described in Example IA.

Example 16B
N-(3,4-dichlorobenzyl)-N-(3-methylcinnolin-5- ly )urea The title compound was prepared using 3,4-dichlorobenzylamine, the product from Example 16A, DBU and the procedure described in Example 1B. MS (ESI+) iu/z 362 (11M+H)+; 'H NMR (DMSO-d6) 6 2.88 (s, 3H), 4.36 (d, 2H), 7.10 (t, 1H), 7.34 (dd, 1H), 7.59 (m, 2H), 7.76 (t, 1H), 8.04 (d, 2H), 8.19 (d, 1H), 8.93 (s, 1H).

Example 17 N-isoguinolin-5-yl-N'-(4-methylbenzyl)urea The title compound was prepared using 4-methylbenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z 292 (M+H)+; 1H NIVIR (DMSO-d6) 6 2.29 (s, 3H), 4.33 (d, 2H), 7.00 (t, 1H), 7.17 (d, 2H), 7.24 (d, 2M, 7.60 (t, 1H), 7.73 (d, 1I1), 7.93 (d, 1H), 8.30 (d, 1H); 8.53 (d, 1H), 8.70 (s, 1H), 9.26 (s, IH).

426934 Example 18 N-(4-fluorobenzyl)-N'-isoguinolin-5-ylurea The title compound was prepared using 4-fluorobenzylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS (APCI+) m/z 296 (M+H)+; 1H NMR (DMSO-d6) S 4.37 (d, 2H), 7.07 (t, 111), 7.18 (t, 2H), 7.40 (dd, 2H), 7.60 (t, 1H), 7.74 (d, 1H), 7.94 (d, 1H), 8.28 (d, 11D, 8.54 (d, 1H), 8.74 (s, 1H), 9.27 (s, 1H).

Example 19 N-isoguinolin-5-yl-N-((trans)-2-phenylcyclopropyl}urea The title compound was prepared using trans 2-phenylcyclopropylamine hydrochloride, the product from Example IA, DBU and the procedure described in Example lB. MS (ESI+) m/z 304 (M+I4)+; 'H NMR (DMSO-d6) 6 1.21 (m, 2H), 2.05 (in, 1H), 2.82 (m, 1H), 7.00 (d, 1H), 7.17 (t, 311), 7.27 (t, 2H), 7.60 (t, 1H), 7.74 (d, 11-1), 7.88 (d, 11-1), 8.26 (d, 11-1), 8.53 (d, 1H), 8.57 (s, 114), 927 (s, 1H).

Example 20 N-[2-(3,4-dichlorophenyl)ethyl]-N'-isoquinolin-5-ylurea The title compound was prepared using 2-(3,4-dichlorophenyl)ethylamine, the product from Example 1A, DBU and the procedure described in Example I.B. MS
(ESI+) m/z 361 (M+H)+; 'H NMR (DMSO-d6) 6 2.82 (t, 2H), 3.43 (q, 2H), 6.63 (t, 1H), 7.29 (dd, 114), 7.59 (m, 311), 7.73 (d, 114), 7.88 (d, 1H), 8.23 (d, 1H), 8.52 (d, 1H), 8.65 (s, 111), 9.26 (s, 114).

Example 21 N-[2-(3 ,5-dimethoxyphenyl)ethyll-N'-isoquino lin-5-ylurea The title compound was prepared using 2-(3,5-dimethoxyphenyl)ethylamine, the product from Example IA, DBU and the procedure described in Example IB. MS
(ESI+) m/z 352 (M+H)+; 'H NMR (DMSO-d6) 6 2.74 (t, 214), 3.42 (q, 21I), 3.73 (s, 6H), 6.36 (t, l H), 6.44 (d, 2H), 6.59 (t, 1H), 7.59 (t, 114), 7.72 (d, 1H), 7.91 (d, 11-1), 8.27 (d, 1H), 8.52 (d, 1H), 8.67 (s, 11-1), 9.26 (s, 1H).

Example 22 N-(4-ehlorobenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 4-chlorobenzylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS (ESI+) m/z 313 (M+I4)+;'H NMR (DMSO-d6) 6 4.37 (d, 2H), 7.14 (t, IH), 7.40 (q, 4H), 7.60 (t, 111), 7.74 (d, 1H), 7.95 (d, 11-1), 8.28 (dd, IH), 8.53 (d, 1H), 8.80 (s, 1H), 9.27 (s, 111).

Example 23 N-i soq uinolin-5-yl-N'- {2-(3 -(trifluoromethyl)phenyll ethyl } urea The title compound Iwas prepared using 2-[3-(trifluoromethyl)phenyl]ethylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS
(ESI+) m/z 360 (M+H)+; 'H NMR (DMSO-d6) S 2.91 (t, 2H), 3.46 (q, 2H), 6.62 (t, 1H), 7.59 (m, 4H), 7.64 (s, IH), 7.73 (d, 1H), 7.87 (d, 1H), 8.23 (d, 1H), 8.51 (d, IH), 8.64 (s, 1H), 9.26 (s, 1H)_ Example 24 N-[2-(2,6-dichlorophenyl)ethyl]-N'-isoq uinolin-5-ylurea The title compound was prepared using 2-(2,6-dichlorophenyl)ethylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS
(ESI+) m/z 361 (M+H)+; 'H NMR (DMSO-d6) S 3.12 (t, 2H), 3.40 (q, 2H), 6.72 (t, 1H), 7.28 (t, IH), 7.46 (d, 2I3), 7.58 (t, 113), 7.72 (d, 1H), 7.87 (d, 1H), 8.19 (d, IH), 8.51 (d, 1H), 8.60 (s, 1H), 9.25 (s, 1H).

Example 25 N-[2-(2,3-dichlorophenyl)ethyl-N'-isoquinolin-5-ylurea The title compound was prepared using 2-(2,3-dichlorophenyl)ethylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS
(ESI+) m/z 361 (M+H)+; 'H NMR (DMSO-d6) S 3.01 (t, 2H), 3.46 (q, 2H), 6.67 (t, 1H), 7.34 (t, IH), 7.38 (dd, 1H), 7.53 (dd, IH), 7.59 (t, IM, 7.74 (d, 1H), 7.87 (d, 111), 8.21 (d, 1H), 8.52 (d, 1H), 8.64 (s, 1H), 9.26 (s, 1H).

Example 26 N-isoquinolin-5-yl-N'-[3-(trifluoromethoxy)benzyllurea The title compound was prepared using 3-(trifluoromethoxy)benzylamine, the product from Example 1A, DBU and the procedure described in Example 113. MS (ESI+) m/z (M+H)+; 'H NMR (DMSO-d6) 6 4.44 (d, 2H), 7.15 (t, 1H), 7.26 (d, 1H), 7.34 (s, 1H), 7.40 (d, 1H), 7.50 (t, 1H), 7.61 (t, 1H), 7.76 (d, 1H), 7.95 (d, IH), 8.25 (d, 1H), 8.53 (d, IH), 8.80 (s, 1H), 9.28 (s, IH).

Example 27 N-[2-(4-ethoxy-3-methoxypheny_1)ethyl]-N'-isoquinolin-5-ylurea The title compound was prepared using 2-(4-ethoxy-3-methoxyphenyl)ethylamuie, the product from Example IA, DBU and the procedure described in Example 113.
MS (ESI+) m/z 366 (M+H)}; 'H NMR (DMSO-d6) 8 1.31 (t, 3H), 2.73 (t, 2H), 3.40 (q, 2H), 3.76 (s, 3H), 3.97 (q, 2H), 6.62 (t, 1H), 6.76 (dd, 1H), 6.87 (d, 2H), 7.59 (t, 1H), 7.72 (d, 1H), 7.93 (d, 11-1), 8.28 (d, 1H), 8.52 (d, 1H), 8.69 (s, 1H), 9.26 (s, 1H).

Example 28 N-(2-(2,4-dichlorophenyl)ethyll-N'-isoquinolin-5-ylurea The title compound was prepared using 2-(2,4-dichlorophenyl)ethylamine, the product from Example IA, DBU and the procedure described in Example 113. 'H
NMR
(DMSO-d6) 5 9.26 (s, 114); 8.62 (s, 111); 8.53 (d, 1I1); 8.22 (dd, 1H); 7.88 (d, 11-1); 7.74 (d, I11); 7.61 (m, 1H); 7.57 (d, 111); 7.42 (m, 2H); 6.64 (t, 1H); 3.43 (q, 2H);
2.93 (t, 2H).

Example 29 N-(3-bromo-4-fluorobenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 3-bromo-4-fluorobenzylamine, the product from Example IA, DBU and the procedure described in Example 113. MS (ESI+) m/z (M+H)+; 'H NMR (DMSO-d6) 6 9.55 (s, 11-1); 9.06 (s, IM; 8.64 (d, 1 H); 8.42 (d, 11-1); 8.25 (d, 1H); 7.95 (d, 1H); 7.76 (t, 111); 7.70 (dd, 1I-1); 7.38 (m, 2H); 7.15 (m, 2H); 4.35 (d, 2H).
Example 30 N-(3,4-dimethylbenzyl)-N-isoquinolin-5-ylurea The title compound was prepared using 3,4-dimethylbenzylamine, the product from Example IA, DBU and the procedure described in Example 113. MS (ESI+) m/z 307 M+H)+;
'H NMR (DMSO-d(,) 5 9.55 (s, 1H); 8.98 (s, 111); 8.62 (d, 1H); 8.46 (d, 1H);
8.25 (d, 1H);
7.94 (d, 1H); 7.78 (t, 111); 7.08 (m, 3H); 6.95 (m, 211); 4.30 (d, 2H); 2.20 (s, 311); 2.18 (s, 3H).

Example 31 N-isoquinolin-5-yl-N-(3-phenylpropyl)urea The title compound was prepared using 3-phenylpropylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z 306 (1\4+H)+; 'H NMR (DMSO-d6) 8 9.61 (s, 1H); 9.05 (s, 111); 8.65 (d, 111); 8.50 (d, I H); 8.40 (d, 1H); 7.96 (d, 1H); 7.80 (t, 1H); 7.21 (m, 6H); 6.92 (t, 1H); 3.18 (q, 2H);
2.65 (t, 2I-I); 1.78 (m, 2H).

Example 32 N-(3 , 5-dichlorob enzyl)-N'-isoguinolin-5 -ylurea The title compound was prepared using 3,5-dichlorobenzylamine, the product from Example I A, DBU and the procedure described in Example 1B. MS (ESI+) m/z 347 (M+I-I)+; 'H NMR (DMSO-d6) 8 9.60 (s, 1H); 9.18 (s, IH); 8.65 (d, 1H); 8.44 (d, 111); 8.35 (d,.1H); 7.96 (d, 1H); 7.80 (t, 1H); 7.43 (dt, 1H); 7.40 (m, 2H); 7.35 (m, 1H); 725 (d, 1ITJ;
4.40 (d, 2H).

432465 Example 33 N-(3-chloro-4-methylbenzyl)-N-isoquinolin-5-ylurea The title compound was prepared using 3-chloro-4-methylbenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z (M+H)+; 'H NMR (DMSO-d6) 6 9.65 (s, 1H); 9.20 (s, 1H); 8.65 (d, 1H); 8.50 (d, 1H); 8.40 (d, 11-1); 8.00 (d, 1H); 7.80.(t, 1H); 7.30 (m, 5H); 4.35 (d, 2H); 2.30 (s, 3H).

Example 34 N-isoquinolin-5-yl-N-(2-phenoxyethyl)urea The title compound was prepared using 2-phenoxyethylamine, the product from Example IA, DBU and the procedure described in Example lB. MS (ESI+) m/z 308 (M+H)+; 'H NMR (DMSO-d6) 6 9.50 (s, 111); 8.98 (s, 111); 8.61 (d, 1H); 8.45 (d, 1H); 8.20 (d, IH); 7.90 (d, 1H); 7.75 (t, 1H); 7.26 (m, 3H); 6.95 (m, 41); 4.00 (t, 2H);
3.50 (m, 2H).
Example 35 N-(3,4-dichlorobenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 3,4-dichlorobenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z 344 (M-H) ;
'H NMR (300 MHz, DMSO-d6) 8 9.27 (s, 111), 8.82 (bs, 1H), 8.54 (d, 1H), 8.25 (m, IM, 7.94 (d, 1H), 7.76 (d, 1H), 7.56-7.65 (m, 31-1), 7.35 (m, 1H), 7.15 (t, 1H), 4.38 (d, 211); Anal.
Calcd for C17H13C12N30: C, 58.98; H, 3.78; N, 12.14. Found: C, 59.02; H, 3.70;
N, 12.10.
Example 36 N-(3-fluorobenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 3-flu orobenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z 294 (M-H)-;
'H NMR (300 MHz, DMSO-d6) 6 9.28 (s, 1I-1), 8.80 (bs, 1H), 8.54 (d, 1H), 8.28 (ni, 1H), 7.95 (d, 1H), 7.76 (d, 1H), 7.60 (t, 1H), 7.35-7.45 (m, 1H), 7.05-7.15 (m, 4H), 4.40 (d, 2H);
Anal. Calcd for C17H14FN30: C, 69.14; H, 4.78; N, 14.23. Found: C, 68.98; H, 4.83; N, 14.27.

Example 37 N-(4-tert-butylbenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 4-tert-butylbenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z 334 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.70 (bs, 1H), 8.53 (d, 1H), 8.31 (dd, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.60 (t, 1H), 7.38 (m, 2H), 7.28 (m, 2H), 7.01 (t, 1H), 4.32 (d, 2H), 1.27 (s, 9H). Anal. Calcd for C21H23N30Ø3 H2O: C, 74.44; H, 7.02; N, 12.40.
Found: C, 74.19; H, 6.88; N, 12.33.

Example 38 N-isoquinolin-5-yl-N'-[2-(3-methylphenyl)ethyl]urea The title compound was prepared using 2-(3-methylphenyl)ethylamine, the product from Example IA, DBU and the procedure described in Example 113. MS (ESI+) m/z (M+H)+; 1H NMR (300 MHz, DMSO-d6) 6 9.26 (m, 1H), 8.66 (bs, 1H), 8.52 (d, III), S28 (dd, 1H), 7.90 (d, IH), 7.72 (d, 1H), 7.59 (t, 1H), 7.21 (t, 1H), 7.00-7.11 (m, 3H), 6.60 (t, 1H), 3.41 (m, 2H), 2.76 (t, 2H), 2.30 (s, 3H); Anal. Calcd for C19H19N30Ø1 H20: C, 74.29;
H, 6.30; N, 13.68. Found: C, 74.06; H, 6.43; N, 13.76.

Example 39 N-isoquinolin-5-yl-N'-[2-(4-methylphenyl)ethyllurea The title compound was prepared using 2-(3-rethylphenyl)ethylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z (M+H)+; 1H NMR (300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.66 (bs, 11-1), 8.52 (d, 1H), 8.28 (m, 114), 7.90 (d, 1H), 7.72 (d, 1H), 7.59 (t, IH), 7.10-7.20 (in, 4H), 6.58 (t, 1H), 3.40 (in, 2H), 2.75 (t, 2H), 2.28 (s, 3H); Anal. Calcd for C,9H,9N30Ø2 H20: C, 73.86; H, 6.33; N, 13.60.
Found: C, 73.69; H, 6.53; N, 13.51.

Example 40 N-[2-(2,4-dimethylphenyl)ethyl]-N'-isoguinolin-5-ylurea The title compound was prepared using 2-(2,4-dimethylphenyl)ethylamine, the product from Example IA, DBU and the procedure described in Example 113. MS
(ESI+) m/z 320 (M+H)+; 'H NMR (300 MHz, DMSO-d6) S 9.26 (s, 1H), 8.66 (bs, 1H), 8.53 (d, 1H), 8.28 (m, 1H), 7.90 (d, 1H), 7.73 (d, 1H), 7.59 (t, 1H), 7.08 (d, 1H), 6.92-7.02 (m, 2H), 6.63 (t, 111), 3.34 (m, 2H), 2.75 (t, 2H), 2.29 (s, 3H), 2.24 (s, 3H); Anal. Caled for C20H21N30Ø45 H20: C, 73.35; H, 6.74; N, 12.83. Found: C, 73.70; H, 6.53; N, 12.45.

Example 41 N-isoguinolin-5-yl-N'-[2-(2-methylphenyl)ethyllurea The title compound was prepared using 2-(2-methylphenyl)ethylanaine, the product from Example 1A, DBU and the procedure described in Example 1B. MS (ESI-) m/z (M-H)-; 'H NMR (300 MHz, DMSO-d6) S 9.26 (s, 1H), 8.64 (bs, 1H), 8.53 (d, IH), 8.25 (m, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.59 (t, 1H), 7.46 (dd, 1H), 7.40 (dd, 1H), 7.23-7.36 (m, 2H), 6.67 (t, IH), 3.44 (m, 2H), 2.94 (t, 2H); Anal. Calcd for C18H16CIN30: C, 66.36; H, 4.95; N, 12.90. Found: C, 66.19; H, 4.87; N, 12.91..

Example 42 N-isoguinolin-5-yl-N- f4-[(trifluoromethyl)thiolbenzyl}urea The title compound was prepared using 4-[(trifluoromethyl)thio]benzylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS
(ESI-) m/z 376 (M-H)-; 1H NMR (300 MHz, DMSO-d6) 5 9.27 (s, 1H), 8.82 (bs, 1H), 8.54 (d, 1H), 8.27 (dd, IH), 7.95 (d, 1H), 7.68-7.78 (m, 3H), 7.60 (t, 1H), 7.51 (d, 2H), 7.17 (t, 1H), 4.45 (d, 2H); Anal. Calcd for C18H14F3N3OS: C, 57.29; H, 3.74; N, 11.13. Found: C, 57.00; H, 3.73;
N, 11.04.

Example 42 N-isoquinolin-5-yl-N'-(3-(trifluoromethyl)benzyl lure a The title compound was prepared using 3-(trifluoromethyl)benzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z (M-I-I)-; 1H NMR (300 MHz, DMSO-d6) 8 9.27 (s, 1H), 8.82 (bs, 1H), 8.53 (d, I
IT), 8.25 (dd, 1H), 7.94 (d, 1H), 7.55-7.79 (m, 6H), 7.18 (t, 1H), 4.47 (d, 2H); Anal. Calcd for CisH14F3N3O: C, 62.61; H, 4.09; N, 12.17. Found: C, 62.39; H, 3.87; N, 12.28.

Example 43 N-isoquinolin-5-yl-N'-(4-m ethox),benzyl)urea The title compound was prepared using 4-methoxybenzylamine, the product from Example IA, DBU and the procedure described in Example lB. MS (ESI-) m/z 306 (hM-H)-;
iH NIvlR (300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.70 (bs, 1H), 8.53 (d, 1H), 8.31 (dd, 1H), 7.92 (d, 1H), 7.73 (d, 114), 7.60 (t, IH), 7.29 (m, 2II), 6.88-7.03 (m, 3H), 4.30 (d, 2H), 3.74 (s, 3H); Anal. Calcd for CjsH17N302: C, 70.34; H, 5.58; N, 13.67. Found: C, 70.21;1-1, 5.47;
N, 13.46.

Example 44 N-(4-chloro-3-(trifluoromethyl)benzyll-N'-isoquinolin-5-ylurea The title compound was prepared using 4-chloro-3-(trifluoromethyl)benzylamine, the product from Example IA, DBU and the procedure described in Example 113. MS
(ESI-) m/z 378 (M-H)-; 'H NMR (300 MHz, DMSO-d6) 6 9.73 (s, 11-1), 9.53 (s, 1H), 8.69 (d, 1H), 8.61 (d, 1H), 8.54 (d, 1H), 8.07 (d, 1H), 7.82-7.92 (m, 2H), 7.63-7.75 (m, 3H), 4.47 (d, 2H); Anal.
Calcd for C18H13C1F3N30.1.2 HCI: C, 51.05; H, 3.38; N, 9.92. Found: C, 51.26;
H, 3.68; N, 9.50.

Example 45 N-(3 , 5-dimethylbenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 3,4-dimethylbenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z 304 (M-H)-;
1H NMR (300 MHz, DMSO-d6) S 9.74 (s, 1H), 9.41 (bs, 1H), 8.69 (d, 1H), 8.62 (d, 2H), 8.05 (d, 1H), 7.88 (t, IH), 7.44 (t, 1H), 6.96 (bs, 2H), 6.89 (bs, 1H), 4.31 (d, 2H), 2.26 (s, 6H); Anal. Calcd for C19H,9N30.1.l HCI: C, 66.05; H, 5.86; N, 12.16. Found: C, 66.09; H, 5.83; N, 12.14.

Example 46 N-(3,5-difluorobenzyl)-N'-isoquinolin-5-ylurea The title compound was prepared using 3,5-difluorobenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z 312 (M-H) 'H NMR (300 MHz, DMSO-d6) 6 9'76 (s, 1H), 9.66 (bs, 1H), 8.65-8.79 (m, 2H), 8.60 (d, 111), 8.08 (d, 1H), 7.89 (t, 1H), 7.77 (t, 1H), 7.02-7.18 (m, 311), 4.43 (d, 2H); Anal. Calcd for C17H,3F2N30=HCl-0.3 H20: C, 57.49; H, 4.14; N, 11.83. Found: C, 57.76; H, 4.59; N, 11.76.

Example 47 N-hexyl-N'-isoguinolin-5-ylurea The title compound was prepared using hexylamine, the product from Example IA, DBU and the procedure described in Example I.B. MS (ESI-) m/z 270 (N4-M-; 'H
NMR
(DMSO-d6) 6 9.25 (s, 1H), 8.60 (s, 11-1), 8.55 (d, 1H), 8.39 (d, 1H), 7.93 (d, IH), 7.71 (d, 1H), 7.59 (t, 1H), 6.60 (t, 1H), 3.15 (q, 2H), 1.49 (m, 2H), 1.32 (m, 6H),.90 (m, 3H).

Example 48 N-(4-bromobenzyl)-N'-isogiiinolin-5-ylurea The title compound was prepared using 4-bromobenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z 355 (M-H)-;
'H NMR (DMSO-d6) S 9.27 (s, 1H), 8.78 (s, 1H), 8.53 (d, 1H), 8.27 (d, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.55 (d, 2H), 7.42 (d, 2H) 7.10 (t, 1H); Anal.
Calcd for C17H14BrN3O: C, 57.32; H, 3.96; N, 11.80. Found C, 57.05; H, 3.79; N, 11.64.

Example 49 N-(3, 5-dimethoxybenzyl)-N'-isoguinolin-5 -ylurea The title compound was prepared using 3,5-dimethoxybenzylamine, the product from Example 1A, DBU and the procedure described in Example 113. MS (ESI-) nilz 336 (M-II)-;
'I-I NMR (DMSO-d6) 6 9.70 (s, 1H), 9.32 (s, 11-1), 8.69 (d, IH), S.55 (dd, 2H), 8.10 (ci, 111), 7.85 (t, 11=I), 7.39 (t, 111), 6.54 (s, 2H), 6.41 (s, 1H) 4.35 (d, 211), 3.75 (s, 6H); Anal. Calcd for C19H19N303 1.25 HCI C, 59.59; H, 5.33; N, 10.97. Found C, 59.22; H, 5.41; N, 10.84.

Example 50 N-isoguinolin-5-yl.-N'-(3,4,5-trimethoxybenzyl)urea The title compound was prepared using 3,4,5-trimethoxybenzylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI-) m/z (M-H) 'H NMR (DMSO-d6) 6 9.79 (s, 1H), 9.50 (s, 1H), 8.69 (d, 1H), 8.80 (d, 1H), 8.65 (dd, 2H), 8.08 (d, 1H), 7.90 (d, 1H), 7.68 (m, IH), 6.71 (s, 2H), 4.53 (d, 2H) 3.79 (s, 6H), 3.53 (s, 3H). Anal. Calcd for C20H21N3041.3 HCI: C, 57.91; H, 5.42; N, 10.13.
Found C, 57.65; H, 5.60; N, 10.09.

Example 51 N-isoguinolin-5-yl-N'-[4-(methyl sulfonyl)benzyl]ure The title compound was prepared using 4-(methylsulfonyl)benzylamine, the product from Example IA, DBU and the procedure described in Example IB. MS (ESI-) m/z (M-H);'H NMR (DMSO-d6) 6 9.65 (s, 1H), 9.30 (s, 1H), 8.65 (d, 1H), 8.49 (d, 1H), 8.42 (d, 1H), 8.00 (d, 1H), 7.91 (d, 2H), 7.82 (t, 1H), 7.61 (d, 2H), 7.47 (t, 1H), 4.50 (d, 2H), 3.20 (s, 3H); Anal. Calcd for C20H21N304 1.0 HCI: C, 55.17; H, 4.63; N, 10.72. Found C, 54.92; H, 4.54; N, 10.42.

Example 52 N-(3,4-dimethoxybenzyl)-N'-isoguinolin-5-ylurea The title compound was prepared using 3,4-dimethoxybenzylamine, the product from Example 1A, DBU and the procedure described in Example 1B. MS (ESI-) m/z (M-H)" 336;
'H NMR (DMSO-d6) S 9.78 (s, 1H), 9.50 (s, IH), 8.70 (s, 211), 8.62 (d, 1H), 8.05 (d, 1H), 7.87 (t, 1H), 7.51 (t, IH), 6.99 (s, 11f), 6.79 (ds, 2H), 4.32 (d, 2H), 3.75 (s, 3H), 3.71 (s. 3H);

Anal. Calcd for C1911, 9N303 1.0 HCl: C, 61.04; H, 5.39; N, 11.24. Found C, 60.82; H, 5.38;
N, 11.19.

Example 53 N-isoguinolin-5-yl-N'-(3-phenoxybnzI)urea The title compound was prepared using 3,4-dimethoxybenzylamine, the product from Example IA, DBU and the procedure described in Example 113. MS (ESI-) m/z 368 (M-H)-;
'H NMR (DMSO-d6) S 9.65 (s, 1H), 9.25 (s, 1H), 8.65 (d, 1H), 8.52 (d 1H), 8.48 (d, IH), 8.03 (d, 1H), 7.82 (t, 1H), 7.35 (m, 4H), 7.15 (d, 2H), 7.05 (s, 2H), 7.00 (s, 1H), 6.84 (d, 1H), 2.37 (d, 2H); Anal. Calcd for C23HI9N302 1.25 HCI: C, 66.57; H, 4.92; N, 10.
13. Found C, 66.49; H, 5.02; N, 10.14.

Example 54 N-iso guino lin-5-yl-N'-(1-naphthylmethyl )urea The title compound was prepared using 1-naphthyhnethylamine, the product from Example IA, DBU and the procedure described in Example 1B. MS (ESI+) m/z 328 (M+H)+; FIRMS (FAB): Calculated for C21H18N30 328.1450; observed 328.1438 (M+H)+;'H
NMR (DMSO-d6) 5 9.25 (s, 1H), 8.48, (d, 1H), 8.39 (d, 114), 8.22 (d, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.78-7.71 (m, 2H), 7.63-7.49 (m, 6H), 4.85 (d, 2H).

Example 55 N-(2,4-dimethylbenzyl)-N'-isoguinolin-5-ylurea The title compound was prepared using 2,4-dimethylbenzylamine, the product from Example IA, DBU and the procedure described in Example 113. MS (ESI+) m/z 306 (M+H)+;'H NMR (DMSO-d6) 5 9.26 (s, 1H), 8.67 (s, 1H), 8.53 (d, 1H), 8.32 (d, 1H), 7.92 (d, I H), 7.72 (d, I H), 7.60 (t, I H), 7.19 (d, 111), 7.03-6.95 (m, 2H), 9.90 (t, IM, 4.31 (d, 2H), 2.30 (s, 3H), 2.26 (s, 3H); Anal. Calcd for C19H19N30Ø2H20: C, 73.86, H
6.33, N 13.60.
Found: C 73.75, H 6.49, N 13.49.

Example 56 N-(4-(dimethylamino)benzy l-N'-isoguinolin-5-ylurea The title compound was prepared using 4-(aminomethyl)-N,N-dinlethylaniluie, the product from Example 1 A, DBU and the procedure described in Example 1B. MS
(ESI+) miz 321 (M+H)*; 'H NMR (DMSO-d6) 6 9.26 (s, 1H), 8.71 (s, 1H), 8.52 (d, 1H), 8.32 (d, IH), 7.93 (d, 1H), 7.72 (d, IH), 7.59 (t, 1H), 7.18 (d, 2H), 6.96 (t, IH), 6.71 (d, 21-1), 4.23 (d, 2H), 2.86 (s, 6H); Anal. Calcd for Ct9H2oN40Ø7H20: C, 68.53, H 6.48, N
16.82. Found: C
68.59, H 6.48, N 16.60.

Example 57 N-isoguinolin-8-yl-N-J4-(trifluoromethyl)benzyl)urea Example 57A
5-bromoisoguinoline Concentrated H2SO4 (260 mL) was cooled to -25 C while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0 C. After the addition was complete. the red solution was recooled to -25 C
and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed -20 C. The reaction mixture was stirred for 5 hours keeping the temperature between -30 C and -18 C. The reaction mixture was then allowed to warm to -10 C and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH.
The mixture was then extracted with diethyl ether (3 x 600 mL). The ether fractions were combined, filtered through a CeliteTM plug and the filtrate concentrated under reduced pressure.
The residue was suspended in hot heptane (600 mL). The heptane was decanted.
This procedure was repeated with hexane (2 x 200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptanc (26.37 g, 50%). nip 78 -80 C;
NIS (ESI+) u7/z 209 (vI+H)k; IH NMR (DMSO, 300 MHz) S 7.65 (t, J 7.9, 1H), 7.94 (d, J
8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 9. 1, 1H), 8.68 (d, 3 6.1, 1H), 9.37 (s, IH); Anal.
Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52;
Br, 38.81.

Example 57B
5-bromo-8-nitroisoguinoline The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (-300 nil). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).

Example 57C
isoguinolin-8-amine The product from Example 57B was treated with Pd/C under a hydrogen atmosphere to provide the title compound.

Example 57D
2,2,2-trichloro-N-isoguinolin-8-ylacetamiide The product from Example 57C and trichloroacetylchloride were processed as described in Example IA to provide the title compound.
Example 57E
N-isoguinoLin-8-y]-N-r4-(trifluoromethyl)benzyI lure The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example I.B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) S 9.58 (s, 111), 9.10 (s, I H), 8.49 (d, I H), 8.12 (d, I H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 214); Anal. Calcd for C18H14F3N30Ø2 H2O: C, 61.96, H
4.16, N 12.04. Found: C 62.06, H 4.23, N 11.91.

Example 58 N-(4-bromobenzyl)-N-isoguinolin-8-ylurea The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) mlz 356 (M+H)+;'H NMR (DMSO-d6) S 9.52 (s, IH), 9.15 (s, IH), 8.49 (d, 1H), 8.11 (d, 111), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H) 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H);
Anal. Calcd for C17H14BrN30Ø25 H20Ø16 MeOH: C 56.34, H 4.17, N 11.49. Found C, 56.32, H
4.45, N

11.70.

Example 60 N-(4-bromobenzyl)-N'-(3-chloroisoquinolin-5- 1 urea Example 60A
isoquinoline-1,3(211,411)-dione 2-(Carboxyrnethyl)benzoic acid (10 g, 55.6 mmol) was dissolved in concentrated NH4OH (15 mL) and then was evaporated to dryness under reduced pressure. The process was repeated with additional NI-140H (5 mL). The resulting residue was treated with 1,2-dichlorobenzene (20 rL) and heated with stirring at 200 C without a condenser allowing the solvent to evaporate. The concentrated mixture was allowed to cool to room temperature, diluted with methanol (20 mL), and allowed to stand overnight. The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to provide the title compound as tan needles (6.6 g, 74%).

Example 60B
1,3-dichloroisoquinoline The product from Example 60A (6.5 g, 40.4 mmol) was treated with phenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160 C for 3 hours. The reaction was allowed to cool to room temperature and stand overnight. The resulting waxy orange material was dissolved in tetrahydrofuran (200 mL), treated with water (60 mL), and then concentrated under reduced to remove the tetrahydrofuran. The remaining aqueous material was neutralized with concentrated NH4OH and extracted with ethyl acetate. The ethyl acetate phases were combined, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as yellow flakes (6.92 g, 74%).

Example 60C
3-chloroisoguinoline The product from Example 60B (6.73 g, 33.8 mmol) was suspended in glacial acetic acid (37 mL) and concentrated HCl (13 mL), treated with tin powder (12.1 g, 101.9 mmol), and heated at 55-60 C for 3 hours with stirring. The mixture was allowed to cool to room temperature and the precipitated tin salts were removed by filtration through Celite. The fi filtrate was basified to pH 9 with concentrated NH4OH and then extracted with ethyl acetate.
The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound as a gummy yellow residue (1.28 g, 23%).

Example 60D
3-chloro-5-nitroisoguinoline The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H2S04 (30 mL) at 0 C was treated with a solution of KNO3 (0.84 g, 8.32 mmol) in concentrated H2S04 (5 mL) dropwise over 5 minutes. The mixture was stirred at 0 C for 10 minutes, allowed to warm to room temperature, and stirred overnight. The mixture was poured onto 65 g of ice and the precipitated yellow solid was collected by filtration. The solid was slurried in water, collected by filtration, washed with water, and allowed to air-dry to provide the title compound as a pale yellow solid (0.45 g, 28%).

Example 60E
3-chloroisoguinolin-5-amine The product from Example 60D (0.45 g, 2.16 mmol) was suspended in glacial acetic acid (4 mL) and warmed to 60 C while adding water (4 mL). The heated mixture was treated with powdered iron (0.33g, 5.91 mmol) in three portions over about 2 minutes. The reaction mixture stirred at 60 C for 2 hours, allowed to cool to room temperature and stir overnight. The mixture was basified with 25% aqueous NaOH, diluted with a little water, and the brown precipitate was collected by filtration and dried overnight at 50 C in a vacuum oven. The filter cake was then broken up and extracted with boiling ethyl acetate. The extracts were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a gold-orange solid (200 mg, 52%).

Example 60F
N-(4-bromobenzyl)-N'-(3-ehloroisoguinolin-5-yl)urea The product from Example 60E (250 mg, 1.4 mmol) and 1-bromo-4-(isocyanatomethyl)benzene (0.22 mL, 1.57 mmol) were heated in toluene (5 mL) at 80 C for 3 hours. The mixture was allowed to cool to room temperature, filtered, the filter cake was .washed with toluene, and air-dried to provide the title compound (335 mg, 61%). 'H NMR
(300 MHz, DMSO-d6) 6 9.18 (s, 111), 8.81 (s, 1H), 8.32 (dd, J=7.8Hz, 0.7 Hz, 1H), 8.09 (s, 1ff), 7.80 (d, J=8.2 Hz, 111), 7.53-7.65 (m, 31-1), 7.32 (m, 2H), 7.05 (t, J=5.7 Hz, Ili), 4.35 (d, JJ5.7 Hz, 2H); MS (EST') m/z 391/393 (111+f, 35C1/37CI).

Example 61 4-cyanobenzyl isoguinolin-S-ylcarbamate Example 61A
5-isocyanatoisoguinoline Phosgene (20 ml, 20% in toluene from Fluka) in CH2C12 (300 mL) at 0 C was treated with DMAP (10 g) in CH2C12 (100 mL) slowly. After complete addition, the mixture was treated with 5-aminoisoquinoline (5 g) in CH2CI2 (100 mL) dropwise. The mixture was allowed to warm to room temperature and then stirred overnight. The solvent was removed under reduced pressure. The solid residue was extracted with diethyl ether (400 mL). The diethyl ether was filtered to provide the title compound in diethyl ether as a pale yellow solution. The diethyl ether solution was used in subsequent reactions without further purification.

Example 61B
4-cyanobenzyl isoquinolin-5-ylcarbamate 4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) in diethyl ether (10 mL) was treated with the product from Example 61 A as an ethereal solution. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound as an off-white solid (150 mg, 44%). 'H NMR (300 MHz, DMSO-d,,) 8 9.95 (s, 1H), 9.32 (d, J=1.0 Hz, IH), 8.52 (d, J=6.1 Hz, IH), 7.88-7.99 (m, 5H), 7.65-7.70 (m, 3H), 5.31 (s, 2H); MS (ES)*) m/z 304 (M+H)+.

Example 62 N-[(4-cyanophenyl)methyl]-N-isoguinolin-5-ylurea N, N-bis(tert-butoxycarbonyl)-4-cyanobenzyl amine (0.75 g, 2.25 mmol, prepared according to Synth. Comm. (1998) 28, 4419) in CH2C12 (1S mL) was treated with trifluoroacetic acid (8 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and then azeotroped with diethyl ether. The residue was taken up in diethyl ether (10 mL) and treated with N,N-diisopropylethylamine (5 mL) and the product from Example 61A. After stirring for 1 hour, the mixture was filtered and the filter was purified by chromatography (95:5 CH2C12-MeOH) to provide the title compound as a white solid (65 mg). The corresponding hydrochloride salt was prepared using methanolic HCI. 'H NMR (300 MHz, DMSO-d6) 8 9.75 (s, 1H), 9.62 (s, 111), 8.69 (s, 2H), 8.58 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.81-7.85 (m, 2H), 7.74 (t, J=6.1 Hz, 1H), 7.54-7.57 (m, 2H), 4.48 (d, J=6.1 Hz, 2H);
MS (ESI) m/z 303 (M+H)*.

Example 63 N-((4-bromophenyl)methyll-N'-(3-methylisoguinolin-5-yl)urea Example 63A
3-methylisoguinolin-5-amine 3-Methylisoquinoline was processed as described in Examples 60D and 60E to provide the title compound.

Example 63B
N-((4-bromophenyl)methyll-N'-(3-methylisoguinolin-5-A)urea The product from Example 63A (500 mg, 3.1 mmol) in toluene (10 mL) was treated with I-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol) with stirring and then the mixture was heated at 80 C overnight. The mixture was allowed to cool to room temperature, filtered, the filter cake was washed with toluene, and allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared using methanolic HCl to afford a tan solid (919 mg, 73%). 'H NMR (300 MHz, DMSO-d6) 8 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=7.8 Hz, 1.0 Hz, IH), 8.02 (d, J=8.2 Hz, 11-1), 7.78-7.83 (m, 1H), 7.67-7.71 (m, 1H), 7.52-7.57 (rn, 21=I), 7.30-7.35 (m, 2H), 4.36 (d, J=5.7 Hz, 214), 2.78 (s, 3H); MS (ES1) m/z 370/372 (M+H, 79Br/81Br).

Example 64 N-[(4-bromophenyl)methyl1-N'-(1-chloroisoquinolin-5-yl)urea Example 64A
I -chloroisoquinolin-5-amine 1-Chloroisoquinoline was processed as described in Examples 60D and 60E to provide the title compound.

Example 64B
N-[(4-bromophenyl)methyl)-N'-(1-chloroisoquinolin-5-yl)urea The product from Example 64A (520 mg, 2.91 ninol) in toluene (8 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.41 mL, 2.93 mmol) with stirring and then the mixture was heated at 90 C for 2 hours. The mixture was allowed to cool to room temperature, filtered, the filter cake washed with toluene, and air-dried to provide the title compound as an off-white solid (717 mg, 63%). 'H NMR (300 MHz, DMSO-d6) S 8.89 (s, 1H), 8.34-8.37 (m, 2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (m, 1H), 7.73 (t, J=8.1, IH), 7.53-7.56 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (t, J=5.8Hz, 1H), 4.35 (d, J=5.8 Hz, 2H); MS
(ESI) m/z 390/392 (M+H+, 35C1/37C1).

Example 65 N-f(4-bromophenyl)methyl}-N'-(1-methylisoquinolin-5-yl urea Example 65A
1-methylisoquinolin-5 -amine 1-Methylisoquinoline was processed as described in Examples 60D and 60E to provide the title compound.

Example 65B
N-[(4-bromophenyl)methyll-N'-(1-methylisoquinolin-5-yl)urea The product from Example 65A (480 mg, 3.04 mmol) in toluene (9 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) with stirring.
After heating the mixture at 90 C for 1 hour, the mixture was allowed to cool to room temperature, filtered, and the filter cake washed with toluene to provide the title compound. The corresponding di-hydrochloride salt was prepared using methanolic HCI (680 mg, 50%). 1H
NMR (300 MHz, DMSO-d6) 6 8.74 (s, 114), 8.38 (d, J=6.1 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 3I-I), 7.32 (d, J=8.5 Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 2.88 (s, 3H); MS (ESl+) m/7,370/372 (M+H+, 79Br/81Br).

Example 66 N-isoguinolin-5-yl-N'-((4-morpholur-4-ylphenyl)methyllurea Example 66A
4-morpholin-4-ylbenzonitrile 4-Fluorobeuzonitrile (1 g, 8.26 mmol) and morpholine (2.2 mL, 25.2 mmol) were combined in DMSO (25 mL) and heated at 100 C for 2.5 hours. The mixture was allowed to cool to room temperature, poured into water, and extracted with diethyl ether.
The organic extracts were combined, washed with water and brine, dried over Na_2SO4, and concentrated under reduced pressure to provide the title compound as a white solid (1.24 g, 80%).

Example 66B
(4-morpholin-4-ylphenyl)methylamine The product from Example 66A (1.24 g, 6.6 mrnol) in THE (25 mL) was treated with LiAIH4 (2.5 g, 65.9 mmol) at 0 C. The mixture was allowed to warm to room temperature and then refluxed for 1 hour. The mixture was allowed to cool to room temperature and then treated with IN NaOH carefully followed by water. The mixture was concentrated under reduced pressure and the resulting aqueous mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a yellow oil (286 mg, 23%).

Example 66C
N-isoguinolin-5-yl-N'-[(4-morpholin-4-ylphenyl)methyllurea The product from Example 66B (285 mg, 1.48 mmol) in diethyl ether (10 m.L) was treated with the product from Example 61A. The mixture was filtered and the filter cake purified by chromatography (95:5 CH2CI2-MeOH, eluant) to provide that title compound as a white solid. The corresponding di-hydrochloride salt was prepared using methanolic HC1 to afford a yellow solid (505 mg, 78%). iH NMR (300 MHz, DMSO-d6) 8 9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 792 (d, J-6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 111), 7.60 (m, 11-I), 7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H), 3.72-3.75 (in, 4H), 3.06-3.12 (m, 4H); MS (ESI) m/z 363 (M+H)+.

