WO2006131807A1 - Preparation of 3-amino-4,5-disubstituted-pyrazole derivatives - Google Patents

Abstract

A process for preparing a compound of Formula (I) is described herein as well as rocesses for using this compound to prepare other useful intermediates and compounds.

Description

PREPARATION OF 3-AMINO-4,5-DISUBSTITUTED-PYRAZOLE DERIVATIVES

FIELD OF INVENTION

The present invention relates to a process for preparing 3-amino-4,5-disubstituted- pyrazole derivatives, in particular, 3-amino-4,5-diphenyl-pyrazole derivatives and the uses thereof to produce intermediates and compounds that are useful CB-1 antagonists.

BACKGROUND

7,8-Diarylsubstituted-pyrazolo[1,5-a][1 ,3,5]triazin-4-yl-amino compounds have been shown to be useful cannabinoid-1 receptor (CB-1) antagonists. See, e.g., US Publication No. 2004/0157839 and PCT Publication No. WO 2005/049615. In US 2004/0157839 and WO 2005/049615, the pyrazolotriazinone intermediates used in the synthesis of these CB-1 antagonists are prepared from a 5-subsituted pyrazole-3-ylamine (e.g., 5-(2-chlorophenyl)- 2H-pyrazol-3-ylamine) starting material. Although this preparation provides a reasonable route of synthesis in good yields, there is a need for a more streamline and operationally friendly synthesis for larger manufacturing scale reactions.

SUMMARY

The present invention provides a process for preparing the intermediate compound of Formula (I)

(D wherein R^Oa, R^ob, R^1a, and R^1b are each independently halo, (C_rC₄)alkoxy, (C_rC₄)alkyl, halo- substituted (C_rC₄)alkyl, or cyano (preferably, R^Oa and R^1a are both chloro); and n and m are each independently 0, 1 or 2 (preferably, n and m are both 0). The process comprises the steps of (i) reacting a compound of Formula (1a) with a compound of Formula (1b) in the presence of an acid (preferably a protic acid)

(1a) (1b) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for the compound of Formula (I) and Pg is an amino-protecting group (preferably, benzyl, allyl or benzhydryl); and (ii) removing the protecting group (Pg) to produce the compound of Formula (I). In a preferred embodiment, steps (i) and (ii) are accomplished in a one-pot reaction.

In another embodiment of the present invention, a process is provided for preparing a compound of Formula (II)

(H) where R^Oa, R⁰ , R^1a, R^1b, n and m are as defined above for the compound of Formula (I) and R³ is hydrogen, (C₁-C₄JaIKyI, halo-substituted (C_rC₄)alkyl, or (C_rC₄)alkoxy. The process comprises the steps of converting the compound of Formula (I) to a compound of Formula (II). In yet another embodiment of the present invention, a process is provided for the preparation of compounds of Formula (III)

(III) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for the compound of Formula (I); R³ is hydrogen, (C_rC₄)alkyl, halo-substituted (C₁-C₄)BIkVl, or (C₁-C₄JaIkOXy; and R⁴ is a group having Formula (IA)

JA where R^4b and R^4b are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (Ci-C₆)alkyl, (C_rC₆)alkoxy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (d-C^alkyl-NH-C^)-, (C₁-C₄)alkyl)₂N-C(O)-, (C_rC₆)alkylamino-, ((Ci-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(C_rC₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4b or R^4b' taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge, or an ethylene bridge; X is a bond, -CH₂CH₂- or -C(R^4c)(R^4c')-, where R^4c and R^4c' are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C_rC₆)alkoxy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁-C₄)alkyl-NH- C(O)-, ((C_rC₄)alkyl)₂N-C(O)-, (C_rC₆)alkylamino-, di(C_rC₄)alkylamino-, (C₃- C₆)cycloalkylamino-, acylamino-, aryl(C_rC₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R⁴⁰ or R^4c' taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge or an ethylene bridge; Y is oxygen, sulfur, -C(O)-, or -C(R^4d)(R^4d')-, where R^4d and R^4d' are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (Ci-C_β)alkyl, (CrC₆)alkoxy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁-C₄)alkyl-NH-C(O)-, ((C₁-C₄)alkyl)₂N-C(O)-, (d-CβJalkylamino-, di(C_rC₄)alkylamino-, (C₃- C₆)cycloalkylamino-, acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or R^4d and R^4d taken together form a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, where said heterocyclic ring, said lactone ring and said lactam ring are optionally substituted with one or more substituents and said lactone ring and said lactam ring optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur, or

Y is -NR^{4d "}-, where R^4d" is a hydrogen or a chemical moiety selected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (d-C^alkylsuIfonyl-, (C₁-C₃)alkylaminosulfonyl-, di(Ci-C₃)alkylaminosulfonyl-, acyl, (d-C₆)alkyl-O-C(O)-, aryl, and heteroaryl, where said moiety is optionally substituted with one or more substituents;

Z is a bond, -CH₂CH₂-, or -C(R^4e)(R^4e')-, where R^4e and R^4e' are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C₁-C₆)BIkOXy, acyloxy, acyl, (Ci-C₃)alkyl-O-C(O)-, (C_rC₄)alkyl-NH- C(O)-, ((C₁-C₄)alkyl)₂N-C(O)-_> (d-CeJalkylamino-, di(C₁-C₄)alkylamino-, (C₃- C₆)cycloalkylamino-, acylamino-, aryKd-C^alkylamino-, heteroaryl(C_rC₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fuily saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4e or R^4e' taken together with R^4b, R^4b', R^4c, or R^4c' forms a bond, a methylene bridge or an ethylene bridge; and

R^4f and R^4f are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C₁-C₆)B^yI, (C₁-C₆)BIkOXy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁-C₄)alkyl-NH-C(O)-_> ((C_rC₄)aikyl)₂N-C(O)-, (C_rC₆)alkylamino-, di(Ci-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(CrC₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyciic ring, where said moiety is optionally substituted with one or more substituents, or either R^4f or R^4f taken together with R^4b, R^4b', R^4c, or R^4c' forms a bond, a methylene bridge or an ethylene bridge. The process comprises the steps of converting the carbonyl group of the compound of Formula (II) to a leaving group and reacting the leaving group with an amino compound R⁴- H, where R⁴ has the same meaning as above. Preferably, R⁴ is 3-ethylamino-azetidine-3- carboxylic acid amide. A preferred compound of Formula (III) is one where R^4b and R^4b are each independently hydrogen, H₂NC(O)-, or a chemical moiety selected from the group consisting of (d-C₆)alkyl, acyl, (C₁-C₃)alkyl-O-C(O)-, (C_rC₄)alkyl-NH-C(O)-, (C_rC₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4b or R^4b' taken together with R^4e, R^4e', R^4f, or R^4r forms a bond, a methylene bridge, or an ethylene bridge;

