WO2003084931A1 - 5h-benzo[4,5]cyclohepta[1,2-b]pyridine nmda/nr2b antagonists - Google Patents

Abstract

Benzo [4,5]cyclohepta[1,2-b]pyridines represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for relieving pain.

Description

TITLE OF THE INVENTION

5H-BENZO[4,5]CYCLOHEPTA[l,2-B]PYRIDINE NMDA/NR2B ANTAGONISTS

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel 5H-benzo [4,5]cyclohepta[l,2- b]pyridine compounds. In particular, this invention relates to novel 5H-benzo [4,5]cyclohepta[l,2-b]pyridine compounds that are effective as NMD A NR2B antagonists useful for relieving pain.

Ions such as glutamate play a key role in processes related to chronic pain and pain-associated neurotoxicity - primarily by acting through N-methyl-D- aspartate ("NMD A") receptors. Thus, inhibition of such action - by employing ion channel antagonists, particularly NMDA antagonists - can be beneficial in the treatment and control of pain.

Known NMDA antagonists include etamine, dextromophan, and 3-(2- carboxypiperazin-4-yl)-propyl-l-phosphonic acid ("CPP"). Although these compounds have been reported (LD.Kristensen, et al., Pain, 51:249-253 (1992); K.Eide, et al., Pain, 61:221-228 (1995); DJ.Knox, et al., Anaesth. Intensive Care 23:620-622 (1995); and M.B.Max, et al, Clin. Neuropharmacol. 18:360-368 (1995)) to produce symptomatic relief in a number of neuropathies including postherpetic neuralgia, central pain from spinal cord injury, and phantom limb pain, widespread use of these compounds is precluded by their undesirable side effects. Such side effects at analgesic doses include psychotomimetic effects such as dizziness, headache, hallucinations, dysphoria, and disturbances of cognitive and motor function. Additionally, more severe hallucinations, sedation, and ataxia are produced at doses only marginally higher than analgesic doses. Thus, it would be desirable to provide novel NMDA antagonists that are absent of undesirable side effects or that produces fewer and/or milder side effects. NMDA receptors are heteromeric assemblies of subunits, of which two major subunit families designated NR1 and NR2 have been cloned. Without being bound by theory, it is generally believed that the various functional NMDA receptors in the mammalian central nervous system ("CNS") are only formed by combinations of NR1 and NR2 subunits, which respectively express glycine and glutamate recognition sites. The NR2 subunit family is in turn divided into four individual subunit types: NR2A, NR2B, NR2C, and NR2D. I. Ishii, et al., J. Biol. Chem., 268:2836-2843 (1993), A.Wenel, et al., Neural Report, 7:45-48 (1995), and DJ Laurie et al., Mol. Brain Res., 51:23-32 (1997) describe how the various resulting combinations produce a variety of NMDA receptors differing in physiological and pharmacological properties such as ion gating properties, magnesium sensitivity, pharmacological profile, as well as in anatomical distribution.

For example, while NR1 is found throughout the brain, NR2 subunits are differentially distributed. In particular, it is believed that the distribution map for NR2B lowers the probability of side effects while producing pain relief. For example, S.Boyce, et al., Neuropharniacology, 38:611-623(1999) describes the effect of selective NMDA NR2B antagonists on pain with reduced side-effects. Thus, it would be desirable to provide novel NMDA antagonists that target the NR2B receptor.

U.S. Patent Nos. 5,994,364, 5,958,940, 5,661,152, and International Patent Publication Nos. WO2000/14089, WO99/37619, WO99/37651, WO98/11098, WO98/11097, WO98/11096, WO98/11091, WO98/04545, WO98/01122, WO96/30363, WO95/10516, WO95/10515, WO95/10514, WO93/20080, WO92/00293, WO89/10369, WO89/10369, WO88/03138, EP497201, EP396083, and EP339978 describe tricyclic fused ring compounds.

International Patent Publication WO94/21615 describes benzimidazole-piperidine compounds utilized as dopamine D4 antagonists. Phenol compounds described as NMDA antagonists are described in U.S. patent Nos. 5,306,723 and 5,436,255, and in International Patent Publications WO91/17156, WO92/19502, WO93/02052, WO94/29571, WO95/28057, WO96/37226, and EP 04422506. Benzyl piperidines substituted with phenols or imidazoles are described in Z.-L. Zhou, et al., J. Medicinal Chemistry, 42:2993-3000(1999); T.F. Gregory, et al, Poster #94, 218^th National Meeting American Chemical Society, New Orleans, Louisiana, August 22-26, 1999. Other NMDA NR2B selective compounds are described in European Patent Publication EP 787493 and British J. Pharmacol, 123:463(1998). However, there continues to be a need for novel NMDA antagonists that target the NR2B receptor.