Example 67 N- (4-(2,6-dimethylmorpholin-4-yl)phenyllmethyl}-N'-isoguinoiin-5-ylurea Example 67A
[4-(2, 6-dimethylmorpholin-4-yl)phenyl]methylamine 4-Fluorobenzonitrile and 2,6-dimethylmorpholine were processed as described in Examples 66A and 66B to provide the title compound.

Example 67B
N- { (4-(2,6-dimethylmorpholin-4-yl)phenyllmethyl} -N'-isoguinolin-5-ylurea The product from Example 67A and the product from Example 61A were processed as described in Example 66C to provide a waxy material which was purified by chromatography (95:5 CH2CI2-MeOH, eluant) to provide the title compound as a white solid.
The corresponding di-hydrochloride salt was prepared using methanolic HCI. 1H
NIvIR (300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.67 (s, 1H), 8.53 (d, J=6.1 Hz, 1H), 8.31 (dd, J=7.6 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92-6.95 (nz, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68 (m, 2H), 3.54-3.57 (m, 211), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 313); MS (ESI+) m/z 391 (M+H).

Example 68 N-isoquinolin-5-yl-N'-{(4-thiomorpholin-4-ylphenyl )m ethyl] urea Example 68A
(4-thiomorpholin-4-ylphenyl)methylamine 4-Fluorobenzonitrile and thiomorpholine were processed as described in Examples 66A and 66B to provide the title compound.

Example 68B
N-isoguinolin-5-y1-N-((4-thiomorpholin-4-ylphenyl)methy1 uurea The product from Example 68A and the product from Example 61A were processed as described in Example 66C to provide the title compound. The free base was treated with methanolic HCl to form the corresponding di-hydrochloride salt. 'H NMR (300 MHz, DMSO-d-6) S 9.26 (s, 1H), 8.67 (s, IH), 8.53 (d, J=6.1 Hz, IH), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, IM, 7.73 (d, J=8.2 Hz, IH), 7.60 (m, 1H), 7.20-7.23 (m, 2H), 6.90-6.96 (m, 31-1), 4.25 (d, J=5.8 Hz, 2H), 3.45-3.51 (m, 411), 2.64-2.67 (m, 4H);
MS (EST) m/z 379 (M+H)+.

Example 69 4-(3,4-dichlorophenyl)-N-isoguinolin-5-ylpiiperazine- l -carboxainide 1-(3,4-Dichlorophenyl)piperazine (1280 mg, 5.55 mmol) in diethyl ether (30 mL) was treated with the product from Example 61A (-40 mL). The mixture was filtered, the filter cake washed with diethyl ether, and dried under reduced pressure to provide the title compound as a white solid (1.78 g, 80%). 'H NMR (300 MHz, DMSO-d6) S 9.29 (d, J=1.0 Hz, 111), 8.84 (s, 1H), 8.49 (d, J=5.8 Hz, 11-1), 7.92 (d, J=7.8 Hz, 1H), 7.78 (m, 1H), 7.61-7.71 (in, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.1 Hz, 111), 7.01 (dd, J=9.1, 2.7 Bz, 1IT), 3.68 (m, 4H), 3.30 (m, 4H); MS (EST) m/z 401/403 (M+H+, 35C1/37C1).

Example 70 2-isoguinolin-5-yl-N-(4-(trifluoromethyl)benzyllacetamide Example 70A
ethyl isoguinolin-5-yl(oxo)acetate The product from Example 57A (11.80 g, 56.6 mmol) in THE (200 mL) at -78 C
was treated with n-butyllithium (30 mL, 75.0 mmol, 2.5M in hexanes) dropwise.
After 30 minutes, the mixture was treated with diethyl oxalate (25.0 mL, 184 mmol).
After 20 minutes, the solution was allowed to warm to room temperature and was treated with saturated NH4C1(150 mL). The mixture was conentrated under reduced pressure.
The residue was treated with dichloromethane (100 mL) filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (20%
ethyl acetate/hexanes) to provide the title compound as light brown oil (4.57 g, 35%). MS (ESI+) m/z 248 (100), 230 (M+H)+, (EST-) m/z 200 (M-Et)-; 'H NMR (DMSO-d,6, 300 MHz) rotomers 8 1.26 (t, J 7.1, 0.6H), 1.37 (t, J 7.1, 2.411), 4.21 (q, J 7.1, 0.411), 4.47 (q, J 7.1, 1.611), 7.89 (t, J 7.5, 111), 8.41 (dd, J 1.0, 7.5, 1H), 8.57 (d, J S. 1, 111), 8.64 (d, J 5.7, 1H), 8.73 (d, J 6.3, 111), 9.50 (s, lfl).

Example 70B
ethyl hydroxy(isoguinolin-5-yl)acetate The product of Example 70A (1.11 g, 4.83 mmol) in absolute ethanol (20 mL) was added to 10% Pd/C (115.5 mg) under an argon atmosphere. The reaction mixture was stirred under H2 (50 psi) for 5 hours at which time an additional 105.9 mg of catalyst was added as a suspension in ethanol. After 3 additional hours, the reaction mixture was filtered though a nylon membrane and the filtrate concentrated under reduced pressure to provide the title compound as dark brown oil (1.02 g, 91%). MS (ESI+) m/z 232 (M+H)+, (ESI-) m/z (M-Et)-; 'H NMR (DMSO-d6, 300 MHz) 8 1.05 (t, J 7.1, 3H), 4.07 (m, 211), 5.77 (d, J 4.7, 111), 6.36 (d, J 4.7, 111), 7.68 (dd, J.7.3, 8.1, 111), 7.85 (d, J 7.0, 111), 8.09 (t, J 7.5, 2H), 8.53 (d, J 6.2, 1H), 9.33 (s, 1H).

Example 70C
ethyl (acetyloxy)(isoguinolin-5-yl)acetate The product of Example 70B (1.0202g, 4.41 mmol) in pyridine (15 nL) was treated with acetyl chloride (0.35 mL, 4.92 mmol) dropwise. The solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (2% methanol/CH2C12) to provide the title compound as yellow oil (0.8100 g, 67%). MS (ESI+) m/z 274 (M+H)+; 'H NMR (DMSO-d6, 300 MHz) 6 1.07 (t, J 7.1, 311), 2.17 (s, 311), 4.13 (m, 2H), 6.62 (s, 111), 7.74 (m, 111), 7.94 (d, J 7.1, 1H), 8.03 (d, J 6.1, 111), 8.22 (d, J 7.6, 111), 8.60 (d, J 5.7, 1H), 9.39 (s, 111).

Example 70D
ethyl isoguinolin-5-ylacetate The product of Example 70C (1.43 g, 5.23 mmol) in absolute ethanol (200 mL) was treated with dry 10% Pd/C (0.122 g) and triethylamine (10.4 mL). The reaction mixture was stirred at 60 C for 6 hours under H2 (60 psi), filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (5%
methanol/CH2C12) to provide the title compound as light brown oil (0.93 g, 67%). MS (ESI+) m/z 216 (M+H)+, (ESI-) m/z 214 (M-H)-; 1H NMR (DMSO-d6, 300 MHz) 6 1.17 (t, J
7.1, 3H), 4.09 (q, J 7.1, 211), 4.17 (s, 2H), 7.64 (m, 1H), 7.72 (d, J 6.2, 111), 7.81 (d, J 5.7, IM, 8.07 (d, J 7.9, 1H), 8.54 (d, J 6.1, 1H), 9.33 (s, IH).

Example 70E
2-isoguinolin-5-yl-N-[4-(trifluoromethyl)benzyll acetanii de The product from Example 70D (0.207 g, 0.96 mmol) in dichloromethane (10 rnL) was treated with trimethylaluminum (1 mL, 2.0 mmol, 2M in toluene) dropwise.
After 30 minutes, the mixture was teated with 4-(trifluoromethyl)benzylamine (0.350 g, 2.0 mmol) in dichloromethane (2 mL) and then refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, treated with IM HCI (3 mL), basified to between pH 9 and 10 with concentrated NH. OH, treated with water and CH2C12 and the phases separated.
The organic layer was washed with water (1 x 10 mL), brine (1 x 10 mL), dried (MgSO4), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (5% methanol/CH2C12) to provide a yellow residue which was triturated with diethyl ether to provide the title compound as a white solid (0.122 g, 37%). MS (ESI+) m/z 345 (M+H)+; MS (ESI-) m/z 343 (M-H)-; 1H NMR (DMSO, 300 MHz) S 4.00 (s, 2H), 4.37 (d, J 5.7, 2H), 7.46 (d, J 7.8, 2H), 7.67 (m, 411), 7.93 (d, J 5.4, 1M, 8.03 (d, J 7.8, 1 H), 8.52 (d, J 5.8, 1H), 8.80 (t, J 5.7, 1H), 9.31 (s, IM; Anal. Calcd for C19H15F3N20: C, 66.28;
H, 4.39; N, 8.14. Found: C, 66.16; H, 4.27; N, 7.96.

Example 71 methyl 5-({ {(4-bromobenzyl)aminolcarbonyl} amino)isoguinoline-3-carboxylate Example 71A
methyl 5-nitroisoguinoline-3-carboxylate Methyl isoquinoline-3-carboxylate (9.58 g, 51.2 rnmol) in concentrated H2S04 (100 mL) at 0 C was treated with sodium nitrate (4.79 g, 56.4 mmol) in small portions such that the temperature was maintained below 5 C. Ten minutes after addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured over ice and adjusted to pH between 7 and 8 and filtered to afford the title compound as a bright yellow solid (11.44 g, 96%). MS (ESI+) m/z 233 (M+H)+; 1H
NMR (DMSO, 300 MHz) S 3.97 (s, 3H), 8.06 (t, J 8.2, 1H), 8.72 (dt, J 1.0, 8.2, 1H), 8.78 (dd, J 1.0, 7.8, 1H), 9.11 (s, 1H), 9.65 (s, IH).

Example 71B
methyl 5-aminoisoguinoline-3-carboxylat The product of Example 71A (10.33 g, 44.5 mmol) in acetic acid/water (3/1) (320 mL) was treated with iron powder (5.06 g, 90.7 mmol). After stirring for 16 hours at room temperature, the reaction mixture was filtered the filtrate concentrated under reduced pressure to approximately half the original volume. The mixture was then extracted with dichloromethane (3 x 200 mL). The organic fractions were combined, dried (MgSO4), and the filtrate concentrated under reduced pressure to afford crude material. A
precipitate formed in the aqueous phase after sitting for several hours. This was filtered to afford additional crude material. The crude material was purfidied by column chromatography (2%
methanol/CH2C12) to provide the title compound. MS (ESI+) mlz 203 (M+H)+; MS
(ESI-) m/z 201 (M-H) 'H NMR (DMSO-d6, 300 MHz) S 3.92 (s, 311), 6.34 (s, 2H), 6.96 (dd, J 1.0, 7.8, IM, 7.31 (d, J 8.1, IH), 7.51 (t, J 7.9, 1H), 8.82 (s, 1H), 9.15 (s, 1H);
Anal. Calcd for C11HION202: C, 65.34; H, 4.99; N, 13.85. Found: C, 65.03; H, 4.95; N, 13.65.

Example 71C
methyl 5-(f f (4-bromobenzyl)aminolcarbonyl} amino)isoguinoline-3-carboxylate The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 ml., 1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene (0.201 g, 0.95 mmol) in THE (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 415 (M+1-1)+; MS
(ESI-) m/z 413 (M-H)-; 'H NMR (DMSO-d6, 300 AEz) S 3.95 (s, 3H), 4.36 (d, J
5.6, 21-1), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m, 2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, IH); Anal. Calcd for C19Hi6BrN3O3:
C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N, 9.84.

Example 72 methyl 5-({((2,4-dichlorobenzyl)amino]carbonyl} amino)isoguinoline-3-carboxylate The product of Example 71B (0.156 g, 0.77 mmol) in THFAoluene (10 niL, 1:1) was treated with a solution of 2,4-dichloro-l-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THE (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.226 g, 73%). MS (ESI+) m!z 404 (-%4+H)'-; MS
(ESI-) m/z 402 (M-H)-; 'H NMR (DMSO-d6, 300 MHz) 8 3.96 (s, 3H), 4.44 (d, J
6.0, 2H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H), 7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s, 1H), 9.35 (s, IH); Anal. Calcd for C19H1SC12N303:
C, 56.45; H, 3.74; N, 10.39. Found: C, 56.08; H, 3.67; N, 10.03.

Example 73 N-(8-bromoisoguino1in-5-yl)-N'-(2,4-dichlorob enzyl)urea Example 73A
8-bromoisoguinolin-5-amine 5-Ami.noisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, nnnol) were combined and heated at 80 C in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glass funnel and the vapour diffused onto the complex over a period of 2 hours. Heating was continued for 2 hours. The suspension was added portionwise to crushed ice and the solution basified with concentrated NaOH solution. The aqueous layer was extracted with ethyl acetate (4 x 100 mL) and the layers were separated. The organic layers were combined, dried (Na2SO4), filtered and the filtrate was concentrated to give a grey solid.
The grey solid was subjected to column chromatography (hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g, 35%). MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-; 'H NMR (CDC13, 300 MHz) S 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 111).

~E -Example 73B
N-(8-bromoisoguinolin-5-yl)-N'-(2,4-dichlorobenzyl)urea The product from Example 73A (120 mg, 0.52 mmol) in THF:toluene (1:4, 5 mL) was treated with a solution of 2,4-dichloro-l-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THE (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake dried under reduced pressure to provide the title compound as a white solid (178 mg, 78%). The hydrochloride salt was obtained by dissolving the product in hot THE and adding HCl in diethyl ether (2M). The yellow precipitate was collected by filtration and dried under reduced pressure. MS (ESI+) m/z 426 (M+H)+; MS (ESI-) m/z 424 (M-M-; 'H NMR. (DMSO-d6, 300 MHz) 6 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (ni, IH), 7.91 (d, J 8.5, 1H), 8.02 (d. J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1II), 9.44 (s, 1H); Anal. Calcd for C17H12BrC12N3O HCI 0.25EtOH: C, 44.41; H, 3.14;
N, 8.88.
Found: C, 44.80; H, 2.76; N, 8.84.

Example 74 N-(8-bromoi soguinolin-5-yl)-N'-(4-fluorob enzyl)urea The title compound was prepared using 1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+) m/z 376 (M+H)+; MS (ESI-) m/z 374 (M-H)"; 'H NMR (DMSO-d6, 300 MHz) 6 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J
8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, IH), 8.69 (d, J 5.8, 1H), 8.88 (s, IH), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.

Example 75 N-(8-bromoisoguinolin-5-yl)-N'-(3-fluorobenzyl)urea The title compound was prepared using 1-fluoro-3-(isocyanatomethyl)benzene, the product of Example 73A and the procedure described in Example 73 (white solid, 108 mg, 65%). MS (ESI+) ni/z 376 (M+H)+; MS (ESI-) m/z 374 (M-M-; 'H NMR (DMSO-d6, 300 MHz) 6 4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J
8.5, 1H), 8.01 (d, J 6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, 3 5.8, 1H), 8.93 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.64; H, 3.33; N, 11.19.

Example 76 N-f 1-(4-chlorophenyl)-1-methylethyll-N'-isoguinolin-5-ylurea Example 76A
2-(4-chlorophenyl)-2-meth lpropanoyl chloride 2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (S
mL) was treated with thionyl chloride (5.00g, 3.1 mL) and heated at 80 C for 2 hours. The cooled solution was concentrated under reduced pressure to provide a yellow oil containing a crystalline residue. The mixture was dissolved in hexane, filtered and the filtrate concentrated to provide the compound as a pale yellow oil (4.10 g, 98%).

Example 76B
1-chloro-4-(1-isocy anato-l-methylethyl)benzene The product of Example 76A (4.00 g, 19.4 mmol) in acetone (9 mL) at 0 C was treated with a solution of sodium azide (1.27 g) in water (9 mL) dropwise over 15 minutes.
After stirring for 30 minutes at 0 C, the mixture was extracted with toluene (20 mL). The organic extract was dried with MgSO4, filtered, and the filtrate heated at reflux for 1 hour.
The mixture was allowed to cool to room temperature and was concentrated under reduced pressure to provide the title compound as a pale yellow oil (3.45 g, 96%).

Example 76C
N-f 1-(4-chlorophenyl)-1-methylethyll-N'-isoguinolin-5-ylurea The title compound was prepared using 5-anainoisoquinoline, the product of Example 76B and the procedure described in Example 73B except that THE was used as solvent. The product was recrystallized from ethyl acetate to provide the title compound as a white solid (840 mg, 34%). MS (ESI+) m/z 355 (M+H)+; MS (ESI-) m/z 353 (M-H)-; 'H NMR
(DMSO-d6, 300 MHz) S 1.63 (s, 6H), 7.23 (s, IH), 7.37 (d, J 8.8, 2H), 7.47 (d, J
8.8, 2I-i), 7.73 (t, J
9.2, 1H), 7.93 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39 (d, J 8.1, 111), 8.67 (d, J 6.4, 1H), 8.87 (s, 111), 9.58 (s, 1H); Anal. Calcd for C19H1SC1N30 HC10.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82; H, 5.23; N, 10.45.

Example 77 N-(4-bromobenzyl)-N'- f 6-[2,2,2-trifluoro-l-hydroxy-1-(trifluoromethyl)ethyl]isoquinolin-5-1 urea Example 77A
2-(5-aminoisoquinolin-6-yl)-1,1,1,3,3,3-hex afluoroprol an-2-o l 5-Aminoisoquinoline (288 mg, 2.00 mmol) and p-toluenesulfonic acid (5 mg) were combined and treated with hexafluoroacetone hexahydrate (0.29 mL, 462 mg, 2.10 nunol).
The mixture was stirred in a sealed pressure tube and heated to 150 C for 18 hours. The reaction was allowed to cool to room temperature and partitioned between CH2C12 (20 mL) and water (10 mL). The organic layer was passed thru Na-2SO4 and then filtered through activated charcoal. The charcoal was washed with methanol (3 x 10 mL) and the filtrate and washuigswere collected and concentrated under reduced pressure to provide the title compound (130 mg, 30%) as a yellow solid. MS (ESI+) m/z 311 (M+H)+; MS (ESI-) m/z 309 (M-H)-; 1H NMR (DMSO, 300 MHz) S 6.64 (br s, 2H), 7.30 (d, J 8.7, 1H), 7.40 (d, J 8.7, IH), 8.09 (d, J 6.1, 1H), 9.49 (d, J 6.1, 1H), 9.14 (s, IH); 13C NMR (DMSO, 100 MIHIz) S
107.02, 110.60, 113.95 (1), 115.46 (1), 122.03, 124.92, 124.92, 1.25.94, 126.98 (1), 128.17, 142.43 (1), 144.82, 151.85 (1).

Example 77B
N-(4-bromobenzyl)-N- f 6-[2,2,2-trifluoro-l-hydroxy-l-(trifluoromethyl)ethyl]isoquinolin-5-Iurea The title compound was prepared using 1-bromo-4-(isocyanatomethyl)benzen.e, the product of Example 77A'and the procedure described in Example 73B except that THE was used as solvent (white solid, 840 mg, 34%). MS (ESI+) m/z 376 (M+H)+; MS (ESI-) m/z 374 (1\2-H)-; 'H NMR (DMSO-d6, 300 MHz) S 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, IH), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C20H14BrF6N3O2: C, 46.00; H, 3.50; N, 11.23. Found:
C, 54.61; H, 3.35; N, 11.14.

Example 78 N-(4-bromobenzyl)-N-1 H-indol-4-ylurea 4-aminoindole (0.13 g, I mmol) in THE (3 mL) was treated with 1-bromo-4-(isocyanatomethyl.)benzene (0.23 g, 1.1 mmol) for 3 hours at ambient temperature. Hexane was added to the reaction mixture to precipitate 0. 26 g of the title compound as a tan solid.
mp 198 C; 'H NMR (300 MHz, DMSO-d6) S 4.30 (d, 2H), 6.51 (t, lii), 6.89 (t, 1H), 6.95 (d, 2H), 7.29 (t, IH), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3 (s, 111), 11.04 (s, 11-1); MS
(DCI+) m/z 346 (M+H); Anal. Calcd. For C16H14N3BrO: C, 55.83; H, 4.10; N, 12.21. Found:
C, 55.71, H, 4.12; N, 12.01.

Example 79 N-(3 ,4-dichl orob enzyl)-N'-1 H-indol-4-y lurea 4-Aminoindole (0.13 g, I mmol) in THE (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature.
Hexane was added to the reaction mixture to precipitate 0. 25 g of the title compound as a tan solid. mp 201 C; 'H NMR (300 MHz, DMSO-d6) S 4.23 (d, 2 H), 6.36 (s, 1H), 6.54 (t, 1H), 7. 0 (dd, 1 H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 21-1),8.31 (s, IH), 10.87 (s, 1H) MS
(DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3C12O: C, 57.50; H, 3.92; N, 12.57. Found:
C, 56.94, H, 3.68; N, 11.97.

Example 80 N- I H-indol-4-yl-N'-(4-(trifluoromethyl)benzyljurea Example 80A
4-isocyanato-1 H-indole 4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated with triphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was taken up in diethyl ether, filtered, and the filtrate was concentrated under reduced pressure to provide title compound as yellow oil (0.4 g). 1H NMR (300 MHz, CDC13-d6) S
6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H), 8.3 (s, IH).

Example 80B
N- 1 H-indol-4-yl-N'-[4-(trifluoromethyl )benzyljurea The product of Example 80A (0.16 g, I mmol) in THE (3 mL) was treated with 4-(trifluoromethyl)benzylamine (0.19 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a solid.
mp 178 C. 'H NMR (300 MHz, DMSO-d6) 8 4.43 (d, 2H), 6.53 (t, 1H), (6.98 m, 3H), 7.26 (t, 111, 7.57 (d, 2H), 7.62 (d, 1H), 7.71 (d, 2H), 8.37 (s, 1H), 11.04 (s, IH); MS (DCI+) nn/z 334 (M+H); Anal. Calcd. For C17H14N3F30: C, 61.26; H, 4.23; N, 12.61. Found:
C, 61.28, H, 3.83; N, 12.31.

Example 81 N-IH-indol-4-yl-N'-r4-(tiifluoromethoxy)ben7-yI urea 4-(Trifluoromethoxy)benzylamine (0.21 g, 1.1 mmol) and the product of Example (0.16 g, 1 mmol) were treated as described in Example SOB to provide the title compound (0.23 g). nip 177 C; 'H NMR (300 MHz, DMSO-d6) 6 4.36 (d, 2 H), 6.52 (m, 1H), 6.95 (m, 3H), 7.24 (t, 1 H), 7.36 (d, 2H), 7.48 (d, 2H), 7. 63 (dd, 1H), 8.32 (1H), 11.06 (s, 1H); MS
(DCI+) m/z 349.9 (M+H)+; Anal. Calcd. For C17H14N3F302: C, 58.63, H, 4.34, N, 12.07.
Found: C, 58.51, H, 3.98, N, 12.03.

Example 82 N-j3-fluoro-4-(trifluoromethyl)benzyll-N'-1 H-indol-4-ylurea 3-Fluoro-4-(trifluoromethyl)benzylamine (0.22g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.24 g). mp 198 C; 1H NMR (300 MHz, DMSO-d6) 8 4.43 (d, 2H), 6.52 (m, 1H), 6.98 (m, 3 H), 7.26 (m, 111, 7.39 (m, 2 H), 7.57 (dd, 1H), 7.77 (t, 1H), 8.40 (s, 1H), 11.05 (s, 1H); MS (DCI+) m/z 349.9 (M+H)+. Anal. Calcd. for C17H13N3F40: C, 58.12; H, 3.73; N, 11.96. Found C, 58.52; H, 3.99; N, 11.55.

Example 83 1 -(4-Chloro-3-trifluoromethyI-benzyl)-3-(1 H-indol-4-yl)-urea 4-Chloro-3-(trifluoromethyl)benzylamine (0.27g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound. mp 197 C;'H NMR (300 MHz, DMSO-d6) 6 4.42 (d, 2H), 6.52 (m, 1H), 6.96 (m, 3H), 7.25 (m, 1H), 7.56 (dd, 11-1), 7.67 (dd, 111), 7.70 (t, 1H), 7.81 (s, 11-1), 8.37 (s, 1H), 11.06 (s, 1H); MS (DCI+) m/z 368 (1VI+H). Anal. Calcd. for C17H13N3C1F30:.C, 55.52, H, 3.56; N, 11.43. Found C, 55.46; H, 3.65; N, 11.58.

Example 84 1-(4-Chloro-3-trifluoromethyl)-3-(1H-indol-4-yl)-urea 4-Chlorobenzylamine (0.2-,1.4 mmol) and the product of Example 80A (0.2 g, 1.27 mmol) were treated as described in Example 80B to provide the title compound.
mp 205 C.
'H NMR (300 MHz, DMSO-d6) 5 4.32 (d, 2H), 6.52 (m, I H), 6.87 (m, I H), 6.97 (m, 2H), 7.25 (m, 1H), 7.37 (m, 4H), 7.6 (m, IM, 8.30 (s, 111), 11.06 (s, 1H). MS
(DCI+) m/z 300 (M+H). Anal. Calcd. for C16H14N3C130: C, 64.11; H, 4.71; N, 14.02. Found: C, 63.99; H, 4.70; N, 13.77.

Example 85 N-[2-(2,4-dichlorophenyl)ethyl)-N-1 H-indol-4-ylurea 2-(2,4-Dichlorophenyl)ethylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1. mmol) were treated as described in Example 80B to provide the title compound. mp 170 C; 1H NMR (300 MHz, DMSO-d6) 8 2.90 (m, 2H), 3.31 (m, 214), 6.47 (m, 2H), 6.93 (m, 2H), 7.23 (m, 1H), 7.40 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 11.02 (s, 114).
MS (DCI+) m/z 347 (M+H). Anal. Calcd. for C17H15N3C120: C, 58.63; H, 4.34; N, 12.07.
Found: C, 58.49; H, 4.49; N, 12.38.

Example 86 4-(trifluoromethyl)benzyl 1H-indol-4-ylcarbamate [4-(Trifluoromethyl)phenyl]methanol (0.09 g, 0.55 mmol) and the product of Example 80A (0.08 g, 0.5 mmol) in THE (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 50%
hexane:ethylacetate to provide the title compound as an oil (0.09 g). 1H NMR
(300 MHz, DMSO-d6) 6 5.32 (s, 2H), 6.73 (s, IH), 7.0 (t, 1H), 7.11 (d, 1H), 7.23 (t, 1H), 7.38 (d, III), 7.66 (d, 2H), 7.78 (d, 2H), 9.52 (s, 1H), 11.08 (s, 1H). Anal. Calcd. for C17H13N2F3O2: C, 61.08; H, 3.92; N, 8.38. Found: C, 60.97; H, 4.21; N, 8.17.

Example 87 4-(trifluoromethoxy)benzyl 1 H-indol-4-ylcarbamate [4-(Trifluoromethoxy)phenyl]methanol (0.13 g, 0.7 mmol) and the product of Example 80A (0.1 g, 0.63 mmol) in THE (5 mL) were heated at reflux for 16 hours with a catalytic amount of triethylamine. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether/hexane to provide the title compound as tan crystals (0.12 g). 'H NMR (300 MHz, DMSO-d6) 8 5.21 (s, 2H), 6.73 (s, 11-1), 7.0 (t, IH), 7.1 (d, 1H), 7.23 (t, IH), 7.38 (dd, 1H), 7.4 (d, 2H), 7.6 (d, 211), 9.5 (s, 111), 11.06 (s, 1H). ). Anal. Calcd. for C17H13N2F303Ø25 H2O: C, 57.55; H, 3.84;
N, 7.90. Found:
C, 57.42; H, 3.81; N, 7.32.

Example 88 N- (4-bromobenzyl)-N-(2,3-dunethyl-lH-indol-4-yl)urea 2,3-Diunethyl-4-aminoindole (0.11 g, 0.7 mmol) in THE (3 mL) was treated with bromo-4-(isocyanatometlryl)benzene (0.17 g, 0.8 nunol) at ambient temperature.
After stirring for 3 hours at ambient temperature, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.12 g). mp 190 C 'H NMR (300 MHz, DMSO-d6) 6 2.24 (s, 31.1), 2.25 (s, 311), 4.25 (d, 2H), 6.51 (t, 1H), 6.82 (t, 1H), 6.85 (d, 2H), 6.95 (m, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.78 (s, 111), 11.04 (s, 1H); MS
(DCI+) m/z 346 (M+H)+; Anal. Calcd. for C13Hi8N3BrO: C, 58.08; H, 4.87; N, 11.29. Found: C, 57.97, H, 4.92; N, 11.30.

Example 89 N-(4-bromobenzyl)-N'-1 H-indazol-4-ylurea Example 89A
1 H-indazol-4-amine 4-Nitro-IH-indazole (1.63 g, 10 mmol) in ethanol (100 mL) was treated with BiC13 (3.46 g, 11 mmol) followed by a portionwise addition of NaBH4. The reaction mixture was stirred at ambient temperature for 20 minutes and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a tan solid (1.0 g) 'H NMR (300 MHz, DMSO-d6) S 5.64 (s, 2H), 6.1 (d, 1H), 6.6 (d, 1H), 6.98 (t, 1H), 8.03 (s, 1H), 12.6 (s, 1H).

Example 89B
N-(4-bromobenzyl)-N'-1H-indazol-4-ylurea hydrochloride salt The product of Example 89A (0.16 g, 1.2 mmol) in THE (10 mL) was treated with bromo-4-(isocyanatomethyl)benzene (0.52 g, 2.4 mmol) at room temperature.
After stirring for 16 hours, the reaction mixture was concentrated and the residue was treated with methanol (20 mL) and 3N HCl (10 mL) and heated at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure, and the residue was treated with water and the pH adjusted to 5. The obtained compound was purified by chromatography eluting with 5% of ethanol:methylene chloride and converted to HCl salt mp 126 C. 'H NMR (300 MHz, DMSO-d6) S 4.32 (d, 2H), 7.0 (t, 111), 7.05 (d, 1 H), 7.18 (t, 111), 7.3 (d, 2H), 7.55 (d, 2H), 7.61 (d, 111), 8.16 (s, 111), 8.92 (s, 111); Analysis Caled for C15H13N4BrO HCI: C, 47.21; H, 3.70; N, 14.68. Found C, 46.99; H, 4.08; N, 14.13.
Example 90 N-(3 ,4-dichlorob enzyl)-N'-1 H-indazol-4-ylurea Example 90A
methyl 4-nitro-lH-indazole-l-carboxylate Sodium hydride (0.3 g, 12.5 mmol) suspended in DMF (5 mL) at 0 C was treated with 4-nitro-lH-indazole (1.33 g, 10 mmol). After stirring at room temperature for 1 hour, the mixture was treated with methylchloroformate (0.9 mL). After stirring at room temperature for 3 hours, the mixture was carefully treated with water and filtered to provide the title compound (1.2 g). 1H NMR (300 MHz, DMSO-d6) S 4.19 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 111).

Example 90B
methyl 4-amino-1 H-indazole- l -carboxylate The product of Example 90A (1.66 g, 7.5 mmol) in ethanol (20 mL) was treated with BiC13 (8.2 g, 2.6 mmol) followed by the addition of NaBH4 (1.13 g, 30.5 mmol).
The reaction mixture was stirred at room temperature for 20 minutes, filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered and the filtrate concentrated under reduced pressure to provide the title compound (1.2 g). 'H NMR (300 MHz, DMSO-d6) 6 6.1 (s, 2H), 6.41 (dd, II-I), 7.21 (m, 2H), 8.42 (s, 1H).

Example 90C
methyl 4-(f ((3,4-dichlorobenzyl)aminolcarbonyl} amino)- 1H-indazole- l -carbo y1ate The product of Example 90B (0.19 g, 1 mmol) in TIC' (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) at ambient temperature. After stirring for 3 hours, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0. 25 g). 'H NMR (300 MHz, DMSO-d6) 6 4.38 (d, 2H), 6.97 (t, IM, 7.36 (dd, I H), 7.48 (t, 1H), 7.6 (m, 2H), 7.7 (d, I H), 7.8 (d, 114), 8.45 (s, 1 H), 9.16 (s, 1H).
Example 90D
N-(3,4-dichlorobenzyl)-N'-1 H-indazol-4-ylurea The product of Example 90C (0.25 g, 0.6 mmol) was heated at reflux in methanol (5 mL) and 0.5N KOH (1 mL) for 0.5 hours. The reaction mixture was allowed to cool to ambient temperature, pH was adjusted to 5, and volume was reduced under reduced pressure.
Methylene chloride and water was added, the phases were separated, and the organic phase concentrated under reduced pressure to provide the title compound. 'H NMR (300 MHz, DMSO-d6) S 4.38 (d, 2H), 6.9 (t, 1H), 7.05 (d, 1H), 7.19 (t, 1H), 7.35 (dd, IH), 7.6 (m, 2 H), 8.06 (s, 1H), 8.82 (s, 1H). MS (DCI+) m/z 336 (M+H)+; Anal. Calcd. For C15H13N4C120: C, 53.75; H, 3.62; N, 16.72. Found: C, 53.84, H, 3.44; N, 16.88.

Example 97 N-(1,1'-biphenyl-4-ylmethyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example IB
using 1,1'-biphenyl-4-ylmethylamine instead of 2-(3-fluorophenyl)ethylamine. NMR
(DMSO-d6) 6 9.78 (s, 1H), 9.57 (s, 1H), 8.69 (s, 2H), 8.53 (d, 1H), 8.11 (d, 1H), 7.87 (t, 1H), 7.64 (m, 5Ii), 7.45 (m, 4H), 7.35 (m, 1H), 4.43 (d, 2H); MS (ESI) (M+H)+ 354.

Example 98 N-(3-fluoro-4-(trifluoromethyl)benzyl]-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 113 using 3-fluoro-4-(trifluoromethyl)benzylamine instead of 2-(3-fluorophenyl)ethylamine. NMR
(DMSO-d6) 6 9.78 (s, 1H), 9.74 (s, 11-I), 8.77 (d, 1H), 8.71 (d, IH), 8.61 (d, 1H), 8.08 (d, 1H), 7.87 (m, 2H), 7.78 (d, 1H), 7.43 (m, 2H), 4.49 (d, 2H); MS (ESI) (M+H)+ 364.

Example 99 N-5-isoguinolinyl-N'-(3-methylbenzyl)urea The title compound was prepared using the procedure described in Example 113 using 3-methylbenzylaminc instead of 2-(3-fluorophenyl)ethylainine. NMR (DMSO-d6) 6 9.68 (s, 1H), 9.18 (s, 11-1), 9.23 (s, 1H), 8.66 (d, 1H), 8.37 (d, IH), 8.48 (d, 1H), 8.04 (d, 1H), 7.85 (t, 1H), 7.35 (t, 1H), 7.23 (t, 1H), 7.7.26 (m, 11-1), 7.06 (m, 1H),4.28 (d, 21-1), 2.31 (s, 3H); MS
(ESI) (M+H)+ 291.

Example 100 N-(4-fluoro-3-(trifluoromethyl)benzyl]-N'-5-isoq uinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-fluoro-3-(trifluoromethyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR
(DMSO-d6) 6 9.31 (s, 111), 8.84 (s, 111), 8.65 (d, 2H), 7.95 (d, 2H), 7.86 (m, 2H), 7.60 (t, 1H), 7.50 (d, 1H), 7.17 (t, 1H), 4.43 (d, 2H); MS (ESI) (M+H)+ 364.

Example 101 N-(3 -chl oro-4-fluorobenzyl)-N'-5 -isoq uino linylurea The title compound was prepared using the procedure described in Example 61B
using 3-chloro-4-fluorobenzylamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) 6 9.72 (s, 1H), 9.42 (s, 1H), 8.68 (d, 1H), 8.58 (d, 2H), 8.05 (d, 1H), 7.88 (t, 1H), 7.67 (m, 2H), 7.20 (m, 2H), 4.38 (d, 2H); MS (ESI) (M+H)+ 330.

Example 102 N-5-isoquinolinyl-N'-pentyl urea The title compound was prepared using the procedure described in Example 60F
using 1-isocyanatopentane and 5-isoquinolinamine instead of the product from Example 60E
and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) 6 9.70 (s, 1H), 9.19 (s, 1H), 8.64 (d, 1H), 8.57 (m, 2H), 8.01 (d, 11I), 7.84 (d, 111), 7.85 (t, 1H), 6.95 (in, 111), 3.17 (m, 2H), 2.48 (m, 2H), 1.23 (m, 4H), 0.86 (M, 3H); MS (ESI) (M+II)+ 339.

Example 103 N-5-isoquinolinyl-N'-octylurea The title compound was prepared using the procedure described in Example 60F
using 1-isocyanatooctane and 5-isoquinolinamine instead of the product from Example 60E
and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) 6 9.53 (s, 11-1), 9.23 (s, 111), 8.65 (d, I H), 8.99 (d, 111), 8.05 (d, 1H), 7.86 (t, 111), 7.01 (m, I H), 3.15 (m, 211), 1.51 (in, 2H), 1.28 (m, 5H), 0.83 (in, 3H); MS (ESI) (M+H)+ 300.

Example 104 N-(1-adamantylmethyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 1-(1-adamantyl)methanamine instead of 4-cyanobenzyl alcohol. NTI (DMSO-d6) 6 9.68 (s, 11-1), 9.20 (s, 1H), 8.64 (d, 2H), 8.60 (d, 111), 8.65 (in, 1H), 8.00 (d, 1H), 7.83 (t, 1H), 6.95 (in, 1H), 2.90 (d, 211), 1.99 (m, 2H), 1.64 (m, 5H), 1.53 (m, 5H); MS
(ESI) (M+H)+ 336.
Example 105 N-(cyclohexylmethyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 1-eyclohexylmethanamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) 6 9.70 (s, IH), 9.18 (s, 1H), 8.67 (d, 2H), 8.57 (m, 3H), 8.00 (d, 1H), 7.84 (t, 1H), 7.00 (in, 1H), 3.06 (m,2H), 1.70 (m, 5H), 1.43(m, 111), 1.21 (m, 3H). 0.97 (m, 2H); MS (ESI) (M+H)+ 284.

619946 Example 107 N-((6, 6-dimethylbicyclo [ 3.1. I lhept-2-yl)methyll-N'-5-iso g uino linylurea The title compound was prepared using the procedure described in Example 61B
using [6,6-dimethylbicyclo[3.1.1]hept-2-yl]methylamine instead of 4-cyanobenzyl alcohol.
NMR (DMSO-d6) S 9.74 (s, 1H), 9.28 (s, 113), 8.64 (d, 11-1), 8.60 (m, 211), 8.03 (s, 1H), 7.85 (t, IM, 7.08 (m, 1H), 3.17 (m, 2H), 2.38 (m, 1H), 2.18 (m,3H), 2.00 (m, IH), 1.88 (in, 5H), 1.20 (s, 3H), 1.03 (s, 3H); MS (ESI) (M+H)+ 324.

Example 108 N-5-isoguinolinyl-N'-14-(1-pyrrolidinyl)benzyllurea The title compound was prepared using the procedure described in Example 61B
using 4-(1-pyrrolidinyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR
(DMSO-d6) S
9.81 (s, 1H), 9.58 (s, 111), 8.80 (d, 1H), 8.71 (m, 2H), 8.11 (d, 1H), 7.93 (t, 1H), 7.48 (bs, 1H), 7.20 (m, 2H), 6.65 (m, 2H), 4.43 (d,2H), 3.13 (m, 4H), 1.97 (m, 4H); MS
(ESI) (M+H)+
347.

Example 109 N-[4-(1-azepanyl)benzyll-N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-(1-azepanyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) 6 9.80 (s, 1H), 9.58 (s, 1H), 8.79 (m, 1H), 8.71 (m, 2H), 8.11 (d, 1H), 7.95 (t, 111), 7.48 (bs, 1H), 7.20 (m, 2H), 6.85 (bs, 2H), 4.23 (d,2H), 3.45 (in, 4H), 1.69 (bs, 4H), 1.50 (bs, 4H); MS
(ESI) (M+H)+ 375.

Example 110 N- f3-fluoro-4-(1-pyrrolidinyl)benzyll-N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 3-fluoro-4-(1-pyrrolidinyl)benzylamine instead of 4-cyanobenzyl alcohol.
NMR
(DMSO-d6) 6 9.82 (s, 1H), 9.72 (s, 1H), 8.85 (d, 111), 8.70 (m, 2H), 8.14 (d, 1H), 7.95 (t, 1H), 7.64 (bs, 1H), 7.03 (m, 2H), 6.75 (t, 1H), 4.25 (d,2H), 3.30 (m, 4H), 1.74 (m, 4H); MS
(ESI) (M+H)+ 365.

Example 111 N-14-(1-azepanyl)-3-fluorobenzyll-N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-(1-azepanyl)-3-fluorobenzylamine instead of 4-cyanobenzyl alcohol. NMR
(DMSO-df) 8 9.85 (s, 1H), 9.77 (s, 1H), 8.71 (m, 2H), 8.13 (d, 111), 7.94 (t, IH), 7.77 (bs, M), 7.64 (bs, 1H), 7.10-6.90 (m, 2H), 4.28 (d,2H), 3.35 (m, 41I), 1.77 (m, 4H), 1.58 (in, 4H); MS (ESI) (h2+H)+ 393.

Example 112 N-[4-(I-azocanyl)benzyl]-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-(l-azocanyl)benzylamine instead of 4-cyanobenzyl alcohol. NMR (DMSO-d6) 6 9.85 (s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 8.77 (m, 211), 8.13 (s, 111), 7.95 (t, 1H), 7.45 (bs, 11-I), 7.17(d, 2H), 6.63 (d, 214), 4.23 (d,2H), 3.43 (m, 6H), 1.68 (m, 3H), 1.44 (m, 5H); MS (ESI) (M+H)+ 389.