X is a bond, -CH₂CH₂- or -C(R^4o)(R^40')-, where R⁴⁰ is hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (Ci-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O-C(O)-, (d-C₄)alkyl-NH-C(O)-, (C₁-C₄)alkyl)₂N- C(O)-, (d-C^alkylamino-, ((C_rC₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, ary!(C_r C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4c taken together with R^4e, R^4e', R^4f, or R^4r forms a bond, a methylene bridge, or an ethylene bridge, and R^4c' is hydrogen, H₂NC(O)-, or a chemical moiety selected from the group consisting of (d-C₆)alkyl, acyl, (C_rC₃)alkyl-O-C(O)-, (C_rC₄)alkyl-NH-C(O)-, (C_rC₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^40' taken together with R^4e, R^4e', R^4f, or R^4r forms a bond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur, -C(O)-, or -C(R^4d)(R^4d')-, where R^4d is hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (d-C₆)alkyl, (C_rC₆)alkoxy, acyloxy, acyl, (C_rC₃)a)kyl-O-C(O)-, (d-C₄)alkyl-NH-C(O)-, (d-C₄)alkyl)₂N- C(O)-, (d-Cg)alkylamino-, ((d-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(d- C₄)alkylamino-, heteroaryl(Ci-C₄)alkylamino-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, and R^4d' is hydrogen, H₂NC(O)-, or a chemical moiety selected from the group consisting of (d-C₆)alkyl, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁- d)alkyl-NH-C(O)-, (C_rC₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6- membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4d and R^4d' taken together form a partially or fully saturated, 3- to 6-membered heterocyclic ring, a 5- or 6-membered lactone ring, or a 4- to 6-membered lactam ring, where the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted and the lactone ring and the lactam ring optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur, or

Y is -NR^4d -, where R^4d is a hydrogen or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C₃-C₆)cycloalkyl, (CrC₃)alkylsulfonyl-, (C_rC₃)alkylaminosulfonyl-, di(C_rC₃)alkylaminosulfonyl-, acyl, (C_t-C₆)a\ky\-O-C(O)-, aryl, and heteroaryl, where the moiety is optionally substituted;

Z is a bond, -CH₂CH₂-, or -C(R^4e)(R^4e')-, where R^4e is hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C_rC₆)alkoxy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁-C₄)B^yI-NH-C(O)-, (C_rC₄)alkyl)₂N- C(O)-, (CrCβJalkylamino-, ((C-|-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, ary^C^ C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4e taken together with R^4b, R^4b', R^4c, or R^4c' forms a bond, a methylene bridge, or an ethylene bridge, and R^4e' is hydrogen, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O-C(O)-, (C_t-C₄)alkyl-NH-C(O)-, (C_rC₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4e taken together with R^4b, R^4b, R^4c, or R⁴° forms a bond, a methylene bridge, or an ethylene bridge; and R^4f and R^4f are each independently hydrogen, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, acyl, (C_rC₃)aIkyl-O-C(O)-, (C₁-C₄)alkyl- NH-C(O)-, (C_rC₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6- membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted, or R^4f or R^4f taken together with R^4b, R^4b', R^4c, or R⁴° forms a bond, a methylene bridge, or an ethylene bridge; a pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.

Preferably, R^4b is hydrogen, an optionally substituted (C_rC₃)alkyl, or taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge, or an ethylene bridge; R^4b' is hydrogen, an optionally substituted (C_rC₃)alkyl, or taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge, or an ethylene bridge; R^4f is hydrogen, an optionally substituted (C_rC₃)alkyl, or taken together with R^4b, R^4b>, R^4c, or R^4c' forms a bond, a methylene bridge, or an ethylene bridge; and R^4f is hydrogen, an optionally substituted (C₁- C₃)alkyl, or taken together with R^4b, R^4b', R^4c, or R^4c' forms a bond, a methylene bridge, or an ethylene bridge, and even more preferably, R^4b, R^4b', R^4f, and R^4r are all hydrogen.

When Y is -NR^{4d '}-, then R^4d" is preferably a hydrogen or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C₃-C₆)cycloalkyl, (C^C^alkylsulfonyl, (C₁- C₃)alkylaminosulfonyl, di(C_rC₃)alkylaminosulfonyl, acy), (C₁-C₆)alkyl-O-C(O)-, aryl, and heteroaryl, where the moiety is optionally substituted (more preferably, R^d is a hydrogen or a chemical moiety selected from the group consisting of (Ci-C₃)alkylsulfonyl, (C₁- C₃)alkylaminosulfonyl, diXCrCsJalkylaminosulfonyl, acyl, (C_rC₆)alkyl-O-C(O)-, and heteroaryl, where the moiety is optionally substituted (preferably the (C_t-Csjalkylsulfonyl, (C₁- C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆JaIKyI-O-C(O)- are optionally substituted with 1 to 3 fluorines, and the heteroaryl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of chloro, fluoro, (C₁- C₃)alkoxy, (C₁-C₃)BlKyI, and fluoro-substituted (C₁-C₃)alkyl); X is -C(R^4c)(R^4c')-, where R^4c and R^4c> are each independently hydrogen, H₂NC(O)-, an optionally substituted (C_rC₆)alKyl, (C_rC₄)alkyl-NH-C(O)-, or ((C₁-C₄JaIKyI)₂N-C(O)-, or either R^4c or R^40' taken together with R^4e, R^4e', R^4f, or R^4r forms a bond, a methylene bridge or an ethylene bridge; and

Z is -C(R^4e)(R^4e')-, where R^4e and R^4e' are each independently hydrogen, H₂NC(O)-, an optionally substituted (C_rC₆)alkyl, (C_rC₄)alkyl-NH-C(O)-, or ((C₁-C₄)alkyl)₂N-C(O)-, or either R^4e or R^4e' taken together with R^4b, R^4b', R^4c, or R^4c' forms a bond, a methylene bridge or an ethylene bridge.

When Y is -C(R^4d)(R^4d')-, then R^4d is hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (Ci-C₆JaIKyI, (C₁-C₆JaIKoXy, acyloxy, acyl, (C_rC₃)alkyl-O-C(O)-, (C₁-C₄JaIKyI-NH-C(OJ-, (C₁-C₄JaIKyI)₂N-C(O)-, (C,-C₆)alkylamino-, ((C_rC₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted (preferably, R^4d is amino, (CrCβJalkylamino, di(C₁- C₄)alkylamino, (C₃-C₆)cycloalkylamino, acylamino, aryl(C₁-C₄)alkylamino-, or heteroary^C^ C₄)alkylamino, more preferably, R^4d is amino, (CpCeJalKylamino, di(C₁-C₄)alkylamino, (C₃- C₆)cycloalkylamino), and

R^4d is hydrogen, H₂NC(OJ-, or a chemical moiety selected from the group consisting of (C₁-C₆JaIKyI, acyl, (C₁ -C₃JaI kyl-O-C(O)-, (C_rC₄)alkyl-NH-C(O)-, (d-C₄)alkyl)₂N-C(O)-, aryl, heteroaryl, a partially or fully saturated 3- to 6-membered heterocycle, and a partially or fully saturated 3- to 8-membered carbocyclic ring, where the moiety is optionally substituted (preferably, R^4d' is (C₁-C₆JaIKyI, H₂NC(OJ-, (C_rC₄)alkyl-NH-C(O)-, or ((C_rC₄)alkyl)₂N-C(O)-, or aryl, more preferably, R^4d' is H₂NC(OJ-, (C₁-C₄ Jalkyl-N H-C(OJ-, or ((C₁-C₄)alkyl)₂N-C(O)-J, or R^4d and R^4d taken together form a partially or fully saturated, 3- to 6-membered heterocyclic ring, a 5- to 6-membered lactone ring, or a 4- to 6-membered lactam ring, where the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted and the lactone ring and the lactam ring optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur;