SUMMARY OF THE INVENTION The present invention relates to novel benzo [4,5]cyclohepta[l,2- bjpyridines. The present invention also forms novel pharmaceutical compositions utilizing these novel compounds. Further, this invention includes novel methods to treat pain by utilizing the novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are represented by Formula (I):

(I) or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Cι_6alkyl group, C2-6*alkenyl group, C2-6^alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R1C* group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Cι_6alkyl, hydroxyCι_6alkyl, haloCι_6alkyl, Ci-βalkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2_> phenyl, halophenyl, phenylCι_6alkyl, phenylCi_6alkyl-O-, phenylC i _6alkyl-O-C i _6alkyl ;

R2, R3, R6_} and R7 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group,^' -N(Ci-6alkyl)(Cι_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci_6alkyl; R77 is hydrogen; optionally R2 and R3 together form =O; optionally R6 and R7 together form =O; optionally R7 and R77 together form a bond; optionally R7 and R77 together form -X-; R4, R41₅ R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Cι_6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Ci_6alkyl(Cι_6alkyl)amino, or arylamino;

R8 is Ci_6alkyl, phenyl, or heterocyclic;

R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Cι_ 6alkoxy, -N(Cθ-6*alkyl)(Cθ-6alkyl), or C3-7cycloalkyl; and

X is O or CH2; but excluding compounds represented by the following exclusion table wherein other R are H:

In one aspect, the compounds of this invention are represented by Formula (I), excluding compounds in the exclusion table above:

(I) or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Ci-βalkyl group, C2-6^alkenyl group, C2-6*alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-βalkyl, hydroxyCι_6alkyl, haloCi-6alkyl, Cι_6alkoxy, -CHO, C3-6cycloalkenyl, Cι_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCι_6alkyl, phenylCι_6alkyl-O-, phenylC i _6alkyl-O-C i -6alkyl;

R2, R3_; R6₅ and R7 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Cι_6alkyl)(Ci_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl;

R77 is hydrogen; optionally R2 and R3 together form =O; optionally R6 and R7 together form =O; R4, R41_; R42_{; an}d R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci-6alkyl, aryl, R8SO2NH-, or -CHO;

R-5 and R5 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Cι_6alkyl)amino, or arylamino; R8 is Ci-.6alkyl, phenyl, or heterocyclic; and

R9 and RlO are each independently hydrogen, Ci-βalkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being C\- βalkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl.

In an embodiment of this first aspect, the compound of the invention is represented by Formula (I), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein

Rl is hydrogen, CI, or Cι_6alkyl group, C2-6*alkenyl group, C2-6^alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci_6alkyl, hydroxyCι_6alkyl, haloCι_6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, Cι_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCi-6alkyl, phenylCι_6alkyl-O-, phenylCi-6alkyl-O-Ci-6alkyl;

R2, R3, R6, and R are each independently hydrogen, OH, -O-Ci-6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci_6alkyl)(Ci-6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci-βalkyl; R77 is hydrogen; optionally R6 and R together form =O;

R4, R41₅ R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Ci-6alkylamino, Cι_6alkyl(Ci-6alkyl)amino, or arylamino; R8 is C _6alkyl, phenyl, or heterocyclic; and R9 and RlO are each independently hydrogen, C _6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3-7cycloalkyl.

In another embodiment of this first aspect, the compound of the invention is represented by Formula (I), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein

Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-βalkyl, hydroxyCi_6alkyl, haloCi_6alkyl, Ci_6alkoxy, -CHO, C3_6cycloalkenyl, Cι-.6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCi-6alkyl, phenylCi_6alkyl-O-, phenylC ι_6alkyl-O-Ci_6alkyl;

R6, and R7 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci-6alkyl)(Cι_ βalkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl;

R77 is hydrogen;

R2 and R3 together form =O; optionally R6 and R7 together form =O;

R4, R41_S R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Cι_6alkyl, aryl, R8SO2NH-, or -CHO; R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Cι_6alkyl)amino, or arylamino; R8 is Ci_6alkyl, phenyl, or heterocyclic; and R and RlO are each independently hydrogen, Ci-6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(CQ-6alkyl)(Cθ-6alkyl), or C3-7cycloalkyl.

In a second aspect, the compounds of this invention are represented by Formula (II), excluding compounds in the exclusion table above:

(π> or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Cι_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Cι_6alkyl, hydroxyCi-6alkyl, haloCι_6alkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Cι_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCι_6alkyl, phenylCi-6alkyl-O-, phenylCi-6alkyl-O-Cι_6alkyl;

R2, R3_; and R6 are each independently hydrogen, OH, -O-Cι_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci_ 6alkyl)(Ci_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl; optionally R and R3 together form =O;

R4, R41₅ R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Cι_6alkyl, aryl, R8SO2NH-, or -CHO; R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, Ci-6alkylamino, Ci-6alkyl(Ci-6alkyl)amino, or arylamino; R8 is Cι_6alkyl, phenyl, or heterocyclic; and R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl.