Example 114 N-1 H-indazol-4-y1-N'-[4-(1-piperidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B
using ]-[4-(isocyanatomethyl)phenyl]piperidine instead of 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) 6 9.23 (s, 1H), 9.30 (s, 1H), 7.78 (d, 2H), 7.64 (d, 1H), 7.63 (d, 211), 7.53 (s, 1H), 7.38 (bs, 1H), 7.19 (t, 1H), 7.06 (d, 1H), 4.39 (d,2H), 3.53 (m, 4H), 1.97 (bs, 411), 1.64 (bs, 2H); MS (ESI) (M+H)+ 350.

Example 115 N-[3-fluoro-4-(1-pip eridinyl)benzyl]-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperi dine instead of 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) 8 9.17 (s, 1H), 8.28 (s, 111), 7.63 (d, 1H), 7.40-7.15 (m, 6H), 7.05 (d, 1H), 4.37 (s,2H), 3.17 (m, 4H), 1.77 (m, 4H), 1.58 (m, 2H).4H), 1.64 (bs, 2H); MS (ESI) (M+H)+ 368.

Example 116 N-I H-indazol-4-y1-N'-[4-(1-pyrrolidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B
using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine instead of 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) b 8.83 (s, 1H), 8.15 (s, 1H), 8.01 (bs, 1H), 7.63 (d, 1H), 7.21 (m, 3H), 7.04 (d, 1H), 6.70 (bs, 1H), 6.63 (m, 1H), 6.56 (d, 1H), 4.12 (d,2H), 3.13 (m, 4H), 1.97 (m, 4H); MS (ESI) (M+H)+ 336.

Example 117 N- [3-fluoro-4-(1-pyrrolidinyl)benzyl -N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine instead of 1-bromo-4-(isoeyanatomethyl)benzene. NMR (DMSO-d6) S 9.89 (s, 1H), 8.17 (s, 1H), 7.63 (d, 1H), 7.19 (t, 1H), 7.07 (m, 1H), 7.02 (d, III), 6.99(s, 113), 6.93 (bs, 2H), 6.74 (t, 1H), 4.23 (s,2H), 3.29 (m, 4H), 1.87 (m, 4H); MS (ESI) (M+H)+ 354.

Example 118 N-14-( 1-azepanyl)benzyll-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 89B
using 1-[4-(isocyanatomethyl)phenyl]azepane instead of 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) S 8.86 (s, 1H), 8.17 (s, 1H), 8.00 (bs, 1H), 7.64 (d, 1H), 7.20 (m, 3H), 7.02 (d, 1H), 6.25 (bs, 2H), 6.70 (d, 1H), 4.21 (s,2H), 1.88 (m, 6H), 1.47 (m, 6H); MS (ESI) (M+H)+ 364.

764293 Example 119 N-[4-( 1-azepanyl)-3-fluorobenzyll-N-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane instead of 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) S 9.04 (s, 1H), 8.13 (s, 1H), 7.63 (d, IH), 7.19 (t, 1H), 7.10 (s, IH), 7.02 (d, 4H), 4.23 (s,2H), 3.37 (m, 4H), 1.79 (m, 4H), 1.57 (m, 4H); MS (ESI) (M+H)+ 382.

Example 120 N-(1-methyl-I H-indazol-4-yl)-N'-[4-(1-piperidinyl)benzyl]urea The title compound was prepared using the procedure described in Example 89B
using l-[4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-IH-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR
(DMSO-d6) 8 9.43 (s, 1H), 8.37 (s, 111), 7.82 (d, 2H), 7.69 (d, 1H), 7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1Hn, 4.40 (d,2H), 3.99 (s, 3H), 3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m. 2H); MS
(ESI) (M+H)+
364.

Example 121 N-[3-fluoro-4-(1-piperidinyl)benzyll-N'-(1-methyl-I H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and 1-methyl-iH-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from-Example 89A. NMR
(DMSO-d6) 6 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H), 4.31 (s,2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS (ESI) (M+H)+ 382.

Example 122 N-(1-methyl- 1H-indazol-4-yl)-N'-[4-(I -pyrrolidinyl)benzyllurea The title compound was prepared using the procedure described in Example 89B
using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR
(DMSO-d6) 6 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H), 7.12 (d, 1H), 6.94 (m, IH),6.73 (bs, 2H), 4.23 (s, 211), 3.99 (s, 31-1), 3.24 (m, 41-i), 1.98 (m, 4H); MS (ESI) (M+H)+
350.

764300 Example 123 N-[3-fluoro-4--l -pyrrolidinyl)benzyll-N'-(1-methyl-1H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-IH-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR
(DMSO-d6) S 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, IH), 7.12 (t, IH), 7.10 (m, 21-1), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H), 3.30 (m, 4H), 1.89 (m, 4H); MS
(ESI) (M+H)+
368.

ps Example 124 N-[4-(1-azepanyl)benzyl]-N'-(1-methyl-1 H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B
using 1-[4-(isocyanatomethyl)phenyl]azepane and 1-methyl-lH-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR
(DMSO-d6) 8 8.97(s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H), 7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H), 1.90 (m, 4H), 1.53 (m, 41-1); MS (ESI) (M+H)+ 378.

Example 125 N-[4-(1-azepanyl)-3 -fluorobenzyl]-N'-(l -methyl- I H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 89B
using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and 1-methyl-IH-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR
(DMSO-d6) S 9.03(s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H), 7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m, 4H), 1.55 (m, 4H); MS (ESI) (M+H)+
396.

Example 126 4-methylbenzyI 5-isoguinolinylcarbamate The title compound was prepared using the procedure described in Example lB
using 4-methylbenzyl alcohol instead of 2-(3-fluorophenyl)ethylamine. 1H NMR (300 A41-1z, d6-DMSO) 9.82 (s, 1H), 9.31 (s, 111), 8.50 (d, 111), 7.93 (m, 3H), 7.68 (t, I H), 7.37 (d, 2H), 7.25 (d, 2H), 5.19 (s, 2H), 2.32 (s, 3H); MS (DCUNH3) m/e 293 (M+H)+.

Example 127 N-5-isoguinolinyl-2-[4-(trifluoromethyl)phenyllhydrazinecarboxamide The title compound was prepared using the procedure described in Example 61B
using 4-tiifluoromethylphenyl hydrazine instead of 4-cyanobenzyl alcohol. ]H
NMR (300 MHz, d6-DMSO) 9.80 (m, 2H), 9.10 (broad s, 1H), 8.90-8.43 (m, 314), 8.40 (broad s, 1H), 8.20 (d, 1H), 7.93 (t, 1H), 7.58 (d, 2H), 6.96 (d, 2H); MS (DCI/NH3) m/e 347 (M+H)+; Anal.
Calcd. For C17H13N4OF3. 1.0 HCl 0.1 H20: C 53.09; H 3.72; N 14.57. Found: C
52.80; H
3.81; N 14.51.

Example 128 4-bromobenzyl 5-isoguinolinylcarbamate The title compound was prepared using the procedure described in Example 1B
using 4-bromobenzyl alcohol instead of 2-(3-fluorophenyl)ethylamine. 1H NMR (300 MHz, d6-DMSO) 10.23 (s, IH), 9.86 (s, 1H), 8.69 (d, 111), 8.50 (d, 1H), 8.30 (d, 2IT), 7.98 (t, 111), 7.60 (m, 211), 7.44 (d, 2H), 5.20 (s, 211); MS (DCI/NH3) m/e 357 (M+H)+; Anal.
Calcd. For C17H13N2O2Br. 1.0 HCI: C 51.87; H 3.58; N 7.12. Found: C 51.95; H 3.45; N
7.03.

Example 129 N-benzhydryl-N'-5-isoguinolin_ylurea The title compound was prepared using the procedure described in Example 61B
using benzhydrylamine instead of 4-cyanobenzyl alcohol. 'H NMR (300 MBz, d6-DMSO) 9.26 (s, 1IT), 8.78 (s, 111), 8.57 (d, 1H), 8.31 (m, 1H), 7.94 (d, 1H), 7.70 (d, 1H), 7.60 (m, 2H), 7.38 (m, 8H), 7.27 (m, 211), 6.02 (d, 1H); MS (DCI/NH3) m/e 354 (M+H)+;
Anal. Calcd.
For C23H19N30. 0.1 H20: C 77.77; H 5.45; N 11.83. Found: C 77.52; H 5.30; N
11.98.

Example 130 N-r(1 S)-1-(4-bromophenyl)ethyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using (1S)-1-(4-bromophenyl)ethanamine instead of 4-cyanobenzyl alcohol. 1H
NMR (300 MHz, d6-DMSO) 9.78 (s, 1H), 9.46 (s, 1H), 8.70 (s, 2H), 8.59 (d, 1H), 8.04 (d, 11-1), 7.84 (t, 111), 7.75 (d, 1H), 7.58 (d, 2H), 7.40 (d, 2H), 4.85 (m, 1H), 1.40 (d, 311);
MS (DCI/NH3) m/e 370 (4+H)+.
Anal. Calcd. For C18H16N3OBr. 1.2 HCl: C 52.22; H 4.19; N 10.15. Found: C
51.86; H 4.28;
N 9.78.

Example 131 N-{(1 R)-1-(4-bromophenyl)ethyll-N'-5 -i soguinolinylurea The title compound was prepared using the procedure described in Example 61B
using (1R)-1-(4-bromophenyl)ethanamine instead of 4-cyanobenzyl alcohol. 'H
NMR (300 MHz, d6-DMSO) 9.65 (s, 1H), 9.46 (s, 1H), 8.71 (s, 2H), 8.60 (d, 111), 8.04 (d, 1H), 7.84 (t, 1H), 7.78 (d, 1H), 7.58 (d, 211), 7.38 (d, 2H), 4.87 (m, 11-1), 1.40 (d, 3H);
MS (DCUNH3) m/e 370 (M+H)+; Anal. Calcd. For C1sH16N3OBr. 1.1 HC1: C 52.69; H 4.20; N 10.24.
Found: C
52.52; H 4.28; N 10.00.

Example 132 N-(4-bromobenzyl)-2-(3 -methyl-5-isoguinolinyl)acetanude Example 132A
5-allyl-3-methylisoguinoline 3-Methyl-5-bromoisoquinoline (1.0 g, 4.5 mmol), tributylallyltin (1.6 mL, 5.0 mmol), and dichlrobis(tri-o-tolylphosphine)palladium (11) were combined in toluene (100 mL) and refluxed for 14 hours. The mixture was cooled, diluted with ethyl acetate, and washed twice with aqueous NH4C1. The organic phase was separated, concentrated, and the residue was purified by chromatography (ethyl acetate:hexanes, 30:70) to provide the title compound. 'H
NMR (300 MHz, d6-DMSO) 9.21 (s, 111), 8.00 (d, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 4.18 (s, 211), 3.62 (s, 3H), 2.62 (s, 3H). MS (DCI/NH3) m/e 216 (M+H) Example 132B
methyl (3-methyl-5-isoguinolinyl)acetate The product from Example 132A (0.8 g, 4.37 mmol) in CH2CL2 (40 mL) and 2.5 MNaOH in MeOH (9 mL, 22 mmol, 5 eq.) was ozonized at -78 C for 3 hours. The mixture was diluted with diethyl ether and washed with aqueous NH4C1. The organic phase was separated, concentrated, and the residue was purified by chromatography (ethyl acetate:hexanes, 40:60) to provide the title compound. 'H NMR (300 MHz, d6-DMSO) 9.20 (s, 1H), 7.92 (d, 1H), 7.73 (s, 1H), 7.55 (m, 21D, 6.08 (m, 111), 5.15-5.04 (m, 2H), 3.80 (d, 21'), 2.63 (s, 3H); MS (DCI/NH3) m/e 184 (M+H)+

Example 132C
N-(4-bromobenzyl)-2-(3-methyl-5-isoguinolinyl)acetamide 4-Bromobenzylamine (3.06 mmol) in CH2C12 (30 mL) was treated with 2M Me3AI
(1.53 mL, 3.06 mmol) in toluene. After 30 minutes, the mixture was treated with the product from Example 132B (0.33 g, 1.53 mmol) and refluxed for 16 hours. The mixture was cooled, quenched with IN HCI, diluted with ethyl acetate, and washed with water, aqueous NaHCO3 and aqueous NH4CI. The organic phase was evaporated and the residue dissolved in CH2C12:MeOH and 1M HCI (3 mL) in diethyl ether. After stirring for 2 hours, the mixture was concentrated under reduced pressure to provide the title compound. 1 H NMR
(300 MHz, d6-DMSO) 9.75 (s, 1H), 8.92 (m, 1H), 8.30 (m, 2H), 8.00 (d, 11-1), 7.82 (m, 1H), 7.60 (d, 2H), 7.20 (d, 2H), 4.22 (d, 2H), 4.08 (s, 2H), 2.78 (s, 3H); MS (DCUNF13) m/e 369 (M-I-H)+; Anal.
Calcd. For C19H17N2OBr. 2.0 HCI. 1.7 H2O: C 48.27; H 4.78; N 5.92. Found: C
47.89; H
4.21; N 6.32.

Example 133 N-(4-bromobenzyl)-2-(5-isoguinolinyI)acetamide Example 133A
5-allylisoguinoline The title compound was prepared using the procedure described in Example 132A
using 5-bromoisoquinoline instead of 3-methyl-5-bromoisoquinoline.

Example 133B
methyl 5-isoguinolinylacetate The title compound was prepared using the procedure described in Example 132B
using the product from Example 133A instead of the product from Example 132A.
Example 133C
N-(4-bromobenzyl)-2 (5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 132C
using the product from Example 133B instead of the product from Example 132B.
'H NMR
(300 MHz, d6-DMSO) 9.78 (s, 1H), 8.85 (m, 1H), 8.68 (d, 1H), 8.42 (d, 1H), 7.90 (d, 1H), 8.01 (d, I H), 7.94 (m, 111), 7.52 (d, 2H), 7.20 (d, 2H), 4.22 (d, 2H), 4.10 (s, 211); MS
(DCI/NH3) m/e 355 (M+H){; Anal. Calcd. For C1SH15N2OBr. 1.0 HCl. 0.3 H2O: C
54.44; H
4.21; N 7.05. Found: C 54.11; H 4.18; N 6.86.

{ Example 134 N-(1-(4-bromophenyl)ethyll-2-(5-isogwinolinyl)acetamide The title compound was prepared using the procedure described in Example 132C
using the product from Example 133B and 1-(4-bromophenyl)ethanamine instead of the product from Example 132B and 4-bromobenzylanline. 1H NMR (300 MHz, d6-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d, 1H), 8.40 (d, 111), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d, 2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS
(DCI/NH3) mle 369 (M+H)+; Anal. Calcd. For C19H17N2OBr. 1.0 HCI. 1.0 H2O: C 53.86; H 4.76; N
6.61. Found:
C 53.47; H 4.53; N 6.76.

Example 135 N-41-(4-bromophenyl)ethyl}-2-(3-methyl-5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 132C
using 1-(4-bromophenyl)ethanamine instead of 4-bromobenzylamine. 'H NMR (300 MHz, d6-DMSO) 9.68 (s, 1H), 8.84 (d, 1H), 8.24 (m, 2H), 7.92 (d, 1H), 7.80 (m, 1H), 7.50 (d, 2H), 7.28 (d, 2H), 4.02 (s, 21-1), 2.75 (s, 311), 1.38 (s, 311); MS (DCI/NH3) mle 383 (M+H)+; Anal.
Caled. For C20H19N2OBr. 0.9 HCI: C 57.73; H 4.82; N 6.73. Found: C 57.69; H
4.80; N 6.07.
Example 136 N-5 -isog uinolinyl-N- { 1-(4-(trifluoromethyl)phenyI{ ethyl } urea Example 136A
1-r4-(trifluoromethyl)phenyllethanone oxime 4-Trifluoromethylacetophenone (13.6 g, 72.3 mmol) and O-methylhydroxylamine hydrochloride were combined in pyridine (100 mL) and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCI, and water. The organic phase was concentrated to provide the title compound. 'H NMR (300 MHz, d6-DMSO) 7.90-7.68 (m, 4H), 3.97 and 3.78 (2S, 1H), 2.20 and 2.17 (2s, 31-1); MS (DCI/NH3) m/e 218 (M+H)+.

Example 136B
1- [4-(tri fluorom ethyl)phenyl l eth an am i n e The product from Example 136A (21.0 g, 100 mmol) in MeOH (220 mL) and ammonia (30 mL) was treated with 10% PdIC tinder 60 psi of hydrogen gas for 2 hours. The mixture was filtered and the filtrate was concentrated to provide the title compound. 'H
NMR (300 MHz, d6-DMSO) 7.60 (q, 4H), 4.07 (q, 1H), 3.28 (broad s, 2H), 1.24 (d, 314); MS
(DCI/NH3) m/e 190 (M+H)+

Example 1.36C
N-5-isoquinolinyl-N'-Il-F4-(trifluoromethyl)phenyllethyl urea The title compound was prepared using the procedure described in Example 61B
using the product from Example 136B instead of 4-cyanobenzyl alcohol. 'H NMR
(300 MHz, d6-DMSO) 9.80 (s, 1H), 9.75 (s, 1H), 8.90 (d, 1H), 8.73 (d, 1H), 8.63 (d, 1H), 8.08 (m, 2H), 7.90 (t, 1H), 7.77 (d, 211), 7.64 (d, 211), 4.95 (in, 1H), 1.41 (d, 3H);
MS (DCI/NH3) m/e 360 (M+H)+; Anal. Calcd. For C19H16N30F3. 1.0 HCI. 0.3 H2O: C 56.88; H 4.42; N
10.47.
Found: C 56.61; H 4.49; N 10.28.

Example 138 O N-5-isoquinolinyl-N-{(1S) 1-[4-(trifluoromethyl)phenyllethyl}urea Example 138A
(1.R)-2-oxo-I-phenyl-2-({1-[4-(trifluoromethyll)phenyl]eth)ll}a.lnino)ethyl acetate 1-[4-(Trifluoromethyl)phenyl]ethanamine (37.5 g, 198.4 mmol) and (R)-acetylmandelic acid (40.4 g, 208.3 mmol, 1.05 eq.) were combined in DMAP (0.7 g, 5.7 nunol) and treated with DCC (45.0 g, 218 mmol). After stirring overnight at ambient temperature, the mixture was filtered through a plug of silica. The filtrate was concentrated and the residue was purified by chromatography on Biotage Flash 75 column (ethyl acetate:hexanes, 25:75) to provide a faster running diastereomer and a slower running diastereomer. (fast diastereomer)'H NMR (300 MHz, CDCI3) 7.58 (d, 2H), 7.39 (m, 711), 6.30 broad (d, 111), 6.08 (s, 1H), 5.18 (m, 1H), 2.20 (s, 3H), 1.29 (d, 3H);
MS (DCI/NH3) m/e 366 (M+H)+. (slow diastereomer)'H NMR (300 MHz, CDC13) 7.58 (d, 2H), 7.40 (m, 5H), 7.31 (d, 2H), 6.21 (broad d, IH), 6.06 (s, 1H), 5.18 (m, 1H), 2.20 (s, 311), 1.50 (d, 3H); MS
(DCI/NH3) m/e 366 (M+H)+.
Example 138B
(-) 1-[4-(trifluoromethyl)phenyllethanamine the raster running diastereomer from Example 138A (29.2 g, 80 mmol) was treated with 48% aqueous HBr (350 nzL) and water (50 nil-) and was refluxed for 16 hours. The mixture was cooled and extracted with diethyl ether. The aqueous phase was basified with 2N NaOH (pH 12-13) and extracted with diethyl ether. The organic phase was concentrated to provide the title compound. 94% ee (by Mosher amide NMR). [a]D -19.1 (c 1.15;
McOH);'H NMR (300 MHz, CDCI3) 7.60 (d, 2H), 7.47 (d, 2H), 4.20 (m, 1H), 1.65 (br s, 2H), 1.40 (s, 3H); MS (DCI/NH3) m/e 190 (M+I'+.

Example 138C
(+) 1-[4-(trifluoromethyl)phenyllethanamine The slower running diastereomer from Example 138A (29.2 g, 80 mmol) was treated with 48% aqueous HBr (350 mL) and water (50 mL) and was refluxed for 16 hours.
The mixture was cooled and extracted with diethyl ether. The aqueous phase was basified with 2N NaOH (pH 12-13) and extracted with diethyl ether. The organic phase was concentrated to provide the title compound. [a]D +20.5 (c 1.47; McOH). 94% ee (Mosher amide NMR);
'H NMR (300 IVIRz, CDCI3) 7.60 (d, 2H), 7.47 (d, 2H), 4.20 (m, 1H), 1.60 (br s, 2H), 1.40 (s, 3H); MS (DCI/NH3) m/e 190 (M+H)+

Example 138D
(-) N-5-isoguinolinyl-N'-{(1S)-1-[4-(trifluorometh_yl)phenyl)ethyl}urea The title compound was prepared using the procedure described in Example 61B
using the product from Example 138B instead of 4-cyanobenzyl alcohol. 'H NMR
(300 MHz, d6-DMSO) 9.90 (s, 1H), 9.83 (s, 1H), 9.00 (d, 1H), 8.72 (d, 1H), 8.66 (d, 1H), 8.23 (d, 1H), 8.10 (d, 1H), 7.90 (t, 1H), 7.72 (d, 2H), 7.64 (d, 2H), 4.98 (m, 111), 1.43 (d, 314); MS
(DCI/NH3) m/e 360 (M+H)+; [all) -18.4 (c 1.24; MeOH); Anal. Caled. For C19H16N30F3.
1.0 HCIØ7 H2O: C 55.88; H 4.54; N 10.29. Found: C 55.70; H 4.40; N 10.12.

Example 139 (+} N-5-isoguinolinyl-N-{(1S)-1-[4-(trifluoromethyl)phenyllethyl}ure The title compound was prepared using the procedure described in Example 61B
using the product from Example 138C instead of 4-cyanobenzyl alcohol. 'H NMR
(300 MHz, d6-DMSO) 9.90 (s, 2H), 8.98 (d, 1H), 8.72 (d, 1H), 8.66 (d, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.90 (t, IH), 7.72 (d, 2H), 7.64 (d, 2H), 4.98 (m, 11), 1.43 (d, 311); MS
(DCIJNH3) m/e 360 (M+H)+. [(X ID +17.0 (c 1.55; MeOH); Anal. Calcd. For C19H16N30F3. 1.0 HCI. 0.4 H2O:
C 56.63; H 4.45; N 10.43. Found: C 56.43; 114.52; N 10.24.

Example 140 N-[ 1-(4-tert-butylphenyl)ethyl l-N'-5-isoquinolinylurea Example 140A
1-(4-tert-butylphenyl)ethanamuie The title compound was prepared using 1-(4-tert-butylphenyl)ethanone and the procedures described in Examples 136A and 136B

Example 140B
N-[ l -(4-tert-butylphenyl)ethyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using the product from Example 140A instead of 4-cyanobenzyl alcohol. 'H NMR
(300 MHz, d6-DMSO) 9.88 (s, 1I1), 9.72 (broad s, IH), 8.90 (d, 1H), 8.70 (d, IH), 8.64 (d, II-I), 8.07 (d, 1H), 7.87 (t, 111), 7.78 (d, 1H), 7.38 (m, 4H), 4.94 (in, 1H), 1.42 (d, 311), 1.27 (s, 9H); MS (DCUNH3) m/e 348 (M+H)+; Anal. Calcd. For C22H25N30. 1.0 HCI. 0.6 H20:
C
66.94; H 6.96; N 10.65. Found: C 66.69; H 6.92; N 10.52.

Example 141 N- {cyclopropyl[4-(trifluoromethyl)phenyllmethyl} -N'-5-isoguinolinylurea Example 141A
N-methoxy-N-methyl-4-(trifluoromethyl)benzamide 4-(Trifluoromethyl)benzoyl chloride (5.0 g, 23.9 minol) and N,O-dimethyihydroxylamine hydrochloride (2.55 g, 26.3 mmol, 1.1 eq.) were combined in CH2CI2 (200 mL) at 0 C and treated with pyridine (4.3 mL, 52.6 mrnol). After stirring for 2 hours, the mixture was allowed to attain ambient temperature, diluted with diethyl ether and washed with water, aqueous HCI, and water. the organic phase was separated and concentrated to provide the title compound which was used directly in the next step. 'H NMR
(300 MHz, d6-DMSO) 7.90 (m, 4H), 3.52 (s, 3H), 3.28 (s, 3H); MS (DCUNH3) m/e 234 (M+H)+.

Example 141B
cyclopropyl(4-(trifluoromethyl)phenyl1methanone The product from Example 141A (1.02 g, 4.38 mmol) in THE (50 mL) at 0 C was treated with 0.8M solution of cyclopropylmagnesium bromide (7.1 mL, 5.7 mmol, 1.3 eq) in THF. After stirring for 1 hour, the mixture was treated with water (51nL), 3N
HCl (0.5 mL), diluted with diethyl ether, and washed with water. The organic phase was separated, evaporated, and and the residue was purified by chromatography (ethyl acetate:hexanes, 5:95) to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 8.24 (d, 2H), 7.92 (d, 2H), 2.92 (m, 1H), 1.10 (m, 4H).

Example 141 C
1 -cyclopropyl- l -T4-(trifluoromethyl)phenyl lmethanamine The title compound was prepared using the product from Example 141B and the procedures described in Examples 136A and 136B. 1H NMR (300 MHz, d6-DMSO) 7.92 (m, 4H), 3.24 (d, 1H), 1.92 (broad s, 2H), 0.93 (m, 1H), 0.50-0.27 (m, 4H); MS
(DCIINH3) m/e 216 (M+H)+.

Example 141D
N- fcyclopropyl[4-(trifluoromethyl)phenyllmethyl}-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using the product from Example 141C instead of 4-cyanobenzyl alcohol. 'H NMR
(300 MHz, d6-DMSO) 9.78 (s, 1H), 9.63 (s, 1H), 8.80 (d, 1H), 8.70 (d, 1H), 8.60 (d, 1H), 8.07 (m, 21), 7.86 (t, 1H), 7.73 (d, 2H), 7.63 (d, 2H), 4.37 (t, 1H), 1.10 (m, 1H), 0.60-0.40 (m, 4H); MS
(DCI NH3) m/e 386 (M+H)+; Anal. Calcd. For C21H1sN30F3. 1.0 HCL 0.25 H2O: C
59.16; H
4.81; N 9.86. Found: C 58.81; H 4.76; N 9.62.

Example 142 (2E)-N-5-isoguinolinyl-3-[4-(trifluoromethyI)phenyl}-2-butenamide Example 142A
ethyl (2E)-3-[4-(trifluoromethyl)phenyll-2-butenoate A suspension of 98% Nall (0.81 g, 33.7 mmol) in THE (100 mL) at ambient temperature was treated with triethyl phosphonate (6.9 g, 31 mmol) dropwise and the resulting mixture was stirred for 15 minutes. The mixture was treated with I -[4-(trifluoromethyl)phenyllethanone (5.0 g, 26.6 nunol) portion wise and refluxed for 6 hours.
After cooling to ambient temperature, the mixture was quenched with aqueous NH4C1, diluted with diethyl ether, and washed with water and aqueous N L1C1. The organic phase was separated, concentrated, and the residue purified by chromatography (ethyl acetate:hexanes, 2:98) to provide the (E) isomer (3.4 g, 50%) and the (Z) isomer (1.3 g, 19 %). Geometry of the double bond was established by NOE studies. (E) isomer:
III NMR for (300 MHz, d6-DMSO) 7.78 (m, 41-1), 6.25 (in, 1H), 4.19, (q, 2H), 2.51, s, 3H), 1.22 (t, 3H);
MS (DCI/NH3) role 259 (M+H)+.

Example 142B
ethyl (2Z)-3-[4-(trifluoromethyl)phenyll-2-butenoate The title compound was isolated from the chromatography described in Example 142A. (Z) isomer: 'H NMR (300 MHz, d6-DMSO) 7.71 (d, 2H), 7.42 (d, 21-1), 6.03 (m, 1H), 3.90 (q, 2H), 2.18 (d, 3H), 1.00 (t, 3II); MS (DCI/NH3) m/e 259 (M+1)+.

Example 142C
(2E)-3-[4-(trifluoromethyl)phenyll-2-buteiioic acid The product from Example 142A (3.5 g, 13.5 mmol) in EtOH (80 mL) was treated with aqueous IM NaOH (40 mL) and stirred for 16 hours at ambient temperature.
The reaction mixture was neutralized with IN HCl (40 mL), diluted with brine, and extracted with diethyl ether to provide the title compound. NMR (CDC13) 2.60 (s, 31), 6.82 (s, IH), 7.58 (d, 2H), 7.65 (d, 2H).

Example 142D
(2E)-N-5-isoguinolinyl-3-[4-(trifluoromethyl)phenyll-2-butenamide The product from Example 142C (0.23 g, 1.00 mmol) in CH2CI2 (5 mL) was treated with oxalyl chloride (0.15 g, 1.2 mmol), 1 drop of DMF, and stirred at ambient temperature for 45 minutes. The mixture was treated with a solution of 5-aminoisoquinoline (0.14 g, 1.0 mmol) and 98% NaH (0.048 g, 1.2 mmol) in DMF (5 mL) prepared separately by stirring for 45 minutes. The resulting mixture was stirred for 15 minutes, poured into water, and extracted with CH2CI2. The organic phase was dried (MgSO4), evaporated, and the residue triturated with diethyl ether. The solid was dried under reduced pressure to provide the title compound. 'H NMR (300 MHz, d6-DMSO) 2.61 (s, 311), 2.73 (s, 0.45H, DMF)), 2.89 (s, 0.45H (DMF)), 6.82 (br s, 1H), 7.70 (t, 1H), 7.83 (s, 4H), 7.95 (d, 1H), 8.04 (d, IH), 8.21 (d, IH), 8.56 (d, 1H), 9.33 (s, 1H), 10.20 (s, IM; MS (ESI+) 357 (M+H)+;
Elemental: Calculated for C20H15N2OF3-HC1-0.l5C3H7NO: C66.87, H4.40, N8.20; Found: C66.83, H4.20, N8.27.

Example 143 N-5-isoguinolinyl-3- f4-. trifluoromethyl)phenyll-3-butenamide The title compound was isolated from the procedure described Example 142D as a side-product. 'H NMR (300 MHz, d6-DMSO) 3.83 (s, 2H), 5.49 (s, 1H), 5.74 (s, 1H), 7.64 (t, 1H), 7.77 (m, 4H), 7.93 (m, 2H), 8.49 (d, 1H), 9.30 (s, 1H), 10.18 (s, 111);
MS (ESI+) 357 (M+H)+; Elemental: Calculated for C20H15N2OF3Ø6H20: C65.43, H4.45, N7.63;
Found:
C65.49, H4.08, N7.93.

Example 144 (2Z)-N-5-isoguinolinyl-3-f 4-(trifluoromethyl)phenyll-2-butenamide Example 144A
(2Z)-3-f4-(trifluorometh_y1)phenyll-2-butenoic acid The title compound was prepared using the procedure described in Example 142C
using the product from Example 142B instead of the product from Example 142A.
Example 144B
(2Z)-N-5-isoguinolinyl-3-(4-(trifluoromethyl)phen ll-2-butenamide The title compound was prepared using the procedure described in Example 142D
using the product from Example 144A instead of the product from Example 142C.
'H NMR
(300 MHz, d6-DMSO) 2.21 (s, 3H), 6.48 (s, 1H), 7.50 (d, 2H), 7.60 (t, 1H), 7.67 (d, 2H), 7.90 (d, 1H), 7.95 (d, 1H), 8.44 (d, 1H), 9.27 (s, 1H), 10.03 (s, 1H); MS (ESI+) 357 (M+H)+;

Elemental: Calculated for CZOH15NZOF3: C67.41, H424, N7.86; Found: C67.16, H4.15, N7.59.

Example 145 (2E)-3- [3-fluoro-4-(trifluoromethyl)phenyl-N-5-isoguinolinyl-2-butenamide Example 145A
(2E)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-butenoic acid The title compound was prepared using 1-[3-fluoro-4-(trifluoromethyl)phenyljethanone and the procedures described in Examples 142A
and 142C.
Example 145B
(2E)-3-{3-fluoro-4-(trifluoromethyl)phenyll-2-butenoic acid The title compound was prepared using the procedure described in 142D using the product from Example 145A instead of the product from Example 142C. 1H NMR
(300 MHz, d6-DMSO) 2.59 (s, 3H), 6.92 (s, 1H), 7.68 (d, 1H), 7.78 (d, 1H), 7.93 (m, 2H), 8.25 (d, 1H), 8.44 (d, 1H), 8.49 (d, 111), 8.70 (d, 11-1), 9.76 (s, 111), 10.59 (s, 1H); MS (ESI+) 375 (M+H)+; Elemental: Calculated for C201:114N2OF4.1.6HC1: C55.52, H3.63, N6.47;
Found:
C55.60, H3.80, N6.09.

Example 146 3-{3-fluoro-4-(trifluoromethyl)phenyl)-N-5-isoguinolinyl-3-butenamide The title compound was isolated from the procedure described in Example 145B
as a side-product. 1H NMR (300 MHz, d6-DMSO) 3.88 (s, 2H), 5.57 (s, 1H), 5.86 (s, 1 H), 7.60-7.88 (m, 4H), 8.18 (m, 3H), 8.64 (d, 1H), 9.65 (s, 1H), 10.50 (s, 1H); MS
(.ESI+) 375 (M+H)+; Elemental: Calculated for C20H14N2OF4=HCl=0.2NH4Cl: C56.99, H3.78, N7.3 1;
Found: C56.73, H3.69, N7.43.

768062 Example 147 (2E)-N-5-isoguinolinyl-3-[4-(1-piperidinyl)phenyl)-2-butenamde Example 147A

(2E)-3-[4-(1-piperidinyl)phenyl]-2-butenoic acid The title compound was prepared using 1-[4-(1-piperidinyl)phenyl]ethanone and the procedures described in Examples 142A and 142C.

Example 147B
(2E)-N-5-isoquinolinyl-3-[4-(1-piperidinyl)phenyl)-2-butenamide The title compound was prepared using the procedure described in 142D using the product from Example 147A instead of the product from Example 142C. 1H NMR
(300 MHz, d6-DMSO) 10.50 (s, 111), 9.82 (s, 1H), 8.71 (d, 1H), 8.58 (d, 111), 8.47 (d, 111), 8.26 (d, lH), 7.95 (m, 2H), 7.62 (m, 2II), 6.80 (s, 1H), 3.20 (m, 4H), 2.58 (s, 3II), 1.90-1.56 (m, 6H);
MS (DCI/NH3) m/e 372 (M+H)+; Anal. Calcd. For C24H25N30. 2.0 HCI. 2.0 H2O. 0.3 DMF:
C 59.24; H 6.69; N 9.27. Found: C 59.44; H 6.83; N 9.24.

Example 148 N-(3-fluorobenzyl)-N-(3 methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 60F
using 1-fluoro-3-(isocyanatomethyl)benzene and 3-methyl-5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatornethyl)benzene. 1H NMR (300 MIIz, DMSO-d6) S 9.18 (s, 1H), 8.69 (bs, iH), 8.87 (bs, 11-1), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s, lH), 7.70 (d, IN, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H), 7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310 (M+H)+. Anal. Calcd for C18H16FN30: C, 69.89; H, 5.21; N, 13.58. Found: C, 69.86; H, 5.24; N, 13.56.

Example 149 N-(4-bromo-3-fluorobenzyl)-N-5-isoquinolinylurea The title compound was prepared using the procedure described in Example I B
using 4-bromo-3-fluorobenzylanline instead of 2-(3-fluorophenyl)ethylamine. 1H NMR
(300 MHz, DMSO-d6) 8 9.74 (s, 1H), 9.55 (s, 1H), 8.67 (m, 2H), 8.57 (dd, IH, J=7.8, 1.5 Hz), 8.06 (d, I H, J=7.8 Hz), 7.8 8 (t, 1 H, J=7.8 Hz), 7.67 (m, 2H), 7.3 5 (dd, I H, J=9.6, 2.4 Hz), 7.17 (dd, 1H, J=8.7,1.8 Hz), 4.39 (d, 2H, J=6.3 Hz). MS (ESI) 374/376 (M+H)+. Anal.
Calcd for C17H13BrFN30=HCI: C, 49.72; H, 3.44; N, 10.23. Found: C, 50.04; H, 3.50; N, 10.25 Example 150 N-(3-amino-5 -isoguinolin I -N'- 4- 1- eeridinyl)benzy1)urea Example 1SOA
N-(3-amino-5-isoguinolinyl)-2,2,2-trichloroacetamide The title compound was prepared using the procedure described in Example IA
using 3,5-isoquinolinediamine instead of 5-arninoisoquinoline.

Example 150B
N-(3-amino-5-isoguinolinyl)-N-[4-(1-piperidinyl)benzyllurea The title compound was prepared using the procedure described in Example IB
using 4-(1-piperidinyl)benzylamine and the product from Example 150A instead of 2-(3-iluorophenyl)ethylarnine and the product from Example IA. 'H NMR (300 MHz, DMSO-d6) 6 8.77 (s, 1H), 8.22 (s, 1H), 7.87 (d, 1H, J=8 Hz), 7.46 (d, 1H, J=8 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.07 (t, 1H, J=8 Hz), 6.91 (d, 2H, J=8.4 Hz), 6.82 (t, 1H, J=6 Hz), 6.70 (s, IH), 5.91 (s, 2H), 4.22 (d, 2H, J=6 Hz), 3.10 (m, 4H), 1.70-1.45 (m, 6II). NIS (ESI) 376 (M+H)+. Anal.
Caled for C22H25N50Ø1H2O: C, 70.04; H, 6.73; N, 18.56. Found: C, 69.66; H, 6.50; N, 18.55.

Example 151 N-(3-amino-5-isoguinolinyl)-N'-[4-(I -azepanyl)benzyllurea The title compound was prepared using the procedure described in Example lB
using 4-(1-azepanyl)benzylamine and the product from Example 150A instead of 2-(3-fluorophenyl)ethylamine and the product from Example IA. 'H NMR (300 MHz, DMSO-d6) 6 8.77 (s, 1H), 8.19 (s, 111), 7.88 (d, 1H, J=8.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.09 (m, 3H), 6.76 (t, 1H, J=5.4 Hz), 6.66 (m, 3H), 5.90 (s, 2H), 4.17 (d, 2H, J=5.4 Hz), 3.24 (m, 4H), 1.71 (m, 4H), 1.44 (m, 4H); MS (ESI) 390 (M+H)+; Anal. Calcd for C23H27N50Ø4H20:
C, 69.64; H, 7.06; N, 17.65. Found: C, 69.53; H, 6.81; N, 17.38.

Example 152 N-(1,1'-biphenyl-3-ylmethyl)-N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 1,1'-biphenyl-3-ylmethylamine instead of 4-cyanobenzyl alcohol. 'H NMIZ
(300 MHz, DMSO-d6) 8 9.73 (s, 1H), 9.47 (s, 111), 8.64 (m, 3H), 8.05 (d, 1H, J=9 Hz), 7.87 (t, IH, J=9 Hz), 7.68 (m, 3H), 7.58 (m, 2H), 7.47 (m, 3H), 7.37 (m, 2H), 4.48 (d, 2H, J=6 Hz); MS (ESI) 354 (M+H)+. Anal. Calcd for C23Hj9N30&HC1: C, 70.86; H, 5.17; N, 10.78. Found:
C, 70.77; H, 5.16; N, 10.74.

Example 153 N-5-isoguinolinyl-N-(4-(2-pyridinyl)benzyl}urea The title compound was prepared using the procedure described in Example 61B
using 4-(2-pyridinyl)benzylamine instead of 4-cyanobenzyl alcohol. 'H NMR (300 MHz, DMSO-d6) 8 9.83 (s, 1H), 9.81 (s, 1H), 8.88 (d, 1H, J=6.3 Hz), 8.72 (m, 3H), 8.10 (m, 5H), 7.92 (m, 2H), 7.56 (m, 3H), 4.49 (d, 2H, J=5.4 Hz); MS (EST.) 355 (M+H)+;
Anal. Calcd for C22H,8N40=l.8HC1: C, 62.91; H, 4.75; N, 13.34. Found: C, 62.95; H, 4.99; N, 13.27.

Example 154 N-(4-bromo-3-fluorob enzyl)-N'-(3 -methyl-5-isog uinolinyl)urea N-CEO
H3C , \
N
Example 154A
5-isocyanato-3-methylisoguinoline The title compound was prepared using the procedure described in Example 61A
using 3-methyl-5-isoquinolinamine instead of 5-aminoisoquinoline.

Example 154B
N-(4-bromo-3-fluorobenzyl)-N-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using 4-bromo-3-fluorobenzylamine and the product from Example 154A instead of cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 6 9.68 (s, I H), 9.46 (s, I H), 8.51 (m, 2H), 8.01 (d, I H, J=7.8 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.36 (dd, 1H, J=9, 1.5 Hz), 7.18 (dd, 1H, J=9, 1 Hz), 4.39 (d, 2H, J=6 Hz), 2.77 (s, 3H); MS (ESI) 388/390 (M+H)t; Anal. Calcd for C18H15BrFN3O-HCl: C, 50.91; H, 3.80; N, 9.89. Found: C, 50.81; H, 3.74; N, 9.87 Example 155 N-f 3-fluoro-4-(4-methyl-l- piperidinyl)benzyll-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using 3-fluoro-4-(4-methyl-l-piperidinyl)benzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) S 9.74 (s, 1H), 9.52 (s, 111), 8.66 (s, 1H), 8.59 (d, IH, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.62 (t, 1H, J=6 Hz), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 3.31 (m, 2H), 2.79 (s, 31-1), 2.69 (m, 2H), 1.71 (m, 2H), 1.49 (m, 1H), 1.32 (m, 2H), 0.95 (d, 3H, J=6 Hz). MS (ESI) 407 (M+H)+; Anal. Calcd for C24H27FN40.2.3HC1: C, 58.79;
II, 6.02; N, 11.43. Found: C, 58.73; H, 6.18; N, 11.19.