X is a bond or -C(R^4c)(R^40')-, where R^4c and R^40' are each hydrogen; and Z is a bond or -C(R^4e)(R^4e')~, where R^4e and R^4e' are each hydrogen. Another preferred compound of Formula (III) is one where Y is

-C(R^4d)(R^4d')-, R^4b, R^4b', R^4f, and R^4f are all hydrogen; R^4d is hydrogen, hydroxy, amino, or a chemical moiety selected from the group consisting of (Ci-CβJalkyl, (C-|-C₆)alkoxy, acyloxy, acyl, (Ci-C₃)aIkyl-O-C(O)-₇ (CrCeJalkylamino-, and difCrG^alkylamino-, where the moiety is optionally substituted (preferably, R^4d is hydrogen, hydroxy, amino, or a chemical moiety selected from the group consisting of (Ci-C₆)alkoxy, acyl, (C-ι-C₆)a!kylamino-, and di(C₁-C₄)alkylamino-); and R^4d is hydrogen, or a chemical moiety selected from the group consisting of (Ci-C₆)alkyl, aryl and heteroaryl, where the moiety is optionally substituted (preferably, R^4d is hydrogen, or a chemical moiety selected from the group consisting of (C₁- C₆)alkyl and aryl, where the moiety is optionally substituted). In this embodiment, X is preferably -C(R^4c)(R^4c')-, where R^4c and R^4c' are each independently hydrogen or an optionally substituted (C_rC₆)alkyl, or either R^4G or R^40' taken together with R^4e or R^46' forms a bond, a methylene bridge or an ethylene bridge (preferably, R^4c and R^4c are each hydrogen or either R^4c or R^4c' taken together with R^4e or R^4e' forms a bond); and Z is preferably - C(R^4e)(R^4e')-, where R^4e and R^4e' are each independently hydrogen or an optionally substituted (Ci-C₆)alkyl, or either R^4e or R^4e' taken together with R^4c or R^4c' forms a bond, a methylene bridge or an ethylene bridge (preferably, R^4e and R^4e are each hydrogen or either R^4e or R^4e taken together with R⁴⁰ or R^4c' forms a bond).

Yet another preferred compound of Formula (III) is one where Y is

-C(R^4d)(R^4d')-, R^4b, R^4b', R^4f , and R^4r are all hydrogen; and R^4d and R^4d' taken together form a partially or fully saturated 3- to 6-membered heterocyclic ring, a 5- to 6-membered lactone ring, or a 4- to 6-membered lactam ring, where the heterocyclic ring, the lactone ring and the lactam ring are optionally substituted and the lactone ring or the lactam ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur (preferably, R^4d and R^4d> taken together form a 5 to 6 membered lactam ring, where the lactam ring is optionally substituted and optionally contains an additional heteroatom selected from nitrogen or oxygen). In this embodiment, X is preferably a bond, -CH₂CH₂- or -C(R^4c)(R^4c')-, where R^4c and R^4ύ are each independently hydrogen or an optionally substituted (C_rC₆)alkyl, or either R^4c or R^40' taken together with R^4e or R^4e' forms a bond, a methylene bridge or an ethylene bridge (more preferably, X is a bond or -C(R^4c)(R^40')-, where R^4c and R^4c> are each hydrogen); and Z is preferably a bond, -CH₂CH₂- or -C(R^4e)(R^4e)-, where R^4e and R^4e' are each independently hydrogen or an optionally substituted (CrC₆)alkyl, or either R^4e or R^4e taken together with R^4c or R^4c forms a bond, a methylene bridge or an ethylene bridge (more preferably, Z is a bond or -C(R^4e)(R^4e')-, where R^4e and R^4e' are each hydrogen).

In yet another embodiment of the present invention, a process is provided for preparing a compound of Formula (IV)

(IV) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for the compound of Formula (I); R³ is hydrogen, (C,-C₄)alkyl, halo-substituted (C_rC₄)alkyl, or (C_rC₄)alkoxy; and R⁵ is (CrCsJalkyl, aryl(CrC₄)alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), or heteroaryl(C₁-C₃)alkyl. The process comprises the step of N-alkylating the compound of Formula (II) to form the compound of Formula (IV).

DEFINITIONS

As used herein, the term "optionally substituted" refers to moieties that may be unsubstituted or substituted with one or more substituents (preferably, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls). The substituents may be the same or different The term "substituted" specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament. The term "alkyl" refers to a hydrocarbon radical of the general formula C_nH_2n+1. The alkane radical may be straight or branched. For example, the term "(Ci-C₄)alkyl" refers to a monovalent, straight, or branched aliphatic group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, s-butyl, and f-butyl). The alkyl portion of an alkoxy group has the same meaning. When substituted, the, alkane radicals or alkyl moieties are preferably substituted with 1 to 3 fluoro substituents, or 1 or 2 substituents independently selected from (d-Cs^lkyl, (C₃-C_δ)cycloalkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6- membered heterocycle, chloro, cyano, hydroxy, (C₁-C₃)BIkOXy, aryloxy, amino, (C_rC₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate (i.e., (C_rC₃)alkyl-O-C(O)-NH-), hydroxy(C₂- C₃)alkylamino, or keto (oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituent selected from (C₁-C₃)BlKyI, (C₃-C₆)cycloalkyl, (C₆)aryl, 6-membered-heteroaryl, 3- to 6- membered heterocycle, (C₁-C₃JaIkOXy, (C₁-C₄JaIRyI amino or d J-(C₁ -C₂)alkyl amino.

The term "halo-substituted alkyl" refers to an alkyl group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, and the like). The term "halo" refers to a chloro, bromo, fluoro or iodo group (including radio-labeled halogen atoms).

The terms "partially or fully saturated carbocyclic ring" (also referred to as "partially or fully saturated cycloalkyl") refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8-membered ring (preferably, 3- to 6- membered ring). For example, partially or fully saturated carbocyclic rings (or cycloalkyl) include groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl, bicyc!o[2.2.2]octyl, and the like. When designated as being "optionally substituted", the partially saturated or fully saturated cycloalkyl group may be unsubstituted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted." A substituted carbocyclic ring also includes groups wherein the carbocyclic ring is fused to a phenyl ring (e.g., indanyl). The carbocyclic group may be attached to the chemical entity or moiety by any one of the carbon atoms within the carbocyclic ring system. When substituted, the carbocyclic group is preferably substituted with 1 or 2 substituents independently selected from (C-,-C₃)alkyl, (C₂-C₃)alkenyl, (C₁- C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (C₁-C₃JaIkOXy, aryloxy, amino, (CrC_θJalkyl amino, di-(C-i-C₄)alkyl amino, aminocarboxylate (i.e., (CrC₃)alkyl-O-C(O)-NH-), hydroxy(C₂-C₃)alky!amino, or keto (oxo), and more preferably 1 or 2 from substituents independently selected from (C^CaJalkyl, 3- to 6-membered heterocycle, fluoro, (C₁-C₃JaIkOXy, (C₁-C₄JaIk^ amino or di^C^CaJalkyl amino. Similarly, any cycloalkyl portion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definition as above. The term "partially saturated or fully saturated heterocyclic ring" (also referred to as