In an embodiment of this second aspect, the compound of the invention is represented by Formula (II), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein

Rl is hydrogen, CI, or Cι_6alkyl group, C2-6^alkenyl group, C2-6alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci_6alkyl, hydroxyCi-6alkyl, haloCi_6alkyl, Ci_6alkoxy, -CHO, C3_6cycloalkenyl, Cι_6alkyl-

S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCi_6alkyl, phenylCi-.6alkyl-O-, phenylCi-6alkyl-O-Ci-6alkyl;

R2, R3_; and R6 are each independently hydrogen, OH, -O-Ci-βalkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci_

6alkyl)(Ci-6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl;

R4, R41₅ R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Cι_6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Ci_6alkyl(Ci-6alkyl)amino, or arylamino; R8 is Ci_6alkyl, phenyl, or heterocyclic; and R9 and RlO are each independently hydrogen, Cι_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(Cθ-6alkyl)(C()-6alkyl), or C3_7cycloalkyl. In another embodiment of this second aspect, the compound of the invention is represented by Formula (II), or pharmaceutically acceptable salts thereof, excluding compounds in the exclusion table above, wherein

Rl is hydrogen, CI, or Ci-6alkyl group, C2-6alkenyl group, C2-6^alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-βalkyl, hydroxyCi-6alkyl, haloCι_6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCι_6alkyl, phenylCι_6alkyl-O-, phenylCi-6alkyl-O-Ci-6alkyl;

R6 is hydrogen, OH, -O-Ci-βalkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Ci_6alkyl) group, -N(Ci-6alkyl)(Cι_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci_6alkyl; R2 and R3 together form =O;

R4, R41 _s R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R-5 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Ci_6alkyl)amino, or arylamino; R8 is Cι_6alkyl, phenyl, or heterocyclic; and R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Cι_ 6alkoxy, -N(Cθ-6alkyl)(C()-6alkyl), or C3_7cycloalkyl.

In a third aspect, the compounds of this invention are represented by Formula (HI):

(HI) or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Cι_6alkyl, hydroxyCi_6alkyl, haloCi-6alkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Ci-6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCι_6alkyl, phenylCi-6alkyl-O-, phenylC 1 _6alkyl-O-C i _6alkyl ;

R2, and R3 are each independently hydrogen, OH, -O-C _6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci_6alkyl)(Cι_ 6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci_6alkyl; optionally R2 and R3 together form =O;

R4, R41, R42, and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Cι_6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R-55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Ci-6alkyl)amino, or arylamino;

R8 is Ci_6alkyl, phenyl, or heterocyclic; R9 and RlO are each independently hydrogen, Ci-6alkyl group,

C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl; and

X is O or CH2.

In an embodiment of this third aspect, the compound of the invention is represented by Formula (HI), or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Ci_6alkyl group, C2-6^alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-βalkyl, hydroxyCi_6alkyl, haloCl_6alkyl, Ci-6alkoxy, -CHO, C3_6cycloalkenyl, Cι_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC ι_6alkyl, phenylCi-6alkyl-O-, phenylC i_6alkyl-O-C i-.6alkyl; R2, and R3 are each independently hydrogen, OH, -O-Ci_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Ci-6alkyl) group, -N(Ci-6alkyl)(Cι_ 6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci_6alkyl; R4, R41_; R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci-6alkyl, aryl, R8SO2NH-, or -CHO;

R5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Ci-6alkyl(Ci_6alkyl)amino, or arylamino; R8 is Cι_6alkyl, phenyl, or heterocyclic;

R9 and RlO are each independently hydrogen, Cι_6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl; and X is O or CH2.

In an embodiment of this third aspect, the compound of the invention is represented by Formula (DI), or pharmaceutically acceptable salts thereof, wherein Rl is hydrogen, CI, or Cι_6alkyl group, C2-6^alkenyl group, C2-6*alkynyl group, C3-8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-βalkyl, hydroxyCi-6alkyl, haloCι_6alkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Cι_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i-6alkyl, phenylCi-βalkyl-O-, phenylCi-6alkyl-O-Ci_6alkyl;

R2 and R3 together form =O;

R4, R41, R42, and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO; R-5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Cι_6alkyl)amino, or arylamino; R8 is Cι_6alkyl, phenyl, or heterocyclic; R9 and RlO are each independently hydrogen, Cι_6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl; and X is O or CH2-

In another embodiment of this third aspect, the compound of the invention is represented by Formula (DI), or pharmaceutically acceptable salts thereof, wherein

Rl is hydrogen, CI, or Ci-βalkyl group, C2-6 lkenyl group, C2-6^alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Cι_6alkyl, hydroxyCi-βalkyl, haloCι_6alkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Ci-6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i_6alkyl, phenylC i-6alkyl-O-, phenylC i-6alkyl-O-C ι_6alkyl; R2, and R3 are each independently hydrogen, OH, -O-Ci-galkyl group,

-O-acyl group, -O-aryl group, -NH2, -NH(Ci_6alkyl) group, -N(Cι_6alkyl)(Cι_ 6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl; optionally R2 and R3 together form =O; R4, R41_; R42_; and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci_6alkyl, aryl, R8SO2NH-, or -CHO;

R-5 and R5 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Ci-6alkyl)amino, or arylamino; R8 is Cι-.6alkyl, phenyl, or heterocyclic;

R9 and RlO are each independently hydrogen, Cι_6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci_ 6alkoxy, -N(Cθ-6alkyl)(Cθ-6 lkyl), or C3_7cycloalkyl; and X is O.