Example 156 N-(3-methyl-5-isoguinolinyl)-N'-[4-(4-methyl-l -piperidinyl)benzyl lure The title compound was prepared using the procedure described in Example 61B
using 4-(4-methyl-l-piperidinyl)benzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 8 9.70 (s, 111), 9.66 (s, 1 H), 8.74 (s, I H), 8.59 (d, IH, J=8.7 Hz), 8.01 (d, I H, J=8.7 Hz), 7.82 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 4.40 (d, 2H, J=6 Hz), 3.54 (m, 41T), 2.78 (s, 3H), 1.90-1.50 (m, 5H), 0.98 (d, 3H, J=6 Hz); MS (ESI) 389 (M+H)+; Anal. Calcd for C24H28N40.2.6HC1: C, 59.64; H, 6.38; N, 11.59. Found: C, 59.31; H, 6.39; N, 11.19.
Example 157 N-[3-fluoro-4-(1-piperidinyl)benzyll-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using 3-fluoro-4-(1-piperidinyl)benzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) S 9.73 (s, 1H), 9.47 (s, 111), 8.62 (s, 1H), 8.58 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.57 (t, 1H), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 2.98 (m, 4H), 2.79 (s, 3H), 1.67 (m, 4H), 1.53 (m, 2H); MS (ESI) 393 (M+H)+; Anal. Calcd for C23I-125FN40.1.5HC1: C, 61.78; H, 5.97; N, 12.53. Found: C, 61.40; H, 6.04; N, 12.18.

Example 158 N-(3-methyl-5-isoguinolinyl)-N'-(4-(l -piperidinyl)benzyllurea The title compound was prepared using the procedure described in Example 61B
using 4-(1-piperidinyl)benzylatnine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 6 9.69 (s, 111), 9.60 (s, 1H), 8.68 (s, 1H), 8.57 (d, III, J=7.5 Hz), 8.00 (d, IH, J=7.5 Hz), 7.85-7.55 (m, 4H), 7.43 (m, 211), 4.40 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.77 (s, 3H), 1.90 (m, 4.H), 1.65 (m, 2H); MS (ESI) 375 (M+H)+; Anal. Calcd for C23H2GN40.2.4HC1: C, 59.80;
H, 6.20; N, 12.13. Found: C, 59.91; H, 6.45; N, 11.78 Example 159 N-L4-(1-azepanyl)benzyll-N'-(3-methyl-5-isoguinolinyrl)urea The title compound was prepared using the procedure described in Example 61B
using 4-(1-azepanyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 NIHz, DMSO-d6) 8 9.16 (s, 1H), 8.53 (s, 1H), 8.28 (d, 1H, J=8 Hz), 7.74 (s, 1H), 7.67 (d, IH, J=8 Hz), 7.50 (t, 1 H, J=8 Hz), 7.14 (d, 2H, J=9 Hz), 6.84 (t, 1 H, J=6 Hz), 6.66 (d, 2H, J=9 Hz), 4.20 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.63 (s, 3H), 1.71 (m, 414), 1.45 (m, 4H). MS (ESI) 389 (M+H)+;
Anal. Calcd for C24H28N40Ø31120: C, 73.18; H, 7.32; N, 14.22. Found: C, 73.08; H, 7.38;
N, 14.22.

Example 160 N-(3-meth),l-5-isoguinolin__yl)-N r4-(1-pyrrolidinyl)benzyllurea The title compound was prepared using the procedure described in Example 61B
using 4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 8 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, IM, 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, IH, J=7.5 Hz), 7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22 (d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (in, 4H); MS (ESI) 361 (M+IFI)i-. Anal. Calcd for C22H24N40-0.2H20: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.33; H, 6.64;
N, 1.522.
Example 161 N-f3-fluoro-4-(1-pyrrolidinyl)benzyll-N'-(3-methyl-5-isp uinolinyl)urea The title compound was prepared using the procedure described in Example 61 B
using 3-fluoro-4-(1-pyrrolidinyl)benzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 6 9.17 (s, ITT), 8.59 (s, 1H), 8.22 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.69 (d, IH, J=7.5 Hz), 7.50 (t, IH, J=7.5 Hz), 7.03 (in, 2H), 6.93 (t, 1H, J=6 Hz), 6.72 (m, 1H), 4.24 (d, 2H, J=6 Hz), 3.28 (m, 4H), 2.64 (s, 3H), 1.88 (m, 4H); MS (EST) 379 (M+H)+; Anal. Calcd for C22H23FN40: C, 69.82; H, 6.13; N, 14.80. Found: C, 69.76; H, 6.06; N, 14.69.

Example 162 N-(4-(1-azepanyl)-3-fluorobenzyll-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61 B
using 4-(1-azepanyl)-3-fluorobenzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 6 9.74 (s, 1H), 8.50 (s, 1H), 8.67 (s, 1H), 8.60 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 7.83 (t, 111, J=8.1 Hz), 7.56 (t, 1H), 7.04 (m, 2H), 6.90 (m, 1H), 4.26 (d, 2H, J=6 Hz), 3.32 (m, 4H), 2.79 (s, 3H), 1.75 (m, 4H), 1.55 (m, 4H); MS (ESI) 407 (M+H)+; Anal.
Calcd for C24H27FN40.2HCI: C, 60.13; H, 6.10; N, 11.69. Found: C, 60.09; H, 6.35; N, 11.47.

Example 163 N-[4-(1 -azoeanyl)b enzyl]-N'-(3 -methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using 4-(1-azocanyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) S
9.15 (s, 111), 8.53 (s, IM, 8.27 (d, 1H, J=7.5 Hz), 7.73 (s, 111), 7.67 (d, 1H, J=7.5 Hz), 7.50 (t, 1H, J=7.5 Hz), 7.15 (m, 21-1), 6.83 (t, 1H, J=5.4 Hz), 6.63 (in, 2H), 4.20 (d, 2H, J=5.4 Hz), 3.43 (in, 4H), 2.63 (s, 3H), 1.67 (m, 4H), 1.48 (m, 6H); MS (EST) 403 (M+H)+;
Anal. Calcd for C25H30N40: C, 74.60; H, 7.51; N, 13.92. Found: C, 74.26; H, 7.48; N, 13.64.

Example 164 N-[4-(1-azocanyl)-3-fluorobenz Iy 1-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using 4-(1-azocanyl)-3-fluorobenzylamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A. 'H NMR (300 MHz, DMSO-d6) 8 9.70 (s, 1H), 9.37 (s, 1H), 8.56 (m, 21-1), 8.01 (d, 1H, J=8.4 Hz), 7.81 (t, 1H, J=8.4 Hz), 7.45 (t, 1H), 7.02 (nl, 2H), 6.90 (in, 1H), 4.25 (d, 2H, J=6 Hz), 3.35 (m, 4H), 2.77 (s, 3H), 1.67 (m, 4H), 1.54 (m, 6H); MS (ESI) 421 (M+H)*; Anal. Calcd for C25H29FN40=HC1: C, 65.71; 11, 6.62; N, 12.26. Found: C, 65.44; H, 6.49; N, 12.15.

Example 165 N-[(1 S)-1-(4-bromophenyl)ethyll-N-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 61B
using (iS)-1-(4-bromophenyl)ethanamine and the product from Example 154A
instead of 4-cyanobenzyl alcohol and the product from Example 61A.

Example 166 N- {(1 S)-1-44-(1-azepanyl)phenyllethyl}-N'-(3-methyl-5-isoguinolinyl)urea.
The product from Example 165 (568 mg, 1.48 mmol, hexamethyleneimine (834 L, 7.39 mmol), Pd2dba3 (271 mg, 0.30 mmol), BINAP (460 mg, 0.74 mmol), and sodium tert-butoxide (1.42 g, 14.8 mmol) were combined in 1,4-dioxane (20 mL) and heated to reflux.
After 16 hours, the reaction was cooled.to ambient temperature and concentrated in vacuo.
The residue was purified by flash chromatography (I% to 5% CH3OH/CH2CI2) to provide the title compound. 'H NMR (300 MHz, DMSO-d6) b 9.15 (s, 111), 8.48 (s, 11D, 8.28 (d, 1H, J=8.4 Hz), 7.72 (s, 1 H), 7.64 (d, 1 H, J=8.4 Hz), 7.47 (t, 1H, J=8.4 Hz), 7.16 (m, 2H), 6.90 (d, 1 H, J=7.5 Hz), 6.66 (m, 2H), 4.74 (m, 1H), 3.43 (m, 4H), 2.64 (s, 3H), 1.71 (m, 4H), 1.44 (m, 71-i). MS (ESI) 403 (M+H)}. Anal. Calcd for C25H30N40Ø2CH30H: C, 74.01; H, 7.59; N, 13.70. Found: C, 74.39; H, 7.60; N, 13.32.

Example 167 N-benzyl-N-(3-chloro-5-isoguinolinyl)urea The product from Example 60E (250 mg, 1.4 mmol) and 1-bromo-4-(isocyanatomethyl)benzene (0.22 mL, 1.57 mmol) were heated in toluene (5 mL) at 80 C for 3 hours. The mixture was cooled to room, temperature and the precipitated solid was collected by filtration, washed with toluene, and air-dried to provide the title compound. 1H
NMR (300 MHz, DMSO-d6) S 9.18 (s, 1H), 8.81 (s, IM, 8.32 (dd, J=7.8Hz, 0.7 Hz, IH), 8.09 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.32 (m, 2H), 7.05 (t, J=5.7 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H); MS (ESI) m/z 391/393 (M+H, 35CU37C1).

Example 168 N-(4-bromobenzyl)-N'-(1-chloro-5-isoguinolinyl)urea Example 168A
1-chloro-5-isoguinolinamine The title compound was prepared using the procedures described in Examples 60D
and 60E using I -chloroisoquinoline instead of the product from Example 60C.

Example 168B
N-(4-bromobenzyl)-N'-(l -chloro-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 60F
using the product from Example 168A instead of the product from Example 60E.
'H NMR
(300 MHz, DMSO-d6) S 8.89 (s, 1H), 8.34-8.37 (m, 2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (nz, 1H), 7.73 (t, J=8.1, 1H), 7.53-7.56 (m, 211), 7.30-7.33 (m, 21-1), 7.12 (t, J=5.8Hz. 1H), 4.35 (d, J=5.8 Hz, 2H); MS (ESr) m/z 390/392 (M+H, 3SC1/37CI).
Example 169 N-(4-cyanobenzyl)-N'-5-isoguinolinylurea Example 169A
4-(aminomethyl)benzonitrile A solution of N, N-bis(tert-butoxycarbonyl)-4-eyanobenzylamine (0.75 g, 2.25 mmol, prepared according to the literature described in Synthetic Communications 4419:28 (1998), in CH2CI2 (15 mL) was treated with trifluoroacetic acid (8 mL). After stirring at room temperature for 3 hours, the mixuture was concentrated under reduced pressure and the residue was azeotroped with diethyl ether.

Example 169B
N-(4-cyanobenzyl)-N-5-isoquinolinylurea The title compound was prepared using the procedure described in Example 61 B
using the product from Example 169A instead of 4-cyanobenzyl alcohol.
Purification was by chromatography (95:5 CI12C12:MeOH) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) 6 9.75 (s, 1 I3), 9.62 (s, I H), 8.69 (s, 2H), 8.58 (dd, J=7.8 Hz, 1.0 Hz, IH), 8.07 (d, J=7.4 Hz, 1H), 7.90 (d, J=8.1 Hz, 111), 7.81-7.85 (m, 21.1), 7.74 (t, J=6.1 Hz, 1H), 7.54-7.57 (m, 2H), 4.48 (d, J=6.1 Hz, 2H); MS (ES1') m/z 303 (M+H)+.

Example 170 N-(4-bromobenzyl)-N-(3-methyl-5-isoguinolinyl)urea The product from Example 63A (500 mg, 3.1 mmol) and 1-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol) were stirred in toluene (10 mL) at 80 overnight. The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration, washed with toluene, and allowed to air-dry. The corresponding hydrochloride salt was prepared using methanolic HCI. to afford a tan solid.
1H NMR (300 MHz, DMSO-d6) 6 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=7.8 Hz, 1.0 Hz, 111), 8.02 (d, J=8.2 Hz, 1H), 7.78-7.83 (m, 1H), 7.67-7.71 (m, 1H), 7.52-7.57 (m, 2H), 7.30-735 (m, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.78 (s, 3H); MS (EST m/z 370/372 (M+H, 79Br/81Br)+.

Example 171 N-(4-bromobenzyl)-N-(1-methyl-5-isoguinolinyl)urea Example 171A
1-methyl-5-isoguinolinamine The title compound was prepared using the procedures described in Examples 60D
and 60E using 1-methylisoquinoline instead of the product from Example 60C.

Example 171B

N-(4-bromobenzyl)-N'-(l-methyl-5-isoquinolin 1)urea The product from Example 171A (480 mg, 3.04 mmol) and 1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) were stirred in toluene (9 mL) at 90 for I
hour, then the mixture was cooled to room temperature. The precipitate was collected by filtration and washed with toluene. The corresponding di-hydrochloride salt was prepared using methanolic HC1. IH NMR (300 MHz, DMSO-d6) fi 8.74 (s, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 311), 7.32 (d, J=8.5 Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 2.88 (s, 3H); MS (ESI+) m/z 370/372 (M+H, 79Br/81Br)+.

Example 172 N-5-isoguinolinyl-N'-[4-(4-morpholinyl)benzyllurea Example 172A
4-(4-iiorpho linyl)b enzoni trile 4-Fluorobenzonitrile (1 g, 8.26 nunol) and morpholine (2.2 mL, 25.2 mmol) were stirred in DMSO (25 mL) at 100 C for 2.5 hours, cooled to room temperature, poured into H2O, and extracted with diethyl ether. The combined organic extracts were washed with H2O
and brine, dried over Na2SO4, and evaporated in vacuo to provide the title compound.

Example 172B
4-(4-morpholinyl)benzylamine 4-(4-Morpholinyl)benzonitrile (1.24 g, 6.6 mrol) in THE (25 mL) at 0 C was treated with LiAIH4 (2.5 g, 65.9 mmol) and refluxed for 1 hour. The mixture was cooled to room temperature and quenched by careful addition of IN NaOH and then H2O. The mixture was concentrated, extracted with diethyl ether. The combined ethereal extracts were washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated in vacuo to provide the title compound which was dried over MgSO4 as a THF:diethylether solution before the next step.
Example 172C
N-5-isoguinolinyl-N'-[4-(4-morpholinyl)benzyllurea The product from Example 172B (285 mg, 1.48 mmol) in diethyl ether (10 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline, causing a white precipitate to form. This precipitate was collected by filtration and purified by chromatography (95:5 CH2C12-MeOH, eluant) to provide the title compound. The corresponding di-hydrochloride salt was prepared using methanolic HO to afford a yellow solid. 1H NMR (300 MHz, DMSO-d6) S 9.26 (s, 111), 8.67 (s, lH), 8.52-8.55 (m, 111), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H), 3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS
(ESI+) m/z 363 (M+H)+.

Example 173 N- 4- 2,6-dimethyl-4-morpholinyl)benzyll-N'-5-isoguinolinylurea Example 173A
4-(2,6-dimethyl-4-morpholinyl)benzylamine The title compound was prepared using the procedures described in Examples and 172B using 2,6-dimethylmorpholine instead of morpholine.

Example 173B
N-f 4-(2,6-dimethyl-4-morpholinyl)benzyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 172C
using the product from Example 173A instead of the product from Example 172B.

(300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.67 (s, 1H), 8.53 (d, J=6.1 Hz, 111), 8.31 (dd, J=7.6 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92-6.95 (m, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68 (m, 2H), 3.54-3.57 (m, 2H), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (ESI) m/z 391 (M+H).

Example 174 N-5-isoguinolinyl-N'-(4-(4-thiomorpholinyl)benzyllurea Example 174A
4-(4-thiomorpholinyl)benzylamine The title compound was prepared using the procedures described in Examples and 172B using thiomorpholine instead of morpholine.

Example 174B
N-5-isoquinolinyl-N'-(4-(4-thiomorphholinyl)b enzyl )urea The title compound was prepared using the procedure described in Example 172C
using the product from Example 174A instead of the product from Example 172B.

(300 MHz, DMSO-d6) 6 9.26 (s, 1H), 8.67 (s, IH), 8.53 (d, J=6.1 Hz, 1H), 8.32 (dd, .1=7.8 Hz, 1.1. Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.20-7.23 (m, 2H), 6.90-6.96 (in, 3H), 4.25 (d, J=5.8 Hz, 2H), 3.45-3.51 (m, 4H), 2.64-2.67 (m, 4H); MS
(ESI) m/z 379 (M+H).

Example 175 N-(4-brornobenzyl)-N'-(3-fluoro-5-isoq uinolinyl)urea Example 175A
3-fluoro-5-isoquinolinamine The title compound was prepared using the procedures described in Examples 60D
and 60E using 3-fluoroisoquinoline, prepared according to the procedure described in J. Am.
Chem. Soc., 687:73 (1951), instead of the product from Example 60C.

Example 175B
N-(4-bromob enzyl_)-N'-(3-fluoro-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 60F
using the product from Example 175A instead of the product from Example 60E.
'H NMR
(300 MHz, DMSO-d6) 6 9.09 (s, 1H), 8.74 (s, IH), 8.28 (d, IH, J=7.8 Hz), 7.83 (d, 1H, J=8.4 Hz), 7.66 (s, 1H), 7.55 (m, 3H), 7.32 (d, 2H, J=8.5 Hz), 7.03 (t, 1H, J=5.9 Hz), 4.35 (d, 2H, J=6.1 Hz); MS (ESI) m/z 373/375 (M+H, 79Br/81Br).

Example 176 N-(3-chloro-5-isoguinolinyl)-N'-(4-(4-morpholinyl)benzylJurea Example 176A
3-chloro-5-isocyanatoisoquinoline 5-Amino-3-chloroisoquinoline (740 mg, 4.15 mmol) was suspended in toluene (20 mL) and treated with 20% w/v phosgene solution in toluene (9 mL) and triethylamine (5 mL).
The mixture was refluxed overnight and was then concentrated in vacuo and used in the next step without further purification.

Example 176B
N-(3-chloro-5-isoguinolinyl)-N-(4-(4-morpholinyl)benzyliurea The product from Example 176A in diethyl ether (40 mL) was treated with the product from Example 172B (300 mg, 1.56 mmol) and triethylamine (3 mL) in 1:1 diethyl ether:CH3CN (10 mL). After stirring for 3 hours, the mixture was filtered, and the collected solid was washed with diethyl ether. The solid was purified by silica gel chromatography (95:5 CH2C12:MeOH) to'provide the title compound. 1H NMR (300 MHz, DMSO-d6) 6 9.18 (s, 1H), 8.71 (s, IH), 8.37 (d, iH, J=6.7 Hz), 8.08 (s, 1I1), 7.79 (d, 2H, J=8.2 Hz), 7.63 (t, 1H, J=8.0 Hz), 7.23 (d, 2H, J=8.7 Hz), 6.94 (d, 2H, J=8.4 Hz), 6.91 (t, 1H, 5.5 Hz), 4.26 (d, 2H, 5.7 Hz), 3.73 (m, 4H), 3.07 (m, 4H); MS (ESI) m/z 397/399 (M+H, 35C1/37C1)_ Example 177 N-(3, 5-difluoro-4-(4-morpholinyl)benzyll-N'-5-isoquinolinylurea Example 177A
3,5-difluoro-4-(4-morpholinyl)benzylamine The title compound was prepared using the procedures described in Examples and 172B using 3,4,5-trifluorobenzonitrile instead of 4-fluorobenzonitrile.

Example 177B
N-(3,5-difluoro-4-(4-morpholinyl)benzyll-N-5-isoguinolinylurea The product from Example 177A (500 mg, 2.19 mmol) in diethyl ether (5 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The resulting waxy precipitate was collected by filtration and air-dried to provide the title compound. 1H
NMR (300 MHz, DMSO-d6) 6 9.27 (s, 1H), 8.79 (s, 1H), 8.54 (d, 1H, J=6.1 Hz), 8.26 (dd, IH, J=7.8 Hz, 1.0 Hz), 7.94 (d, 1H, 6.1 Hz), 7.76 (d, 1H, 8.2 Hz), 7.60 (t, 3H, J=7.6 Hz), 7.10 (t, 1H, J=6.0 Hz), 7.03 (m, 2H), 4.31 (d, 2H), 3.68 (m, 4H), 3.07 (m, 4H); MS (ESI+) mlz 399 (M+H).

Example 178 N-(4-bromobcnzyl)-N'-(1,3-dimethyl-5-isoguinolinyl)urea Example 178A
1,3-dimethyl-5-isoquinolinamine The title compound was prepared using the procedures described in Examples 60D
and 60E using 1,3-dimethylisoquinoline, prepared according to the procedure described in Helv. Chim. Acta 1627:75 (1992), instead of the product from Example 60C.

Example 178B
N-(4-bromobenzyl)-N'-(1,3-dimethyl-5-isoguinolinyl)urea The product from Example 178A(375 mg, 22 mmol) in toluene (7 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.31 mL, 2.2 mmol). After stirring at 85-90 C
for 3 hours, the mixture was cooled to room temperature and filtered. The filter cake was treated with methanolic HCl to provide the title compound as the hydrochloride salt. 'H
NMR (300 MHz, DMSO-d5) S 8.62 (s, 1H), 8.17 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.45-7.60 (m, 4H), 7.32 (d, 2H, J=8.1 Hz), 7.06 (t, 1H, 5.7 Hz), 4.34 (d, 2H, 5.8 Hz), 2.84 (s, 3H), 2.75 (s, 311); MS (ESI) m/z 383/385 (M+H, 79Br/s'Br).

Example 179 N-(3,4-dimethylbenzyl)-N'-(3-methyl-5-isoguinolinyl urea 3,4-Dimethylbenzylamine (0.3 mL, 2.1 mmol) in toluene (11 mL) was added carefully to a 20% w/v solution of phosgene in toluene (4.5 mL). The mixture was refluxed overnight and was then concentrated in vacuo. The residue was then taken up in toluene (10 mL) and treated with DIEA (1.5 mL, 8.63 mmol) and 5-amino-3-methylisoquinoline (155 mg, 1.08 mmol). The reaction mixture was stirred at 80 for 2 h and was then cooled to room temperature. The precipitated solid was collected by filtration and was chromatographed on silica gel (97:3 CH2CI2-CH3OH to 9:1 CH2C12-CH3OH, eluant gradient) to afford the desired product, A-473191. Treatment of this solid with methanolic HCl yielded the corresponding hydrochloride salt. 'H NMR (300 MHz, DMSO-d6) 8 9.16 (s, 1H), 8.59 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 7.74 (s, 111), 7.68 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=7.9 Hz), 7.08-7.12 (m, 3H), 6.95 (m, 1H), 4.28 (d, 2H, 5.8 Hz), 2.64 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H);
MS (ESI) m/z 320 (M+H).

Example 180 N-f3,5-bis trifluoromethyl)benzyl7-N-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 179 using 3,5-bis(trifluoromethyl)benzylamine instead of 3,4-dimethylbenzylamine. 'H NMR
(300 MHz, DMSO-d6) S 9.18 (s, 1H), 8.79 (s, 1H), 8.01-8.13 (in, 4M, 7.73 (m, 2H), 7.51 (t, 1H, J=8.0 Hz), 7.23 (t, 1H, J=6.0 Hz), 4.55 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS
(ESI) m/z 428 (M+H).

Example 181 N-(3 -amino-5-isoguinolinyl)-N-(4-bromobenzyl)urea Example 181A
N-3-isoguinolinylaeetamide 3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac20 (9 mL) at 60 for hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.

Example 181B
3, 5 -isoguinolinedi amine The title compound was prepared using the pr9cedures described in Examples 60D
and 60E using the product from Example 181A instead of the product from Example 60C.
Example 181 C
N-(3-amino-5-isoguinolinyl)-N'-(4-bromobenzyl)urea The title compound was prepared using the procedure described in Example 179 using 4-bromobenzylamine and the product from Example 181B instead of 3,4-dirnethylbenzylamine and 5-amino-3-methylisoquinoline. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) S 8.78 (s, 1H), 8.33 (s, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.47-7.56 (m, 3H), 7.29 (d, 2H, J=8.1 Hz), 7.08 (t, 1H, J=7.8 Hz), 6.99 (m, 1H), 6.71 (s, 1H), 5.94 (br s, 21-I), 4.31 (d, 2H, J=6.1 Hz); MS (ESI+) m/z 370/372 (M+H, 79Br/s"Br).

Example 182 N-(3-methyl-5-isoguinolinyl)-N'-[4-(trifluoromethy1 benzyl urea 4-(Trifluoromethyl)benzylarnine (1 mL, 7.02 mmol) in toluene (4 mt) was treated with 20% w/v phosgene solution in toluene (5 mL), and the whole mixture was refluxed overnight. After this time, the mixture was concentrated in vacuo, then was taken up again in toluene (8 mL). To this was added 5-amino-3-methylisoquinoline (340 mg, 2.15 mmol) and DIEA (4 mL) in toluene (8 mL). The reaction was allowed to stir at 80 for 3 h and then was cooled to room temperature. The precipitate was collected by filtration and purified by chromatography on silica gel (97:3 CH2C12-CH3OH to 95:5 CH2C12-CH3OH, eluant gradient) to afford A-638488 as a white solid. Treatment with methanolic HCl yielded the corresponding hydrochloride salt. 'H NMR (300 MHz, DMSO-d6) S 9.18 (s, 1H), 8.73 (s, 1H), 8.20 (d, 1H, J=7.3 Hz), 7.69-7.75 (m, 4H), 7.58 (d, 2H, J=8.2 Hz), 7.50 (t, 1H, 7.8 Hz), 7.16 (t, 1H, J=5.9 Hz), 4.47 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI}) m/z 360 (M+H).

Example 183 N-(4-ter-butylbenzyl)-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepard using the procedure described in Example 182 using 4-tert-butylbenzylanune instead of 4-(trifluoromethyl)benzylamine. The corresponding hydrochloride salt was obtained after treatment of the free base with methanolic HC1. 1H
NMR (300 MHz, DMSO-d6) S 9.16 (s, 1H), 8.60 (s, 1H), 8.24 (dd, 1H, J=7.8 Hz, 1.1 Hz), 7.74 (s, 1H), 7.68 (d, 2H, J=8.2 Hz), 7.50 (t, 1 H, J=7.9 Hz), 7.38 (m, 2H), 7.29 (m, 2H), 6.99 (t, 1H, J=5.8 Hz), 4.32 (d, 2H, J=5.8 Hz), 2.64 (s, 3H), 1.28 (s, 9H); MS
(EST) mlz 348 (M+H).

Example 184 N-(4-tert-butylbenzyl)-N-(1,3-dimethyl-5-isoguinolinyl)urea Example 184A
1-(isocyanatomethyl)-4-(trifluoromethyl)benzene The title compound was prepared using the procedure described in Example 61A
using 4-(trifluoromethyl)benzylamuie instead of 5-arninoisoquinoline.

Example 184B
N-(4-tert-butylbenzyl)-N'-(1,3-dunethyl-5-isoguinolinyl)urea The product from Example 184A (3.16 mmol) in toluene (12 mL) was treated with the product from Example 178A (273 mg, 1.59 mmol) and DIEA (5 mL). The mixture was heated at 80 for 3 hours before being cooled to room temperature and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2CI2-CH3OH to 95:5 CH2C12-CH3OH, eluant gradient) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) S 8.68 (s, 1H), 8.16 (d, 1H, J=7.5 Hz), 7.80 (d, 1H, J=8.1 Hz), 7.73 (d, 21-1, J=8.2 Hz), 7.56-7.61 (m, 3H), 7.48 (t, 1H, J=8.1 Hz), 7.15 (t, 1H, J=5.7 Hz), 4.46 (d, 2H, J=5.7 Hz), 2.84 (s, 3H), 2.58 (s, 3H); MS (ESO m/z 374 (M+H).

Example 185 4-(3-chlorophenyl)-N-5-isoguinolinyl-l -piperazinecarboxamide 1-(3-Chlorophenyl)piperazine (206 mg, 1.05 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) 8 9.30 (s, 1H), 8.84 (s, 1H), 8.49 (d, 1H, J=7.1 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.78 (d, 1H, 6.8 Hz), 7.61-7.72 (m, 2H), 7.25 (t, 1H, J=8.1 Hz), 6.96-7.04 (m, 2H), 6.81-6.84 (m, 1H), 3.68 (m, 4H), 3.29 (m, 4H); MS (ESI+) m/z 367 (M+H).

Example 186 N-(4-tert-butylbenzyl)-N'-(1,3 -dimethyl-5-isoquinolinyl)urea Example 186A
1-tert-butyl-4-(isocyanatomethyl)benzene The title compound was prepared using the procedure described in Example 61A
using 4-tert-butylbenzylamine instead of 5-aminoisoquinoline.

Example 186B
N-(4-tert-butylbenzy N'-(1,3-dimethyl-5-i soquinolinyl)urea The product from Example 186A (3.42 mmol) in toluene (12 mL) was treated with amino-l,3-dimethylisoquino line (245 mg, 1.42 mmol) and DIEA (5 mL). The mixture was heated at 80 for 3 hours, cooled to room tempoerature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2CI2:CH3OH to 95:5 CH2CI2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) 6 8.55 (s, 1H), 8.21 (d, 1H, J=7.1 Hz), 7.78 (d, 111, 8.5 Hz), 7.59 (s, 114), 7.48 (t, 1H, J=8.0 Hz), 7.36-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.98 (m, 1H), 4.31 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 2.58 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z 362 (M+II).

Example 187 4-(3,4-dimethylphenyl)-N-5-isoguinolinyl- l -piperazinec arboxaniide 1-(3,4-Dimethylphenyl)piperazine (194 mg, 1.02 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) 8 9.29 (d, 1H, J=0.7 Hz), 8.82 (s, 1H), 8.49 (d, J=6.2 Hz, 111), 7.90-7.93 (m, 1H), 7.76-7.79 (m, 1H), 7.61-7.71 (m, 2H), 7.00 (d, 1H, 8.5 Hz), 6.83 (d, 1H, J=2.4 Hz), 6.73 (dd, 1H, J=8.3 Hz, 2.5 Hz), 3.67 (m, 4H), 3.15 (m, 4H), 2.19 (s, 3H), 2.13 (s, 311); MS (ESI) m/z 361 (hZ+H).

Example 188 4-(4-chlorophenyl)-N-5-isoquinolinyl-l -piperazinecarboxamide 1-(4-Cblorophenyl)piperazine (197 mg, 1.01 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 'H NMR (300 MT-Iz, DMSO-d6) S 9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 111), 8.49 (d, 1H, 6.1 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.77 (in, 1H), 7.61-7.72 (m, 2H), 7.26-7.29 (m, 2H), 7.01-7.04 (in, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESt) mlz 367 (M+H).

Example 189 N S isoquinolinyl 3 methyl 4 4-methylphenyl)_l1iperazinecarboxamide The title compound was prepared using the procedure described in Example 188 using 2-methyl-l-(4-niethylphenyl)piperazine instead of 1-(4-chlorophenyl)piperazine. 1H NMR
(300 MHz, DMSO-d6) S 9.29 (d, 1H, J=0.6 Hz), 8.77 (d, 1H, J=5.1 Hz), 8.49 (d, 1H, J=5.7 Hz), 7.92 (d, 1H, 7.5 Hz), 7.61-7.77 (m, 311), 7.06 (d, 2H, 8.2 Hz), 6.86-6.91. (in, 2H), 3.61 and 4.53 (2m, IM, 4.09 (m, 1H), 3.93 (m, 1H), 3.49 (m, 1H), 3.39 (m, IH), 2.62-3.24 (m, 2H), 2.22 (s, 3H), 1.35 and 0.98 (2d, 3H, J=6.4 and 6.1 Hz); MS (ESI+) m/z 361 (M+H).

Example 190 4-(2,3-dimethylphenyl)-N-5-isoquinolinyl-l -piperazinecarboxamide The title compound was prepared using the procedure described in Example 188 using 1-(2,3-dimethylphenyl)piperazine instead of 1-(4-chlorophenyl)piperazine. 1H
NMR (300 MHz, DMSO-d6) 6 9.29 (d, 1H, J=1.0 Hz), 8.80 (s, 1H), 8.50 (d, 1H, J=5.7 Hz), 7.92 (d, 1H, J=8.2 Hz), 7.79 (dd, lH, J=6.lHz, 1.0 Hz), 7.61-7.73 (m, 2H), 7.07 (m, 1HO, 6.90-6.96 (m, 21-1), 3.70 (m, 4H), 2.87 (m, 4H), 2.23 (s, 311), 2.23 (s, 31); MS (ESI) m/z 361 (M+H).

Example 191 4-(2,3_dichlorophenyl)-N-5-isoquinolinyl-l -piperazinecarboxamide The title compound was prepared using the procedure described in Example 188 using 1-(2,3-dichlorophenyl)piperazine instead of 1-(4-chlorophenyl)piperazine. 1H
NMR (300 MHz, DMSO-d6) S 9.30 (d, 1H, J=0.7 Hz), 8.83 (s, 1H), 8.50 (d, 1H, J=5.8 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.79 (dd, 1H, J=5.1 Hz, 1.0 Hz), 7.62-7.73 (m, 2H), 7.33-7.36 (m, 2H), 7.21-7.24 (m, 1H), 3.71 (m, 4H), 3.07 (m, 4H); MS (ESI+) m/z 401/403 (M+H, 35C1/37C1).

Example 192 N-[3-fluoro-4-(trifluoromethyl)benzyl]-N`-(3-methyl-5-isoguinolinyl)urea Example 192A
2-fluoro-4-(isocyanatomethyl)-1-(trifluorometbyl)benzene The title compound was prepared using the procedure described in Example 61A
using 3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-aminoisoquinoline.

Example 192B
N-(3-fluoro-4-(trifluoromethyl)benzyll-N'-(3-methyl-5-isoguinolinyI urea The product from Example 192A (4.4 mmol) in toluene (10 mL) was treated with 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL). The mixture was heated at 80 for 1.5 hours, cooled to room temperature, and filtered. The precipitate thus obtained was purified by silica gel chromatography (97:3 CH2CI2:CH3OH to 95:5 CH2CI2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) 8 9.18 (s, 1H), 8.77 (s, IH), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H), 7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H. J=5.8 Hz), 2.65 (s, 3H); MS (ESI) m/z 378 (M+H).

Example 193 N-[ 1 -(4-b romophenyl) ethyl]-N'-(3 -methyl-5 -is o g ui no linyl) urea Example 193A
1-bromo-4-(1-isocyanatoethyl)benzene The title compound was prepared using the procedure described in Example 61A
using 1-(4-bromophenyl)ethylamine instead of 5-aminoisoquino]ine.

Example 193B
N-[ 1-(4-bromophenyl)ethyl)-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example I92B
using the product from Example 193A instead of the product from Example 192A.
The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. TI-I NMR
(300 MHz, DMSO-d6) 8 9.16 (s, 1H), 8.56 (s, 11), 8.20 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.72 (s, IH), 7.67 (d, 1H, J=8.2 Hz), 7.56 (m, 2H), 7.47 (t, III, J=7.8 Hz), 7.35 (m, 2H), 7.12 (d, 1H, J=7.4 Hz), 4.85 (m, 1H), 2.65 (s, 3H), 1.43 (d, 3H, J=7.1 Hz); MS (EST") m/z 384/386 (M+H, 79Br/81Br).

Example 194 N-(3,4-dichlorobenzyl)-N'-(3-methyl-5-isoguinolinyl)urea Example 194A
1,2-dichloro-4-(isocyanatomethyl)benzene The title compound was prepared using the procedure described in Example 61A
using 3,4-dichlorobenzylamine instead of 5-aminoisoquinoline.

Example 194B
N-(3 ,4-dichlorob enzyl)-N-(3 -methyl-5-isoguinolinyl)urea 5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 194A (0.36 mL, 2.45 mmol) were heated in toluene (10 mL) at 80 for 2.5 hours.
Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2CI2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) S 9.17 (s, IH), 8.27 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.74 (s, 1H), 7.71 (d, 1H, J=8.1 Hz), 7.61 (m, 2H), 7.50 (t, 1H, J=8.0 Hz), 7.35 (dd, 1H, J=8.3 Hz, 2.2 Hz), 7.12 (t, 1H, 5.9 Hz), 4.37 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI*
mlz 360/362 (M+H, 35CU37Cl).

Example 195 N-(2,4-dichlorobenzyl)-N-(3 -methyl-5-isoguinolinyl)urea Example 195A
2,4-dichloro-l-(isocyanatomethyl)benzene The title compound was prepared using the procedure described in Example 61A
using 2,4-dichlorobenzylamine instead of 5-aminoisoquinoline.

Example 195B
N-(2,4-dichlorobenzyl)-N-(3-methyl-5-isoguinolinyl)urea 5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80 for 2.5 hours.
Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2C12:CH3OH and then filtering the mixture to provide the title Compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCI. 'H NMR (300 MHz, DMSO-d6) S 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 111), 7.70 (d, 1 H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, I H, J=6.1 Hz), 4.38 (d, 211., J=6.0 Hz), 2.65 (s, 31-1); MS (ESF1) mlz 360/362 (M+H, 35Cl/37C1).

Example 196 N-(3-chlorob enzyl)-N'-(3 -methyl-5 -isoguino linyl)urea 3-chlorobenzylamine (141 mg, 1.0 mmol) in ether (20 mL) was treated with an ethereal solution of 5-isocyanato-3-methylisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound.
'H NMR (300 MHz, DMSO-d6) 6 9.18 (s, 1H), 8.69 (s, 1H), 8.20 (d, 1 H, J=7.S
Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=8.2 Hz), 7.51 (t, 1H, J=7.8 Hz), 7.31-7.43 (m, 4H), 7.10 (m, 111), 4.38 (d, 2H, J=5.7 Hz), 2.65 (s, 3H); MS (ESI') m/z 326/328 (M+H, 35C1137C1)_ Example 197 N-(3 -methyl-5-isoguinolinyl)-N'-(4-(trifluoromethoxy)benzyllurea The title compound was prepared using the procedure described in Example 196 using 4-(trifluoromethoxy)benzylamine instead of 3-chlorobenzylamine. 'H NMR
(3001VMz, DMSO-d6) b 9.17 (s, 1H), 8.68 (s, 1H), 8.21 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.46-7.53 (m, 3H), 7.35-7.37 (m, 2H), 7.10 (t, 1H, 5.9 Hz), 4.40 (d, 2H, J=5.7 Hz), 2.64 (s, 3H); MS (ESI+) m/z 376 (M+H).

Example 198 N-[2-(3,4-dichlorophenyl)ethyl]-N'-(3-methyl-5-isoguinolinyl)urea The title compound was prepared using the procedure described in Example 196 using 2-(3,4-dichlorophenyl)ethylamine instead of 3-chlorobenzylamine. 'H NMR (300 MHz, DMSO-d6) S 9.16 (s, 1H), 8.54 (s, IH), 8.17 (d, 1H, J=7.5 Hz), 7.67-7.70 (m, 2H), 7.57-7.60 (m, 2H), 7.49 (t, 1H, 7.8 Hz), 7.29 (dd, 1H, J=8.1 Hz, 2.0 Hz), 6.57 (t, 1H, J=5.7 Hz), 3.43 (m, 2H), 2.82 (m, 2H), 2.64 (s, 3H); MS (ESI) mlz 374/376 (M+H, 35C1/37C1).

Example 199 N-(4-ethylbenzyl)-N'-(3-methyl-5 -i soquinolinyl )urea The title compound was prepared using the procedure described in Example 196 using 4-ethylbenzylamine instead of 3-chlorobenzylamine. 'H NMR (300 MHz, DMSO-d6) 5 9.17 (s, IH), 8.61 (s, 1H), 8.24 (d,.1H, J=7.8 Hz), 7.74 (s, 111), 7.68 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.19-7.29 (m, 4H), 6.99 (m, 1H), 4.32 (d, 2H, J=5.7 Hz), 2.64 (s, 3H), 2.59 (q, 2H, J=7.6 Hz), 1.17 (t, 3H, J=7.6 Hz); MS (ESI+) m/z 320 (M+H).

Example 200 N-(3-methyl-5-isoguinolinyl)-N'- {2-[4-(trifluoromethyl)phenyllethyl} urea The title compound was prepared using the procedure described in Example 196 using 2-[4-(trifluoromethyl)phenyl]ethylamine instead of 3-chlorobenzylamine. 'H NMR
(300 MHz, DMSO-d6) S 9.16 (s, 1H), 8.55 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 7.67-7.70 (m, 4H), 7.46-7.53 (m, 3H), 6.60 (t, IH, J=5.6 Hz), 3.46 (m, 2H), 2.91 (m, 2H), 2.64 (s, 3H); MS
(ESI+) m/z 374 (M+H).

Example 201 N-(3-methyl-5-isoquinolinyl)-N- {4-((trifltloromethyl)thiolbenzyl}urea The title compound was prepared using the procedure described in Example 196 using 4-[(trifluoromethyl)thio]benzylamine instead of 3-chlorobenzylamine. III NMR
(300 MHz, DMSO-d6) 8 9.18 (s, 111), 8.72 (s, 1H), 8.21 (d, 1H, J=7.8 Hz), 7.69-7.76 (m, 4H), 7.50-7.53 (m, 3H), 7.15 (m, 1H), 4.44 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI+) m/z 392 (M+H).

Example 202 N-(4-chlorobenzyl)-N-(3-methyl-5-isoquinolinyl)urea The title compound was prepared using the procedure described in Example 196 using 4-chlorobenzylamine instead of 3-chlorobenzylamine. 1H NMR (300 MHz, DMSO-d6) 9.17 (s, 1H), 8.67 (s, 1H), 8.21 (m, 1H), 7.66-7.74 (m, 2H), 7.37-7.53 (m, 5H), 7.08 (m, 1H), 4.36 (d, 2H, J=5.8 Hz), 2.64 (s, 311); MS (ESI{) m/z 326/328 (M+H, 35C1/37C1).