"partially saturated or fully saturated heterocycle") refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the heterocyclic ring is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently independently selected from sulfur, oxygen or nitrogen. Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, and the like. When indicated as being "optionally substituted", the partially saturated or fully saturated heterocycle group may be unsubstiuted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted." A substituted heterocyclic ring includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, 2,3- dihydroindolyl, 2,3-dihydrobenzothiophenyI, 2,3-dihydrobenzothiazolyl, etc.). When substituted, the heterocycle group is preferably substituted with 1 or 2 substituents independently selected from

(C₃-C₆)cycloalkyl, (C₂-C₄)alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (C₁-C₃JaIkOXy, aryloxy, amino, (Ci-C₆)alkyl amino, di-(CrC₃)alkyl amino, aminocarboxylate (i.e., (C₁-C₃)alkyl-O-C(O)-NH-), or keto (oxo), and more preferably with 1 or 2 substituents independently selected from (C₁- C₃)a!kyl, (C₃-C₆)cycloalkyl, (C₆)aryl, 6-membered-heteroaryl, 3- to 6-membered heterocycle, or fluoro. The heterocyclic group may be attached to the chemical entity or moiety by any one of the ring atoms within the heterocyclic ring system. Similarly, any heterocycle portion of a group (e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.) has the same definition as above.

The term "aryl" or "aromatic carbocyclic ring" refers to aromatic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a 6- to 10-membered aromatic carbocyclic ring(s). When indicated as being "optionally substituted", the aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted." Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.). When substituted, the aromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (C₁-C₄)alkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C₁-C₄)BIkOXy, aryloxy, amino,

amino, di-(Ci-C₃)alkyl amino, or aminocarboxylate (i.e., (C_rC₃)alkyl-O-C(O)-NH-), and more preferably, 1 or 2 substituents independently selected from (CrC^alkyl, chloro, fluoro, cyano, hydroxy, or (C₁-C₄JaIkOXy. The aryl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the aromatic ring system. Similarly, the aryl portion (i.e., aromatic moiety) of an aroyl or aroyloxy (i.e., (aryl)-C(O)-O-) has the same definition as above. The term "heteroaryl" or "heteroaromatic ring" refers to aromatic moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.). The heteroaromatic moiety may consist of a single or fused ring system. A typical single heteroaryl ring is a 5- to 6-membered ring containing one to three heteroatoms independently selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen. When indicated as being "optionally substituted", the heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted." When substituted, the heteroaromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (Ci-C₄)alkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C₁-C₄)alkoxy, aryloxy, amino, (C-|-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, or aminocarboxylate (i.e., (CVCsJalkyl-O-C^OJ-NH-), and more preferably, 1 or 2 substituents independently selected from (Ci-C₄)alkyl, chloro, fluoro, cyano, hydroxy, (C_rC₄)alkoxy, (C₁-C₄)alkyl amino or di-(CrC₂)alkyl amino. The heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-y!, imidazol- 2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl). Similarly, the heteroaryl portion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaroyloxy (i.e., (heteroaryl)-C(O)-O-) has the same definition as above.

The term "acyl" refers to alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. For example, acyl includes groups such as (CVC₆)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, f-butylacetyl, etc.), (C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thiophenyl-2- carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyrroylr2-carbonyl, 1 H-pyrroyl-3-carbonyl, benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions above. When indicated as being "optionally substituted", the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted" or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively. The term "protecting group" or "Pg" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include benzyl, allyl and benzhydryl.

The term "protic acid" refers to a compound that donates at least one hydrogen ]on (H+) to another compound. Typical protic acids include acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzensulfonic acid, acetic acid, and the like.

DETAILED DESCRIPTION

The starting materials used in the processes described herein are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4,. Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

Scheme I below summarizes the process of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives.

(1a) (I)

SCHEME I The α-bromo-benzyl ketone starting material (1 a) may be prepared from the desired

Oa p-R -substituted benzyl bromide (i.e., p-chlorobenzyl bromide) and the desired o-R - substituted benzoyl chloride (e.g., o-chlorobenzoyl chloride) by the combined use of Zn and a palladium catalyst under mild conditions followed by bromination using a conventional α- bromination procedure well-known to those skilled in the art (e.g., treating with bromine in a mildly acidic solvent, such as methylene chloride/acetic acid mixture). The thiosemicarbazide starting material (1b) may be prepared using procedures analogous to those described in Chem. Ber., 45, 2194 (1912). For example, the desired amino-protected isothiocyanate may be reacted with hydrazine hydrate in a polar protic solvent (e.g., ethanol) at or near room temperature.

The α-bromo-benzyl ketone starting material (1a) is condensed with the thiosemicarbazide starting material (1b) in the presence of a protic acid (e.g., hydrochloric acid, hydrobromic acid, and acetic acid) in a polar protic or aprotic solvent (e.g., ethanol, methanol, isopropanol, and acetonitrile). Once condensed to the cyclic product, the protecting group is then removed using conventional methods for the particular protecting group employed. The amino-protected cyclic compound may be isolated prior to the removal of the protecting group (e.g., compounds where Pg is benzyl or allyl) or removed without isolation of the amino-protected compound (e.g., Pg is benzhydryl). A benzyl-protecting group may be removed by hydrogenation in the presence of Pd/C. An allyl-protecting group may be removed using the procedures described by Jaime-Figueroa, et al., in Tetrahedron Lett. 39, 1313 (1998), e.g., treatment with catalytic amounts of 10% Pd/C in boiling ethanol containing an equivalent of methanesulfonic acid. A benzhydryl-protecting group may be removed in a single pot reaction by heating the condensation reaction mixture to an elevated temperature in the presence of a protic acid (e.g., aqueous hydrogen bromide and/or hydrogen chloride).

The process described above in Scheme I provides an intermediate that may be used in the preparation of 7,8-diarylsubstituted-pyrazolo[1,5-a][1 ,3,5]triazin-4-yl-amino compounds which is more streamlined by incorporating the second aryl group onto the pyrazole ring prior to formation of the pyrazolotriazinone intermediate, thus eliminating the iodination and the Suzuki process steps described in US Patent No. 2004/0157839. Scheme Il illustrates the improved process for preparing pyrazolotriazinone intermediates using the disubstituted pyrazole compounds from Scheme I above.

(D (2a)

(H)

SCHEME Il

Amidine (2a) may be formed in a reaction inert solvent (e.g., acetonitrile, methylene chloride, chloroform) from the condensation of 3-aminopyrazole Q) with an alkyl imidate (R³C(=NH)OAIkyl) in the presence or absence of an acid. Preferred alkylimidates include ethyl acetimidate, methyl acetimidate, and ethyl formimidate. Acids include alkanoic acids (e.g., acetic acid, trifluoroacetic acid), sulfonic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid) and hydrochloric acid. Isolation of amidine (2a) as its acetic acid salt is particularly preferred.