In an embodiment of this third aspect, the compound of the invention is represented by Formula (III), or pharmaceutically acceptable salts thereof, wherein Rl is hydrogen, CI, or Ci_6alkyl group, C2-6alkenyl group, C2-6alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Ci-6alkyl, hydroxyCi-6alkyl, haloCi-βalkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Ci_6alkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylC i_6alkyl, phenylC ι_6alkyl-O-, phenylC i _6alkyl-O-C i -6alkyl;

R2, and R3 are each independently hydrogen, OH, -O-Cι_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Cι_6alkyl)(Cι-. 6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci-6alkyl; optionally R2 and R3 together form =O;

R4, R41₅ R42₅ and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci-6al yl, aryl, R8SO2NH-, or -CHO;

R-5 and R55 are each independently hydrogen, chloro, amino, phenyl, aryl, Cι_6alkylamino, Cι_6alkyl(Ci_6alkyl)amino, or arylamino;

R8 is Ci-βalkyl, phenyl, or heterocyclic;

R9 and RlO are each independently hydrogen, Ci-6alkyl group, C3_7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Ci- 6alkoxy, -N(Cθ-6^alkyl)(Cθ-6^alkyl), or C3_7cycloalkyl; and

X is CH2.

As used herein, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond.

The term "cycloalkyl" means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphalene and the like. Similarly, "cycloalkenyl" means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

Unless otherwise stated, the term "aryl" includes phenyl and napthyl.

Unless otherwise stated, the term "heteroaryl" includes pyridyl, thiazolyl, thiophenyl, furanyl, terazolyl, and isoquinolinyl. Generally, heteroaryls are connected through a carbon unless the nomenclature indicates otherwise (such as N-, or N-yl). Substituents on heteroaryls can be attached to the hetero ring atom as well as to the carbon ring atoms.

Unless stated otherwise, the term "heterocyclic" includes piperidinyl, piperidin-N-yl, perhydroazepinyl, perhydroazepin-N-yl, pyrrolidinyl, pyrrolidin-N-yl, piperazinyl, piperazin-N-yl, morpholinyl, morpholin-N-yl, oxazin-N-yl, tetrahydropyridyl, l-azabicyclo[2.2.2]octenyl, and l-aza[1.1.3]octan-N-yl.

Unless stated otherwise, a pyridyl nitrogen includes the Ν-oxide form.

Unless otherwise stated, the terms "carbonyl" and "aminocarbonyl" include short C1-C2 termini. The terms include, for example, -CH2COΝH-, -CH2CO-, -C2H4CONHCH2-, and -CH2COC2H4-.

Unless otherwise stated, the term "carbamate" is used to include -NHCOOCi-C4alkyl, and -OCONHCj_.-C4alkyl.

Unless stated otherwise, the term "amino" refers to -N(Co-C4alkyl) (C₀-C₄alkyl).

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "SEM" is used to describe -CH2-O-CH2CH2-Si(CH3)3- The term "Co" means that the carbon is not present. Thus, "C0-C5" means that there are from none to five carbons present - that is, five, four, three, two, one, or no carbons present. A bridging alkyl without a carbon present is a direct bond. A terminal alkyl without a carbon present is a hydrogen.

The term "optionally substituted" is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, substitution may be at any site as determined by a chemist. That is, substituted alkylaryl may be substituted at the alkyl, the aryl, or at both. If substitution is limited, such limitation will be stated as in, for example, "alkylaryl substituted at the alkyl" is not substituted at the aryl. Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I and Formula D are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and Formula D or pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. The pharmaceutical compositions of the present invention comprise a compound represented by Formula I, Formula It, or Formula HI (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds represented by Formula I, Formula D, or Formula ID, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, Formula E, or Formula DI, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation. Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I, Formula π, or Formula HI. The compounds of Formula Formula I, Formula -3, or Formula IE, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about lmg to about 500mg of the active ingredient and each cachet or capsule preferably containing from about 1 to about 500mg of the active ingredient. Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I or Formula H of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, Formula H, or Formula -H, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Experimental Protocols

Assessing the Activity of Selected Compounds to Inhibit NR1A/2B NMDA Receptor Activation (FLIPR Assay)

The activity of selected compounds to inhibit NR1A/2B NMDA receptor activation measured as NR1 A/2B receptor-mediated Ca²⁺ influx is assessed by the following procedure:

NR1A/2B receptor transfected L(tk) cells are plated in 96-well format at 3 x 10⁶ cells per plate and grown for one - two days in normal growth media