Example 203 4-(3,4-dichlorophenyl)-N-(3-methyl-5-isoguinolinyl)-1-piperazinecarboxamide The title compound was prepared'using the procedure described in Example 196 using 1-(3,4-dichlorophenyl)piperazine instead of 3-chlorobenzylamine. 'II NMR (300 MHz, DMSO-d6) S 9.20 (s, 1H), 8.74 (s, 1H), 7.86 (d, 1H, J=8.1 Hz), 7.51-7.66 (m, 3H), 7.43 (d, 1H, J=8.8 Hz), 7.22 (d, 1H, J=3.1 Hz), 7.01 (dd, 1H, J=9.1 Hz, 3.1 Hz), 3.67 (m, 411), 328 (m, 4H), 2.62 (s, 3H); MS (ESI) m/z 415/417 (M+H, 35C1/37C1).

Example 204 N-(2,4-di fluorobenzyl)-N'-(3-methyl-5-isoguuiolinyl)urea The title compound was prepared using the procedure described in Example 196 using 2,4-difluorobenzylatnine instead of 3-chlorobenzylamine. 'H NA4R (300 MIIz, DMSO-d6) S
9.17 (s, 1H), 8.67 (s, 1H), 8.21 (dd, 1H, J=7.5 Hz, 1.0 Hz), 7.74 (s, IH), 7.70 (d, 1H, J=8.1 Hz), 7.47-7.52 (m, 2H), 7.05-7.29 (m, 3H), 4.38 (d, 2H, J=5.7 Hz), 2.64 (s, 3H); MS (ESI) m/z 328 (M+H).

Example 205 N-(1,3-dimethyl-5-isoguuiolinyl)-M-(3-fluoro-4-(trifluoromethyl)benzyl)ure Example 205A
2-fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene The title compound was prepared using the procedure described in Example 61 A
using 3-fluoro-4-(trifluoromethyl)benzylamin.e instead of 5-aminoisoquinoline.

Example 205B
N-(1,3-dimethyl-5-isoguinolinyl)-N'-(3-fluoro-4-(trifluoromethyl)benzyl1urea The product from Example 205A (4.4 mmol) in toluene (10 mL) was treated with 1,3-dimethyl-5-isoquinolinamine (375 mg, 2.18 mmol) and DIEA (3.5 mL). The mixture was heated at 80 overnight. After cooling to room temperature, the precipitated solids were collected by filtration and chromatographed on silica gel (98:2 CH2CI2:CH3OH
to 95:5 CH2C12:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. iH NMR (300 MHz, DMSO-d6) S 8.72 (s, 1H), 8.13 (d, 1H, J=7.8 Hz), 7.75-7.83 (m, 2H), 7.61 (s, 1H), 7.38-7.51 (m, 3H), 7.18 (t, 1H, J=6.1 Hz), 4.46 (d, 211, J=5.8 Hz), 2.84 (s, 311), 2.59 (s, 311); MS (ES1{) m/z 392 (M+H).

Example 206 N-5-i soguinolinyl-4-(3-(trifluoromethyl)phenyll- l -piperazinecarboxamide The title compound was prepared using the procedure described in Example 188 using 1-[3-(trifluoromethyl)phenyl]piperazine instead of 1-(4-chlorophenyl)piperazine. 'H NMR
(300 MHz, DMSO-d6) 8 9.30 (d, 1H, J=1.0 Hz), 8.85 (s, 1H), 8.49 (d, 1H, J=5.7 Hz), 7.93 (d, lH, J=7.7 Hz), 7.78 (m, 1H), 7.61-7.72 (m, 2H), 7.46 (m, 1H), 7.26-7.31 (m, 2H), 7.12 (d, 1H, J=7.5 Hz), 3.70 (m, 4H), 3.35 (in, 4H); MS (ESI*) m/z 401 (M+H).

Example 207 4-(4-bromophenyl)-N-5-isoguinolinyl- l -piperazinecarboxami de The title compound was prepared using the procedure described in Example 188 using 1-(4-bromophenyl)piperazine instead of 1-(4-chlorophenyl)piperazine. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried.
Purification by silica gel chromatography provided the title compound. 1H NMR (300 MHz, DMSO-d6) S
9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 1H), 8.49 (d, 1H, J=6.1 Hz), 7.92 (d, 1H, J=7.8 Hz), 7.77 (in, 1H), 7.61-7.71 (in, 211), 7.37-7.40 (m, 2H), 6.96-6.99 (m, 21D, 3.68 (m, 4H), 3.23 (m, 411);
MS (ESI+) m/z 411/413 (M+H, 79Br/81Br).

Example 208 N-(4-isopropylben 1)-N'-(3-methyl-5-isoguinolinyl)urea 4-Isopropylbenzylamine (748 mg, 5.02 mmol) in toluene (20 mL) was refluxed with 20% w/v phosgene solution in toluene (3 mL) overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in toluene (20 niL) and was treated with DIEA (4 mL) and 5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The reaction mixture was stirred was at 80 C for 6 hours. After cooling to room temperature, a precipitate formed which was collected by filtration and purified by silica gel chromatography (98:2 CH2C12:CH3OH) to provide the title compound. The corresponding hydrochloride salt was formed by treatment with methanolic HCI. 1H NMR (300 MHz, DMSO-d6) S 9.16 (s, 1H), 8.60 (s, 1H), 8.24 (dd, 1H, J=7.5 Hz, 1.0 Hz), 7.74 (s, 1H), 7.68 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=8.0 Hz), 7.22-7.30 (m, 4H), 6.99 (t, 111, 5.6 Hz), 4.32 (d, 2H, J=7.8 Hz), 2.88 (m, 1H), 2.64 (s, 3H), 1.20 (d, 6H, J=6.8 Hz); MS (ESI') m/z 334 (M+H).

Example 209 N_[4-fluoro-3-(trifluoromethyl)benzyl]-N'-(3-methyl- 5-isoogj inoluiyl urea 4-Fluoro-3-(trifluoromethyl)benzylanvne (0.8 g, 4.15 mmol) in toluene (20 mL) was refluxed with 20% w/v phosgene solution in toluene (2.1 mL) overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was again taken up in toluene (25 mL) and was stirred overnight at 80 C with DIEA (2 mL, 11.5 mmol) and 5-amino-3-methylisoquinoline (500 mg, 3.16 nimol). The mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by silica gel chromatography (97:3 CH2C12:CH3OH, eluant) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 1H NMR
(300 MHz, DMSO-d6) 6 9.18 (s, 1H), 8.72 (s, 1H), 8.16 (d, 1I1, J=7.8 Hz), 7.70-7.77 (m, 4H), 7.48-7.54 (m, 3H), 7.14 (t, 1H, J=5.9 Hz), 4.42 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS (E Sr) mlz 378 (M+H).

Example 210 N-(3-amino-5-isoquinolinyl)-N'- { 1-[4-(trifluoromethyl)phenyll ethyl[ urea 1-(1-Isocyanatoethyl)-4-(trifluoromethyl)benzene (1.64 mmol) in toluene (8 inL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (220 mg, 1.09 mmol) and DIEA
(1.4 mL). The mixture was heated at 80 C for 6 hours, cooled to room temperature, and the precipitate was collected by filtration. The solid was triturated with 97:3 CH2CI2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60 C for 4 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL) and filtered.
The solid was washed with water and air-dried to provide the title compound.
The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 1H NMR
(300 MHz, DMSO-d6) 6 9.05 (s, 1H), 8.64 (s, 111), 7.91 (d, 1H), 7.58-7.74 (m, 4H), 7.22-7.36 (m, 3H), 7.14-7.18 (m, 2H), 6.97 (s, 1H), 4.94 (m, 111), 1.44 (d, 3H, J=6.8 Hz); MS (ESF ) mlz 375 (M+H).

Example 211 N-(3-amino-5-isoquinolinyl)-N'-[3-fluoro-4-(trifluoromethyl)benzyllurea 2-Fluoro-4-(isocyanatomethyl)-1-(trifluoramethyl)ben.zene (2.59 mmol) in toluene (10 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (400 mg, 1.99 rninol) and DIEA (1.8 mL). The mixture was heated at 80 C for 5 hours, cooled to room temperature, and filtered. The solid was triturated with 97:3 CH2CI2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60 C for 2 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL). The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 'H NMR (300 MHz, DMSO-d6) S 8.81 (s, 1H), 8.68 (s, 1 H), 7.94 (s, IH), 7.76 (t, 1 H, J=7.9 Hz), 7.3 5-7.49 (m, 311), 7.26 (s, I H), 7.09 (s, IH), 6.92 (s, 1H), 6.84 (t, 1H, J=6.0 Hz), 6.62 (s, 11-1), 4.41 (d, 2H, J=6.1 Hz).

Example 212 N-f(2,4-dichlorobenzyl)oxy]-N'-5-isoquinolinylurea The title compound was prepared using the procedure described in Example 61B
using O-(2,5-dicblorobenzyl)hydroxylamuie instead of 4-cyanobenzyl alcohol. MS
(ESI) m./z: 361.96 (M+H)+; 'H NMR (DMSO-d6) 8 5.03 (s, 2H), 7.52 (dd, 1H), 7.69 (m, 4H), 7.88 (d, 1H), 7.93 (d, 1H), 8.52 (d, 1H), 9.00 (s, 1H), 9.31 (s, 1H), 9.77 (s, 1H).

Example 213 N-(5-bromo-2-fluorobenzyl)-M-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 5-bromo-2-fluorobenzylamine instead of 4-cyanobenzyl alcohol. MS (ESI) m/z:
373.93 (M+H)+; 'H NMR (DMSO-d6) S 4.42 (d, 2H), 7.22 (t, IH), 7.54 (m, 2H), 7.60 (dd, IH), 7.86 (t, IH), 8.05 (d, 1H), 8.56 (t, 2H), 8.69 (d, 1H), 9.45 (s, 1H), 9.72 (s, IM.

Example 214 N (4..chloro-2-fluorobenzyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-chloro-2-fluorobenzylamine instead of 4-cyanobenzyl alcohol. MS (ESI) mlz:
329.99 (M+fff ;'H NMR (DMSO-d6) 6 4.41 (d, 2H), 7.31 (dd, 1H), 7.47 (m, 3H), 7.85 (t, iH), 8.04.(d, 1H), 8.56 (d, 2H), 8.68 (d, 1H), 9.42 (s, IH), 9.71 (s, 111).

Example 215 2-(4-chlorophenyl)ethyl 5-isoguinolinylcarbamate The title compound was prepared using the procedure described in Example 61B
using 2-(4-chlorophenyl)ethanol instead of 4-cyanobenzyl alcohol. MS (ES1) n-/z: 327.04 (M+H)+; 'H NMR (DMSO-d6) 6 2.99 (t, 2H), 4.37 (t, 2H), 7.36 (q, 4H), 7.89 (t, 1H), 8.12 (d, IH), 8.20 (d, 1H), 8.30 (d, IH), 8.63 (d, IH), 9.72 (s, 111), 9.97 (s, 111).

Example 216 2- 2-(trifluoromethyl)phenyllethyl 5-isoquinolinylearbamate The title compound was prepared using the procedure described in Example 61B
using 2-[2-(trifluoromethyl)phenyl]ethanol instead of 4-cyanobenzyl alcohol.
MS (ESI) m/z:
361.06 (M+H)+; 'H NMR (DMSO-d6) 6 3.18 (t, 2H), 4.42 (t, 2H), 7.48 (t, 1H), 7.63 (m, 2H), 7.72 (d, 1H), 7.90 (t, 1H), 8.13 (d, 1H), 8.20 (d, 1H), 8.30 (d, 1H), 8.63 (d, 1H), 9.72 (s, 1H), 10.01 (s, 1H).

Example 217 N-(4-tert-butylbenzyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4(-tert-butyl)benzylamine instead of 4-cyanobenzyl alcohol. MS (ES1) m/z: 333 (M+H)+; 'H NMR (DMSO-d6) S 1.27 (s, 9H), 2.80 (t, 2H), 2.95 (t, 2H), 7.22 (d, 2H), 7.33 (d, 2H), 7.67 (t, 1I-1), 7.80 (d, 1H), 7.96 (t, 2H), 8.48 (d, 1H), 9.33 (s, 1H), 9.99 (s, IH).

Example 218 N-r(4-tert-butyleyclohexyl)methyll-M-5-isoquinolinylure The title compound was prepared using the procedure described in Example 61 B
using (4-tert-butylcyclohexyI)methylamine instead of 4-cyanobenzyl alcohol. MS
(ESI) m/z:
340.18 (M+H)+; 'H NMR (DMSO-d6) 6 0.82 (d, 9H), 0.93 (d, 4H), 1.09-1.50 (m, 2H), 1.74 (d, 2H), 1.82 (d, 2H), 3.01 & 3.19 (t & dd, 2H), 7.19 & 7.24 (t & t, 1H), 7.87 (t, 1H), 8.03 (d, 1H), 8.63 (dd, 1H), 8.67 (d, 1H), 8.76 (dd, 1H), 9.47 (d, 1H), 9.74 (s, 1H).

Example 219 N-(3,4-difluorobenzyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 3,4-difluorobenzylamine instead of 4-cyanobenzyl alcohol. MS (ESI) m/z:
314.07 (M+H)+; 1H NMR (DMSO-d6) S 4.36 (d, 2H), 7.12 (t, IH), 7.20 (in, IH), 7.40 (t, 2H), 7.60 (t, I H), 7.75 (d, IH), 7.94 (d, I FD, 8.26 (dd, I H), 8.54 (d, l II), 8.79 (s, I
H), 9.27 (s, I H).

Example 220 N-5-isoquinolinyl-N'- f[4-(trifluoromethyl)cyclohexyl)methyl) urea The title compound was prepared using the procedure described in Example 61B
using [4-(trifluoromethyl)cyclohexyl]methylamine instead of 4-cyanobenzyl alcohol. MS
(ESI) n-i1z: 352.07 (M+H)+; 'H NMR (CDC13) 5 1.05 & 1.27 (q & q, IH), 1.58 (in, 2H), 1.66 (m, 2H), 1.70 (m, 21-1), 1.94 (m, 2H), 2.08 (m, 1H), 3.21 & 3.34 (d & d, 2H), 7.16 (br, IH), 7.84 (s, 2H), 8.35 (s, 1H), 8.82 (d, 1H), 9.12 (d, 1H), 9.36 (s, 111), 9.49 (s, 1H).

Example 221 ethyl 5-isoquinolinylacetate 5-Bromoisquinoline (7.19 g, 34.5 mmol) in toluene (80 mL) was treated with dichlorobis(tri-o-tolylphosphine)palladium(II) (5 mol%, 1.3639 g, 1.7 mmol) and tributylstannanylacetic acid ethyl ester in toluene (20 mL). This mixture was heated at 125 C overnight, cooled, diluted with ethyl acetate (1001nL), washed with water (2 x 50 mL), dried (MgSO4), and the filtrate was concentrated under reduced pressure. The residue was pruified by column chromatography (20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes) to provide the title compound. MS (ESI+) m/z 216 (M+H)+, (ESI-) m/z 214 (M-H)-;'H NMR (DMSO, 300 MHz) S 1.17 (t, J 7.1, 3H), 4.09 (q, J 7.1, 2H), 4.17 (s, 2H), 7.64 (m, 111), 7.72 (d, J 6.2, 1H), 7.81 (d, J 5.7, 1H), 8.07 (d, J 7.9, 1H), 8.54 (d, J 6.1, 1H), 9.33 (s, 1H); Anal. Caled for C13H13NO2 - 0.6 H20: C, 69.07; H, 6.33; N, 6.2. Found: C, 59.4; H, 6.09; N, 5.89.

Example 222 2-(5-isoguinolinyl)-N-f4-(rifluoromethoxy)benzyl)acetamide Example 222A
5-isoguinolinylacetic acid Ethyl 5-isoquinolinylacetate (1.15 g, 5.34 mmol) was dissolved in concentrated H2SO4 (12 mL) and heated at 100 C for 2 hours. The reaction mixture was poured into ice (20g) and the pH was adjusted to 6 with 50% NaOH/H2O. The mixture was allowed to set of several hours, filtered, and the filter cake was rinsed with water to provide the title compound. MS (ESI+) m/z 188 (M+H)i; 'H NMR (DMSO, 300 MHz) d 4.07 (s, 2II), 7.67 (m, 211), 7.83 (d, J 5.7, IH), 8.05 (d, J 8.1, IH), 8.53 (d, J 6.1, 1H), 9.32 (s, IH), 12.50 (s, 1H); 13C NMR (DMSO, 75 N1Hz) S 37.6 (CH2CO), 117.1 (CH, C4), 126.8, 127.0 (CH, C7 &
C8),128.4 (C), 131.1 (C), 132.0 (CH, C6), 134.4 (C), 143.0 (CH, C3), 152.7 (CH, Cl), 172.3 (CO); Anal. Calcd for C11H9N02: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.42;
H, 4.93; N, 7.34.

Example 222B
2-(5-isoguino luryl)-N-(4-(trifluoronrethoxy)benzyl) acetami de Polymer supported 1,3-dicyclohexylcarbodiunide (0.845 g) in dichloromethane (5 mL) was treated with 5-isoquinolinylacetic acid (0.075 g, 0.40 mmol) in dichloromethane (1 mL), 1-hydroxy-7-azabenzotriazole (0.049 g), and triethylamine (0.080 g) in dichloromethane (1 mL). After stirring for 5 minutes, the mixture was treated with 4-(trifluoromethoxy)benzylaiuine (0.40 mmol). After stirring for 16 hours, the mixture was treated with MP-Carbonate resin (0.310 g), stirred for 5 minutes, and filters-d. The filtrate was diluted with dichloromethane (40 mL), washed with water (4x20 mL), brine (1 x20 mL) dried (NaSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was purified by forming the hydrochloride salt and triturating the solid with.hot ethyl acetate. MS (ESI+) mlz 361 (M+H)+; MS (ESI-) rnlz 359 (M-H) 111 NUR (DMSO, 300 MHz) 6 3.99 (s, 2H), 4.31 (d, J 5.7,2H), 7.31 (d, J 8.8, 2H), 7.36 (d, J
6.4, 2H), 7.66 (n, 2H), 7.93 (d, J 6.1, 1H), 8.03 (d, J 8.2, 1H), 8.51 (d, J
6.1, 1H), 8.74 (t, J
6.1, IH), 9.31 (s, 114); Anal. Calcd for C,9H15F3N202 + 1 HCI: C, 57.51; H, 4.06; N, 7.06.
Found: C, 57.42; H, 3.98; N, 6.72.

Example 223 N-(4-tert-butylbenzyl)-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 4-(tert-butyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z .i.i.3 (1V1+Y1) ; 1V1b (t 1-) rn/Z jj 1 (M-H)-; 1H NMR (DMSO, 300 MHz) 6 1.26 (s, 9H), 3.96 (s, 2H), 4.24 (d, J 6.1, 21-1),7.17 (d, J 8.5,2M, 7.32 (d, 1 6.4, 2H), 7.66 (m, 2H), 7.83 (d, j 6.1, 1H), 8.03 (d, J 8.1, 1H), 8.51 (d, J 6.1, 1H), 8.65 (t, J 5.8, IH), 9.30 (s, 111); Anal. Calcd for C22H24N20 + 1.15 HCI: C, 70.58; H, 6.77; N, 7.48. Found: C, 70.56; H, 6.80; N, 7.39.

Example 224 N-[3-fluoro-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)acetunide The title compound was prepared using the procedure described in Example 222B
using 3-fluoro-4-(trifluoromethyl)benzylarnine instead of 4-(trifluoromethoxy)benzylamine.
MS (ESI+) m/z 363 (M+H)+; MS (ESI-) rn/z 361 (M-H)-; 'H NMR (DMSO, 300 MIIz) S
4.21 (s, 2H), 4.38 (d, J 6.1,2H), 7.32 (m, 2H), 7.73 (t, 3 7.8, 1H), 7.98 (t, J 8.1, 1H), 8.13 (d, J
7.1, 1H), 8.44 (d, J 8.4, 1H), 8.72 (d, J 6.8, IH), 9.07 (t, J 6.1, IH), 9.88 (s, IH); Anal. Calcd for C19H14F4N20 + 1.15 HCl: C, 56.45; H, 3.78; N, 6.93. Found: C, 56.57; H, 3.69; N, 6.88.

Example 225 N- { 1-[3-fluoro-4-(trifluoromethyI)phenyl]ethyl)-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine instead of 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)+; MS (ESI-) m/z 375, 411 (NM-H)-; 'H NMR (DMSO, 300 MHz) ,5 1.41 (d, 3 7.1, 3H), 4.17 (s, 2H), 4.93 (q, J
7.4, 1H), 7.39 (m, 2H), 7.72 (t, J 7.8, 1 H), 7.96 (t, J 8.1, 1 I-1), 8.10 (d, 3 6.4, 1 H), 8.42 (d, J 8.2, 1 H), 8.55 (d, J 6.8, 1H), 8.71 (d, J 6.8, 1H), 9.07 (d, J 7.5, IH), 9.86 (s, 1H); Anal.
Cased for C20H16F4N20 + 1.55 HCI: C, 55.50; H, 4.18; N, 6.52. Found: C, 55.49; H, 4.09; N,6.47.

Example 226 N- f I -[3-fluoro-4-(trifluoromethyl)phenyllpropyll -2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 1-[3-fluoro-4-(trifluoromethyl)phenyl)propylamine instead of 4-(trifluorometho),)benzylamine. MS (ESI+) m/z 391 (M+H)+; MS (ESI-) rn/z 389, 425 (M-H)'; 'H NMR (DMSO, 300 MHz) 61.06 (t, J 6.8, 3H), 3.44 (q, J 7.1, 2H), 4.20 (s, 2H), 4.73 (q, J 7.5, 1H), 7.41 (m, 2H), 7.72 (t, J 7.8, 1H), 7.97 (t, J 8.2, 1H), 8.12 (d, J 7.1, 1H), 8.44 (d, J 8.1, 1H), 8.59 (d, J 6.7, 111), 8.72 (d, J 6.8, 1H), 9.10 (d, J 8.2, 1H), 9.88 (s, 1H); Anal.

Lalcd for L21HISr4N2(J + 1.:3 1-.L1: C, 57.46; H, 4.70; N, 6.51. Found: C, 57.62; I-1, 4.44; N, 6.40.

Example 227 2-(3-methyl-5-isouinolinyl)-N44- trifluoromethyl)benzyllacetalnide Example 227A
ethyl (3-methyl-5-isoquinolinyl)acetate The title compound was prepared using the procedure described in Example 221 using 5-bromo-3-methylisquinoline instead of 5-brornoisoquinoline. MS (EST+) Inlz 230 (M+H)};
MS (ESI-) m/z 228 (M-H)-;'H NMR (DMSO, 300 MHz) 5 1.18 (t, J=7.1, 3H), 2.63 (s, 3H), 4.10 (m, 5H), 7.54 (t, J=7.1, 1H), 7.65 (m, 2H), 8.01 (d, J 8.1, 114), 9.22 (s, 1H).

Example 227B
(3-methyl-5-isoguinolinyl)acetie acid The title compound was prepared using the procedure described in Example 222A
using ethyl (3-methyl-5-isoquinolinyl)acetate instead of ethyl 5-isoquinolinylacetate. MS
(ESI+) in/z 202 (M+H)+; MS (ESI-) m/z 200, 156 (M-H)-; 'H NMR (DMSO, 300 MHz) 2.62 (s, 3H), 4.03 (s, 2H), 7.58 (t, J 8.2, 1H), 7.64 (m, 21T), 7.99 (d, J 8.
1, 1H), 9.21 (s, IH), 12.46 (s, 1H); Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found:
C, 71.00; H, 5.42; N, 6.79.

Example 227C
2-(3-methyl-5-isoguinolinyl)-N-(4-(trifluoromethyl)benzyll acetamide The title compound was prepared using the procedure described in Example 222B
using (3-methyl-5-isoquinolinyl)acetic acid and 4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 359 (M+H)+;
MS (ESI-) m/z 357 (M-H)-; 'H NMR (DMSO, 3001\*Iz) 8 2.77 (s, 3H), 4.12 (s, 211), 4.37 (d, J 6.1, 2H), 7.47 (d, J 7.8, 2H), 7.68 (d, J S. 1, 2H), 7.86 (t, J 7.4, 1H), 8.03 (d, J 6.4, IH), 8.36 (m, 2I1), 9.03 (t, J 5.8, 1H), 9.77 (s, 1H); Anal. Calcd for C20H17F3N20 + 1.85 HC1: C, 56.44; H, 4.57. Found: C, 56.41; H, 4.46.

Example 28 N-[3-fluoro-4-(trifluoromethyl)benzyl}- -methyl-5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using (3-methyl-5-isoquinolinyl)acetic acid and 3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 377 (M+H)+; MS (ESI-) mlz 375 (M-H)-;1H NMR (DMSO, 300 MHz) 6 2.77 (s, 3H), 4.14 (s, 2H), 4.38 (d, J 6.1, 21-1), 7.33 (m, 21-1), 7.72 (t, J 7.8, 1H), 7.86 (t, J 7.5, 1H), 8.04 (d, J 6.8, 1H), 8.36 (m, 2H), 9.07 (t, J 6.1, 1H), 9.77 (s, 1H); Anal. Calcd for C20H16F4N2O + 1.2 HCl +
0.3 DMF: C, 56.62; H, 4.20; N, 7.48. Found: C, 56.79; H, 4.40; N, 7.29.

Example 229 2-(5-isoguinolinyl)-N- f 2-[3-(trifluoromethyl)phenyllethyl}acetamide The title compound was prepared using the procedure described in Example 222B
using 2-[3-(trifluoromethyl)phenyl]ethylamine instead of 4-(trifluoromethoxy)benzylamine.
MS (ESI+) mlz 359 (M+H)+; MS (ESI-) m/z 357, 393 (M-H)-; 1H NMR (DMSO, 300 MHz) S 2.83 (t, J 7.1, 2H), 3.35 (q, J 6.8, 2H), 4.03 (s, 2H), 7.50 (m, 4H), 7.98 (m, 2H), 8.47 (m, 311), 8.68 (d, J 6.8, 1H), 9.89 (s, 111); Anal. Calcd for C2oH17F3N20 + 1.55 HCI: C, 57.94; H, 4.64; N, 6.73. Found: C, 57.90; H, 4.51; N, 6.75.

Example 230 N-(3,3-diphenylpropyl)-2-(5-isoguinolinyl)acetami de The title compound was prepared using the procedure described in Example 222B
using 3,3-diphenylpropylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 381 (M+H)+; MS (ESI-) m/z 379 (M-H)-; 1H NMR (DMSO, 300 MHz) 6 2.17 (q, J
7.8,21D, 2.96 (q, J 5.8, 2H), 3.99 (s, 2H), 7.16 (m, 21D, 7.25 (m, 9H), 7.84 (t, J 7.5, 1H), 7.93 (d, J 6.5, 1H), 8.29 (m, 3H), 8.63 (d, J 6.5, 111), 9.64 (s, 1B); Anal. Calcd for C26H24N20 + 1-HCl +
0.45 H2O: C, 73.47; H, 6.14; N, 6.59. Found: C, 73.84; H, 6.17; N, 6.07.

Example 231 N-(3-butoxypropyl)-2-(5 -isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 3-butoxypropylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 301 (M+H)+; MS (ESI-) m/z 299 (M-1-1)'; 111 NMR (DMSO, 300 MHz) b 0.85 (t, J 7.5, 3H), 1.28 (in, 2H), 1.43 (ni, 2H), 1.63 (m, 2H), 3.11 (in, 2H), 3.32 (m, 4H), 3.97 (s, 211), 7.81 (t, J 7 .2, 1H), 7.89 (d, J 6.8, 1H), 8.22 (in, 3H), 8.63 (d, J 5.9, 1H), 9.59 (s, 1H).

Example 232 2-(5-isoguino linyl)-N-(3-phenylpropyl~ac etamide The title compound was prepared using the procedure described in Example 222B
using 3-phenylpropylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 305 (M+H)+; MS (ESI-) in/z 303 (M-H)-;'H NMR (DMSO, 300 MHz) 6 1.70 (p, J 7.1, 2H), 2.55 (t, J 7.1, 2H), 3.07 (q, J 6.8, 21-1), 4.05 (s, 2H), 7.21 (m, 5H), 7.92 (t, J
7.5, 1H), 8.04 (d, J 6.4, 1H), 8.38 (m, 2H), 8.48 (d, J 6.5, 1H), 8.69 (d, J 6.5, 1H), 9.79 (s, IH);
Anal. Calcd for C2oH20N20 + 1.5 HCI: C, 66.97; H, 6.18; N, 8.06. Found: C, 66.90; H, 6.04; N, 7.80.
Example 233 2-(5 -i soguinolinyl)-N-(2-(2-thienyl)ethyll acetam ide The title compound was prepared using the procedure described in Example 222B
using 2-(2-thienyl)ethylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 297 (M+H)+; MS (ESI-) mlz 295 (M-H)'; 'H NMR (DMSO, 300 MHz) S 2.93 (t, J 6.8, 2H), 3.32 (q, J 6.9,2H), 3.96 (s, 2H), 6.83 (d, J 2.5, 1H), 6.93 (q, J 3.4, 1H), 7.31 (t, J 3.7, IH), 7.77 (t, J 8.1, 1H), 7.82 (d, J 7.2, 1H), 8.14 (d, J 6.2, 1H), 8.18 (d, J 8.1, IH), 8.35 (t, J 6.1, 1H), 8.59 (d, J 6.2, 1H), 9.53 (s, 1H).

Example 234 N-(3 -(l H-imidazol-1-yl)propyll-2-(5-isoquinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 3-(1H-imidazol-1-yl)propylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 295 (M+H)+; MS (ESI-) m/z 293 (M-M-; 'H NMR (DMSO, 300 MHz) S 1.96 (m, 2H), 3.07 (q, J 6.9, 211), 3.97 (s, 2H), 4.19 (t, J 6.8, 2H), 7.73 (m, 4H), 8.09 (d, J 5.9, 11), 8.14 (d, J 8.1, 1H), 8.32 (t, J 5.3, 1H), 8.58 (d, J 5.9, IH), 9.07 (s, 1H), 9.46 (s, 1H).

Example 235 2-(5-isoguinolinyl)-N-[3-(2-oxo-l -pyrrolidinyl)propyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 1-(3-aminopropyl)-2-pyrrolidinone instead of 4-(trifluorornethoxy)benzylamine. MS
(ESI+) m/z 312 (M+H)+; MS (ESI-) m/z 310 (M-H)-;'H NMR (DMSO, 300 MHz) S 1.59 (p, J 7.5, 15.3, 2H), 1.89 (p, J 7.2, 14.0, 211), 2.19 (t, J 8.2, 2H), 3.04 (q, J
5.9, 2H), 3.15 (t, J 7.1, 2H), 3.28 (t, J 7.2, 2H), 3.99 (s, 2H), 7.81 (t, J 7.2, 1H), 7.99 (d, J 6.9, 1H), 8.23 (m, 3H), 8.63 (d, J 6.3, 1H), 9.60 (s, 1H).

Example 236 N-(2,2-diphenyl ethyl)-2 -(5-isoguinolinyl)acetami de The title compound was prepared using the procedure described in Example 222B
using 2,2-diphenylethylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 367 (M+H)+; MS (ESI-) m/z 365 (M-H)-; 'H NMR (DMSO, 300 MHz) S 3.73 (q, J 6.0, 2H), 3.83 (s, 2H), 4.18 (t, J 8.1, 1H), 7.18 (m, 2H), 7.25 (m, 9H), 7.60 (m, 2H), 7.81 (d, J 6.5, 1 ), 8.06 (d, J 8.1, 1H), 8.25 (t, J 4.7, 114), 8.43 (d, J 5.6, IH), 9.37 (s, 1H).

Example 237 N-benzyl-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 2,2-diphenylethylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 277 (M+H)+; MS (ESI-) rn/z 275 (1\4-M-; 'H NMR (DMSO, 300 MHz) 6 4.05 (s, 2H), 4.29 (d, J 5.9,2H), 7.23 (t, J 5.3, 3H), 7.30 (t, J 3.4, 2H), 7.78 (t, J 7.8, 1H), 7.88 (d, J 6.9, 1H), 8.20 (t, J 7.8, 2H), 8.60 (d, J 6.3, 1 H), 8.72 (t, J 5.3, 1 H), 9.54 (s, 1 H).

Example 238 2-(5-isoguinolinyl)-N-{4-((trifluoromethyl)thio]benzyll acetamide The title compound was prepared using the procedure described in Example 222B
using 4-[(trifluoromethyl)thio]benzylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 377 (M+H)+; MS (ESI-) m/z 375 (M-M-; IN NMR (DMSO, 300 MHz) S 4.06 (s, 2H), 4.35 (d, J 5.9, 2H), 7.40 (d, J 8.1, 2H), 7.66 (d, 1 8.2, 2H), 7.75 (t, J
7.5, 11-I), 7.85 (d, J
6.6, 1H), 8.16 (m, 2H), 8.59 (d, J 5.9, 1H), 8.79 (t, J 5.9, IH), 9.50 (s, IH).

Example 239 2-(5-isoguinolinyl -N-(2-phenylethyl)acetalnide The title compound was prepared using the procedure described in Example 222B
using 2-phenylethylamine instead of 4 (trifluoromethoxy)benzylamine. MS (ESI+) mlz 291 (M+H){; MS (ESI-) m/z 289 'H NMR (DMSO, 300 MHz) S 2.71 (t, J 7.1, 2H), 3.31 (q, J 7.1, 2H), 3.94 (s, 2H), 7.17 (m, 311), 7.25 (t, J 7.5, 2H), 7.77 (t, J
7.5, 1H), 7.82 (d, J 6.6, 1H), 8.15 (d, J 6.2, 1H), 8.19 (d, J 7.8, 1H), 8.27 (t, J 5.3, 1H), 8.59 (d, J
5.0, 11-1), 9.55 (s, 1H).

Example 240 2-(5-isoguinolinyl)-N-[2-(3-pyridinyl)ethyllacetaroide The title compound was prepared using the procedure described in Example 222B
using 2-(2-pyridinyl)ethylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) rn/z 292 (M+H)+; MS (ESI-) m/z 290 (M-H)-;'H NMR (DMSO, 300 MHz) 8 2.84 (t, J
6.9, 2H), 3.39 (q, J 6.5, 2H), 3.92 (s, 2H), 7.58 (t, J 5.3, IM, 7.75 (m, 2H), 7.97 (d, J 7.8, 1H), 8.05 (d, J 5.9, 1H), 8.16 (d, J 7.8, 1H), 8.29 (t, J 5.6, 1H), 8.57 (m, 3H), 9.51 (s, 1H).

Example 241 N-{ 1-[3-fluoro-4-(trifluoromethyl)phenyllethyl; -N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine instead of 4-cyanobenzyl alcohol.
MS (ESI+) m/z 378 (M+H)+; MS (ESI-) m/z 376 (M-H)-; 'H NMR (DMSO, 300 MHz) S
1.46 (d, J 7.1, 3H), 4.97 (p, J 7.1, 1H), 7.51 (m, 2H), 7.77 (t, J 7.8, 1H), 7.86 (t, J 8.2, 1H), 7.99 (d, J 7.1, 1H), 8.06 (d, J 8.1, 1H), 8.58 (d, J 6.8, IH), 8.71 (d, J 6.8, 1H), 8.78 (d, J 6.8, IH), 9.62 (s, IH), 9.76 (s, 1H); Anal. Calcd for C19H15F4N30 + 1 HCI: C, 54.93; H, 3.99; N, 10.09. Found: C, 55.15; H, 3.90; N, 10.15.

Example 242 N- { 1-[3-fluoro-4-(trifluoromethyl)phenyllpropyl} -N'-5-isoquinolinylurea The title compound was prepared using the procedure described in Example 61B
using 1-[3-fluoro-4-(trifluoromethyl)phenyl]propylamine instead of 4-cyanobenzyl alcohol.
MS (ESI+) m/z 392 (M+H)+; MS (ESI-) m/z 390 (M-H)-; 'H NMR (DMSO, 300 MHz) S
0.94 (t, J 7.4, 311), 1.78 (m, 2H), 4.80 (q, J 7.5, IH), 7.59 (m, 2H), 7.77 (t, J 8.1, 1H), 7.84 (t, J 8.2, 1H), 7.96 (d, J 8.2, 1H), 8.04 (d, J 8.1, 1H), 8.56 (d, J 7.1, 1H), 8.73 (m, 2H), 9.59 (s, 1H), 9.73 (s, 11-1); Anal. Calcd for C2oH17F4N3O + 1 HCI: C, 56.1.0; H, 4.26;
N, 9.81. Found:
C, 56.15; H, 4.24; N, 9.82.

Example 243 N-[3-bromo-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)acetamide Example 243A
3-bromo-4-trifluoromethylbenzoic acid 3-Amino-4-trifluoromethylbenzoic acid (8.20 g, 40.0 mmol), prepared according to Astrid Giencke and Helmut Lackner, Liebigs Ann. Chem., 569-579:6 (1990), in 48% HBr (20 mL) and H2O (67 mL) at 0 C was treated with NaNO2 (2.99 g) in small portions over 15 minutes. After stirring for 30 minutes, the mixture was treated with urea (0.250 g) and then the mixture was added dropwise to a solution of CuBr (10.0 g) in 48% HBr (40 mL) and H2O
(100 mL). The reaction mixture was heated at 75 C, stirred for 2 hours, cooled to room temperature, and stirred overnight. The mixture was treated with with 20% NaOH
until the pH > 10. The resulting blue copper salts were removed by filtration through Celite. The mixture was acidified to pH 1 with HCI, extracted with CH2CI2 (3 x 200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.

Example 243B
3-bromo-4-(trifluoromethyl)benzamide The product from Example 243A (4.00 g, 14.9 mmol) in thionyl chloride (20 mL) was heated at 80 C for 2 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (30 mL) and cooled to -60 C. The mixture was treated with ammonium hydroxide(10 mL) and allowed to reach room temperature over 3 hours.
The solvent was removed to give crude 3-bromo-4-trifluoromethylbenzamide. mp 148-150 C.

Example 243C
3-bromo-4-(trifluoromethyl)benzylarnine LiAIH4 (0.906 g, 23.9 imnol) was suspended in 60 mL of dry THE and cooled to 0 C.
The mixture was treated with the product from Example 243B (3.2 g, 11.9 mmol) in THE (10 mL) dropwise with stirring. After 20 minutes, the mixture was warmed to room temperature 12 hours and treated in succession with ethyl acetate (2 mL), NaOH (50%, 5 mL), and diethyl ether (100 mL). The organic phase decanted, dried (Na2SO4), filtered and the filtrate was concentrated under reduced pressure to provide the title compound-Example 243D
N-[3 -bromo-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 3-bromo-4-(trifluoromethyl)benzylaniine instead of 4-(trifluoromethoxy)benzvlamine.
MS (ESI+) m/z 425, 423 (M+H)+; MS (ESI-) mlz 423, 421 (M-H)-; 'H NMR (DMSO, MHz) 5 4.09 (s, 2H), 4.36 (d, J 6.1, 2H), 7.43 (d, J 7.2, 2H), 7.67 (s, 1H), 7.79 (in, 2H), 7.90 (d, J 7.9, 1H), 8.22 (m, 2H), 8.61 (d, J 6.4, 1H), 8.86 (t, J 6.8, 1H), 9.56 (s, 1H); Anal. Calcd for C29H14BrF3N2O + 0.9 TFA: C, 47.51; H, 2.86; N, 5.33. Found: C, 47.53; H, 2.92; N, 522.
Example 244 N-(4-bromo-3-methylbenzyl)-2-(5-isog uinolinyl)acetami de Example 244A
4-bromo-3-methylbenzyl Amin e LiAIH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was, cooled to 0 C and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4i filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) rn/z 194 (M+1-1)+; MS
(ESI-) m/z 192 (M-H)-; 'H NMR (DMSO, 300 MHz) S 3.97 (s, 2H), 7.30 (m, 1H), 7.46 in, 2H).

Example 244B
N-(4-bromo-3-methylbenz)rl)-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 4-bromo-3-methylbenzylamine instead of 4-(trifluoromethoxy)benzylamine.
MS
(ESI+) m/z 371, 369 (M+H)F; MS (ESI-) m/z 369, 367 (M-H)-; 'H NMR (DMSO, 300 MHz) S 2.28 (s, 3H), 4.13 (s, 2H), 4.22 (d, J 6.1, 2H), 7.00 (d, J 8.1, 1H), 7.10 (s, 1H), 7.50 (d, J 8.1, 1H), 7.92 (m, 1H), 8.05 (d, J 7.1, IH), 8.38 (d, J 8.1, 1H), 8.48 (d, J 6.8, 1H), 8.70 (d, J 6.8, 1H), 8.86 (t, J 6.8, 1H), 9.80 (s, 1H); Anal. Calcd for C19H17BrNZO + 1.1 HC1:
C, 55.75; H, 4.46; N, 6.84. Found: C, 55.76; H, 4.23; N, 6.93.

Example 245 N-r2,4-bis(trifluorometbyl)benzyll-2-(5-isoguinolinyl)acetamid e The title compound was prepared using the procedure described in Example 222B
using 2,4-bis(trifluoromethyI)benzylanvne instead of 4-(trifluoromethoxy)benzylamine. MS
(BSI+) m/z 413 (M+H)+; MS (ESI-) m/z 411 (M-H) 1H NMR (DMSO, 300 MHz) rotamers 6 4.22 (s, 2H), 4.53 (d, J 6.1, 2H), 5.97 (d, J 6.4, 1H), 7.57-8.48 (m, 6H), 8.72 (d, J 6.4, 1I-I), 8.84 (m, 1H), 9.12 (t, J 6.8, 111), 9.73 (s, 1H), 9.82 (s, 1H); Anal. Calcd for C20H14F6N20 1.2 HCI: C, 52.67; H, 3.36; N, 6.14. Found: C, 52.67; H, 3.21; N, 6.09.

