# US 7,745,440 B2 · Pyrazole analogs acting on cannabinoid receptors

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- Number: US 7,745,440 B2
- Document ID: US7745440B2
- Status: Granted
- Kind: B2
- Application number: 11/244,770
- Filed: 2005-10-06
- Published: 2006-02-09
- Granted: 2010-06-29
- Earliest claimed: 1999-10-18
- Assignees: University of Connecticut
- Inventors: Alexandros Makriyannis; Qian Liu; Rajesh Thotapally
- Web page: https://patentgrep.com/patent/US7745440B2

## CPC

- C07D 401/00: Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

One aspect of the invention is concerned with cannabimimetic pyrazole analogs. Another aspect of the invention is concerned with new and improved pyrazole analogs having high affinities and/or selectivities for the CB1 cannabinoid receptor. A further aspect of the invention is concerned with pharmaceutical preparations employing the inventive analogs and methods of administering therapeutically effective amounts of the inventive analogs to provide a physiological effect.

## Claims

### Claim 1

A compound of formula I below, and physiologically acceptable salts thereof, comprising:
wherein:
A is a direct bond
B is N;
R1 is —(CH2)n—Z, wherein,
n is an integer from 0 to about 10,
Z is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CH═CH2, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino and di-alkylamino,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2, and
d is an integer from 0 to about 6;
R2 is selected from
wherein Y is selected from H, halogen, N3, NCS, Ph (phenyl), CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkyl, CH═CH2, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2;
R3 is selected from H, halogen, N3, NCS, Ph, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino or di-alkylamino, alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently selected from H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R3 is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; or
R3 is selected from
R3 is —CH2—Z,
Z is selected from H, halogen, N3, NCS, Ph, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently selected from H or alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R3 is selected from —CH2OH and —CH2Oalkyl; or
R3 is —CH2—Z,
Z is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring or a heterotricyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R3 is —CH2—Z,
Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n—group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R3 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from H, halogen, N3, NCS, Ph, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, O(CH2)dOH, O(CH2)dNX1X2, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R3 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n—group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R3 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R3 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from
wherein X and Y are each independently selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF3, alcohol, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and (when Z comprises a structure having two adjacent carbon atoms) methylene dioxy,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2;
R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, O(CH2)dOH, O(CH2)dNX1X2, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently is selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from
wherein X and Y are each independently is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and (when Z comprises a structure having two adjacent carbon atoms) methylene dioxy,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
X4 is selected from H and alkyl; or
R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino and di-alkylamino,
X1 and X2 are each independently is selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3-or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from
wherein X and Y are each independently selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF3, alcohol, COOX3, SO3H, SO2NX1X2, COONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and (when Z comprises a structure having two adjacent carbon atoms) methylene dioxy, and X4 is selected from H and alkyl; or
R4 is —(CH2)n-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
each n is independently an integer from 0 to about 7,
Z is selected from an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members; or
R4 is —CH2-Q-(CH2)n—Z,
Q is selected from N, O, S, CH3, SO2 and OSO2,
n is an integer from 0 to about 7,
Z is selected from
R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino alkylsulfinyl and alkylsulfonyl,
X1 and X2 are each independently is selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2, and
d is an integer from 0 to about 6; or
R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the —(CH2)n— group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or
R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from
wherein X and Y are each independently selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, alcohol, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl and (when Z comprises a structure having two adjacent carbon atoms) methylene dioxy,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
X4 is selected from H and alkyl; or
R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members, and an unsaturated ring having 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members; or
R4 is -Ph-(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, O(CH2)dOH, O(CH2)dNX1X2, NH-acyl, NH-aroyl, CHO, CF3, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino and di-alkylamino,
X1 and X2 are each independently selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
d is an integer from 0 to about 6; or
R4 is -Ph-(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from
wherein X and Y are each independently selected from H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, CHO, CF3, alcohol, COOX3, SO3H, SO2NX1X2, CONX1X2, alkoxy, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, lower-alkylsulfonyl and (when Z comprises a structure having two adjacent carbon atoms) methylene dioxy,
X1 and X2 are each independently is selected from H and alkyl, or
X1 and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally a second heteroatom selected from O, N or S, or
X1 and X2 together comprise part of an imide ring having about 5 to about 6 members,
X3 is selected from H, alkyl, hydroxyloweralkyl and alkyl-NX1X2,
X4 is selected from H and alkyl; or
R4 is -Ph-(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from
E is selected from a C1 to about C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; or
R4 is -Ph-(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from
m is an integer from 1 to about 5,
A1 and A2 are each independently selected from a C1 to about C4 alkyl group, a phenyl group and a substituted phenyl group; or
wherein B, D and F are each independently selected from halogen, N3, NCS, OCH3, CH3, CH2CH3, NO2, NH2, phenyl and phenyl with at least one substituent selected from H, halogen, N3, NCS, OCH3, CH3, CH2CH3, NO2, and NH2; and
R5 is present only when B is N and if present is selected from H, alkyl and substituted alkyl;
with the provisos that:
when A is a direct bond and B is N then R1 cannot be H;
when A is not a direct bond and B is N then R3 cannot be H or a C1-C3 alkyl;
when A is a direct bond and B is N and R5 is hydrogen and R2 has a nitrogen directly connected to the nitrogen of the amide at the 3-position of pyrazole ring, then R4 can not be a phenyl ring or a phenyl ring having one to three substitutions selected from halogen, trifluoromethyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl, lower-alkyl substituted 1-pyrrolidinyl, lower-alkyl substituted 1-piperidinyl, lower-alkyl substituted 4-morpholinyl, and lower-alkyl substituted 1-piperazinyl.

### Claim 2 (depends on 1)

The compound of claim 1, and physiologically acceptable salts thereof, wherein R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members, and an unsaturated ring having 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members.

### Claim 3 (depends on 1)

The compound of claim 1, and physiologically acceptable salts thereof, wherein R4 is —(CH2)n—Z,
n is an integer from 0 to about 7,
Z is selected from an unsaturated ring having 5 to 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 to 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members.

### Claim 4 (depends on 1)

The compound of claim 1, and physiologically acceptable salts thereof, wherein R4 is -T-(CH2)n—Z,
n is an integer from 0 to about 7,
T is selected from a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring,
Z is selected from an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members, and an unsaturated ring having 6 ring atoms and 0 to 5 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 5 independently selected heteroatoms as ring members.

### Claim 5 (depends on 1)

The compound of claim 1, and physiologically acceptable salts thereof, wherein R4 is a phenyl ring linked to a terminal unsaturated ring having 5 ring members and 4 nitrogen atoms as ring members.

### Claim 6 (depends on 1)

A pharmaceutical composition for an individual or animal comprising a therapeutically effective amount of at least one compound of claim 1 or a physiologically acceptable salt thereof.