(Dulbeccos MEM with Na pyruvate, 4500 mgglucose, pen/strep, glutamine, 10% FCS and 0.5mg/ml geneticin). NRlA/2B-expression in these cells is induced by the addition of 4nM dexamethasone in the presence of 500μM ketamine for 16 - 24 hours. After receptor induction cells are washed using a Labsystem Cellwasher two times with assay buffer (Hanks balanced salt solution (HBSS-Mg⁺⁺ free) containing 20mM HEPES, 0.1% BSA, 2mM CaCl₂ and 250μM probenecid). The cells of each 96 well cell plate are loaded with the Ca⁺⁺ sensitive dye Fluo-3 (Molecular Probes, Inc.) at 4μM in assay buffer containing 0.5% FBS, and 0.04% pluronic F-127 (Molecular Probes, Inc.) for lh at 37 °C avoiding light. The cells are then washed with the Cellwasher four times with assay buffer leaving them in 1 OOμl buffer. Test compounds in solution are pipetted by FLIPR (Fluorometric Imaging Plate Reader) into each test well for a 2min pretreatment. During this time the fluorescence intensity is recorded (excitation at 488nm and emission at 530nm). The glutamate/glycine 50μL agonist solution (final concentration lμM/lμM) is then added by FLIPR into each well already containing 150μL of buffer (containing the test compound or vehicle) and the fluorescence is continuously monitored for lOmin. The endpoint fluorescence values are used to determine an IC₅₀ value comparing the agonist-stimulated signal for the vehicle alone sample and that for the cells incubated with each concentration of test compound. Determining the Apparent Dissociation Constant (Ki) of Compounds for Human NR1A/NR2B Receptors (Binding Assay):

The radioligand binding assay is performed at room temperature in 96-well microtiter plates with a final assay volume of l.OmL in 20mM Hepes buffer (pH 7.4) containing 150mM NaCI. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 20μL of each of 10 solutions differing by 3-fold in concentration. Non-specific binding (NSB) using hot AMD-1 (lOμM final concentration) and total binding (TB) by using DMSO (2% final concentration). A solution of NR1 A/NR2B receptors (40pM final concentration) and tritiated AMD-2 (InM final concentration) were added to the test compounds. After 3h of incubation at room temperature, samples are filtered through Packard GF/B filters (presoaked in 0.05% PEI, polyethyleninine Sigma P-3143) and washed 10 times with lmL of cold 20mM Hepes buffer per wash. After vacuum drying of the filter plates, 40μL of Packard Microscint-20 was added and bound radioactivity determined in a Packard TopCount. The apparent dissociation constant (Ki), the maximum percentage inhibition (%Imax)-* the minimum percentage inhibition (%Imin) and the hill slope (nH) were determined by a non-linear least squares fitting the bound CPM data to Equation #1 below.

Equation#l:

(SB) (%I_maχ - %Imin) CPM Bound = + NSB + (SB) (1 - %I_max)

(1 + ( [Drug] / (Ki [AMD-2]/K_D) )^nH )

where, Kp is the apparent dissociation constant for the radioligand for the receptor as determined by hot saturation and SB is the specifically bound CPM determined from the difference of TB and NSB .

AMD-1

AMD-2

Compounds AMD-1 and AMD-2 can be synthesized in accordance with the following general reaction schemes.

SCHEME 1

la

In accordance with Scheme 1, hydrogen chloride is bubbled through a solution of the appropriately substituted benzonitrile 1 in methanol at room temperature. The volatiles are removed under reduced pressure and the resulting residue is triturated with ether and filtered to yield the desired imidate 2. Imidate 2 is dissolved in methanol at ambient temperature, treated with amine 3 at ambient temperature and stirred under argon. The volatiles are removed under reduced pressure and the residue purified by preparative HPLC or trituration with ether to afford amidine la.

SCHEME 2

R²-C₀.₆ alkyl-NR³H ^• HCI Me₃AI

Me₂CI AI-NH₂-C₀.₆ alkyl -R²

3a 6

la

In accordance with Scheme 2, at rt under argon, amine 3a is dissolved in ether and was treated with 1M hydrogen chloride in ether (1 equiv.) in a single portion. The resulting precipitate is stirred vigorously for 10 minutes. The volatiles are removed under reduced pressure. The residue is suspended in toluene, cooled to 0°C under argon, treated with 2.0M trimethylaluminum (1.05 equiv.) in a dropwise manner, and stirred for 45min at rt to afford intermediate 6 (not isolated). Compound 6 is added to a solution of nitrile 1 in toluene. The reaction is heated to 80°C without stirring in a sealed tube for 18h, cooled to ambient temperature, poured onto a silica gel column and eluted with methanol/dichloromethane to give the amidine la.

Preparation of [¹²⁵I]AMD-1

] AMD-1

Tritiated AMD-1 was prepared by the following procedure: A mixture of AMD-1, hydrochloride salt, (5mg, 0.012mmol) in dioxane (0.2mL) containing triethylamine (4μL) was treated with hexamethylditin (5μL), a catalytic amount of palladium catalyst and heated at 100°C for 45 minutes. The reaction was cooled to room temperature, filtered through a glass wool plug, rinsed with methanol and concentrated in vacuo to give 10.7mg of a brown oil. The oil was dissolved in methylene chloride and passed through a small silica column eluting with methylene chloride followed by 5% methanol/methylene chloride. Fractions containing the trimethylstannane (Rf 0.26 in 10% methanol/methylene chloride) were pooled and concentrated in vacuo to give 4.5mg of the trimethylstannane as a clear colorless oil. This material was further purified by HPLC (C18 Econosil, 10x250mm, 20 minute linear gradient, 30% MeCN:70% H₂O (0.1% TFA) to 90% MeCN, 3mL/min, 254nm, retention time 15 minutes) to give 3mg of the trimethylstannane.