Example 246 N-(2-clrloro-4-(trifluoromethyl)bent:yl l-2-(5-isoguinolinyl)aeetamide Example 246A
2-chloro-4-(trifluoromethyl)benzylamine The title compound was prepared using the procedure described in Example 244A
using 2-chloro-4-(trifluoromethyl)benzonitrile instead of 4-bromo-3-methylbenzonitrile. MS
(ESI+) m/z 209 (M+H)+; 'H NMR (DMSO, 300 MHz) 5 3.97 (s, 2H), 7.50-7.70 (m, 3H).
Example 246B
N_ j2-chloro-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 2-ehloro-4-(trifluoromethyl)benzylamine instead of 4-(trifluoromethoxy)benzylamine.
MS (ESI+) m/z 379 (M+H)+; MS (ESI-) m/z 377 (M-H)"; 'H NMR (DMSO, 300 MHz) 6 4.19 (s, 2H), 4.41 (d, J 6.1, 2H), 7.56 (d, J 8.1, IH), 7.70 (d, J 8.1, 1H), 7.83 (s, 111), 7.92 (m, 1H), 8.06 (d, J 7.1, 1H), 8.37 (d, J 8.1, 1H), 8.45 (d, J 6.8, 1H), 8.70 (d, J
6.8, 1H), 8.97 (t, J

6.8, 1H), 9.77 (s, 1H); Anal. Calcd for C19H14CIF3N2O + 1 HCI: C, 54.96; H, 3.64; N, 6.75.
Found: C, 54.75; H, 3.47; N, 6.90.

Example 247 N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-2 5-isoguuiolinyl)a letaiiudc Example 247A
2, 3 -difluoro-4-(trifluoromethyl)b enzylamine The title compound was prepared using the procedure described in Example 244A
using 2,3-difluoro-4-(trifluoromethyl)benzonitrile instead of 4-bromo-3-inethylbenzonitrile.
Example 247B
N-(2,3-difluoro-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)acetamid.e The title compound was prepared using the procedure described in Example 222B
using 2,3-difluoro-4-(trifluoromethyl.)benzylamine instead of 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 381 (M+H)+; MS (ESI-) m/z 379 (M-H) ;
1H NMR (DMSO, 300 MHz) rotamers 8 4.16 (s, 2H), 4.42 (d, J 6.1, 21-1), 7.35 (m, 1H), 7.59 (m, 111), 7.93 (m, 1H), 8.07 (in, I H), 8.39 (d, J 7.1, I H), 8.46 (m, 1H), 8.70 (d, J 6.8, 11I), 9.05 (t, J 6.8, 1H), 9.81 (s, 1H); Anal. Calcd for C19H14C1F3N20 + I HCI: C, 54.96; H, 3.64;
N, 6.75. Found: C, 54.75; H, 3.47; N, 6.90.

Example 248 ethyl 2-(5-isoquinolinyl)propanoate Lithium diisopropylamide (12.75 mL, 2M, 25.5 mmol) in THE (160 mL) at -78 C
under nitrogen was treated with ethyl 5-isoquinolinylacetate (5.00 g, 23.2 mmol) in THE (5 mL). After stirring for 30 minutes at -78 C, the mixture was treated with HMPA (5.2 mL) and methyl iodide (1.62 mL, 25.5 mmol). After stirring for 30 minutes at -78 C, the mixture was warmed to 0 C over 1 hour and quenched by addition of saturated NH4CI
solution. The mixture was concentrated under reduced pressure to a volume of -10 mL, diluted with ethyl acetate (200 mL), washed with water (100 mL x 5), washed with brine, dried with anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) mlz 230 (M+H)+; MS (ESI-) m/z 228 (M-H)-; 1H NMR (DMSO, MHz) 5 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, IH), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6. 8, 1H), 9.32 (s, 1H);
Anal. Calcd for C2oH16F4N20 + 1.25 HC1: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45;
N, 7.03.
Example 249 N-(3-fluoro-4-(trifluoromethyl)bepall-2-(5-isoquinolinyl)propanamide Example 249A
245-isoguinolinyl)propanoic acid Ethyl 2-(5-isoquinolinyl)propanoate (1.00 g, 4.36 mmol) was heated at 85 C in NaOH (25%, 20 mL) for 1 hour. The mixture was allowed to coot to room temperature, acidified to around pH 1 with HCI, and concentrated to a dry residue. The solid was extracted with CHC13:isopropyl alcohol (3:1, 50 mL x 4). The extracts were combined, filtered, and the filtrate concentrated under reduced pressure to provide the title compound.
MS (ESI+) m/z 202 (M+W; MS (ESI-) m/z 200 (M-D-; 'H NMR (D11IS0, 300 MHz) b 1.42 (d, J 7.1, 3H), 4.01 (q, J 7.1, 1H), 7.58 (t, 3 8.1, 1H), 7.63 (d, J 7.5, 1H), 7.86 (d, J 8.1, 1H), 8.19 (d, J 6.8, 1H), 8.43 (d, J 6.8, 111), 9.22 (s, iN); Anal. Calcd for C12HI0N02Na+ 0.9 1120: C, 60.20; H, 4.97; N, 5.85. Found: C, 60.45; H, 5.26; N, 5.46.

Example 249B
N-(3 -fluoro-4-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 3-fluoro-4-(trifluoromethyl)benzylamiine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)}; MS (ESI-) m/z 375 (M-H)-; 'H NMR (DMSO, 300 MHz) b 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 111), 9.32 (s, IH); Anal. Calcd for C2oH,6F4N20 + 1.25 HC1: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.

Example 250 2-(5-isoguinolinyl)-N-f 4-(lnfluoromethyl)benzyllpropanamide The title compound was prepared using the procedure described in Example 222B
using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 357 (M-H) 'II NMR (DMSO, 300 MHz) b 1.59 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.69 (q, J 7.1, 1H), 7.40 (d, J 8.1, 1H), 7.65 (d, J 8.1, 1FI), 7.78 (in, 2H), 8.03 (t, 1H), 8.20 (d, J 7.1, 1H), 8.47 (d, J 7.8, 1H), 8.65 (br s, 1H), 8.75 (s, 1H), 9.05 (t, J 5.8, ll-f), 9.93 (s, 1H); Anal. Calcd for C20H17F3N2O + 1.6 HCl + 1.3 H2O: C, 54.58; H, 4.86.
Found: C, 54.70; H, 5.10.

Example 251 2-(5-isoguinolinyl)-N- [3-(trifluoromethyl)benzyllprop anamide The title compound was prepared using the procedure described in Example 222B
using 3-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaeetic acid. MS (ESI+) rn/z (M+H)+; MS (ESI-) m/z 357 (M-H)-; 1H NMR (DMSO, 300 MHz) 6 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.41 (s, 1H), 7.49 (m, 2H), 7.56 (m, 1H), 7.80 (t, J 7.8, 1H), 7.95 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.60 (d, J 6.8, 1H), 8.72 (t, J 5.8, 1H), 9.56 (s, 1H).

Example 252 2-(5-isoguinolinyl)-N-14-f (trifluoromethyl)thio)benzyl, propanamide The title compound was prepared using the procedure described in Example 222B
using 4-[(trifluoromethyl)thio]bcnzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylaniine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 389 (N4-M-; 1H NMR (DMSO, 300 MHz) S 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33 (d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J 7.1, IH), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J
6.8, 1H), 8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, i1), 9.86 (s, 1H); Anal. Calcd for C20H17F3N2OS + 2.1 HCI: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.

Example 253 N-(4-bromobenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222E
using 4-bromobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 371, 369 (M+H)+; MS (ESI-) m/z 369, 367 (M-H) 'H NMR (DMSO, 300 MHz) S 1.57 (d, J 7.1, 3H), 4.23 (d, J 6.1, 2H), 4.63 (q, J 7.1, 111), 7.14 (m, 2H), 7.47 (m, 2H), 7.76 (m, 1H), 7.98 (t, J
7.5, 1H), 8.17 (d, J 7.1, 1H), 8.43 (d, J 7.8, 1H), 8.69 (br s, 1H), 8.74 (d, J 6.8, 1H), 8.92 (t, J
5.8, 1H), 9.88 (s, IM; Anal. Calcd for C29HI7BrN;O + 1.4 HCI: C, 54.30; H, 4.41; N, 6.66.
Found: C, 54.49; H, 4.28; N, 6.75.

Example 254 N-(4-tert-butylbenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 4-(tert-butyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinol nylacetic acid. MS (ESI+) mlz (M+H)+; MS (ESI-) m/z 345 (M-H)-;'H NMR (DMSO, 300 MHz) S 1.56 (d, J 7.1, 3H), 4.22 (d,J6.1,2I1),4.57(q,J7.1, 1H),7.10(d,J8.5,2H),7.29(d,J8.5,211),7.98(t,17.5, 1H), 8.13 (d, J 7.1, 11-1), 8.34 (d, J 7.8, 1H), 8.56 (d, J 6.8, IH), 8.69 (m, 211), 9.78 (s, III); Anal.
Calcd for C23H26N20 + 1.1 HCI: C, 71.46; H, 7.07; N, 7.25. Found: C, 71.13; H, 7.17; N, 7.02.

Example 255 N-(3-fluoro-5-(trifluoromethyl)benzyll-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 3-fluoro-5-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI-) m/z 375 (M-H)";'H NMR (DMSO, 300 MHz) 5 1.55 (d, J 7.1, 3H), 4.36 (m, 2H), 4.53 (q, 7 7.1, 1H), 7.29 (m, 2H), 7.49 (d, J 8.7, 1H), 7.80 (t, J
7.8, 11-1), 7.93 (d, J
6.5, 1H), 8.21 (d, J 8.1, 1H), 8.31 (d, 1 6.4, 1H), 8.60 (d, J 6.2, IH), 8.73 (t, J 5.8, 1H), 9.56 (s, 1H).

Example 256 2-(5-i sog uinolinyl)-N-14-(trifluoromethoxy)benzyl lpropanami d e The title compound was prepared using the procedure described in Example 222B
using 2-(5-isoquinolinyl)propanoie acid instead of 5-isoquinolinylacetic acid.
MS (ESI+) rn/z 375 (M+H)-"; MS (ESI-) rnlz 373 (M-H)-;'H NMR (DMSO, 300 MHz) 8 1.54 (d, J 7.1, 311), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.28 (q, J 8.5, 4H), 7.79 (t, J 7.8, 111), 7.93 (d, J
7.2, 11-1), 8.18 (d, J S. 1, IH), 8.26 (d, J 6.2, 1H), 8.59 (d, J 6.8, 1H), 8.65 (t, J 5.8, 1H), 9.53 (s, 1H).

Example 257 2-(5 -isog uino linyl)-N- (3 -(trifluoromethoxy)benzyl lpropanamide The title compound was prepared using the procedure described in Example 222B
using 3-(trifluoromethoxy)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (hM+H)+; MS (EST-) m/z 373 'H NMR (DMSO, 300 MHz) S 1.54 (d, J 7.1, 311), 4.28 (d, J 6.1, 211), 4.50 (q, J 7.1, 1H), 7.05 (s, 1H), 7.20 (m, 2H), 7.40 (m, 1H), 7.81 (t, J 7.8, 1H), 7.96 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, IH), 8.61 (d, J 6.8, 111), 8.70 (t, J 5.8, 111), 9.57 (s, 1H).

Example 258 N-( ,4-dimethylbenz),l)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 2,4-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamirne and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) mlz 317 (M-H)-l- 'H NMR (DMSO, 300 MHz) 6 1.52 (d, J 7.1, 31-1), 2.13 (s, 3H), 2.21 (s, 3H), 4.20 (m, 2H), 4.51 (q, J 7.1, 1H), 6.88 (d, J 7.5, 1H), 6.94 (s, 1H), 6.98 (d, J 7.5, 1H), 7.82 (t, J 7.8, 1 H), 7.99 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.35 (d, J 6.4, 1H), 8.44 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s, IH).

Example 259 N-(2, 5-dimethylbenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 2,5-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 317 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 1.54 (d, J 7.1, 3H), 2.09 (s, 3I1), 2.12 (s, 3H), 4.20 (m, 211), 4.53 (q, J 7.1, 1H), 6.79 (s, li-i), 6.91 (d, 3 7.8, 1I1), 6.98 (d, J 7.8, I H), 7.83 (t, J 7.8, I H), 8.00 (d, 3 6.5, I H), 8.21 (d, J 8.1, 111), 8.37 (d, J 6.4, IM, 8.46 (t, J 5.8, 1H), 8.62 (d, J 6.2, IH), 9.57 (s, 1H).

Example 260 N-(2,3-dichlorobenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 2,3-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) mlz (M+H)+; MS (ESI-) m/z 357 (M-H)"; 1H NMR (DMSO, 300 MHz) 8 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, IH), 7.17 (d, J 7.8, 1H), 7.26 (t, J 7.8, IH), 7.52 (d, J 8.1, 1H), 7.78 (t, J 7.8, 1H), 7.91 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.24 (d, J 6.4, 1H), 8.59 (d, J 6.2, 111), 8.66 (t, J 5.8, 1H), 9.50 (s, 1H).

Example 261 N-(2, -dichlorobenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 2,4-dichlorobenzylanline and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) mlz (M+H)+; MS (ESI-) m/z 357 (M-H) ; 'H NMR (DMSO, 300 MHz) S 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.22 (d, 7 8.4, 1H), 7.33 (m, 2H), 7.56 (s, 111), 7.78 (t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.25 (d, J 6.4, IH), 8.62 (m, 2H), 9.51 (s, 1H).

Example 262 N-(2,5-dichlorobenzyl)-2-(5-isoguinolinyl)propanamide The title compound was prepared using the procedure described in Example 222B
using 2,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 357 (M-H)";'H NMR (DMSO, 300 MHz) S 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.06 (s, lH), 7.32 (d, J 8.4, 1H), 7.44 (d, J
8.4, 1H), 7.51 (s, 1H), 7.78 (t, J 7.8, IH), 7.90 (d, J 6.5, lII), 8.16 (d, J 8.1, 1H), 8.26 (d, J
6.4, IH), 8.60 (d, J 6.2, 111), 8.65 (t, J 5.8, I H), 9.49 (s, IH).

Example 263 N-(3,4-dichlorobenzyl)-2-(5-isoguinolinyl)prop anamide The title compound was prepared using the procedure described in Example 222B
using 3,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (117+H)+; MS (ESI-) m/z 357 (M-H) 'H NMR (DMSO, 300 MHz) S 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.16 (d, J 8.4, 1H), 7.31 (s, IH), 7.52 (d, J
8.4, 1H), 7.77 (t, J 7.8, 111), 7.89 (d, J 6.5, 1H), 8.16 (d, J 8.1, lH), 8.22 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J
5.8, 111), 9.49 (s, 1H).

Example 264 N-(3,5-dichlorobenzyl)-2-(5-isoguinolinyl propanamide The title compound was prepared using the procedure described in Example 222B
using 3,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)4; MS (ESI-) m/z 357 (M-H)-;'H NMR (DMSO, 300 MHz) S 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 11-1), 7.13 (s, 2H), 7.42 (s, 11-1), 7.78 (t, J 7.8, II1), 7.89 (d, J 6.5, 11-1), 8.17 (d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J 5.8, IM, 9.51 (s, 11-1).

Example 265 N-[4-(1-azepanyl)-3-fluorobenzyll-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 4-(1-azepanyl)-3-fluorobenzylamine instead of 4-(trifluoromethoxy)benzylamine. MS
(ESI+) m/z 392 (M+H)+; MS (ESI-) m/z 390 (M-H)-; 'H NMR (DMSO, 300 MHz) S 1.53 (m, 4H), 1.72 (m, 4H), 3.32 (m, 4H), 3.96 (s, 2H), 4.18 (d, J 6.1, 2H), 6.86 (m, 3H), 7.69 (m, 2H), 7.94 (d, J 7.5, 1H), 8.03 (d, J 7.1, 11-1), 8.50 (d, J 7.8, 1H), 8.62 (t, J
5.8, 1H), 9.30 (s, 111);
Anal. Calcd for C24H26FN3O + 0.3 H2O: C, 72.63; H, 6.76; N, 10.59. Found: C, 72.78; H, 7.05; N, 10.80.

Example 266 N-[4-(1-azepanyl)benzyl]-2-(5-isoguinolinyl)propanaxnide The title compound was prepared using the procedure described in Example 222B
using 4-(l-azepanyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m!z (M+H)+; MS (EST-) m/z 366 (M-H) 'H NMR (DMSO, 300 MHz) S 1.53 (m, 7H), 1.72 (m, 4H), 3.85 (s, 2H), 4.03 (q, J 7.1, 1H), 6.76 (m, 3H), 7.26 (m, 211), 7.58 (m, 111), 7.71 (m, 1H), 8.10 (m, 2H), 8.72 (t, J 5.8, 1H), 9.91 (s, 1H); Anal. Calcd for C25H29N3O +
2.15 HCI + 2 H2O: C, 59.82; H, 7.06. Found: C, 59.59; H, 7.28.

Example 267 N-[4-(1-azepanyl)-3-fluorobenzyll-2-(5-isoquinolinyl)propanainide The title compound was prepared using the procedure described in Example 222B
using 4-(I-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluorometho3.y)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 404 (M-H) 'H NMR (DMSO, 300 MHz) S 1.53 (m, 711), 1.72 (m, 41), 3.32 (m, 4H), 3.65 (s, 2H), 4.18 (q, J 7.1, 1H), 6.86 (m, 3H), 7.58 (m, 211), 7.74 (m, 1H), 8.13 (m, 2H), 8.52 (d, J 7.8, 1H), 9.30 (s, 1H); Anal. Calcd for C25H2sFN30 +
3.25 HCI: C, 57.30; H, 6.01. Found: C, 57.26; H, 5.98.

Example 268 ethyl 2-(5-isoguinolinyl)butanoate The title compound was prepared using the procedure described in Example 248 using ethyl iodide instead of methyl iodide. MS (ESI+) m/z 244 (M+H)+; MS (ESI-) m/z 242 (M-H) 'H NMR (DMSO, 300 MHz) S 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 21-1),7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J
6.8, 1H), 9.32 (s, 1H);
Anal. Calcd for C,5H17NO2 + 0.4 H2O: C, 71.92; H, 7.16; N, 5.59. Found: C, 72.23; H, 7.32;
N, 5.31.

Example 269 N-[3-fluoro-4-(trifluoromethyl)benzyll-2-(5-isoquinolinyl)butanamide Example 269A
2-(5-isoquinolinyl)butanoic acid The title compound was prepared using the procedure described in Example 249A
using ethyl 2-(5-isoquinolinyl)butanoate instead of ethyl 2-(5-isoquinolinyl)propanoate.
Example 269B
N-[3-fluoro-4-(trifluoromethyl)benzyll-2-(5-isoquinolinyl)butanami de The title compound was prepared using the procedure described in Example 222B
using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m!z 391 (M+H)+; MS (ESI-) m/z 389 (M-H)-;'H NMR (DMSO, 300 MHz) 6 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.17 (m, IH), 4.35 (m, 2H), 7.17 (m, 2H), 7.69 (t, J 7.8, 1H), 7.86 (t, J 7.8, 1H), 8.04 (d, J 7.1, 1H), 8.23 (d, J 8.1, 1H), 8.65 (d, 16. 8, IH), 8.83 (t, J 6.8, 11-1), 9.60 (s, IH); Anal.
Calcd for C21H1sF4N20 + I HCI: C, 54.77; H, 3.80; N, 5.55. Found: C, 54.62; H, 3.57; N, 5.50.

Example 270 2-(5-isoquinolinyl)-N-r4-(trifluoromethyl)benzyl]butanamide The title compound was prepared using the procedure described in Example 222B
using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m!z (M+H)+; MS (ESI-) m!z 371 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 0.91 (t, J 7.5, 311), 1.91 (m. IH), 2.19 (m, 1H), 4.38 (m, 2H), 7.38 (d, J 8.5, 2H), 7.64 (d, J 8.5, 2H), 7.96 (t, J 7.8, 1H), 8.20 (d, 1 7.1, 1H), 8.39 (d, J 8.1, 1H), 8.72 (s, IM, 9.02 (t, J 6.8, 1H), 9.81 (s, 1H), 10.12 (br s, 11-1); Anal. Calcd for C21H19F3N2O: C, 67.73; H, 5.14; N, 7.52.
Found: C, 67.46;
H, 4.90; N, 7.90.

Example 271 (4brornobenzyl)-2-(5-isoquinolinyl)butanamide The title compound was prepared using the procedure described in Example 222B
using 4-bromobenzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 385, 383 (M+H)+; MS (ESI-) m/z 383, 381 (M-H)-;'H NMR (DMSO, 300 MHz) 6 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.19 (m, IB), 3.39 (m, IH), 4.22 (m, 2M, 7.13 (d, J 8.5, 2H), 7.44 (m, 3H), 7.57 (t, J 7.8, 1H), 8.00 (in, 1H), 8.21 (d, J 7.1, 111), 8.41 (d, J 8.1, 1H), 8.72 (s, 1I-1), 8.93 (t, J
6.8, 1H), 9.81 (s, 1H), 10.16 (br s, IH); Anal. Calcd for C20H19BrN2O: C, 62.67; H, 5.00.
Found: C, 62.52; H, 4.95.

Example 272 2-(5-isoguinolinyl)-N- {4-((trifluoromethyl)thiolbenzyl}butanamide The title compound was prepared using the procedure described in Example 222B
using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z (M+H)+; MS (ESI-) m/z 403 (M-H) 'H NMR (DMSO, 300 MHz) S 0.91 (t, J 7.5, 3H), 1.81 (m, 11.1), 2.21 (in, 1H), 3.39 (m, IM, 4.34 (m, 2H), 7.31 (in, 2H), 7.58 (m, 2H), 7.62 (d, J 7.8, 1H), 8.00 (m, 2H), 8.22 (d, J 7.1, 1H), 8.45 (m, 1H), 8.77 (m, 1H), 8.82 (m, 1H), 9.06 (t, J
6.8, 1H), 9.87 (s, 1H), 10.30 (br s, 1H); Anal. Calcd for C21H19F3N20S + 0.65 HCI: C, 58.91;
H, 4.63; N, 6.54. Found: C, 59.24; H, 4.30; N, 6.60.

Example 273 N-(4-(1-azepanyl)-3-fluorobenzyll-2-(5-iso uinolinyl)butanamide The title compound was prepared using the procedure described in Example 222B
using 4-(1-azepanyl)-3-fluorobenzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m!z (M+H)+; MS (ESI-) m/z 418 (M-H)-; 1H NMR (DMSO, 300 MHz) S 0.90 (t, J 7.5, 3H), 8 1.55 (m, 411), 1.76 (in, 6H), 2.20 (m, 1H), 3.34 (m, 5H), 4.18 (m, 2H), 6.81 (m, 1H), 7.62 (m, 1H), 8.00 (m, 2H), 8.27 (d, J 7.1, 1H), 8.45 (d, 1H), 8.77 (d, 1H), 8.82 (m, 1H), 9.90 (s, IH), 10.18 (br s, 1H); Anal. Calcd for C26H3oFN30 + 0.45 H2O: C, 73.02; H, 7.28.
Found: C, 73.05; H, 7.20.

Example 274 ethyl 2-(5-isoguinolinyl)-2-methylpropanoate The title compound was prepared using the procedure described in Example 248 using ethyl 2-(5-isoquinolinyl)propanoate instead of ethyl 5-isoquinolinylacetate.
MS (ESI+) m/z 244 (11M+H)+; MS (ESI-) m/z 242 (M-H)-; 'H NMR (DMSO, 300 MHz) rotalners 6 0.98, 1.08 (t, J 7.1, 3H), 1.67 (s, 6H), 4.58 (q, J 7.1, 1H), 7.53 (m, 1H), 7.82 (ni, 1H), 7.97 (m, IH), 8.05 (m, 111), S.55, 8.50 (d, J 6.1, 11-1), 9.33 (s, 1H).

Example 275 2-(5-isoquinolinyl)-2-methyl-N- f 4-f (trifluoromethyl)thiolbenzyl propanamide Example 275A
22- 5-isoquinolinyl)-2-methylpropanoic acid The title compound was prepared using the procedure described in Example 249A
using ethyl 2-(5-isoquinolinyl)-2-methylpropanoate instead of ethyl 2-(5-isoquinolinyl)propanoate.

Example 275B
2-(5-isoquinolinyl)-2-methyl-N- {4-((trifluoromethyl)thiolbenzyl}propanamide The title compound was prepared using the procedure described in Example 222B
using 4-[(trifluoromethyl)thio]benzylainme and 2-(5-isoquinolinyl)-2-methylpropanoic acid instead of 4-(trifluorometboxy)benzylamine and 5-isoquinolinyl acetic acid. MS
(ESI+) m/z 405 (M+H)+; NIS (ESI-) m/z 403 (M-H)-; 'H NMVIR (DMSO, 300 MHz) 6 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.52 (m, 2H), 7.82 (m, 111), 8.11 (m, 1H), 8.36 (d, J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd for C21H19F3N20S + 2 HCI: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.

Example 276 ethyl hydroxy(5-isoguinolinyl)acetate The title compound was prepared using the procedure described in Example 248 using (S) camphorsulfonyloxaziridine (2 equivalents) instead of methyl iodide.

Example 277 N-(4-tert-butylbenzyl)-2-hydroxy-2-(5-isoguinolinyl)acetamide Example 277A

hydroxy(5-isoguinolinyl)acetic acid The title compound was prepared using the procedure described in Example 249A
using ethyl hydroxy(5-isoquinolin yl)acetate instead of ethyl 2-(5-isoquinolinyl)propanoate.
MS (ESI+) m/z 204 (M+H)+; MS (ESI-) m/z 202 (M-H) 'H NMR (DMSO, 300 MHz) S 4.97 (d, J 3.1, 1H), 5.34 (d, J 3.3, 1H), 7.55 (m, 1H), 7.68 (d, J 7.5, 1H), 7.90 (d, J 8.1, IH), 8.21 (d, J 6.8, 1H), 8.40 (d, J 6.8, 1H), 9.22 (s, IH);
Anal. Calcd for C1!H9N03 + 1.9 HCI: C, 51.96; H, 5.00. Found: C, 51.89; H, 5.25.
Example 277B
N-(4-tert-butylbenzyl)-2-hydroxy-2-(5 -i soguinolinyl)acetamid e The title compound was prepared using the procedure described in Example 222B
using 4-(tert-butyl)benzylamine and hydroxy(5-isoquinolinyl)acetic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. [aI22D -47.2 (c 0.7, McOH); MS (ESI+) m/z 349 (M+H)+; MS (ESI-) m/z 347 (M-1-1)-; 'H NMR (DMSO, 300 MHz) S 1.26 (s, 9H), 3.69 (s, 1H), 4.27 (d, J 6.1, 2H), 5.62 (s, 111), 6.52 (br s, IH), 7.17 (d, J
8.1, 211), 7.29 (m, 3H), 7.67 (t, J 8.1, 1H), 7.82 (d, J 7.1, 1H), 8.10 (m, 2H), 8.44 (d, J 5.8, 111), 8.71 (t, J 6.1, 111), 9.30 (s, IH); Anal. Calcd for C72H24N202 + 0.25 H20: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.

Example 278 N-(4-tert-butyl-3-fluorobenzyl)-2-hydroxy-2-(5-isoguinolinyl)acetamide The title compound was prepared using the procedure described in Example 222B
using 3-fluoro-4-(trifluoromethyl)benzylannine and hydroxy(5-isoquinolinyl)acetic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS
(ESI+) m/z 379 (M+H)+; MS (ESI-) m/z 377 (M-H) 'H NMR (DMSO, 300 MHz) 6 4.37 (d, J 6.1, 211), 5.65 (d, 1H), 6.63 (d, 1H), 7.27 (m, 211), 7.29 (m, 3H), 7.67 (m, 2H), 7.82 (d, J 7.1, 1H), 8.15 (m, 2H), 8.44 (d, J 5.8, 1H), 8.96 (t, 1 6.1, 111), 9.30 (s, 1H); Anal. Calcd for C22H24N202 +
0.25 H2O: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.

Example 279 4-tert-butyl 1-ethyl 2-(5-isoguinolinyl)succinate The title compound was prepared using the procedure described in Example 248 using tert-butyl bromoacetate instead of methyl iodide. MS (ESI+) mlz 330 (M-I-II)4;
MS (ESI-) m/z 328 (M-H)-; 1H NMR (DMSO, 300 MHz) 6 1.06 (t, J 7.1, 3H), 1.30 (s, 911), 2.76 (dd, J1 16.7, J2 6.1, 1H), 3.14 (dd, J1 9.5, J2 6.1, 1H), 4.12 (q, J 7.1, 1H), 4.76 (dd, J1 16.7, J2 9.5, 1H), 7.70 (m, 2I1), 8.05 (m, 2I1), 8.58 (d, J 6.1, 1H), 9.34 (s, IH); Anal.
Calcd for C19I123N04 + 1 H2O: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.37; H, 6.91; N, 3.67.

Example 280 tert-butyl 4-f (4-tert-butylbenzyl)aminol-3-(5-isoguinolinyl)-4-oxobutanoate Example 280A
4-terl-butoxy-2-(5-isoguinolinyl)-4-oxobutanoic acid 4-Tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate (1.00 g, 3.04 mmol) and LiOH
(0.29 g) were stirred in McOH:H20 (3:1, 20 mL) at room temperature for 5 hours. The solution was poured into aqueous H3PO4 (0.1M, 30 mL) and extracted with CHC13:IPA (3:1, 30 mL x 3). The extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) mlz 302 (M+H)-"; MS
(ESI-) m/z 300 (N4-M-; 1H NMR (DMSO, 300 MHz) 6 1.28 (s, 91-1), 2.74 (dd, J1 16.7, J2 6.1, Ili), 3.10 (dd, J1 9.5, J2 6.1, 111), 4.68 (dd, J1 16.7, J2 9.5, 111), 7.70 (m, 2H), 8.05 (m, 21-1), 8.57 (d, J 6.1, IM, 9.33 (s, 1H); Anal. Calcd for C17H19NO4 + 1.25 H2O: C, 63.05; H, 6.69.
Found: C, 63.27; H, 6.95.

Example 280B
tert-butyl 4-[(4-tert-butylbenzyl)amino]-3 -(5-isoguinolinyl)-4-oxobutano ate The title compound was prepared using the procedure described in Example 222B
using 4-(tert-but),l)benzylamine and 4-tert-butoxy-2-(5-isoquinolinyl)-4-oxobutanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS
(ESI+) mlz 447 (N1+11)+; 'H NMR. (DMSO, 300 MHz) S 1.23 (s, 9H), 1.25 (s, 9H), 2.71 (dd, 1H), 3.02 (dd, 1H), 4.22 (m, 211), 4.71 (m, 1H), 6.57 (s, 111), 7.08 (d, 3 8.5, 2H), 7.24 (d, J 8.5, 2H), 7.67 (m, 1H), 7.78 (m, 1H), 8.03 (d, 3 7.8, 1H), 8.13 (d, J 7.1, 111), 8.55 (d, J 6.8, 1H), 8.63 (m, 1H), 9.31 (s, 1H); Anal. Calcd for C2sH34N203 + 1 CH3CN + 0.8 H2O: C, 71.77; H, 7.75;
N, 8.37. Found: C, 71.64; H, 7.38; N, 8.16.

Exam lp e 281 2-[(4-tert-butylbenzyl)amino-1-(5-isoguinohliyj)-2-oxoethyl acetate The product from Example 277B (100 mg, 0.287 mmol) and DMAP (59 mg, 0.480 uunol) in CH2CI2 (1 mL) was treated with acetic anhydride (38 [LL). After stirring for 30 minutes, the mixture was treated with CH2C12 (5 mL) and the phases separated.
The organic layer was washed with water (10 mL x 3), dried (Na2SO4), filtered, and the filtrate was concentrated to provide the title compound. MS (ESI+) m/z 391 (M+M+; MS (ESI-) m/z 389 (M-H)-;'H NMR (DMSO, 300 MHz) 6 1.25 (s, 911), 4.27 (dq, J, 14.9, J2 6.1, 2H), 6.56 (s, 1H), 7.09 (d, J 8.5, 2M, 7.28 (d, J 8.5, 2H), 7.72 (t, J 7.1, 1H), 7.90 (d, J
6.1, 1H), 8.07 (d, J
6.1, 1H), 8.17 (d, J 8.1, 1H), 8.53 (d, J 6. 1, 1H), 8.86 (t, J 6.1, 1H), 9.35 (s, 1H);Anal. Calcd for C24H26N203 + 0.8 H2O: C, 71.19; H, 6.87; N, 6.92. Found: C, 70.87; H, 6.47; N, 6.92.

Example 282 2-((4-tert-butylbenz)l)aminol-l-(5-isoguinolinyl)-2-oxoethyl methanesulfonate The product from Example 277B (1.00 g, 2.87 mmol) in pyridine (5 mL) was treated with methanesulfonyl chloride (5.56 L, 7.17 mmol). After stirring for 30 minutes, the mixture was concentrated under reduced pressure and diluted with CH2C12 (50 ML). The organic layer was washed with water (50 mL x 3), dried (Na2SO4), filtered, and the filtrate concentrated under reduce pressure to provide the title compound. MS (ESI+) m/z 427 (M+H)+; MS (ESI-) m/z 425 (M-H) 'H NMR (DMSO, 300 MHz) 5 1.27 (s, 9H), 2.37 (s, 3H), 4.27 (dq, J, 14.9, J2 6.1, 2H), 6.84 (s, 1H), 7.17 (d, J 8.5, 2H), 7.38 (d, 1 8.5, 2I-1), 8.07 (m, 2H), 8.37 (d, J S. 1, 11-1), 8.60 (d, J 6.1, 1H), 8.97 (m, 1H), 9.21 (t, J
6.1, 111), 9.96 (s, 1H).

Example 283 N-(4-tert-butylbenzyl)-2-(5-isoguinolinyl)-2-methoxyacetamide The product from Example 277B (100 mg, 0.287 mm.ol) in THE (2 mL) was treated with NaH (95%, 8.7 mg, 0.344 mmol). After stirring at room temperature for 20 minutes, the mixture was treated with methyl iodide (1.2 eq, 21.4 L) and stirred for 1 hour. The mixture was concentrated under reduced pressure and CH2C12 (10 mL) was added. The organic layer was washed with water (5 mL x 3), dried (Na2S04), filtered, and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 363 (M+H)+; MS

(ESI-) m/z 361 (M-H)-; 'H NMR (DMSO, 300 MHz) rotamers 5 1.25 (s, 9H), 3.32 (s, 3H), 4.27 (d, J 6.1, 2H), 5.37 (s, IH), 7.18 (d, J 8.5, 2H), 7.32 (d, J 8.5, 2H), 7.70 (t, J 7.1, 1H), 7.83 (d, J 6. 1, 1H), 8.07 (m, 2H), 8.43 (d, J 6.1, 1H), 8.80 (t, J 6.1, 1H), 9.35 (s, IH); Anal.
Caled for C23H26N202 + 0.3 H2O: C, 75.09; H, 7.29; N, 7.61. Found: C, 75.02;
IT, 7.34; N, 7.43.

Example 284 N 4-tent butylbenz 1~ }-2 chloro 2 (5-isoquinolinyl)acetamide The product from Example 182 (300 mg, 0.704 mmol) in toluene (10 mL) was treated with Bu.;NCI (458 mg, 1.408 mmol) and heated at 100 C for 12 hours. The mixture was concentrated under reduced pressure and diluted with CH2C12 (50 mL). The organic layer was washed with water (50 mL x 3), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. MS (ESI+) m/z 367 (M+H)+; MS (ESI-) m/z 365 (M-H)-; 1H
NMR
(DMSO, 300 MHz) S 1.26 (s, 911), 4.11 (d, J 5.1, 2H), 6.59 (s, 1H), 7.16 (d, J
8.1, 211), 7.36 (d, J 8.1, 2H), 7.97 (d, J 8.1, 2H), 8.30 (d, J 7.5, 1H), 8.48 (d, J 8.1, IH), 8.56 (d, J 6.8, IH), 8.73 (d, J 6.8, 1H), 8.97 (m, 111), 9.18 (t, J 6.1, 1H), 9.81 (s, 1H); Anal.
Calcd for C22H23C1N20 + I HC1 + 1.5 CH3OH: C, 62.53; H, 6.70; N, 6.21. Found: C, 62.75;
H, 6.87; N, 6.11.

Example 285 N-5 -i sog uinolinyl-3 - [4-(trifluoromethyl )phenyl ] acry l amid e 5-Aminoisoquinoline (0.50 g, 3.47 mmol) and 3-[4-(trifluoromethyl)phenyl]acrylic acid (3.47 inmol) were combined in a sealed tube and heated at 175 C for 16 hours with stirring. The mixture was cooled to room temperature, diluted with MeOH, transferred to a flask, and concentrated under reduced pressure. The residue was triturated with ethyl acetate and filtered to provide the title compound. MS (ESI+) m/z 343 (M+H)+; MS (EST-) m/z 341 (M-H)-; 'H NMR (DMSO, 300 MHz) rotamers 8 6.68 (d, J 15.9, 1H), 7.29 (d, J
15.9, 1H), 7.60 (d, J 15.9, 1H), 7.80 (m, 1H), 8.25 (d, J 6.8, IH), 8.57 (d, J 5.8, 1H), 9.35 (s, IH), 10.36 (s, 1H); Anal. Calcd for C19H13F3N20 + 2 HCI + 0.3 H2O: C, 54.25; H, 3.74; N, 6.66. Found:
C, 53.90; H, 3.94; N, 7.20.

Example 286 i-4-3-isoguinoiinyt-3-[3-(tritluoromethyl)phM llacrylamide The title compound was prepared using the procedure described in Example 285 using 3-[3-(trifluoromethyl)phenyl]acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid.
MS (ESI+) m/z 343 (M+H)+; MS (ESI-) m/z 341 (M-H)-; 'H NMR (DMSO, 300 MHz) rotamers S 6.72 (d, J 15.9, 1H), 6.87 (d, J 7.4, 1H), 7.23 (d, J 8.1, 1H), 7.36 (t, J 7.8, IH), 7.70 (m, 2H), 7.93 (d, J 6.1, 1H), 8.10 (m, 2H), 8.35 (d, J 5.8, 1H), 9.09 (s, IH); Anal. Calcd for C19H13F3N2O + 2.15 HCI: C, 54.24; H, 3.63; N, 6.66. Found: C, 53.96; H, 3.93; N, 6.93.
Example 287 3-(4-isopropylphenyl)-N-5-isoguinolinylacrylarnide The title compound was prepared using the procedure described in Example 285 using 3-(4-isopropylphenyl)aciylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid. MS
(ESI+) m/z 317 (M+H)+; MS (ESI-) m/z 315 (M-H) 'H NMR (DMSO, 300 MHz) S 1.24 (d, J 6.8, 3H), 2.94 (sept, J 6.8, 1H), 7.10 (d, J 15.6, 11-1), 7.35 (d, J 7.4, 2H), 7.61 (d, J 8.1, 211), 7.63 (d, J 15.6, IH), 7.84 (t, J 7.8, 1H), 8.12 (d, J 7.8, 1H), 8.26 (d, J
6.4, 1H), 8.35 (d, J 7.1, 1H), 8.64 (d, J 6.8, 111), 9.56 (s, 1H), 10.35 (s, 1H); Anal. Calcd for C21H20N20 + 0.35 TFA:
C, 73.15; H, 5.76; N, 7.86. Found: C, 73.02; H, 5.50; N, 7.88.

Example 288 N-5-isoguinolinyl-2-phenylcyclopropanecarboxamide The title compound was prepared using the procedure described in Example 285 using 2-phenylcyclopropanecarboxylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid.
MS (ESI+) mJz 289 (M H)+; MS (ESI-) m/z 287 (M-H) 1H NMR (DMSO, 300 MHz) 8 1.46 (in, 1H), 1.56 (m, IH), 2.46 (m, 2H), 7.24 (m, 3H), 7.32 (m, 2H), 7.82 (t, J 7.8, lH), 8.10 (d, J 7.8, 1H), 8.28 (d, 7 6.4, 1H), 8.62 (d, J 6.8, 1H), 9.58 (s, 1H), 10.46 (s, lH); Anal.
Calcd for C19H16N2O + 0.65 TFA: C, 67.27; H, 4.63; N, 7.73. Found: C, 67.27;
H, 4.31; N, 7.52.

Example 289 3-(3,4-dichlorophenyl)-N-5-isoguinolinylacrylamide The title compound was prepared using the procedure described in Example 285 using 3-(3,4-dichlorophenyl)acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid. MS

(ESI+) in/z 344 (M+H)*; MS (ESI-) m/7- 342 (M-H)";'H NMR (DMSO, 300 MHz) 6 7.20 (d, 3 15.6, 1H), 7.67 (rn, 3H), 7.84 (d, J 15.6, 111), 7.97 (d, J 1.7, IH), 8.10 (d, J 7.8, IH), 8.22 (d, J 6.4, 111), 8.35 (d, J 7.1, 1H), 8.64 (d, J 6.8, 1H), 9.53 (s, 1H), 10.37 (s, 1H); Anal. Calcd for Ci8H12C12N2O + 0.75 TFA: C, 54.63; H, 3.00; N, 6.53. Found: C, 54.43; H, 2.92;
N, 6.39.

Example 290 3-(1,1'-biphenyl-4-yl)-N-5-isoguinoluiylacrylamide The title compound was prepared using the procedure described in Example 285 using 3-(1,1'-biphenyl-4-yl)acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid. MS
(ESI+) m/z 351 (M+H)+; MS (ESI-) m/z 349 (M-H) ; 'H NMR (DMSO, 300 MBz) S 7.21 (d, J 15.6, 111), 7.39-7.79 (m, 10H), 7.9.7 (d, J 7.8, 1H), 8.08 (d, J 6.4, 11-1), 8.29 (d, J 7.1, 1H), 8.58 (d, J 6.8, 1H), 9.34 (s, IH); Anal. Calcd for C24H,8N2O + 0.85 HCI: C, 75.58; H, 4.98.
Found: C, 75.69; H, 4.69.

Example 291 3-(3-bromo-4-fluorophhenyl)-N-5-isoguinolinylacrylamide The title compound was prepared using the procedure described in Example 285 using 3-(3-bromo-4-fluorophenyl)acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid.
MS (ESI+) m/z 374, 372 (M+H)}; MS (ESI-) m/z 372, 370 (M-H)-; 'H N (DMSO, 300 MHz) 6 7.14 (d, J 15.6, 1H), 7.50 (t, J 8.8, 1H), 7.65 (d, J 15.6, 1H), 7.76 (m, 1H), 7.83 (t, J
7.8, 111), 8.05 (dd, 3, 6.8, J2 2. 1, 111), 8.11 (d, J 7.8, IH), 8.24 (d, J
6.4, 1H), 8.36 (d, J 7.1, 1H), 8.64 (d, J 6.8, 1H), 9.55 (s, 1H), 10.35 (s, 1H); Anal. Calcd for C18Hl2BrFN2O + 1 TFA:
C, 49.51; H, 2.70; N, 5.77. Found: C, 49.78; H, 2.71; N, 5.768.