Pyrazolotriazinone (H) may be formed by treating amidine (2a) with dialkyl carbonates (e.g., diethyl carbonate, dimethylcarbonate) or dialkyl dithiocarbonates in the presence of base (e.g., sodium methoxide, sodium ethoxide) in a suitable solvent (e.g., methanol, ethanol) at reaction temperatures from about 30 ⁰C to 150 ⁰C. Alternatively, pyrazolotriazinone (H) may be formed by treating amidine (2a) with reagents such as phosgene, triphosgene, or carbonyl diimidazole in the presence or absensce of base (e.g., triethylamine, diisopropylethyl amine, pyridine, imidazole) in a reaction inert solvent (e.g., methylene chloride, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether and acetonitrile) at reaction temperatures from about -40 ⁰C to 100 ⁰C. Alternatively, pyrazolotriazinone (H, R³ = H) may be formed by treating 3- aminopyrazole Q) with 1 ,3-dimethyl-5-azauracil in the presence of a strong base (e.g., sodium ethoxide) according to procedures described by CK. Chu et al. in Nucleic Acid Chern., 4, 19- 23 (1991).

As illustrated in Scheme III below, the pyrazolotriazinone (II) may be converted to the CB-1 antagonists of Formula III (described in US Publication No. 2004/0157839, incorporated herein by reference (see, Scheme I and associated text in US 2004/0157839 A)) or CB-1 antagonists of Formula IV (described in PCT Publication No. WO 2005/049615, incorporated herein by reference, (see, Scheme I and associated text in WO 2005/049615)) using the procedures described therein and reproduced below.

(III)

SCHEME

Conversion of the pyrazolotriazinone (N) to the 7-halopyrazolotriazine ((3a), X = Cl, Br) may be accomplished by treatment with a halogenating agent (e.g., SOCI₂, POCI₃, PCi₃, PCI₅, POBr₃, PBr₃, PBr₅, or PPha/NBS) in the presence of absence of base (e.g., triethylamine, diisopropylethylamine, pyridine, N,N-diethylaniline) in the presence or absence of a reaction inert solvent (e.g., toluene, xylenes, dioxane) at temperatures ranging from about -40 ⁰C to 200 ⁰C (For analogous transformations, see: WO 02/072202 and O. Sugimoto et al., Tetrahedron Lett.. 40, 7477-7478 (1999)). In a preferred example, pyrazolotriazinone (I]) is treated with phosphorus oxychloride in the presence of a trialkylamine base (e.g., triethylamine, diisopropylethylamine) in refluxing toluene to give the corresponding 7-chloropyrazolotriazine (3a). Alternatively, pyrazolotriazinone (M) may be activated ((3a), X = leaving group) by treatment with reagents like methanesulfonic anhydride, methanesulfonyl chloride, trifluormethanesulfonic anhydride, or p-toluenesulfonyl chloride in a reaction inert solvent (e.g., methylene chloride) in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, pyridine, or collidine).

Substituent R⁴ _, where R⁴ is an amino group or an amino group substituted with one or more substituents, may be introduced via a coupling reaction between intermediate (3a) and the corresponding amino compound (R⁴-H) to produce the compound of Formula III. For example, intermediate (3a) is generally stirred with the desired amine (R⁴-H). The amine may act as the solvent (e.g., butylamine, morpholine, or pyrollidine) or a solvent (e.g., methylene chloride, N,N-dimethylformamide, water, or dimethoxyethane) may be added to assist in solubilization of the reactants and/or provide a media having the appropriate refluxing temperature to complete the substitution. The reaction may be heated to accelerate the process. Suitable reaction temperatures range from about -40 ⁰C to 100 ⁰C, and are preferably conducted at around 30 ⁰C. In addition, a suitable base (e.g., triethylamine or diisopropylethylamine) may be employed to quench the acid produced in the process. Suitable amino compounds can be either purchased commercially or easily prepared using standard procedures well-known to those skilled in the art. Preferred amino compounds (R⁴- H) include 4-alkylaminopiperidine-4-carboxamides and 3-alkylaminoazetidine-3- carboxamides.

Compounds of Formula IV may be produced by N-alkylation of pyrazolotriazinone (M) using a desired alkylating agent, such as an alkyl iodide, alkyl triflate, or a substituted benzyl bromide, and a base, preferably cesium carbonate or potassium carbonate, in a polar non- protic solvent such as DMF or THF, at temperatures ranging from about 37 ⁰C to about 150 ⁰C (preferably, from about 20 ⁰C to 40 ⁰C).

Conventional methods and/or techniques of separation and purification known to one of ordinary skill in the art can be used to isolate the various intermediates. Such techniques will be well-known to one of ordinary skill in the art and may include, for example, all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel, and thin-layer chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction techniques. It is possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the pyrazole moiety where the proton may migrate between the two ring nitrogens. Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. EXAMPLES

Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), and Tyger Scientific (Princeton, NJ). GENERAL EXPERIMENTAL PROCEDURES

NMR spectra were recorded on a Varian Unity™ 400 or 500 (available from Varian Inc., Palo Alto, CA) at room temperature at 400 and 500 MHz ¹H, respectively. Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet; v br s, very broad singlet; br m, broad multiplet; 2s, two singlets. In some cases only representative ¹H NMR peaks are given.

Mass spectra were recorded by direct flow analysis using positive and negative atmospheric pressure chemical ionization (APcI) scan modes. A Waters Apcl/MS model ZMD mass spectrometer equipped with Gilson 215 liquid handling system was used to carry out the experiments

Mass spectrometry analysis was also obtained by RP-HPLC gradient method for chromatographic separation. Molecular weight identification was recorded by positive and negative electrospray ionization (ESI) scan modes. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometer equipped with Gilson 215 liquid handling system and HP 1100 DAD was used to carry out the experiments.

Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for ³⁵CI/³⁷CI-containing ions and 1 :1 for ⁷⁹Br/⁸¹Br-containing ions) and only the lower mass ion is given. MS peaks are reported for all examples. Column chromatography was performed with either Baker™ silica gel (40 μm; JT.

Baker, Phillipsburg, NJ) or Silica Gel 50 (EM Sciences™, Gibbstown, NJ) in glass columns or in Biotage™ columns (ISC, Inc., Shelton, CT) under low nitrogen pressure. Radial chromatography was performed using a Chromatotron™ (Harrison Research). Preparation of Starting Materials

Preparation of 2-Bromo-1-(2-chloro-Dhenyl)-2-(4-chloro-Dhenyl)-ethanone (SM-Ia):

SM-Ia To a suspension of zinc (30 mesh, 17.98 g, 275 mmol) and tetrakis(triphenylphosphin)palladium (0) (2.0Og, 1.73 mmol) in 1 ,2-dimethoxyethane (DME, 50 ml) was added a solution of o-chlorobenzoyl chloride (23.8g, 136.4 mmol) in DME (50 ml) at room temperature under N₂ atmosphere. To this mixture was added a solution of p- chlorobenzyl bromide (28.25g, 137.5 mmol) in DME (100ml) dropwise with cooling by an ice- bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. The insoluble material was removed by filtration through celite, and the filtrate was concentrated in vacuo. The residue was redissolved in 200 ml of EtOAc. The organic layer was washed with 100 ml of 2N HCI and brine. The organic solvent was removed by evaporation in vacuo. The residue was slurried in 200 ml of hexane and the precipitates were collected by filtration to give 28 g (78%) of 1-(2-chloro-phenyl)-2-(4-chloro-phenyl)-ethanone which was used in the next step without further purification. ¹H NMR (CDCI₃) δ 4.26 (s, 2H), 7.20-7.44 (m, 8H).