A Na¹²⁵I shipping vial (lOmCi, Amersham) was charged with a stir bar, an iodobead, 50μL of methanol and stirred five minutes at room temperature. A solution of the trimethylstannane (O.lmg) in 50μL of methanol containing 5μL of trifluoroacetic acid was added and the reaction was stirred for five minutes. The reaction was quenched with 50μL of ammonium hydroxide and purified by HPLC (C18 Vydac protein and peptide column, 4.6 x 250 mm, 20 minute linear gradient, 30% MeCN:70% H₂O (0.1 % TFA) to 90% MeCN, lmL/min, retention time llminutes). Fractions containing the radioactive product were pooled and concentrated in vacuo to give 989μCi of [¹²⁵I]AMD-1 with a specific activity of 898Ci/mmol as measured by UV absorbance at 272nm.

Synthesis of Tritiated AMD-2

Tritiated AMD-2 was prepared by the following procedure: The phenol of AMD-2 (2mg, 0.008mmol) dissolved in dimethylformamide (0.6mL) and potasium carbonate (1.2mg) for lhr. High specific activity tritiated methyl iodide (50mCi, 0.0006mmol, in toluene ImL, American Radiolabeled Chemicals) was added at room temperature and stirred for 2 hours. The reaction mixture was filtered using a Whatman PTFE 0.45μm syringeless filter device to remove any insoluable potassium carbonate, washed with Abs. ethanol (2mL, Pharmco), and the combined filtrates were concentrated to dryness at room temperature using a rotary evaporator; this also removed any unreacted tritiated methyl iodide. The residue was purified by HPLC chromatography on a Phenomenx Luna C8 semi-prep column ( Luna 5 micro C8(2), 250x10.0 mm) using a gradient system of 20/80 acetonitrile/water with 0.1% trifluoroacetic acid to 100% acetronitrile with 0.1% trifluoroacetic acid in 20min. Total activity of the product was 8mCi. Further purification was effected by absorption onto a Waters C-18 Sep-pak column (Waters Sep-Pak PLUS C18) and elution with water followed by absolute ethanol. The product was diluted with absolute ethanol (lOmL) before submission for final analysis.

The following excluded compounds represented by the following table, referring to Formula (I) wherein other R are H, exhibit greater than 25 μM in the FLIPR and binding assays:

The compounds of this invention exhibit 25 μM or less in the FLIPR and binding assays. It is advantageous that the compounds of this invention exhibit less than 5μM in the FLIPR and binding assays. It is still more advantageous that the compounds of this invention exhibit less than lμM in the FLIPR and binding assays. It is most advantageous that the compounds of this invention exhibit less than 0.05μM in the FLIPR and binding assays.

Thus, the compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as NMDA NR2B antagonists. Accordingly, another aspect of the invention is the treatment of pain, migraine, depression, anxiety, schizophrenia, Parkinson's disease, or stroke - maladies that are amenable to amelioration through inhibition of NMDA NR2B receptors - by the administration of an effective amount of the compounds of this invention.

The following examples are provided to more fully illustrate the present invention, and are not to be construed as limiting the scope of the claims in any manner.

EXAMPLES

Preparation of benzo[4,5]cyclohepta[l ,2-b]pyridine compounds.

In one Example, substituted 3-aryl-5H-benzo[4,5]cyclohepta[l,2- b]pyridines COMPOUND 1 to COMPOUND 9 were prepared by Scheme 3 shown below:

In another Example, 9-Bromo-3-phenyl-5H-benzo[4,5]cyclohepta[l,2- bjpyridine compounds were prepared by Scheme 4 shown below:

13 12

Intermediate 1

Example 3

Example 1

EXAMPLE 1 and EXAMPLE 3 9-Bromo-3-phenyl-5H-benzo[4,5]cyclohepta[l,2-b]pyridine

Example 1

Examples 1 and 3 were prepared by the following procedure: COMPOUND 11: (Dimethylamino-phenyl-allylidene)-dimethyl-ammonium; perchlorate

Phosphorus oxychloride (41.0mL, 441mmol) was added dropwise to N,N-dimethylformamide at 15-20°C. After lh, phenylacetic acid (Compound 10) (20.0g, 147mmol) was added and the contents of the reaction flask were heated at 85°C for 24h. The contents were then cooled and the resulting reaction solution was poured onto 450g of ice. Addition of a solution of sodium perchlorate (26.9g, 221mmol) in water (60mL) followed by vacuum filtration of the resulting precipitate gave Compound 11 as a tan solid. 1H ΝMR (DMSO-d₆, 300MHz) δ 7.75 (s, 2H); 7.45 (m, 3H); 7.30 (m, 3H); 3.25 (s, 6H), 2.43 (s, 6H).