Example 292 3 -(4-tert-butyllphenyl)-N-5 -isoguino linyl acrylami de The title compound was prepared using the procedure described in Example 285 using 3-(4-tert-butylphenyl)acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylie acid. MS
(ESI+) m/z 331 (M+H)+; MS (ESI-) m/z 329 (M-H)'; 'H NMR (DMSO, 300 MHz) 8 1.31 (s, 9H), 7.10 (d, J 15.6, 1H), 7.51 (d, J 8.5,2H), 7.62 (d, J 8.5,2H), 7.67 (d, J
15.6, 1H), 7.86 (t, J 8.2, 1H), 8.14 (d, J 6.1, IH), 8.31 (d, J 8.2, 1H), 8.40 (d, J 6.1, 1H), 8.66 (d, J 6.1, 1H), 9.60 (s, 1H), 10.39 (s, 1H); Anal. Calcd for C22H22N20 + I TFA: C, 64.86; H, 5.22;
N, 6.30.
Found: C, 64.54; H, 5.13; N, 6.18.

Example 293 3-[3-fluoro-4-(trifluoromethyl)phenyll-N-5-isoguinolinylacrylamide The title compound was prepared using the procedure described in Example 285 using 3-[3-fluoro-4-(trrifluoromethyl)phenyl]acrylic acid instead of 3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 361 (M+H)+; MS (ESI-) m/z 359 (M-H)-;'H NMR (DMSO, 300 MHz) S 7.30 (d, J 15.6, 1H), 7.72-7.85 (m, 4H), 7.91 (t, J 8.2, 1H), 8.13 (d, J 6. 1, 1H), 8.24 (d, J 8.2, 1H), 8.35 (d, J 6. 1, 1H), 8.65 (d, J 6.1, 111), 9.56 (s, 1H), 10.50 (s, 1H); Anal. Calcd for Cj9Hi2F4N2O + 0.8 TFA: C, 54.80; H, 2.86;
N, 6.20.
Found: C, 54.59; H, 2.82; N, 6.06.

Example 294 N-(8-bromo-5-isoguinolinyl)-N'-(2,4-dichlorobenzyl)ure Example 294A
8-bromo-5-isoguinolinamine 6, 8-dbromo-5-i soguinolinamine 5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1 g, 113 mmol) were combined and heated at 80 C in a 3-necked flask equipped with a dropping funnel, stirrer bar, needle and sintered glass tube. The mixture was treated with bromine (3.04 g, 19.05 mmol) via the sintered glass funnel dropwise. After stirring at 80 C for 2 hours, the suspension was treated with crushed ice in small portions and the solution was basified with concentrated sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (4 x 100 mL). The organic layers were combined, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexanes:ethyl acetate, 3:1) to provide the separate title compounds.
Monobromo: MS (ESI+) m/z 225 (M+H)+; MS (ESI-) m/z 223 (M-H)-;
'H NMR (CDC13, 300 MHz) 8 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d, J 5.8, 111), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H); Dibromo: MS
(ESI+) m/z 303 (M+H)+; MS (ESI-) m/z 301 (M-D-; 'H NMR (DMSO, 300 MHz) S 6.41 (hr s, 2H), 7.92 (s, 1H), 8.18 (d, J 6.1, 1H), 8.59 (d, J 6.1, 1H), 9.30 (s, 1H).

Example 294B
N-(8-bromo-5-isoquinolinyl) N' (2,4-dichlorobenzyl)urea 8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 niL, 1:4) was treated with 2,4-dichloro-l-(isocyanatomethyl)benzene (108 mg, 0.52 mrnol) in THE (0.5 niL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to provide the title compound. MS (ESI+) m/z 426 (M+H)+; MS (ESI-) mlz 424 (M-M 'H NMR (DMSO, 300 MHz) 3 4.42 (d, 5.8, 21=1), 7.22 (t, J 5.8, 11-1), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1I-1), 9.44 (s, 1H); Anal. Calcd for C17H12BrC12N3O.HC1 + 0.25EtOH:
C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84.

Example 295 N-(8-bromo-5-isoquinolinyl)-N'-(4-fluorob enzyl)urea The title compound was prepaid using the procedure described in Example 294B
using 1-fluoro-4-(isocyanatomethyl)benzene instead of2,4-dichloro-l-(isocyanatomethyl)benzene. MS (ESI+) m/z 376 (M+H)+; MS (ESI-) .m/z 374 (M-H) 'H NMR (DMSO, 300 MHz) S 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, IH), 8.88 (s, IH), 9.44 (s, 1H); Anal. Calcd for Ci7H13BrFN3O: C, 54.56; H, 3.50; N, 11.23.
Found: C, 54.61;
H, 3.35; N, 11.14.

Example 296 N-(8-bromo-5-isoquinolinyl)-N'-(3-fluorobenzyl)ure The title compound was prepard using the procedure described in Example 294B
using 1-fluoro-4-(isocyanatomethyl)benzene instead of 2,4-dichloro-l-(isocyaiiatolnethyl)benzene. MS (ESI+) m/z 376 (M+H){; MS (ESI-) m/z 374 (M-H);'H
NMR (DMSO, 300 MHz) S 4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 211), 7.40 (m, 1H), 7.91 (d, J 8.5, IM, 8.01 (d, J 6.1, 1H), 8,23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.93 (s, 11f), 9.44 (s, 11I); Anal. Calcd for C H13BrFN3O: C, 54.56; H, 3.50; N, 11.23. Found: C, 54.64; H, 3.33;
N, 11.19.

Example 297 Nj1 -(4-chlorophenyl)-1-methylethyll-N'-5-isoguinolinyhu-ea Example 297A
2-(4-chlorophenyl)-2-methylpropanoyl chloride 2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (5 mL) and thionyl chloride (5.008, 3.1 mL) was heated at 80 C for 2 hours. The mixture was cooled and concentrated under reduced pressure to provide the title compound.

Example 297B
1-chloro-4-(1-isocyanato- I -methylethyl)benzene The product from Example 297A (4.00 g, 19.4 mmol) in acetone (9 mL) at 0 C ws treated with sodium azide (1.27 g) in water (9 mL) dropwise over 15 minutes.
after stirring for 30 minutes at 0 C, the mixture was extracted with toluene (20 mL). The toluene solution was dried over MgSO4, filtered, and the filtrate was heated to reflux for 1 hour. The cooled solution was concentrated under reduced pressure to provide the title compound.
Example 297C
Nil -(4-chlorophenyl)-1-methylethyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 60F
using 1-chloro-4-(1-isocyanato-l-methylethyl)benzene and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. MS (ESI+) m/z 355 (M+H)}; MS (ESt) m/z 353 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 1.63 (s, 6H), 7.23 (s, 1H), 7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8, 2H), 7.73 (t, J 9.2, 1H), 7.93 (d, J
8.1, 1H), 8.25 (d, J
6.4, 1H), 8.39 (d, J 8.1, 1H), 8.67 (d, 3 6.4, 1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal. Calcd for C19H18CIN30.HCI + 0.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82; H, 5.23; N, 10.45.

Example 298 N(4-bromo-3-methylbenzyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 4-bromo-3-methylbenzylamine instead of4-cyanobenzyl alcohol. MS (EST+) m/z 372, 370 (M+H)+; MS (ESI-) m/z 370, 368 (M-IHI) 1H NMR (DMSO, 300 MHz) 6 2.34 (s, 3H), 4.31 (s, 2H), 4.09 (s, 21-1), 7.13 (d, J 7.2, 2H), 7.34 (s, 11I), 7.55 (m, 2H), 7.82 (d, J 7.9, 11-1), 7.90 (m, 1H), 8.09 (d, IH), 8.65 (m, 2H), 8.80 (d, J 6.4, 1H), 9.68 (s, 1H), 9.79 (s, 1H); Anal.
Calcd for C18H16BrN3O + 1.05 HCI: C, 52.66; H, 4.86; N, 10.24. Found: C, 53.00; H, 4.27;
N, 10.37.

Example 299 N-[2-fluoro-4-(trifluoromethyl)benzyl]-N'-5-i soquinolinylurea Example 299A
2-fluoro-4-(trifluoromethyl)benzylamine The title compound was prepared using the procedure described in Example 172B
using 2-fluoro-4-(trifluoromethyl)benzonitrile instead of 4-(4-morpholinyl)benzonitrile. MS
(ESI+) m/z 194 (M+H)+; MS (ESI-) m/z 192 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 3.97 (s, 2H), 7.30 (m, 1H), 7.46 m, 2H).

Example 299B
N-f 2-fluoro-4-(trifluoromethyl)benzyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61..B
using 2-fluoro-4-(trifluoromethyl)benzylamine instead of 4-cyanobenzyl alcohol. AIS (ESI+) m/z 364 (M+H)+; MS (ESI-) m/z 362 (M-H)-; 1H NMR (DMSO, 300 MHz) S 4.51 (d, J
5.8, 2H), 7.65 (m, 4H), 7.90 (t, J 8.1, 114), 8.09 (d, J 7.8, 1H), 8.59 (d, J 7.8, 1H), 8.71 (s, 2H), 9.66 (s, 1H), 9.76 (s, 111); Anal. Calcd for C18H13F4N3O + 1 HC1: C, 54.08; H, 3.53; N, 10.51.
Found: C, 54.40; H, 3.60; N, 10.61.

Example 300 N-(4-bromobenzyl)-N'-(3-hydroxy-5-isoguinolinyl)urea Example 300A
5-nitro-3-isoguinolinol 3-Hydroxyisoquinoline (1.09 g, 7.53 mmol) in concentrated H2S04 (20 mL) at 0 C
was treated with NaNO3 (0.71 g, 8.34 mmol) in concentrated H2SO4 (5 mL) dropwise over 15 minutes. After stirring for 90 minutes, the mixture was allowed to warn to room temperature, stir for 2 hours, poured over an ice-NH4C1 mixture, and the pH
was adjusted to 7-8 with 50% NaOH solution. The mixture was filtered and the filter cake dried to provide the title compound. Structure analysis determined a 2:1 mixture of the 5-nitro and 7-nitro isomers which were not separated. MS (ESI+) mlz 191 (M+H)+; MS (ESI-) m/z 189 (M-H
'iT NMR (DMSO, 300 MHz) 6 4.60 (s, 1H), 7.48 (t, J 8.0, IH), 7.57 (s, 1H), 8.42 (d, 1 8.0, 1H), 8.57 (d, J 7.7, lii), 9.19 (s, 1H).

Example 300B
5-nitro-3-isoguinolinyl acetate 5-Nitro-3-isoquinolinol (3.40 g, 17.9 nunol) in acetic anhydride (40 mL) was treated with acetic acid (5 n-LL) and pyridine (5 mL) and heated at 120 C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. MS
(ESI+) m/z 233 (M+H)+; MS (ESI-) m/z 231 (M-H)-; 'H NMR (DMSO, 300 MHz) isomers S 2.39 (s, 3H), 7.88 (m, 1H), 8.27 (m, 1H), 8.50 (m, IH), 8.65, 8.74 (d, J 7.8, 1H), 9.47, 9.55 (s, 1H).

Example 300C
5-amino-3-isoquinolinyl acetate 5-Nitro-3-isoquinolinyl acetate (50 mg, 0.21 mmol) in 1,4-dioxane (20 rnL) was treated with RancyTM-nickel powder (85 mg) and exposed to a hydrogen atmosphere via a balloon for 16 hours. The mixture was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to provide the title compound which was used without further purification.

Example 3001) N-(4-bromobenzyl)-N'-(3-hydroxy-5-isoquinolinyl urea 5-Amino-3-isoquinolinyl acetate in toluene:THF (5:1, 5 m.L) was treated with 1-bromo-4-(isocyanatomethyl)benzene (105 mg). After stirring for 1 hour, the mixture was concentrated under reduced pressure and the residue dissolved in MeOH (20 mL) and treated with K2C03 (4 eq) and stirred for 16 hours. The mixture was concentrated under reduced pressure and partitioned between CH2C12 and water. The aqueous phase was separated and the pH was adjusted to approximately 6 with HCI. The acidified solution was filtered, and the filter cake was dried. The solid was purified by reverse-phase chromatography (using TFA as eluent) to provide the title compound. MS (ESI+) m/z 374, 372 (M+1-1)+;
MS (ESI-) m/z 372, 370 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 4.33 (d, J 5.8, 2H), 7.06 (m, 1H), 7.29 (m, 3H), 7.57 (m, 31-1), 8.07 (d, J 7.8, 1H), 8.48 (s, lH), 8.80 (s, 1H), 8.87 (s, 1H); Anal.
Calcd for C17H14BrN3O2 + 0.2 TFA: C, 53.08; H, 3.42; N, 10.43. Found: C, 52.91; H, 3.62;
N, 10.43.

Example 301 N-5-isoquinolinyl-N- t ~5-(trifluoromethyl)-2-pyridinyl}methyl} urea Example 301A
5-(trifluoromethyl)-2-pyridinecarbonitrile Copper (1) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00 g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180 C for 2 hours, cooled, and poured into NH4OH (3M). The mixture was then extracted with ethyl acetate (3 x 500 mL), washed with water (1 x 200 mL), dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (DMSO, 300 MHz) 6 8.22 (m, 11-1), 8.42 (m, 1I.1), 9.01 (s, 1H).

Example 301B
f 5-(trifluoromethyl)-2-pyridinyl}methylaniine The title compound was prepared using the procedure described in Example 172B
using 5-(trifluoromethyl)-2-pyridinecarbonitrile instead of 4-(4-morpholinyl)benzonitrile.
Example 301C
N-5-isoguinolinyl-N'- f L5-(trifluoromethyl)-2-pyridinyl]methyl}urea The title compound was prepared using the procedure described in Example 61B
using {5-(trifluoromethyl)-2-pyridinyl]methylamine instead of 4-cyanobenzyl alcohol. 1H
NMR (DMSO, 300 MHz) S 4.51 (m, 2H), 7.97 (m, 2H), 8.12 (m, 1H), 8.47 (d, J
7.8, 1H), 8.72 (m, 3H), 9.13 (d, J 6.8, 1H), 9.78 (m, 2H), 10.80 (s, I H); Anal. Calcd for C]7H,3F3N4O +
0.8 HCI + 0.7 CH3OH: C, 53.43; H, 4.20; N, 14.08. Found: C, 53.41; H, 4.31; N, 14.11.
Example 302 N-[3-bromo-4-(trifluoromethyl)benzyl]-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 3-bromo-4-(trifluoromethyl)benzylamine instead of 4-cyanobenzyl alcohol.
MS (ESI+) m/z 426, 424 (M+H)+; MS (EST-) m/z 424, 422 (M-Td)-; 'H NMR (DMSO, 300 MHz) S
4.46 (d, J 5.8, 2H), 7.26 (t, J 6.1, IH), 7.56 (d, J 8.8, 1H), 7.90 (m, 2H), 7.97 (d, J 8.1, 1H), 8.21 (d, J 6.4, 1H), 8.39 (d, J 8.8, 1H), 8.64 (d, f 6.4, 1H), 9.08 (s, IH), 9.57 (s, 1H); Anal. Calcd for C,5H13BrF3N3O + 0.9 TFA: C, 45.14; H, 2.66; N, 7.98. Found: C, 45.18; H, 2.64; N, 7.86.

Example 303 N f2,4-bis(trifluoromethyl)benzyl)-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 2,4-bis(trifluoromethyl)benzylamine instead of 4-cyanobenzyl alcohol. MS
(ESI+) m/z 414 (M+H)+; MS (ESI-) m/z 412 (M-H)-; 'H NMR (DMSO, 300 MHz) rotamers b 4.63 (d, J
5.8,2M, 7.70-8.20 (m, 6H), 8.60 (m, 3H), 9.60 (m, 2H); Anal. Calcd for C19H13F6N30 + I
HCI: C, 50.74; H, 3.14; N, 9.34. Found: C, 50.88; H, 3.08; N, 9.10.

Example 304 N-(2,3-difluoro-4- trifluoromethyl)benzyl]-N-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 2,3-difluoro-4-(trifluoromethyl)benzylamine instead of 4-cyanobenzyl alcohol. MS
(ESI+) m/z 382 (M+H)+; MS (ESI-) m/z 380 (M-H)-; 'H NMR (DMSO, 300 MHz) rotamers S 4.55 (d, J 5.8,2H), 7.45 (m, 1H), 7.63 (t, J 6.1, 113), 7.82 (m, 1H), 8.05(d, J 8.1, 1H), 8.56 (m, 2H), 8.69 (d, J 6.4, IH), 9.51 (s, 1H), 9.70 (s, IR); Anal. Calcd for C15H12F5N3O + 0.8 HCl: C, 52.67; H, 3.14; N, 10.24. Found: C, 52.53; H, 3.38; N, 10.22.

Example 305 N-[2-chloro-4-(trifluoromethyl)benzyl]-N-S-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 2-chloro-4-(trifluoromethyl)benzylarnine instead of 4-cyanobenzyl alcohol. MS (ESI+) m/z 380 (M+H)+; MS (ESI-) m/z 378 (M-H) 1H NMR (DMSO, 300 MHz) S 4.53 (d, J
5.8, 2H), 7.69 (m, 2H), 7.87 (m, 1H), 8.06 (d, J 8.1, 1H), 8.56 (d, J 7.8, IH), 8.63 (d, J 6.8, IH), 8.70 (d, J 6.8, 1H), 9.59 (s, 1H), 9.72 (s, 1H); Anal. Caled for C18H13CIF3N3O
+ 1.3 HCI: C, 50.61; H, 3.37; N, 9.84. Found: C, 50.60; H, 3.42; N, 9.61.

Example 306 N-S-isoquinolinyl-N'-f 1-methyl-l-[4-(trifluorometlyl)phenyl eth 1 urea The title compound was prepared using the procedure described in Example 61B
using 2-[4-(trifluoromethy])phenyl]-2-propanamine instead of 4-cyanobenzyl alcohol. MS
(ESI+) m/z 374 (M+H)+; MS (ESI-) miz 372 (M-H)-; 'H NMR (DMSO, 300 MHz) 6 1.67 (s, 6H), 7.67 (s, 4H), 7.82 (t, J 8.1, 1H), 8.02 (d, J 8.1, IH), 8.54 (d, J 7.8, 1H), 8.72 (d, J 6.8, IH), 8.87 (d, J 6.8, 1H), 9.65 (s, 1H), 9.77 (s, IH); Anal. Calcd for C20H18F3N30 + 1 HCI: C, 58.61; H, 4.67. Found: C, 58.62; H, 4.65.

Example 307 N-[2-(4-bromophenyl)-2-hydroxyethyll-N'-5-isoguinolinylurea The title compound was prepared using the procedure described in Example 61B
using 2-amino-l-(4-bromophenyl)ethanol instead of 4-cyanobenzyl alcohol.
MS (ESI+) m/z 388, 386 (M+H)+; MS (ESI-) m/z 386, 384(M-H)-;
1H NMR (DMSO, 300 MHz) rotamers 6 3.27 (in, 1H), 3.42 (m, 1Ii), 4.70 (in, 111), 6.82 (t, J
5.0, 2H), 7.38 (d, J 8.5, lH), 7.56 (d, J 8.5, 1H), 7.81 (t, 3 7.8, IH), 7.98 (d, 3 8.7, 11-1), 8.29 (d, J 7.5, I H), 8.50 (d, J 5.9, I W, 8.67 (d, J 6.4, Ili), 9.01 (s, 111), 9.64 (s, I H);
Anal. Caled for C1sH16BrN3O2 + 2.35 TFA: C, 41.68; H, 2.83; N, 6.42. Found: C, 41.69; H, 2.86; N, 6.43.

Example 309 methyl 4-(f [(1-naphthyl.methyl)aminolcarbonyl}amino)-1H-indazole-l-carboxylate Example 309A
4-nitro- I H-indazole 2-Methyl-3-rv.troaniline (20 g) in acetic acid (-200 mL) was treated with NaNO2 (20 g) in water (50 mL) at 4 C (mechanical stirring). The reaction mixture was allowed to warm to room temperature and stir overnight. The solvent was removed under reduced pressure.
The residue was treated with water (700 mL) and the mixture was filtered. The solid was dried at 45 C in a vacuum oven overnight to provide the title compound. 'H
NMR (DMSO-d6) 6 13.91 (s, 1 H), 8.55 (s, 1 H), 8.18 (d, 1 H), 8.10 (d, I H), 7.61 (dd, 1 H); MS (ESI) m/z 164 (M+H) Example 309B
methyl 4-nitro-lH-indazole- l -carboxylate NaH (0.3 g, 12.5 mmol) in DMF (5 mL) was treated with 4-nitro-IH-indazole (1.33 g, 10 mmol) at 0 C. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. The mixture was treated with methyl chloroformate (0.9 mL) and stirred at room temperature for 3 hours. The mixture was treated with water and filtered to provide the title compound as a solid. 'H NMR (300 MHz, DMSO-d6) 6 4.1 9 (s, 3H), 7.9 (t, 1H), 8.38 (d, I H), 8.62 (d, 1H), 8.85 (s, 1H).

Example 309C
methyl 4-amino-IH-indazole-l -carboxylate Methyl 4-nitro-IH-indazole-l-carboxylate 1.66 g, 7.5 mmol) and 10% PdIC were combined in ethanol (20 mL) and exposed to a hydrogen atmosphere. The reaction mixture was heated at 80 C for 20 minutes, allowed to cool to room temperature, and filtered through Celite. The filtrate was evaporated to provide title compound. 'H NMR (300 MHz, DMSO-d6) S 6.1 (s, 2H), 6.41 (dd, 1IT), 7.21 (m, 2H), 8.42 (s, 1H).

Example 309D
methyl 4-({ f.(2,5-dioxo-1 -pyrrolidinyl)oxylearbonyll amino)-1 H-indazole-l -carboxylate Methyl 4-amino-lH-indazole-l-carboxylate (1.9 g, 10 mmol) and 1-({[(2,5-dioxo-l-pyrrolidinyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (2.8 g, 11 mmol) were combined in acetonitrile (100 mL), stirred for 48 hours at ambient temperature, and filtered. The filter cake was washed with acetonitrile (10 mL) and dried under reduced pressure at ambient temperature to provide the title compound.

.u, Example 309E
methyl 4-({ [(1-naphthylmethyl)aminolcarbonyl} amino)-1H-indazole-l-carboxylate 1-Naphthylmethylamine (2.1 mmol) and diisopropylethylamine (2 mrnol, 0.26 g) were combined in DMF (6 mL) and treated with methyl 4-({[(2,5-dioxo-l-pyrrolidinyl)oxy]carbonyl}amino)-IH-indazole-l-carboxylate (6.6 g, 2 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was diluted with water (6 ml) and filtered. The filter cake was washed with water:acetoniirile (1:1) and dried to provide the title compound. 'H NMR (DMSO-d6) S 4.02 (s, 3 H); 4.81 (d, 2 H))- 6.85 (in, 1 H); 7.42-7.64 (in, 5 H); 7.67 (d, 1 H); 7.87 (in, 2 H); 7.97 (d, 1 H); 8.15 (d, 1 H); 8.38 (s, 1 H); 8.99 (s, 1 H).

Example 310 methyl 4-({ [(l, l'-biphenyl-3-yllmethyl)aminolcarbonyl} amino)-1 H-indazole-l -carboxylate The title compound was prepared using the procedure described in Example 309E
except using 1,1'-biphenyl-3-ylmethylamine instead of 1-naphthylmethylamine.
'H NMR
(DMSO-D6) 6 4.02 (S, 3 H); 4.43 (D, 2 H); 6.89 (M, 1 H); 7.36 (M, 2 H); 7.42-7.51 (M, 4 H); 7.56 (1t4, 1 H), 7.60-7.72 (M, 4 H); 7.82 (M, I H); 8.42 (S, 1 H); 9.04 (S, 1 H).

Example 311 methyl 4-({[(2-chlorobenzyl)aminolcarbonyl} amino)-1H-indazole- l-carboxylate The title compound was prepared using the procedure described in Example 309E
except using 2-chlorobenzylamine instead of 1-naphthylmethylamine. 1H NMR
(DMSO-D6) 6 4.02 (S, 3 H); 4.43 (D, 2 H); 6.89 (M, 1 H); 7.25-7.39 (1\4, 2 H); 7.41-7.52 (M, 3 H); 7.68 (D, 1 H); 7.81 (D, 1 H); 8.44 (S, 1 H); 9.14 (S, 1 H).

methyl 4-[({ [2-fluoro- 5-(t dfluoromethyl)b enzyll amino } carbonyl)aminol- l H-indazol e- l -carboxylate The title compound was prepared using the procedure described in Example 309E
except using 2-chloro-5-(trifluoromethyl)benzylamine instead of 1-naphthylmethylaznine.'H

NMR (6, DMSO-d6) 6 4.02 (s, 3 H); 4.471 (d, 2 H); 6.97 (m, 1 H); 7.41-7.52 (m, 2 H); 7.69 (d, 1 H); 7.71-7.80 (in, 3 H); 7.97 (d, 1 H); 8.42 (s, I H); 9.14 (s, I H).

Example 313 N-1 H-indazol-4-yl-N'-(1-naphthylmethyl)urea Methyl 4-( {{(l -naphthyhnethy1)aminocarbony1} amino)-1 H-indazole-l-carboxylate in methanol was treated with 5M sodium hydroxide (8 equivalents) (prepared by dissolution of 1 gram of sodium hydroxide in 20 mL of methanol). After stirring for 30 minutes, the mixture was diluted with water (10 mL) and filtered. The filter cake was washed with water (10 mL), water:niethanol (1:1), and dried under reduced pressure to provide the title compound. MS (M+H)+ 317.

Example 314 N-(1,1'-biphenyl-3-yhnethyl)-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 313 except using methyl 4-({[(1,1'-biphenyl-3-yhnethyl)amino]carbonyl} amino)-1H-indazole-l-carboxylate instead of methyl 4-({[(1-naphthylmethyl)amino]carbonyl} amino)-1H-indazole-1-carboxylate. MS (M+H)+ 343.

Example 315 N-(2-chlorobenzyl)-M-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 313 except using methyl 4-( { [(2-chlorobenzyl)amino]carbonyl} amino)-1 H-indazole-l -carboxylate instead of methyl 4-(([(1-naphthyhnethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate. MS (M+H)+ 301.

Example 316 N-[2-fluoro-5-(trifluoromethyl)benzyll-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 313 except using methyl 4-[({[2-fluoro-5-(trifluoromethyl)benzyl]amino}
carbonyl)amino]-1H-indazole-1-carboxylate instead of methyl 4-({[(1-naphthylmethyl)amino]carbonyl}amino)-IH-indazole-l-carboxylate. MS (M+H)+354.

Example 317 N- 1 H-indazol-4-yl-N'-(3 -phenylpropyl)urea Methyl 4-amino-IH-indazole-l-carboxylate (0.46 g, 2.4 mmol) and phosgene (20%
in toluene, 2.4 ml, 4.8 mmol) were combined in toluene (80 nil) and heated at reflux for 3 hours.
The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was treated with diethyl ether (80 ml) and triethyl amine (2 ml) and then filtered. The filtrate was treated with 3-phenylpropylamine (2.4 mrnol, 324 mg) and stirred for 16 hours at ambient temperature. The solvent was concentrated to half volume under reduced pressure and filtered. The filter cake was washed with diethyl ether:hexanes (1:1). The obtained solid in methanol (10 ml) was treated with a 5M solution of sodium hydroxide in methanol (4 ml, 20 mmol) and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (2 X 25 mL). The organics were combined, washed with water (2 X 25m1), brine, dried over Mg2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was treated with ethanolic HCI to provide the title compound as the HCI salt. 1H NMR (DMSO-d6) S 8.81 (s, 1H), 8.18 (s, 1H), 7.62 (d, 1H), 7.22 (m, 611), 7.03 (d, 1H), 3.17 (t, 2H), 2.62 (t, 2H), 1.78 (m, 2H); MS (ESI) m/z 295 (M+H)+.

Example 318 N- f 2-(2,4-dimethylphenyl)ethyll-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 2-(2,4-dimethylphenyl)ethylamine instead of 3-phenylpropylamine.

(DMSO-d6) S 8.80 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.18 (t, IH), 7.05 (t, 2H), 6.88 (in, 2H), 3.30 (t, 2H), 2.74 (t, 2H), 2.25 (s, 3H), 2.22 (s, 3H); MS (ESI) m/z 309 (M+H)+

Example 319 N-f2-(3 4-dichlorophenyl)ethyll-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 2-(3,4-dichlorophenyl)ethylamine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d6) 6 8.82 (s, 1H), 8.17 (s, 11-1), 7.58 (m, 4H), 7.27 (dd, 1H), 7.18 (t, 1H), 7.03 (d 2H), 6.58 (bs, 1H), 3.40 (t, 2H), 2.80 (t, 2H); MS (ESI) m/z 349 (M+H) Example 320 N-1H-indazol-4-y1N'-[2-(4-metl ylphenyl)ethyl urea The title compound was prepared using the procedure described in Example 317 except using 2-(4-methylphenyl)ethylamine instead of 3-phenylpropylamine. 1H
NMR
(DMSO-d6) S 8.77 (s, IH), 8.20 (s, IN), 7.62 (d, 1H), 7.28 (m, 211), 7.15(m, 5H), 3.38 (t, 2H), 2.73 (t, 211); MS (ESI) mlz 395, (M+H)+.

Example 321 N-[4-azep an- l -yl-3-(trifluoromethyl)benzyl]-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-azepan-1-yl-3-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine.
'HNMR (DMSO-d6) S 8.98 (s, 1H), 8.18 (s, 1H), 7.60 (m, 3f1), 7.48 (d, 1H), 7.19(t, 1H), 7.06, (d, 211), 4.37 (d, 2H), 3.00 (m, 4H), 2.64 (s, 8H); MS (ESI) m/z 432, (M+If+.

Example 322 N-[4-azepan-1-yl-2-(trifluoromethyl)benzyllN'-IH-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-azepan-1-yl-2-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine.
'H NMR (DMSO-d6) 6 9.00 (s, 1H), 8.19 (s, 11), 7.64 (d, 1H), 7.41 (d, 1H), 7.19 (t, 1 H), 7.03, (d, 1H), 6.91 (m, 4H), 4.37 (s, 2H), 3.43 (t, 4I-1), 1.71 (s, 413), 1.43 (i, 4H); MS (ESI) mlz 432, (M+H)+.

Example 323 N- [4-(2-azabicyclo [2.2.1lhept-2-yl)-2-(trifluoromethyl)benzyl]-N'- I H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-(2-azabicyclo[2.2. I ]hept-2-yl)-2-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine. 1H NMR (DMSO-d6) S 9.00 (s, 1H), 8.19 (s, 1H), 7.64 (d, 1H), 7.40 (d, 1H), 7.19 (t, 1H), 7.04 (d, 1H), 6.91 (bs, 111), 6.80 (dd, IH), 6.70 (d, 1H), 4.38 (s, 2H), 4.21 (s, 1H), 3.43 (m, 2H), 2.71 (d, 111), 2.60 (s, 1H), 1.1.65 (m, 3H), 1.50 (m, 111), 1.28 (m, 111); MS (ESI) m/z 430, (M+H)+.

Example 324 N-[4-(8-azabicyclo[3.2.lloct-8-yl)-2-(trifluoromethyl)benzyl]-N'-1H-indazo l-4-ylurca The title compound was prepared using the procedure described in Example 317 except using 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine. 'H NMR (DMSO-d6) 8 9.02 (s, 1H), 8.20 (s, IH), 7.63 (d, 1H), 7.44 (d, 1H), 7.19 (t, 1H), 7.05 (m, 2H), 7.00 (m, 2H), 4.38 (s, 2H), 4.23 (s, 2H), 2.01 (m, 2H), 1.80 (m, 5H), 1.41 (m, 114), 1.26 (m, 2H); MS (ESI) m/z 444 (M- -H)+.

Example 325 N-f4-(8-azabicyclo[3.2.1 ]oct-8-yl)-3-fluorobenzyl]-N'-1H-indazol-4-ylurca Example 325A
4-(8-azabicyclo[3.2.1 ]oct-8-yl)-3-fluorobenzonitrile 3,4-Difluorobenzonitrile (1.75g; 25.1mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (2.1g; 13.8 mmol), and diisopropylethylamine (3.2g; 25.1 mmol), were combined in DMSO (30 mL) and heated at 120 C overnight. The mixture was allowed to cool to ambient temperature, poured into brine (75 mL), and extracted with diethyl ether (2 X
50 mL). The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel (ethyl acetate as eluent) to provide the title compound. 'H NMR (DMSO-d6) 8 7.69 (dd, 1H), 7.42 (dd, 1H), 7.15 (t, 1H), 4.41 (s, 2H), 1.98 (m, 2H), 1.62-1.86 (m, 5H), 1.41 (m, 31-1); MS
(ESI) m/z 231, (M+H)+.

Example 325B
4-(8-azabicyclo[3.2.1 ]oct-8-yl)-3-fluorobenzylamine Lithium aluminum hydride (1.6 g; 43.2 mmol) in THE was treated with 4-(8-azabicyclo[3.2.1]oet-8-yl)-3-fluorobenzonitrile (2.48 g; 10.8 mmol) dropwise. After complete addition, the slurry was refluxed for 2 hours, allowed to cool to ambient temperature, and quenched with sodium sulfate decabydrate. The mixture was filtered and the filter cake was washed with THE (2 x 50 mL). The organics were combined and concentrated under reduced pressure. The residue was chromatographed (Si02; 5%
methanol in methylene chloride) to provide the title compound. 'H NMR (DMSO-d6) 8 7.03 (dd, 1H), 7.92 (dd, 1H), 7.85 (t, 1H), 4.21 (s, 2H), 3.60 (s, 2H), 1.93 (m, 2H), 1.77 (n7, 5H), 1.42 (m, 1H), 1.32 (m, 2H); MS (ESI) m/z 235, (M+H)+.

N-(4-(8-azabicyclo {3.2. l loct-8-_yl)-3-fluorobenzyll-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-(8-azabicyclo[3.2.1 ]oet-8-yl)-3-fluorobenzylamine instead of 3-phenylpropylamine. 'H NMR (DMSO-d6) 6 9.00 (s, 1H), 8.20 (s, 111), 7.64 (d, 1H), 7.18 (t, 1H), 7.03 (m, 5H), 4.24 (s, 2H), 4.17 (s, 2H), 1.95 (m, 2H), 1.80 (m, 6H), 1.41 (in, 2H);
MS (ESI) m/z 394 (M+H)+

Example 326 N-(3-chloro-4-azepan-1-ylbenzyl)-N-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3-chloro-4-azepan-1-ylbenzylamine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d5) 6 8.90 (s, 1H), 8.19 (s, 1H), 7.62 (d, 1H), 7.36 (d, 1H), 7.20 (m, 4H), 7.03, (d, 1H), 6.98 (bs, 1H), 4.26 (s, 2H), 3.18 (m, 4H), 1.78 (m, 4H), 1.62 (in, 4H);
MS (ESI) m/z 398, (M+H)+.

Example 327 N-1H-indazol- -yl N'-{[6-(trifluoromethyl)-3-pyridinyllmethyl}urea The title compound was prepared using the procedure described in Example 317 except using [6-(trifluoromethyl)-3-pyridinyl]methylamine instead of 3-phenylpropylamine.
'H NMR (DMSO-d6) 6 9.09 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.03 (d, 1H), 7.90 (d, IH), 7.60, (d, 1H), 7.22 (m, 2H), 7.05 (d, 1H), 4.49 (dd, 2H); MS (ESI) m/z 336 (M+H)+.

Example 328 N-((1 S)-1-(4-bromophenyl)ethyll-N-lH-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using (1 S)-1-(4-bromophenyl)ethylamine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d6) 6 8.82 (s, 1H), 8.16 (s, 1H), 7.57 (m, 3H), 7.35 (d, 2H), 7.17 (t, 1H), 7.03, (d, 2H), 4.82 (m, 1H), 1.41 (d, 3H); MS (ESI) m/z 336 (M+H)+.

Example 329 N- 3-bromo-4-fltiorobenzyl)-N'-I,H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3-bromo-4-fluorobenzylamine instead of 3-phenylpropylamine. 1H
NMR
(DMSO-d6) S 9.02 (s, 1H), 8.20 (s, 1H), 7.63 (m, 21-1), 7.38 (m, 2H), 7.19 (t, 1H), 7.14 (bs, 1H), 7.03, (d, 1f ), 4.35 (m, 1H); MS (EST) m/z 364, (M+H).

Example 330 N-(2,4-dimethylbenzyl)-N'-1 H-indazol-4 lurea The title compound was prepared using the procedure described in Example 317 except using 2,4-dimethylbenzylamine instead of 3-phenylpropylamine. 'H NMR
(DMSO-d6) b 8.88 (s, 1H), 8.17 (s, 1H), 7.63 (d, 2H), 7.19 (m, 2H), 7.01 (m, 4H), 6.83 (bs, 1H), 4.28 (s, 2H), 2.20 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z 295 (M+H)+.

Example 331 N-(4-chlorobenzyl)-N-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-chlorobenzylamine instead of 3-phenylpropylamine. 1H NMR (DMSO-d6) 6 8.96 (s, 1H), 8.18(s, 1H), 7.62 (d, 1H), 7.39 (m, 4H), 7.19 (t, 1H), 7.06 (d, 2H), 4.36 (d, 2H);
MS (ESI) m/z 301 (NI+H)+.

Example 332 N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3-fluoro-4-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine. 1H
NMR (DMSO-d6) 8 9.17 (s, 1H), 8.22 (s, 1H), 7.77 (t, 1H), 7.60 (d, 1H), 7.41 (m, 2H), 7.28 (bs, 114), 7.19 (t, 2H), 7.05 (d, 111), 4.47 (d, 2H); MS (ESI) m/z 353, (M
ff)+.

Example 333 N- 1 H-indazol-4-yl-N'-(4-methylb enzyl)urea The title compound was prepared using the procedure described in Example 317 except using 4-methylbenzylamine instead of 3-phenylpropylamine. 1H NMR (DMSO-d6) S

9.02 (s, 1H), 8.21 (s, 1H), 7.64 (d, 1H), 7.19 (m, 6H), 7.05 (d, 1H), 4.30 (s, 1H); MS (ESI) m/z 281, (I\M+H)+.

Example 334 N-1H-indazol-4-yl-N'-(3-(trifluoromethoxy)ben ,yl urea The title compound was prepared using the procedure described in Example 317 except using 3-(trifluoromethoxy)benzylamine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d6) S 9.07 (s, 1H), 8.22 (s, IH), 7.48 (t, 1H), 7.39 (d, 1H), 7.32 (s, 111), 7.20 (m, 3H), 7.03 (d, 1H), 4.20 (s, 1H); MS (ESI) m/z 351 (M+H)+.

Example 335 N-(3-chloro-4-fluorobenzyl)-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3-chloro-4-fluorobenzylamine instead of 3-phenylpropylamine. 'H
NMR
(DMSO-d6) S 9.20 (s, 1H), 8.29 (s, 1H), 7.63 (d, 1H), 7.35 (dd, 1H), 7.38 (m, 3H), 7.20 (t, 1H), 7.03 (d, 1H), 4.38 (s, 1H); MS (ESI) m/z 353, (M+I-I)+

Example 336 N-(3,4-dimethylbenzyl)-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3,4-dimethylbenzylamine instead of 3-phenylpropylamine. 'H NMR
(DMSO-d6); 9.00 (s, 1H), 8.21 (s, 1H), 7.64 (d, 1H), 7.20 (t, 1H), 7.07 (m, 5H), 4.23 (s, 1I-1), 2.21 (s, 3H), 1.98 (s, 3H); MS (ES1) m/z 295, (M+H)+.

Example 337 N-(3 -fluoro-5 -(trifluoromethyl)benzyl)-N'-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3-fluoro-5-(trifluoromethyl)benzylamine instead of 3-phenylpropylamine. 'H
NMR (DMSO-d6) S 9.25 (s, 1H), 8.30 (s, 1H), 7.57 (m, 5H), 7.43 (bs, IH), 7.20 (t, IH), 7.05 (d, IH), 4.42 (s, 2H); MS (ESI) m/z 351 (M-H)".

Example 338 N-(2-chloro-4-azepan- I -ylbenzyl)-N'-1 H-indazol-4-yl4rea The title compound was prepared using the procedure described in Example 317 except using 2-chloro-4-azepan-1-ylbenzylamine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d6) 6 9.00 (s, 1H), 8.20 (s, IH), 7.63 (d, 1H), 7.23 (d, IFI), 7.19 (t, 1H), 7.03 (d, 111), 6.98 (bs, 1H), 6.64 (m, 3H), 4.25 (s, 2H), 3.42 (m, 4H), 1.70 (m, 4H), 1.43 (m, 4H); MS (EST) m/z 398 (M+H)+.

Example 339 N-(2,3-dichlorobenzyl)-N'- 1-i-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 2,3-dichlorobenzylamine instead of 3-phenylpropylamine. 'H NMR
(DMSO-d6) S 9.06 (s, 1H), 8.18 (s, 1H), 7.61 (d, 1H), 7.58 (d, 1H), 7.40 (m, 2H), 7.19 (m, 1H), 7.12 (t, 1H), 7.06 (d, 1H), 4.25 (s, 2H), 4.23 (d, 2H); MS (ESI) m/z 336 (M+H)+.