To a solution of 1-(2-chloro-phenyl)-2-(4-chloro-phenyl)-ethanone (21.12g, 80 mmol) in CH₂CI₂ (200 ml) was added a solution of Br₂ (14.3 g, 89.6 mmol) in acetic acid (200 ml) and the mixture was stirred at room temperature overnight. The reaction was diluted with 200 ml of water and the two layers were separated. The aqueous layer was extracted with CH₂CI₂ (2x100 ml) and the combined CH₂CI₂ was washed with H₂O. The solvent was removed and the residue was slurried in hexanes (250 ml). The slightly yellow solids were collected by filtration to give 20 g (73%) of titled compound (SM-Ia). ¹H NMR (CDCI₃) δ 6.24 (s, 1 H), 7.20-7.44 (m, 8H). Preparation of 4-benzhvdrylthiosemicarbazide (SM-Ib-D:

SM-1b-1

Hydrazine hydrate (55%, 2.5 ml, about 44 mmoi) was added to a solution of benzhydryl isothiocyanate (9.5 g, 42 mmol) in 120 ml EtOH at room temperature. The solution became warm and turned slightly yellow. The solution was allowed to stir for 2 hours at room temperature. The resulting white crystalline solid was filtered, washed with EtOH and dried to afford 9 g (83%) of 4-benzhydryl-thiosemicarbazide (SM-Ib-D, m.p =144-146 ⁰C.

4-Allylthiosemicarbazide (SM- 1b-2) : 4-Allylthiosemicarbazide was prepared using the procedures described above for SM-1b-1 except that allyl isothiocyanate was used instead of benzhydryl isothiocyanate, m.p =98-99 ⁰C.

4-Benzylthiosemicarbazide (SM-1b-3): 4-Benzylthiosemicarbazide was prepared using the procedures described above for SM-1b-1 except that benzyl isothiocyanate was used instead of benzhydryl isothiocyanate, m.p =150-151 ⁰C.

Example 1 illustrates the preparation of 4,5-disubstituted-1 H-pyrazol-3-ylamine using a benzyhydryl-protected thiosemicarbazide.

EXAMPLE 1 Preparation of 4-(4-Chloro-phenyl )-5-(2-chloro-phenyl)-1 H-pyrazol-3-ylamine (1A):

SM-Ia SM-1b-1 (1A)

2-Bromo-1-(2-chloro-phenyl)-2-(4-ch!oro-phenyl)-ethanone (SM-Ia: 3.42g, 10 mmol) and 4-benzhydrylthiosemicarbazide (SM-1 b-1 : 2.58g, 10 mmol) were suspended in 120 ml of ethanol at 0 ⁰C. The mixture was allowed to warm to room temperature and stirred overnight. After addition of 2 ml of 48% aqueous hydrobromic acid the resulting slurry was heated to 80 ⁰C for 4 hours and was then cooled to room temperature as a clear yellow solution with a small amount of insoluble material. The yellow solution was again heated to 80 ⁰C for 16 hours after addition of 10 ml of 6N HCI and cooled to room temperature. The resulting suspension was concentrated and the residue was partitioned between 50 ml of 2N NaOH and 100 ml of ethyl acetate. The insoluble material was filtered and the two layers were separated. The organic phase was concentrated to a crude product and then purified by silica gel chromatography (4:1 ethylacetaterhexanes) to afford the title compound (I) as a slightly tan solid (2.1 g, 70%).

HPLC (3.0x50 mm Luna phenyl Hexyl column 3 μm 90/10 to 10/90 0.1% triethylamine (pH=7)/acetonitrile ramp over 10 minutes with a 2 minute hold, then switch back, 30 ⁰C, 0.7 ml/minute) Retention time: 6.808 minutes

LCMS (50/50 MeCN-0.02% formic acid, Zorbax SB-CN 4.6x150 mm, 1.0 ml/minute) Retention time: 3.631

¹H NMR(CDCI₃) δ 7.08-7.43 (m, 8H).

Example 2 illustrates the preparation of 4,5-disubstituted-1H-pyrazol-3-ylamine using a benzyl-protected thiosemicarbazide.

EXAMPLE 2 Preparation of4-(4-Chloro-phenyl)~5-(2-chloro-phenyl)-1H-pyrazol-3-ylamine (1A):

2-Bromo-1-(2-chloro-phenyl)-2~(4-chloro-phenyl)-ethanone (SM-Ia: 1.7g, 5 mmol) and 4-Benzylthiosemicarbazide (SM-1 b-3|( 0.905g, 5 mmol) were suspended in 60 ml of ethanol at 0 ⁰C. The mixture was allowed to warm to room temperature and stirred overnight After addition of 1 ml of 48% aqueous hydrobromic acid the resulting slurry was heated to 80 ⁰C for 4 hours and was then cooled to room temperature as a clear yellow solution with a small amount of insoluble material. The yellow solution was again heated to 80 ⁰C for 16 hours after addition of 5 ml of 6N HCI and cooled to room temperature. The resulting suspension was concentrated and the residue was partitioned between 25 ml of 2N NaOH and 50 ml of ethyl acetate. The insoluble material was filtered and the two layers were separated. The organic phase was concentrated and the residue purified by silica gel chromatography (4:1 ethylacetate:hexanes) to afford the benzyl-protected title compound (I) as a slightly tan solid (1.7 g, 87%).¹H NMR(CDCI₃) δ 4.5 (d, 2H) 7.14-7.47 (m, 13H).

Example 3 illustrates the preparation of 4,5-disubstituted-1 H-pyrazol-3-ylamine using a allyl-protected thiosemicarbazide. EXAMPLE 3

Preparation of 4-(4-Chloro-phenyl)-5-(2-chloro-phenyl)-1H-pyrazol-3-ylamine (1A):

SM-Ia SM-1b-3 (1A)

2-Bromo-1 -(2-chloro-phenyl)-2-(4-chloro-phenyl)-ethanone (SM-I a: 3.41 g, 10 mmol) and 4-Allylthiosemicarbazide (SM-1 b-2)( 1.31g, 10 mmol) were suspended in 120 ml of ethanol at 0 ⁰C. The mixture was allowed to warm to room temperature and stirred overnight. After addition of 2 ml of 48% aqueous hydrobromic acid the resulting slurry was heated to 80 ⁰C for 4 hours and was then cooled to room temperature as a clear yellow solution with a small amount of insoluble material. The yellow solution was again heated to 80 ⁰C for 16 hours after addition of 10 ml of 6N HCI and cooled to room temperature. The resulting suspension was concentrated and the residue was partitioned between 50 ml of 2N NaOH and 100 ml of ethyl acetate. The insoluble material was filtered and the two layers were separated. The organic phase was concentrated and the crude product was purified by silica gel chromatography (4:1 ethylacetate:hexanes) to afford the allyl-protected title compound (I) as a slightly tan solid (2.8 g, 82%). ¹H NMR(CDCI₃) δ 3.94 (d, 2H, J=5.6Hz) 5.13-5.28 (2H, dd, J=12, 50 Hz) 7.01-7.43 (m, 8H). The deallylation was accomplished in -30% yield (unoptimized) with a catalytic amount of 10% palladium on carbon in boiling ethanol containing an equivalent of methanesulfonic

Example 4 illustrates the preparation of 4,5-disubstituted-1 H-pyrazol-3-ylamine using thiosemicarbazide with no amino-protecting group.