COMPOUND 12: 2-Methyl-5-phenyl-nicotinonitrile

A solution of Compound 11 (26.9g, 88.9mmol), 3-aminocrotonitrile

(7.29g, 88.9mmol) and ethanol (500mL) was stirred in a IL reaction flask under argon. To this mixture was added a solution of sodium methoxide (0.5 M, 178mL, 88.9 mmol). The reaction mixture was heated to reflux for 24h and then concentrated in vacuo. Water was added and the mixture was extracted with ethyl acetate (4x). The combined organic extracts were washed with water, brine, dried over magnesium sulfate, and filtered. Removal of the solvent in vacuo gave a dark oil which was subjected to flash column chromatography (hexane:ethyl acetate 95:5 then 90:10) to give Compound 12 as an orange solid. 1H NMR (CDC1₃, 300MHz) δ 8.90 (d, IH); 8.08 (d, IH); 7.58-7.42 (m, 5H); 2.80 (s, 3H).

COMPOUND 13: 2-Methyl-5-phenyl-nicotinic acid hydrochloride

To a solution of Compound 12 (12.0g, 61.8mmol) in ethanol (150mL) was added 50% sodium hydroxide (20mL). The reaction mixture was heated to reflux for 24h, cooled and concentrated. Addition of water followed by 6N hydrochloric acid yielded Compound 13 which was isolated by vacuum filtration. MS m/z 214.0

(Mtf)

COMPOUND 14: 2-Methyl-5-phenyl-nicotinic acid methyl ester hydrochloride

Thionyl chloride (50mL) and Compund 13 (15.3g, 61.6mmol) were combined and heated to reflux for 15min. Thionyl chloride was removed in vacuo and toluene was added. Toluene was removed in vacuo and methanol was added and the resulting solution was heated to reflux for lOmin. Removal of the methanol in vacuo followed by trituration with ethyl acetate gave Compound 14 as a tan solid. MS m/z 228.0 (MH⁺)

COMPOUND 15: 2-[2-(2-Bromo-phenyl)-vinyl]-5-phenyl-nicotinic acid hydrochloride

To a tetrahydrofuran solution of Compound 14 (5.00g, 18.9mmol) under argon at 0°C was added a solution of potassium-t-butoxide (1.0M, 66.2mL, 66.2 mmol). After 0.75h, a solution of 2-bromobenzaldehyde (2.43mL, 20.8mmol) in tetrahydrofuran was added and the reaction mixture was warmed to room temperature. The solvent was removed in vacuo and water (50mL) and 6N hydrochloric acid (50mL) were added. The resulting precipitate was isolated by vacuum filtration to give Compound 15 as a yellow solid. 1H NMR (OMSO-d₆, 300MHz) δ 13.6 (s, IH); 9.08 (d, IH); 8.43 (d, IH); 8.13 (m, IH), 7.90 (m, IH); 7.82 (m, 2H); 7.65-7.45 (m, 7H).

INTERMEDIATE 1: 9-Bromo-3-phenyl-benzo[4,5]cyclohepta[l,2-b]pyridin-5- one

A mixture of polyphosphoric acid (lOOg) and Compound 15 (5.60g, 13.4mmol) was heated to 200°C under argon. After 5h, the reaction mixture was poured onto ice with stirring. The resulting suspension was made basic with 20% sodium hydroxide then extracted with methylene chloride (4x). The combined organic portions were washed with brine then dried with magnesium sulfate. Removal of the solvent in vacuo followed by trituration with methanol gave Intermediate 1 as a gray solid. 1H NMR (CDC1₃, 300MHz) δ 9.15 (d, IH); 8.55 (d, IH); 8.10 (m, IH); 7.95 (m, IH), 7.83-7.68 (m, 3H); 7.58-7.40 (m, 5H).

EXAMPLE 3: 9-Bromo-3-phenvl-5H-benzor4,51cvcloheptari,2-blpyridin-5-ol

Example 3

Sodium borohydride (443mg, 27.6mmol) was added to an ethanol solution of Intermediate 1 (l.OOg, 2.76mmol) and the resulting suspension was heated to reflux for lh. Ice was added to the reaction flask and 6N hydrochloric acid was added dropwise until gas evolution stopped. The solvent was removed in vacuo and water and 2N sodium hydroxide were added. The mixture was extracted with methylene chloride (4x). The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. Trituration with ethyl acetate gave Example 3 as a tan solid. MS m/z 365.9 (MH*)

EXAMPLE 1: 9-Bromo-3-phenyl-5H-benzo[4,5]cycIohepta[l,2-b]pyridine

Example 1

A suspension of Example 3 (50mg, 0.137mmol), zinc (22mg, 0.343mmol) and acetic acid (0.5mL) was heated at reflux for 24h. The solvent was removed in vacuo and saturated sodium bicarbonate was added. The resulting suspension was extracted with methylene chloride (4x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient, 100% hexane to hexane:ethyl acetate 50:50). Trituration with hexane/ether gave Example 1 as a white solid. 1H NMR (CDC1₃, 400MHz) δ 8.74 (d, IH); 7.79 (m, IH); 7.62-7.24 (m, 9H); 7.16 (m, IH), 3.80 (s, 2H).