Example 340 N-1 H-indazol-4-yl-N'- {4- f (trifluoromethyl)thiolbe 1 urea The title compound was prepared using the procedure described in Example 317 except using 4-[(trifluoroinethyl)thio)benzylamine instead of 3-phenylpropylamine. 'H NMR
(DMSO-d6) 6 9.06 (s, 111), 8.21 (s, 1H), 7.71 (d, 2H), 7.62 (d, 1H), 7.50 (d, 2H), 7.18 (m, 2H), 7.05 (d, 111), 4.21 (s, 2H); MS (ESI) m/z 367 (1\M+H)+.
Example 341 N-1H-indazol-4-yl-N'-f 3-(trifluoromethyl)benzyllurea The title compound was prepared using the procedure described in Example 317 except using 3-(trifluoromethyl)benzylarnine instead of 3-phenylpropylamine.
'H NMR
(DMSO-d6) 6 9.17 (s, 1H), 8.24 (s, 1H), 7.63 (m, 6H), 7.30 (bs, 1H), 7.19 (t, III), 7.16 (d, IH), 4.43 (s, IH), 421; MS (ESI) m/z 335 (M+H)+.
Example 342 N-(3,5-difluoro-4-azepan-1-ylbenzyl)-N'-1 H-indazol-4-ylurea Example 342A

3,5-difluoro-4-azepan- l -ylbenzonitrile The title compound was prepared using the procedure described in Example 325A
except using 3,4,5-trifluorobenzonitrile and azepane instead of 3,4-difluorobenzonitrile and 8-aza-bicyclo[3.2. 1 ]octane hydrochloride. 'H NMR (DMSO-d6) S 7.62 (d, 2H), 3.39 (m, 4H), 1.73 (m, 4H), 1.61 (m, 4H); MS (ESI) m/z 237 (M+I1)+.

Example 342B
3,5-difluoro-4-azepan-1-ylbenzylamine The title compound was prepared using the procedure described in Example 325B
except using 3,5-difluoro-4-azepan-1-ylbenzonitrile instead of4-(8-azabicyclo[3.2.1]oct-8-yl)-3-fluorobenzonitrile. 'H NMR (DMSO-d6) S 6.97 (d, 2H), 3.62 (s, 2H), 3.27 (m, 4H), 1.63 (m, 8H); MS (ESI) rn/z 241 (M+H)+

Example 342C
N-(3,5-difluoro-4-azepan-1-ylbenzyl)-N-1 H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 3,5-difluoro-4-azepan-1-ylbenzylanline instead of 3-phenylpropylamine. 'H
NMR (DMSO-d6) 5 9.00 (s, 1H), 8.20 (s, 1H), 7.62 (d, 1H), 7.20 (t, 1H), 7.06 (d, 2H), 6.98 (d, 2H), 4.26 (s, 2H), 3.18 (m, 4H), 1.62 (m, 8H); MS (ESI) m/z 400 (M+H)+.

Example 343 N-[4-(8-azabicyclo[3.2.1loct-8-yl)-3,5-difluorobenzyll-N'-1H-indazol-4-ylurea Example 343A
4-(8-azabicyclo[3.2.11oet-8-yl)-3,5-difluorobenzonitrile The title compound was prepared using the procedure described in Example 325A
except using 3,4,5-trifluorobenzonitrile instead of 3,4-difluorobenzonitrile.
'H NMR
(DMSO-d6) 6 7.58 (dd, 211), 4.34 (s 211), 1.95 (m, 2H), 1.78 (m, 5H), 1.46 (m, 3H); MS (ESI) m/z 249 (M+H)+.

Example 343B
4-(8-azabicyclo 3.2.1loct-8-yl)-3,5-difluorobenzylamine The title compound was prepared using the procedure described in Example 325B
except using 4-(8-azabicyclo[3.2.1]oct-8-y1)-3,5-difluorobenzonitrile instead of'4-(8-aza.bicyclo[3.2.1 ]oct-8-yl)-3-fluorobenzonitrile. 1H NMR (DMSO-d6) S 6.97 (d, 2H), 4.00 (s, 21-1), 3.59 (in, 211), 1.91 (m, 21-1), 1.76 (m, 5H), 1.42 (m, 3H); MS (ESI) M/7,253 (M+H)+

Example 343C
N-[4-(8-azabicyclo[3.2.1loct-8-yl) 3,5-difluorobenzyll-N'-IH-indazo1-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-(S-azabicyclo[32.1 ]oct-8-yl)-3,5-difluorobenzylamine instead of 3-phenylpropylamine. 1H NMR (DMSO-d6) S 8.98 (s, I1), 8.20 (s, 1H), 7.62 (d, I
H), 7.19 (t, 1H), 7.06 ( d, 2H), 6.93 (d, 2H), 4.23 (s, 2H), 4.06 (s, 2H), 1.91 (m, 2H), 1.74 (m, 5H.), 1.41 (m, 3H); MS (ES1) m/z 412, (M+H)+.

Example 344 N-(4-chlorobenzyl)-N'-(1-methyl-lH-indazol-4- =1 urea Example 344A
1-methyl--4-nitro-lH-indazole A suspension of NaH (1.1 g, 32.2 mmol; 60% dispersion in mineral oil) in DIM
(40 mL) was treated with 4-nitro-IH-indazole (5 g, 30.6 mmol) in DMF (40 mL) at 0 C. After stirring for 30 minutes, the mixture was treated with methyl iodide (4.6 g, 32.18 nunol) in DMF (20mI) drop wise. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was poured into water (250 ml) and extracted with ethyl acetate (2 x 100 mL). The organics were combined, washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure.
The residue was chromatographed (Si02, ethyl acetate/hexanes) to provide the title compound.

(DMSO-d6) b 8.50 (s, 1H), 8.24 (d, 1H), 8.19 (d, 1H), 7.65 (t, 111).

Example 344B
1-methyl-I H-indazol-4-amine 1-Methyl-4-nitro-1H-indazole (6.1g; 35.4 mmol) and 10% Pd/carbon (500 mg) were combined in ethanol and hydrogenated in a Parr apparatus at 60 PSI hydrogen at 50 C for 1 hour. The mixture was allowed to cool to ambient temperature, filtered through Celite, and concentrated under reduced pressure to provide the title compound. 1H NMR
(DMSO-d6) 6 8.02 (s, IM, 7.02 (t, 111), 6.62 (d, IM, 6.14 (d, J H), 5.75 (s, 2H), 3.90 (s, 2H).

Example 344C
N-(4-chlorobenzyl)-N'-(1-methyl-lH-indazol-4-yl)urea 1-Methyl-lH-indazol-4-amine (1.00 g, 6.8 mmol) in toluene (225 mL) was treated with phosgene (20% in toluene, 7 nil, 13.2 mmol). The mixture was heated at reflux for 3 hours, cooled, and the solvent removed under reduced pressure. The residue was taken in diethyl ether (100 ml) and triethyl amine (6 ml), and filtered. The filtrate was treated with 4-chlorobenzylamine (963 mg, 6.8 mmol). After stirring at ambient temperature for 16 hours, the solvent was reduced to half volume under reduced pressure, filtered, and the filter cake washed with diethyl ether:hexanes (1:1) to provide the title compound. The title compound was treated with HCI/ethanol and evaporated to dryness to provide the hydrochloride. 1H
NMR (DMSO-d6) 6 9.25 (s, 1H), 8.25 (s, 1H), 7.68 (d, 1H), 7.39 (m, 5H), 7.24 (t, 1H), 7.13 (d, 1H), 4.34 (s, 2H), 3.99 (s, 3H); MS (ESI) m/z 315 (M+H)+.

Example 345 methyl 4-((f (4-(8-azabicyclo[3.2.lloct-8-yl)-2-chlorobenzyllamino}carbonyl)aminol-lH-indazole- l -carboxylate Example 345A
8-azabicyclo[3.2.lloctane 8-Methyl-8-azabicyclo[3.2.1]octane in dichloroethane (400 mL) was treated with chloroethylchloroformate (29.3 g, 205 mmol) in dichloroethane (75 mL) dropwise via addition funnel at 0 C. After complete addition, the mixture was heated at reflux for four hours. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was filtered through a silica gel plug eluting with 1:1 ethyl ether:hexane and the filtrate was concentrated under reduced pressure. The residue was taken up in 250 mL methanol, heated at reflux for 1 hour, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was triturated with diethyl ether and filtered. The filter cake was washed with diethyl ether and dried under reduced pressure at 60 C to provide the title compound as a solid. 1H NNIR (300 MHz, DMSO-d6) 6 8.90 (bs, 2H), 3.87 (in, 2H), 2.02-1.76 (in, 61-1), 1.74-1.40 (in, 4H); MS (DCI) 112 (M+H)+.

Example 345B
4-(8-azabicyclo[3.2.1 ]oct-8-yl)-2-chlorobenzonitrile 2-Chloro-4-fluorobenzonitrile (0.97 g, 6.2 mmol), 8-aza-bicyclo[32.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120 C for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated. and extracted with diethyl ether.
The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.

Example 345C
4-(8-azabicyclo [ 3.2.11oct- 8-yl)-2-chl orobenzylamine 4-(8-Azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile in THE (50 mL) was treated with solid LAH (0.47 g, 12 mmol) at 0 C portionwise. The mixture was heated at reflux for 1 hour, allowed to cool to 0 C, and quenched by addition of (Na2SO4 10H20).
The mixture was stirred for 30 minutes, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% to 10%
McOH/CH2CI2 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) S 7.27 (d, 1H, J=8.6 Hz), 6.74 (d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=8.6, 2.4 Hz), 4.16 (bs, 2H), 3.65 (s, 2H), 2.05 (bs, 2H), 1.97 (m, 2H), 1.88-1.65 (m, 5H), 1.40 (m, 1H), 1.23 (m, 2H); MS (ESI) 234 (M-NH2)+.

Example 345D
methyl 4-[({[4-(8-azabicyclo[3.2.11oct-8-yl)-2-chlorobenzyllamino}
earbonyl)aminol-11-I-indazole-1-carboxylate A suspension of methyl 4-amino-lH-indazole-l-carboxylate (554 mg, 2.90 mmol) in toluene (100 mL) was treated with phosgene in toluene (2.90 mL, approx. 20%
w/w) via syringe. The mixture was heated at reflux for 3.5 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was taken up in diethyl ether and concentrated under reduced pressure. The residue was again taken up in diethyl ether (100 rnL) and treated with triethylamine (3 mL). After stirring for 10 minutes, the mixture was filtered. The filtrate was treated with 4-(8-azabicyclo[3.2.1]oet-8-yl)-2-chlorobenzylamine (484 mg, 1.93 mmol) in THE (10 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 2% to 5% McOHICH2C12 to provide the title compound as a solid. 'H NMR (300 MHz, DMSO-d6) 6 9.00 (s, 1H), 8.41 (s, 111), 7.85 (d, 1H, J=7.8 Hz), 7.68 (d, 1 H, J=8.5 Hz), 7.48 (t, I H, J=8.1 Hz), 7.25 (d, I H, J=8.5 Hz), 6.82 (d, 1H, J=2.4 Hz), 6.73 (dd, IH, J=8.5, 2.4 Hz), 6.68 (t, IH, J=5.4 Hz), 4.30 (d, 2H, J=5.4 Hz), 4.19 (m, 2H), 4.03 (s, 3H), 2.05-1.65 (m, 7H), 1.40 (m, 1H), 1.25 (m, 2H); MS (ESI) 468 (M+H)+.

Example 346 N-[4-(8-azabicyclo [3.2.1loct-8-yl)-2-chlorobenzyll-N'-1H-indazol-4-ylurea Methyl 4-[({ [4-(8-azabicyclo [3.2. 1 ]oct-8-yl)-2-chlorobenzyl] amino) carbonyl)amino]-1H-indazole-l-carboxylate (803 mg, 1.72 mmol) in methanol (40 mL) was treated with 1.2N
NaOH in McOH (20 mL). After stirring for 30 minutes, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The separated aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (7%
to 10%
McOHJCH2CI2) to provide the title compound as a solid. The obtained solid was treated with ethanolic HC1 followed by precipitation with diethyl ether to provide the hydrochloride salt.
'H NMR (300 MHz, DMSO-d6) S 8.91 (s, 1H), 8.16 (s, 1H), 7.65 (d, 1H, f=7.5 Hz), 7.27 (d, IH, J=8.5 Hz), 7.19 (t, IH, J=8.1 Hz), 7.05 (d, 1H, J=8.5 Hz), 6.87 (m, 2H), 6.79 (m, 1H), 4.29 (m, 2H), 4.21 (m, 2H), 2.05-1.65 (m, 7H), 1.40 (m, 1H), 1.26 (m, 2H); MS
(ESI) 410 (M+H)+; Anal. Calcd for C22H24C1N50.1.6HCI: C, 56.43; H, 5.51; N, 14.96.
Found: C, 56.30; H, 5.29; N, 14.81.

Example 347 methyl 4-[({[4-(8-azabicyclo[3.2.Ijoct-8-y1)-3-(trifluoromethyl)benzyllamino) carbonyl)aminol-IH-indazole-l-carboxylate Example 347A
4-(8-azabieyclo(3.2.1oct-8-yl)-3-(trifluoromethyl)benzonitrile 4-Fluoro-3-(trifluoromethyl)benzonitrile (1.35 g, 7.14 mmol), 8-aza-bieyelo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropyleth.ylamine (1.79 g, 13.8 rnmol) were combined in DMSO (15 mL) and heated at 120 C for 24 hours.
The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.

Example 347B
4-(8-azabicyclo[3.2. l loct-8-yl)-3-(trifluoromethyl)benzylamine 4-(8-Azabicyclo[3.2.1]oct-8-y1)-3-(trifluoromethyl)benzonitrile in THE (50 mL) was treated with solid LAH (0.68 g, 18 mmol) at 0 C portionwise. The mixture was heated at reflux I hour, allowed to cool to 0 C, and quenched by addition of (Na2SO4 I
OH2O). The mixture was stirred 30 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% to 10%
McOI-I/CH2C12 to provide the title compound. 'H NMR (300 MHz, DMSO-d6) S 7.57 (d, IH, J=2.0 Hz), 7.42 (dd, IH, J=8.1, 2.0 Hz), 7.08 (d, 1H, J=8.4 Hz), 3.658 (m, 4H), 2.15 (bs, 2H), 1.92 (m, 2H), 1.88-1.55 (m, 5H), 1.48 (in, 3H); MS (ESI) 268 (M-NH2)}.

Example 347C
methyl 4-[( {[4-(8-azabicyclo(3.2.1)oct-8--yl)-3-(ttrifluoromethyl)benzyllamino } carbonyl)aminol-1 H-indazole- l -carboxylat Methyl 4-amino-lH-indazole-l-carboxylate (1.72 g, 9.00 rnmol) in toluene (300 mL) was treated with phosgene in toluene (9.00 mL, approx. 20% w/w) via syringe.
The mixture was heated at reflux for 3.5 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was taken up in diethyl ether and concentrated under reduced pressure. The residue was again taken up in diethyl ether (325 mL) followed by addition of triethylamine (10 mL). The mixture was stirred briefly and then filtered. An aliquot of the filtrate (150 mL, 4.14 mmol) was treated with 4-(8-azabicyclo[3 2.l]oct-8-yl)-3-(trifluoromethyl)benzylamine (1.03 g, 3.62 mmol) in THE (10 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure to approximately 30 mL and filtered. The filter cake was washed with diethyl ether:hexane (1:1) and dried under reduced pressure to provide the title compound. 'H NMR (300 MHz, DMSO-d6) 6 9.07 (s, 111), 8.43 (s, 111), 7.80 (d, 1H, J=7.8 Hz), 7.69 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=2.0 Hz), 7.47 (m, 2H), 7.14 (d, 1H, J=8.1 Hz), 6.86 (t, 1H, J=5.8 Hz), 4.32 (d, 2H, J=5.8 Hz), 4.03 (s, 3M, 3.72 (nl, 211), 1.93 (m, 2H), 1.88-1.55 (m, 5H), 1.49 (m, 311); MS (ESI) 502 (M+H)+.

Example 348 N-[4-(8-azabicyclo(3.2.1loct-8-yl)-3-(trifluoromethyl)benzyll-N'-1 H-indazol-4-ylurea A suspension of methyl 4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-l-carboxylate (1.65 g, 3.29 mmol) in methanol (30 mL) was treated with 1.2 N NaOH in MeOH (10 mL). The mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The separated aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (7% to 10% McOHICH2C12) to provide the title compound as a solid. The obtained solid was treated with ethanolic HCl followed by precipitation with diethyl ether to provide the hydrochloride salt. 'H NMR
(300 MHz, DMSO-d6) S 8.99 (s, 1H), 8.19 (s, 1H), 7.62 (d, 1H, J=7.5 Hz), 7.57 (d, IH, J=2.0 Hz), 7.46 (dd, 111, J=8.5, 2.0 Hz), 7.19 (t, 1H, J=8.1 Hz), 7.10 (m, 3H), 4.31 (m, 2H), 3.72 (m, 2H), 1.93 (m, 2H), 1.87-1.56 (m, 51), 1.48 (m, 3H); MS (ESI) 444 (4+H)+; Anal.
Calcd for C23H24F3N5O.1.6HCl: C, 55.05; H, 5.14; N, 13.96. Found: C, 54.95; H, 4.66; N, 13.53.

Example 349 N-[4-(8-azabicyclo[3.2.1 loct-8-yl)-3-chlorobenzyll-N-1 H-indazol-4-ylurea Example 349A
4-(8-azabicyclo[3.2.11oct-8-yl)-3 -chlorobenzonitrile The title compound was prepared using the procedure described in Example 347A
except using 4-fluoro-3-cblorobenzonitrile instead of 4-fluoro-3-(trifluoromethyl)b enzonitrile.

Example 349B
4-(8-azabicyclo[3.2.11oct-8-yl)-3-chlorobenzylamine The title compound was prepared using the procedure described in Example 347B
except using 4-(8-azabicyclo[3.2.1 ]oct-8-yl)-3-chlorobenzonitrile instead of 4-(8-azabicyclo[3 2.1 ]oct-8-yl)-3-(tri.fluoromethyl)benzonitrile.

Example 349C
N-[4-(8-azabicyclo [3.2.1 lost-8-y1)-3 -chlorobenzyll-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-(8-azabicyclo[3.2.1 ]oet-8-yl)-3-chlorobenzylamine instead of 3-phenylpropylaniine. 1H NMR (300 MHz, DMSO-d6) 8 8.84 (s, 1H), 8.13 (s, 111), 7.62 (d, 11-1, J=7.5 Hz), 7.35 (d, 1H, J=2.0 Hz), 7.16 (m, 2H), 7.03 (m, 2H), 6.91 (m, 1H), 4.25 (d, 2H, J=4.4 Hz), 3.91 (m, 2H), 1.84 (m, 4H), 1.67 (m, 3H), 1.50 (m, 3H); MS (ESI) 410 (M+H)+;
Anal. Calcd for C22H24C1NT50Ø8HC1: C, 60.18; H, 5.69; N, 15.95. Found: C, 60.09; H, 5.37; N, 15.64.

Example 350 N-[4-(8-azabicyclo[3.2.1 lost-8-yl)bnzyll-N'-1 H-indazol-4-ylure Example 350A
4-(8-azabicyclo [3.2. l feet-8-yl)benzonitrile The title compound was prepared using the procedure described in Example 347A
except using 4-fluorohenzonitrile instead of 4-fluoro-3-(trifluoromethyl)benzonitrile.
Example 350B
4-(8-azabicyclo[3.2.Iloct-8-yl)benzylamine The title compound was prepared using the procedure described in Example 347B
except using 4-(8-azabieyclo[32.1]oct-8-yl)benzonitrile instead of4-(8-azabicyclo[3.2.lJoct-8-yl)-3-(trifluoromethyl)benzonitrile.

Example 350C
N-[4-(8-azabicyclo[3.2.1)oct-8-yl)benzyll-N'-1H-indazol-4-ylurea The title compound was prepared using the procedure described in Example 317 except using 4-(8-azabicyclo[3.2.1 ]oct-8-yl)benzylamine instead of 3-phenylpropylamine.
111 NMR (300 MHz, DMSO-d6) S 8.85 (m, 1H), 8.15 (s, 1H), 7.65 (d, IH, J=7.8 Hz), 7.25 (m, 2H), 7.19 (t, 1 H, J=8.0 Hz), 7.05 (d, 1 H, J=8.1 Hz), 6.87 (m, 2f), 4.26 (m, 4H), 2.10-1.65 (m, 7H), 1.60-1.15 (m, 3H); MS (ESI) 376 (M+H)+; Anal. Calcd for C22H25N5O.1.1HC1:
C, 63.58; H, 6.33; N, 16.85. Found: C, 63.36; H, 6.05; N, 16.57.

Example 351 N-(4-tert-butylbenzyl)-N-(1-methyl-lH-indazol-4-yl)urea 4-tert-Butylbenzylamine (0.46 mL, 2.62 mmol) in toluene (8 mL) was treated with 20% phosgene solution (1.4 mL) and refluxed for 3 hours. The mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was then taken up in toluene (10 mL) and treated with diisopropylamine (3 niL) and 1-methyl-IH-indazol-4-amine (prepared as described in J. Med. Chem. 45:742 (2002); 200 mg, 1.36 mmol). The reaction mixture was heated at 80 C for 3 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (98:2 CH-2C12:CH3OH to 95:5 CH2C12:CH3OH, eluant gradient) to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCI. 'H
NMR (300 MHz, d6-DMSO) 8 8.72 (s, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, 0.6 Hz, 1H), 7.37 (m, 2H), 7.27 (m, 2H), 7.24 (m, 1H), 7.13 (m, 1H), 6.74 (m, 1H), 4.30 (d, J=5.8 Hz, 21-1), 3.99 (s, 3H), 1.27 (s, 9H); MS (ESI+
) mlz 337 (M+H)}.
Example 352 N-[3-fluoro-4-(trifluoromethyl)benzyll-N'-(1-methyl- I H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 351 except using 3-fluoro-4-(trifluoromethyl)benzylamine instead of 4-tert-butylbenzylamine. 'H

NMR (300 MHz, d6-DMSO) 6 8.92 (s, 1H), 8.08 (d, J=1.1 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.62 (dd, J=7.3 Hz, 0.7 Hz, 1H), 7.41 (m, 11I), 7.25 (m, 114), 7.15 (m., 1H), 6.98 (t, J=6.1 Hz, 114), 4.45 (d, J=6.1 Hz, 2H), 4.00 (s, 3H); MS (ESI+) m/z 367 (M+H)+.

Example 353 a N-[4-chloro-3-(trifluoromethyl benzyl}-N'-(1-methyl-lH-indazol-4-y1)ure The title compound was prepared using the procedure described in Example 351 except using 4-chloro-3-(trifluoromethyl)benzylan3ine instead of 4-tent-butylbenzylamine. 'H
NMR (300 MHz, d6-DMSO) S 8.89 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.82 (s, 1I1), 7.60-7.70 (m, 3H), 7.22 (m, 1H), 7.17 (m, 1H), 6.92 (m, 1H), 4.42 (d, J=5.8 Hz, 211), 3.99 (s, 3M-, MS
(ESI) m/z 383/385 (M+H, 35C1/37C1)+

Example 354 N-(1-meth)rl-lH-indazol-4-yl)-4-[4-(trifluoromethyl)-2-pyridinyll-1-piperazineearboxamide 1-Methyl-lH-indazol-4-amine (560 mg, 3.81 mmol) in toluene (20 mL) was treated with 20% phosgene solution (2.5 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in THE (20 mL) and treated with diisopropylam.ine (5 mL) and 1-[4-(trifluoromethyI)-2-pyridinyl)piperazine (450 mg, 1.95 mmol). The mixture was refluxed overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3 CH2C12:CH3OH
to 95:5 CH2CI2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 'H NMR (300 MHz, d6-DMSO) b 8.78 (s, 1H), 8.44 (m, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.83 (m, 1H), 7.19-7.31 (m, 3H), 7.02 (d, 9.2 Hz, 1H), 4.00 (s, 3H), 3.74 (m, 4H), 3.63 (m, 4H); MS (ESI) m/z 405 (M+H)+.

Example 355 N-(3,4-dichlorob enzyl)-N-(1-methyl- I H-indazol-4-yl)ure a 1-Methyl-lH-indazol-4-amine (390 mg, 2.65 mmol) and 3,4-dichlorobenzyl isocyanate (0.39 mL, 2.65 mmol) were combined in toluene (20 mL) and heated overnight at 80 C. The mixture was allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HC1. 'H NMR (300 MHz, d6-DMSO) 6 8.86 (s, 111), 8.06 (d, J=1.0 Hz, IM, 7.59-7.64 (in, 3H), 7.33 (m, 111), 7.25 (in, 111), 7.15 (m, III), 6.91 (t, J=6.0 Hz), 4.35 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS (ESI) m/z 349/351 (M+H, 35C1/37C1)+

Example 356 N-(2,4-dichlorob enzyl)-N'-(l -methyl-1 H-indazol-4-yl)urea 1-Methyl-lH-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80 C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCI. 1H NMR (300 MHz, d6-DMSO) 6 9.22 (s, 111), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (in, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI') m/z 349/351 (M+H, 35Cl/37C1)+.

Example 357 N-(4-ethylbenzyl)-N'-(1-methyl- I H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 354 except using 4-ethylbenzylamine instead of 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine. 'H
NMR (300 MHz, d6-DMSO) S 8.73 (s, 1H), 8.03 (d, 1H, J=0.7 Hz), 7.66 (d, J=7.4 Hz, 1H), 7.12-7.28 (m, 6H), 6.75 (t, J=5.8 Hz, 1H), 3.99 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (ESI) m/z 309 (M+H)+.

Example 358 N-(2-chlorobenzyl)-N'-(1-methyl-1 H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 355 except using 2-chlorobenzyl isocyanate instead of 3,4-dichlorobenzyl isocyanate. 'H NMR
(300 MHz, d6-DMSO) S 8.88 (s, 1H), 8.06 (d, J~=0.7 Hz, 1H), 7.65 (dd, J=7.4 Hz, 0.7 Hz, 1H), 7.44-7.49 (m, 2H), 7.28-7.39 (m, 2H), 7.25 (m, 1H), 7.14 (m, 1H), 6.87 (t, J=6.0 Hz, 111), 4.43 (d, J=6.1 Hz, 2H), 4.00 (s, 3H); MS (ESI) m/z 315/317 (M+H, 35C1/37C1)+.

Example 359 N-(4-fluorobenzyl)-N'-(1-methyl-1 H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 355 except using 4-fluorobenzyl isocyanate instead of 3,4-dichlorobenzyl isocyanate. 'II NMR
(300 MHz, d6-DMSO) 8 8.78 (s, 1H), 8.05 (d, J=1.0 Hz, 1II), 7.65 (m, 1H), 7.36-7.41 (m, 2H), 7.12-7.28 (m, 4H), 6.82 (t, J=5.9 Hz, 1H), 4.33 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS
(ESF') m/z 299 (M+H)+.

Example 360 N-(2-fluorobenzyl)-N'-(1-methyl-1 H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 355 except using 2-fluorobenzyl isocyanate instead of 3,4-dichlorobenzyl isocyanate. 'H NMR
(300 MHz, d6-DMSO) S 8.83 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 7.05-7.28 (m, 4H), 6.89 (t, J=5.9 Hz, 1H), 4.37 (d, J=5.8 Hz-, 2H), 3.99 (s, 3H); MS (ESl+) mlz 299 (M+H)+.

Example 361 N-(l -(4-bromophenyl)ethyll-N'-(1-methyl-1 H-indazol-4-yl)urea The title compound was prepared using the procedure described in Example 355 except using 1-bromo-4-(1-isocyanatoethyl)benzene instead of 3,4-dichlorobenzyl isocyanate. 'H NUR (300 MHz, d6-DMSO) 6 8.66 (s, l1), 8.02 (s, 1H), 7.61 (d, J=7.4 Hz, 11-1), 7.54 (m, 2H), 7.33 (m, 2H), 7.23 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.85 (d, J=7.4 Hz, 1H), 4.83 (quintet, J=7.0 Hz, 1H), 3.99 (s, 3H), 1.42 (d, J=6.8 Hz, 31-1); MS
(ES[) m/z 373/375 (M+H, 79Br/I'Br)+.

Example 362 N-(1-methyl-IH-indazol-4-yl)-N'- j4 [(trifluoromethyl)thio}benzyl}urea The title compound was prepared using the procedure described in Example 355 except using 4-[(trifluoromethyl)thio]benzylamine instead of 4-tert-butylbenzylamine. 1H
NMR (300 MHz, d6-DMSO) S 8.86 (s, 1H), 8.06 (d, J=0.7 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.65 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.13-7.28 (m, 3H), 6.92 (t, J=5.9 Hz, 1H), 4.43 (d, J=6.1 Hz, 2H), 4.00 (s, 3H); MS (ESI) m/z 381 (M+H)+.

Example 363 N-(4-tert-butylbenz 1)-N'-(7-methyl-lH-indazol-4-yl)urea Example 363A
2,2,2-trichloro-N-(7-methyl-lH-indazol-4-yl)acetamide 7-Methyl-lH-indazol-4-amine (J. Chem. Soc. 1955, 2412; 550 mg, 3.74 mmol) and triethylamine (1.6 mL, 11.5 mmol) were combined in CH2C12 (22 rnL) and treated with trichloroacetyl chloride (0.54 mL, 4.84 mmol) dropwise at 0 C. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was concentrated and the residue was purified by flash chromatography (98:2, CH2C12:CH3OH), to provide the title compound.

Example 363B
N-(4-tert-butylbenzy1)-N'-(7-methyl- l H-indazol-4-y1)urea 2,2,2-Trichloro-N-(7-methyl-lH-indazol-4-yl)acetamide (72 mg, 0.25 mmol), 4-tert-butylbenzylamine (55 mg, 0.34 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.09 mL, 0.60 mmol) were combined in CH3CN (6 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with saturated aqueous solution. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to provide the title compound. The corresponding hydrochloride salt-was prepared with methanolic_HCI. 'H
NMR (300 MHz, d6-DMSO) 6 12.90 (br s, 1H), 7.94 (d, J=1.3 Hz, lH), 7.91 (s, 1H), 7.47 (m, 2H), 7.37 (m, 2H), 7.25 (m, 2H), 6.84 (t, J=5.8 Hz, 11), 4.26 (d, J=5.7 Hz, 2H), 2.35 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z 337 (M+11)+.

Example 364 N-(7-methyl1 H-indazol-4-yl)-N'-(4-(trifluoromethyl)benzyllurea The title compound was prepared using the procedure described in Example 363B
except using 4-(trifluoromethyl)benzylamine instead of 4-tert-butylbenzylamine. 'H NMR
(300 MHz, d6-DMSO) S 12.93 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=1.4 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.43 (m, 2H), 6.96 (m, 1H), 4.40 (d, J=5.8 Hz, 2H), 2.36 (s, 3H); MS (ESI+) m/z 349 (4+H) + .

Example 365 N-(7-methyl-lH-indazol-4-yl)-N'-{4-((trifluoromethyl)thio)benz 1 urea The title compound was prepared using the procedure described in Example 363B
except using 4-[(trifluoromethyl)thio]benzylamine instead of 4-tert-butylbenzylamine. 1H
NMR (300 MHz, d6-DMSO) 6 12.93 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=1.4 Hz, IH), 7.70 (d, J=8.1 Hz, 2H), 7.43-7.49 (m, 4H), 6.94 (m, 1H), 4.37 (d, J=6.1 Hz, 2H), 2.36 (s, 3H); MS
(ESI) m/z 381 (M+H)+.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims (18)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein --- is single bond;
X1 is CR1;
X2 is CR2;
X3 is N;
X4 is CR4;
X5 is N;
Z1 is O;
Z2 is NH;
L is alkylene;
R1, R5, R6, and R7 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NR A S(O)2R B, -S(O)2OR A, -S(O)2R B, -NZ A Z B, (NZ A Z
B)alkyl, (NZ A Z B)carbonyl, (NZ A Z B)carbonylalkyl or (NZ A Z B)sulfonyl, wherein Z A
and Z B are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl;
R2 and R4 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NR A S(O)2R B, -S(O)2OR A, -S(O)2R B, -NZ A Z B, (NZ A Z
B)alkyl, (NZ A Z B)alkylcarbonyl, (NZ A Z B)carbonyl, (NZ A Z B)carbonylalkyl, (NZ A Z
B)sulfonyl, (NZ A Z B)C(=NH)-, (NZ A Z B)C(=NCN)NH-, or (NZ A Z B)C(=NH)NH-;
R A is hydrogen or alkyl;
R B is alkyl, aryl, or arylalkyl;
R8a is hydrogen or alkyl;
R8b is absent; and R9 is hydrogen or cycloalkyl.

2. A compound according to claim 1 wherein X5 is N;
R8b is absent;
Z1 is O;
Z2 is NH;
L is alkylene; and R9 is cycloalkyl.

3. The compound according to claim 1 wherein X5 is N;
R1, R6 and R7 are each hydrogen;
R2 and R4 are independently hydrogen, alkyl, halogen, hydroxy, or -NZ A Z B;
R5 is hydrogen or halogen;
R8a is hydrogen;
R8b is absent;
Z1 is O;
Z2 is NH;
L is alkylene;
R9 is cycloalkyl wherein said cyloalkyl is adamantanyl, bicyclo[3.1.1]heptane, or cyclohexyl, wherein the cycloalkyl is optionally substituted with 1 or 2 alkyl substituents; and Z A and Z B are independently hydrogen or alkyl.

4. The compound according to claim 1 that is:
N-(1-adamantylmethyl)-N'-5-isoquinolinylurea;
N-(cyclohexylmethyl)-N'-5-isoquinolinylurea;
N-[(6,6-dimethylbicyclo [3.1.1 ]hept-2-yl)methyl]-N'-5-isoquinolinylurea;
N-[(4-tert-butylcyclohexyl)methyl]-N'-5-isoquinolinylurea; or N-5-isoquinolinyl-N'-{[4-(trifluoromethyl)cyclohexyl]methyl} urea.

5. The compound according to claim 1 wherein X5 is N;
Z1 is O;
Z2 is NH;
R8b is absent; and R9 is hydrogen.

6. The compound according to claim 1 wherein X5 is N;
R1, R2, R4, R5, R6 and R7 are each hydrogen;
R8a is hydrogen;
R8b is absent;
Z1 is O;
Z2 is NH;
L is alkylene; and R9 is hydrogen.

7. The compound according to claim 1 that is:
N-hexyl-N'-isoquinolin-5-ylurea;
N-5-isoquinolinyl-N'-pentylurea; or N-5-isoquinolinyl-N'-octylurea.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein --- is single bond;
X1 is CR1;
X2 is CR2;
X3 is N;
X4 is CR4;
X5 is C;
Z1 is O;
Z2 is NH;
L is -(CH2)m O(CH2)n- wherein the left end of -(CH2)m O(CH2)n- is attached to and the right end is attached to R9;
m and n are each independently 0-6;
R1, R5, R6, and R7 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NR A S(O)2R B, -S(O)2OR A, -S(O)2R B, -NZ A Z B, (NZ A Z
B)alkyl, (NZ A Z B)carbonyl, (NZ A Z B)carbonylalkyl or (NZ A Z B)sulfonyl, wherein Z A
and Z B are each independently selected hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl;
R2 and R4 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF3)2(HO)C-, -NR A S(O)2R B, -S(O)2OR A, -S(O)2R B, -NZ A Z B, (NZ A Z
B)alkyl, (NZ A Z B)alkylcarbonyl, (NZ A Z B)carbonyl, (NZ A Z B)carbonylalkyl, (NZ A Z
B)sulfonyl, (NZ A Z B)C(=NH)-, (NZ A Z B)C(=NCN)NH-, or (NZ A Z B)C(=NH)NH-;
R A is hydrogen or alkyl;
R B is alkyl, aryl, or arylalkyl;
R8a is hydrogen or alkyl;
R8b is hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, or hydroxy; and R9 is hydrogen.

9. The compound according to claim 8 wherein X5 is C;
R1, R6 and R7 are each hydrogen;
R2 and R4 are independently hydrogen, alkyl, halogen, hydroxy, or -NZ A Z B;
R5 is hydrogen or halogen;
R8a is hydrogen;
R8b is hydrogen;
Z1 is O;
Z2 is NH;
L is -(CH2)m O(CH2)n- wherein the left end is attached to Z2 and the right end is attached to R9;
m is 0-4;
n is 0-4;
R9 is hydrogen; and Z A and Z B are independently hydrogen or alkyl.

10. The compound according to claim 8 that is N-(3-butoxypropyl)-2-(5-isoquinolinyl)acetamide.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein --- is single bond;
X1 is CR1;
X2 is CR2;
X3 is N;

X4 is CR4;
X5 is C;
Z1 is O;
Z2 is O;
L is alkylene;
R1, R6, and R7 are each hydrogen;
R2 and R4 are independently hydrogen, alkyl, halogen, hydroxy, or -NZ A Z B;
R5 is hydrogen or halogen;
R8a is hydrogen or alkyl;
R8b is hydrogen, alkoxycarbonylalkyl, alkyl, or hydroxy;
R9 is hydrogen; and Z A and Z B are independently hydrogen or alkyl.

12. The compound according to claim 11 that is:
ethyl 5-isoquinolinylacetate;
ethyl 2-(5-isoquinolinyl)propanoate;
ethyl 2-(5-isoquinolinyl)butanoate;
ethyl 2-(5-isoquinolinyl)-2-methylpropanoate;

ethyl hydroxy(5-isoquinolinyl)acetate; or 4-tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate.

13. A compound that is:

methyl4-({[(1-naphthylmethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;

methyl4-({[(1,1'-biphenyl-3-ylmethyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;
methyl4-({[(2-chlorobenzyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;

methyl4-[({[2-fluoro-5-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;
N-(1,1'-biphenyl-3-ylmethyl)-N'-1H-indazol-4-ylurea;
N-(2-chlorobenzyl)-N'-1H-indazol-4-ylurea;
N-[2-fluoro-5-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-[2-(2,4-dimethylphenyl)ethyl]-N'-1H-indazol-4-ylurea;
N-[2-(3,4-dichlorophenyl)ethyl]-N'-1H-indazol-4-ylurea;
N-1H-indazol-4-yl-N'-[2-(4-methylphenyl)ethyl]urea;
N-[4-azepan-1-yl-3-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-[4-azepan-1-yl-2-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-[4-(2-azabicyclo[2.2.1]hept-2-yl)-2-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-2-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-[4-(8-azabicyclo [3.2.1]oct-8-yl)-3 -fluorobenzyl]-N'-1H-indazol-4-ylurea;
N-(3-chloro-4-azepan-1-ylbenzyl)-N'-1H-indazol-4-ylurea;
N-[(1S)-1-(4-bromophenyl)ethyl]-N'-1H-indazol-4-ylurea;
N-(3-bromo-4-fluorobenzyl)-N'-1H-indazol-4-ylurea;
N-(2,4-dimethylbenzyl)-N'-1H-indazol-4-ylurea;
N-(4-chlorobenzyl)-N'-1H-indazol-4-ylurea;
N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-1H-indazol-4-yl-N'-(4-methylbenzyl)urea;

N-1H-indazol-4-yl-N'-[3-(trifluoromethoxy)benzyl]urea;

N-(3-chloro-4-fluorobenzyl)-N'-1H-indazol-4-ylurea;
N-(3,4-dimethylbenzyl)-N'-1H-indazol-4-ylurea;
N-[3-fluoro-5-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-(2-chloro-4-azepan-1-ylbenzyl)-N'-1H-indazol-4-ylurea;
N-(2,3-dichlorobenzyl)-N'-1H-indazol-4-ylurea;
N-1H-indazol-4-yl-N'-{4-[(trifluoromethyl)thio]benzyl}urea;
N-1H-indazol-4-yl-N'-[3-(trifluoromethyl)benzyl]urea;
N-(3,5-difluoro-4-azepan-1-ylbenzyl)-N'-1H-indazol-4-ylurea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-3,5-difluorobenzyl]-N'-1H-indazol-4-ylurea;

N-(4-chlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzyl]-N'-1H-indazol-4-ylurea;
methyl4-[({[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-chlorobenzyl]-N'-1H-indazol-4-ylurea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)benzyl]-N'-1H-indazol-4-ylurea;
N-(4-tert-butylbenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea;
N-[4-chloro-3-(trifluoromethyl)benzyl]-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(3,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(2,4-dichlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(4-ethylbenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(2-chlorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(4-fluorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(2-fluorobenzyl)-N'-(1-methyl-1H-indazol-4-yl)urea;
N-[1-(4-bromophenyl)ethyl]-N'-(1-methyl-1H-indazol-4-yl)urea;
N-(1-methyl-1H-indazol-4-yl)-N'-{4-[(trifluoromethyl)thio]benzyl}urea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzyl]-N'-1H-indazol-4-ylurea;
N-[4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzyl]-N'-1H-indazol-4-ylurea;
N-(4-tert-butylbenzyl)-N'-(7-methyl-1H-indazol-4-yl)urea;
N-(7-methyl-1H-indazol-4-yl)-N'-[4-(trifluoromethyl)benzyl]urea;
N-(7-methyl-1H-indazol-4-yl)-N'-{4-[(trifluoromethyl)thio]benzyl}urea;
N-1H-indazol-4-yl-N'-(1-naphthylmethyl)urea;

N-1H-indazol-4-yl-N'-(3-phenylpropyl)urea;
N-1H-indazol-4-yl-N'-{[6-(trifluoromethyl)-3-pyridinyl]methyl}urea; or N-(1-methyl-1H-indazol-4-yl)-4-[4-(trifluoromethyl)-2-pyridinyl]-1-piperazinecarboxamide.

14. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1, 8, or 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant or carrier.

15. Use of the compound of formula (I) according to any one of claims 1, 8, or 11, or a pharmaceutically acceptable salt thereof for treatment of a disorder that is ameliorated by inhibition of vanilloid receptor subtype 1(VR1) receptor in a host mammal in need of such treatment.

16. Use of the compound of formula (I) according to any one of claims 1, 8, or 11, or a pharmaceutically acceptable salt thereof for treatment of bladder overactivity in a host mammal in need of such treatment.

17. Use of the compound of formula (I) according to any one of claims 1, 8, or 11, or a pharmaceutically acceptable salt thereof for treatment of urinary incontinence in a host mammal in need of such treatment.

18. Use of the compound of formula (I) according to any one of claims 1, 8, or 11, or a pharmaceutically acceptable salt thereof for treatment of inflammatory thermal hyperalgesia in a host mammal in need of such treatment.