EXAMPLE 4 (COMPARATOR) Preparation of 4-(4-Chloro-phenyl)-5-(2-chloro-phenyl)-1 H-pyrazol-3-ylamine (1A):

2-Bromo-1-(2-chloro-phenyl)-2-(4-chloro-phenyl)-ethanone (SM-Ia: 3.41 g, 10 mmol) and thiosemicarbazide( 0.91 g, 10 mmol) were suspended in 120 ml of ethanol at 0 ⁰C. The mixture was allowed to warm to room temperature and stirred overnight. After addition of 2 ml of 48% aqueous hydrobromic acid the resulting slurry was heated to 80 ⁰C for 4 hours and was then cooled to room temperature as a clear yellow solution with a small amount of insoluble material. The yellow solution was again heated to 80 ⁰C for 16 hours after addition of 10 ml of 6N HCI and cooled to room temperature. The resulting suspension was concentrated and the residue was partitioned between 50 ml of 2N NaOH and 100 ml of ethyl acetate. The insoluble material was filtered and the two layers were separated. The organic phase was concentrated to a crude product and then purified by silica gel chromatography (4:1 ethylacetate:hexanes) to afford the title compound (I) in about 15% yield (determined by HPLC).

EXAMPLE 5 Preparation of 7-(2-Chlorophenyl)-8-(4-chlorophenyl)-3H-pyrazolo[1 ,5-aiπ ,3, 51triazin-4- one(ll):

(H)

2-Bromo-1-(2-chloro-phenyl)-2-(4-chioro-phenyl)-ethanone (SM-Ia: 10.26g, 30 mmol) was dissolved in 360 ml of warm ethanol and cooled to 0 ⁰C. To this turbid solution was added 4-benzhydrylthiosemicarbazide (SM-1b-1 : 8.1g, 31.5 mmol) and the resulting suspension was allowed to warm to room temperature and stirred overnight. After addition of 6 ml of 48% aqueous hydrobromic acid the resulting slurry was heated to 80 ⁰C for 4 hours and was then cooled to room temperature. The turbid solution was again heated to 80 ⁰C for 24 hours after addition of 30 ml of 6N HCI and cooled to room temperature. The solution was cooled to room temperature and the insoluble material was filtered. The filtrate was concentrated and water was azetroped off with toluene (about 400 ml). The resulting salt was filtered and washed with toluene. The salt was free based with 100 ml of 2N NaOH/100 ml of 2-methyl-tetrahydrofuran (2-MeTHF). The NaOH layer was extracted one more time with 2- MeTHF (100 ml). The combined 2-MeTHF solution was dried over MgSO4, filtered and concentrated to give about 8 g of foaming solid 4-(4-Chloro-pheny!)-5-(2-chloro-phenyl)-1 H- pyrazol-3-y!amine (IA). The above 8 g of crude solid 4-(4-Chloro-phenyl)-5-(2-chloro- phenyl)-1 H-pyrazol-3-ylamine (1A) was dissolved in 130 ml of ethanol and cooled to 0 ⁰C. To this solution was added S-2-naphthylmethyl thioacetimide hydrobromide (7.47 g, 25.2 mmol). The ice-bath was removed and the resulting mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in 25 ml of methanol. The methanol solution was added to 250 ml of isopropyl ether and the resulting solid was filtered and dried. The salt was free-based with 100 ml of 2N NaOH/100 ml of 2-MeTHF. The NaOH layer was extracted one more time with 2-MeTHF (100 ml). The combined 2-MeTHF solution was dried over MgSO4, filtered and concentrated to give a crude solid. The above crude solid was dissolved in 100 ml of DMSO and treated with 1,1'-carbonyldiimidazole (23 mmol, 3.73 g) at room temperature. The resulting solution was stirred at room temperature for 3h. The DMSO solution was added to 500 ml of 1 N HCI solution. The resulting precipitate was filtered, washed with water, stirred in hexanes and dried overnight. A 5.9 g (53%) of 7-(2-Chlorophenyl)-8-(4-chlorophenyl)-3H-pyrazolo[1 ,5- a][1 ,3,5]triazin-4-one (H) was obtained. HPLC: Zorbax SB-8 10% CH3CN/aq-90% CH3CN/aq over 10 min back to 10%

CH3CN/aq over 4 minutes.

Aq = 2 ml H3PO4 and 1g SDS/L

Retention time: 7.48 minutes

Claims

CLAIMSWhat is claimed is:

1. A process for preparing a compound of Formula (I)

(D wherein R^Oa, R^ob, R^1a, and R^1b are each independently halo, (C_rC₄)alkoxy, (C_rC₄)alkyl, halo- substituted (C₁-C₄JaIkYl, or cyano; and n and m are each independently 0, 1 or 2; said process comprising the steps of

(i) reacting a compound of Formula (1a) with a compound of Formula (1b) in the presence of an acid

(1a) (1 b) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for the compound of Formula (I) and Pg is an amino-protecting group; and

(ii) removing the protecting group (Pg) to produce the compound of Formula (I).

2. The process of Claim 1 wherein Pg is selected from the group consisting of benzyl, allyl, and benzhydryl.

3. The process of Claim 2 wherein Pg is benzhydryl, and steps (i) and (ii) are accomplished in a single pot reaction.

4. The process of Claim 1 wherein R^Oa, R^ob, R^1a, and R^1b are each independently selected from the group consisting of chloro, fluoro, (C₁-C₄)BIkOXy, (C_rC₄)alkyl, fluoro-substituted (C₁-C₄JaIkYl), and cyano; and n and m are each independently 0 or 1.

5. The process of Claim 4 wherein R .Oa a —nd ^ _D R1b are both chloro; and n and m are both 0.

6. A process for preparing a compound of Formula (II)

(H) wherein R^Oa, R^ob, R^1a, and R^1b are each independently halo, (C₁-C₄)BIkOXy, (C_rC₄)alkyl, halo- substituted (C₁-C₄)BlKyI, or cyano; n and m are each independently 0, 1 or 2; and R³ is hydrogen, (CτC₄)alkyl, halo-substituted (C₁-C₄JaIRyI, or (C₁-C₄JaIkOXy; said process comprising the steps of converting a compound of Formula (I) to a compound of Formula (II)

. (I) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above.

7. The process of Claim 6 wherein said compound of Formula (I) is prepared by a process according to Claim 1.

8. The process of Claim 6 wherein R^Oa, R^ob, R^1a, and R^1b are each independently selected from the group consisting of chloro, fluoro, (CrC₄)alkoxy,

fluoro-substituted (C_rC₄)alkyl), and cyano; and n and m are each independently 0 or 1.

9. The process of Claim 8 wherein R^Oa and R^1b are both chloro; and n and m are both 0.

10. A process for preparing a compound of Formula (III)

(III) wherein R^Oa, R^ob, R^1a, and R^1b are each independently halo, (Ci-C₄)alkoxy, (C₁-C₄)alkyl, halo- substituted (C₁-C₄)alkyl, or cyano; n and m are each independently 0, 1 or 2; R³ is hydrogen, (Ci-C₄)alkyl, halo-substituted (C-ι-C₄)alkyl, or (C₁-C₄)BIkOXy; and R⁴ is a group having Formula (IA)

IA where

R^4b and R^4b are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (Ci-C₆)alkyl, (C₁-C₆JaIkOXy, acyloxy, acyl, (C₁-C₃)alkyl-O-C(O)-, (CrC^alkyl-NH-C^)-, (C_rC₄)alkyl)₂N-C(O)-, (CrC₆)alkylamino-, ((Ci-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4b or R^4b> taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge, or an ethylene bridge;

X is a bond, -CH₂CH₂- or -C(R^4c)(R^4c')-, where R^4c and R^4c' are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C₁-C₆JaIkOXy, acyloxy, acyl, (CrC₃)alkyl-O-C(O)-, (CrC^alkyl-NH- C(O)-, ((C_rC₄)alkyl)₂N-C(O)-, (C_rC₆)alkylamino-, di(C_rC₄)alkylamino-, (C₃- C₆)cycloalkylamino-, acylamino-, aryl(Ci-C₄)alkylamino-,

aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4cor R^4c' taken together with R^4e, R^4e', R^4f, or R^4f forms a bond, a methylene bridge or an ethylene bridge;

Y is oxygen, sulfur, -C(O)-, or -C(R^4d)(R^4d')-, where R^4d and R^4d> are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C₁-C₆JaIKyI, (CrC₆)alkoxy, acyloxy, acyl, (C-_i-C₃)a\ky\-O-C(O)-, (C₁-C₄JaIKyI-NH-C(O)-, ((C_rC₄)alkyl)₂N-C(O)-,

di(C_rC₄)alkylamino-, (C₃- C₆)cycloalKylamino-, acylamino-, aryl(C₁-C₄)alKylamino-_> heteroaryl(C-(-C₄)alKylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or R^4d and R^4d taKen together form a 3-6 membered partially or fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, where said heterocyclic ring, said lactone ring and said lactam ring are optionally substituted with one or more substituents and said lactone ring and said lactam ring optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur, or

Y is -NR^4d -, where R^4d is a hydrogen or a chemical moiety selected from the group consisting of (C_rC₆)alKyl, (C₃-C₆)cycloa)Kyl, (C₁-C₃)alkylsulfonyl-,

di(C_rC₃)alkylaminosulfonyh acyl, (C₁-C₃)alkyl-O-C(O)-, aryl, and heteroaryl, where said moiety is optionally substituted with one or more substituents; Z is a bond, -CH₂CH₂-, or -C(R^4e)(R^4e')-, where R^4e and R^4e' are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C_rC₆)alkyl, (C_rC₆)alkoxy, acyloxy, acyl, (C_rC₃)alKyl-O-C(O)-, (C₁-C₄JaIKyI-NH- C(O)-, ((C_rC₄)alkyl)₂N-C(O)-, (C_rC₆)alkylamino-, di(C_rC₄)alkylamino-, (C₃- C₆)cycloalkylamino-, acylamino-, aryl(C_rC₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4e or R^4e' taken together with R^4b, R^4b', R^4c, or R^40' forms a bond, a methylene bridge or an ethylene bridge; and R^4f and R^4f are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)-, or a chemical moiety selected from the group consisting of (C₁-C₆JaIKyI, (C₁-C₆JaIkOXy, acyloxy, acyl, (C₁-C₃)alkyl-O-C(O)-, (C_rC₄)alkyl-NH-C(O)-, ((C_rC₄)alkyl)₂N-C(O)-, (C_rC₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-, aryl(Ci-C₄)alkylamino-, heteroaryl(d-C₄)alkylamino-, aryl, heteroaryl, a 3-6 membered partially or fully saturated heterocycle, and a 3-6 membered partially or fully saturated carbocyclic ring, where said moiety is optionally substituted with one or more substituents, or either R^4f or R^4f taken together with R^4b, R^4b', R^4c, or R^40' forms a bond, a methylene bridge or an ethylene bridge; said process comprising the steps of:

(i) reacting a compound of Formula (1a) with a compound of Formula (1b) in the presence of an acid

(1a) (1 b) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for the compound of Formula (111) and Pg is an amino-protecting group; and

(ii) removing the protecting group (Pg) to produce a compound of Formula (I);

(I) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for said compound of Formula (III); (iii) converting said compound of Formula (I) to a compound of Formula (II)

(H) where R , R , R , R and R are as defined above for said compound of Formula (III); (iv) converting the carbonyl group of said compound of Formula (II) to a leaving group;

(v) reacting said leaving group with an amino compound R⁴-H, where R⁴ has the same meaning as above for said compound of Formula (III), to produce said compound of Formula (III).

11. The process of Claim 10 wherein R^Oa, R^ob, R^1a, and R^1b are each independently selected from the group consisting of chloro, fluoro, (Ci-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), and cyano; and n and m are each independently 0 or 1.

12. The process of Claim 11 wherein R^Oa and R^1b are both chloro; and n and m are both 0.

13. The process of Claim 11 wherein R⁴ is 3-ethylamino-azetidine-3-carboxylic acid amide.

14. A process for preparing a compound of Formula (IV)

(IV) wherein R Oa , r R-.0b , R ι-,1^ιa^a, a __nd _i R r-»1¹b are each independently hal Io _,

(C_rC₄)alkyl, halo- substituted (C₁-C₄)BIk^, or cyano; n and m are each independently 0, 1 or 2; R is hydrogen, (CrC₄)alkyl, halo-substituted (C₁-C₄JaIKyI, or (d-C₄)alkoxy; and R⁵ is (C-j-CsJalkyl, aryl(C_r C₄)alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), or heteroaryl(Ci~ C₃)alkyl; said process comprising the steps of:

(i) reacting a compound of Formula (1a) with a compound of Formula (1b) in the presence of an acid

(1a) (1b) where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for said compound of Formula (IV) and Pg is an amino-protecting group; and

(ii) removing the protecting group (Pg) to produce a compound of Formula (I);

⁽D where R^Oa, R^ob, R^1a, R^1b, n and m are as defined above for said compound of Formula (IV); (Ni) converting said compound of Formula (I) to a compound of Formula (II)

(H) where R^Oa, R^ob, R^1a, R^1b and R³ are as defined above for said compound of Formula (IV); and (iv) N-alklating said compound of Formula (II) to form said compound of Formula

(IV).

15. The process of Claim 14 wherein R^Oa, R^ob, R^1a, and R^1b are each independently selected from the group consisting of chloro, fluoro, (C₁-C₄JaIkOXy, (Ci-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), and cyano; and n and m are each independently 0 or 1.