Intermediates 2-5 were prepared by procedures similar to that described for Intermediate 1. These intermediates are summarized in Table 1 below.

Table 1: Derivatives of Benzo[4,5]cyclohepta[l,2-b]pyridin-5-one

Ex. Rl R41 R43 MS m/z

Int. 2 Ph H H 284.0 Int. 3 Ph Br H 363.8

Int. 4 Ph H CI 318.0

Int. 5 H H Br 288.26

Examples 9-13 were prepared by procedures similar to that described for Example 3. These Examples are summarized in Table 2 below.

Table 2: Derivatives of 5H-Benzo[4,5]cyclohepta[l,2-b]pyridin-5-ol

Ex. Rl R41 R43 MS m/z

Ex. 2 Ph H H 286.0

Ex. 4 Ph Br H 365.8

Ex. 5 Ph H CI 320.0

In another Example, 3-phenyl-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile compounds were prepared by Scheme 5 shown below:

Intermediate 1 Example 6

Example 7

Example 9

HOAc, Zn

Example 10 EXAMPLE 6: 5-Oxo-3-phenvl-5H-benzor4_<51cvcloheptan.2-b1pvridine-9- carbonitrile

Copper (I) cyanide (93.0mg, 1.03mmol) was added to a N,N- dimethylformamide (2mL) solution of Intermediate 1 (250mg, 0.691mmol) under argon. The resulting suspension was heated at 160°C for 24h. The solvent was removed in vacuo and sat. sodium bicarbonate was added. The mixture was extracted with methylene chloride (4x) and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated to a dark solid. Flash column chromatography (methylene chloride:methanol 98:2) gave an off-white solid which was triturated with ether to give EXAMPLE 6. Η MR (CDC1₃, 300MHz) δ 9.20 (d, IH); 8.65 (d, IH); 8.43 (m, IH); 8.05 (m, IH), 7.80-7.45 (m, 8H).

EXAMPLE 7: 5-Hvdroxv-3-phenvl-5H-benzor4,51cvcloheptan,2-b1pvridine-9- carbonitrile

Sodium borohydride (50mg, 1.30mmol) was added to an ethanol (5mL) suspension of EXAMPLE 6 (40mg, 0.130mmol) under argon and the reaction mixture was heated to reflux. After lOmin, the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride (3x). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated to a foam. Trituration with ether/ethyl acetate gave EXAMPLE 7 as a solid. Η ΝMR (CDC1₃. 400MHz) δ 8.78 (m, IH); 8.35 (s, IH); 8.13 (d, IH); 7.70-7.38 (m, 9H), 5.38 (s, br, IH); 5.29 (m, IH). EXAMPLE 8: 5-Hvdroxv-3-phenvl-10,ll-dihvdro-5H-benzor4,51cvcloheptari,2- b]pyridine-9-carbonitrile

Palladium on barium sulfate (25mg) was added to an ethanol (20mL) solution of EXAMPLE 7 (50.0mg, 0.161mmol) in a Parr^® jar and the mixture was hydrogenated at 60psi. After 24h, the reaction mixture was filtered through Celite^® and the filtrate was evaporated in vacuo. Purification by flash column chromatography (hexane:ethyl acetate 50:50) gave a white solid which was triturated with ether to give EXAMPLE 8. Η NMR (CDC1₃, 400MHz) δ 8.66 (m, 1H); 8.13 (s, 1H); 7.82 (d, 1H); 7.60 (m, 3H), 7.50-7.31 (m, 4H); 6.31 (m, 1H); 3.72 (m, 1H); 3.58-3.40 (m, 3H); 2.74 (d, 1H).

EXAMPLE 9: Acetic acid 9-cyano-3-phenyl-10,ll-dihydro-5H-benzo[4,5]cyclo hepta[l,2-b]pyridin-5-yl ester

Acetic acid (ImL) and EXAMPLE 7 (30.0mg, 0.097mmol) were combined under nitrogen and heated to reflux. After 24h, the acetic acid was removed in vacuo and sat. sodium bicarbonate was added to the remaining residue. The mixture was extracted with methylene chloride (3x) and the combined organic extracts were dried with sodium sulfate. Filtration followed by removal of the filtrate in vacuo gave a white solid which was triturated with ether to give EXAMPLE 9. ^XH NMR (CDC1₃, 400MHz) δ 8.85 (s, br, IH); 8.04 (s, IH); 7.80 (d, IH); 7.72 (m, 2H), 7.64-7.40 (m, 7H); 6.50 (s, br, IH); 2.30 (s, br, 3H).

EXAMPLE 10: 3-Phenvl-5H-benzor4.51cvcloheptan,2-blpvridine-9-carbonitrile EXAMPLE 11: 3-Phenyl-10,ll-dihydro-5H-benzo[4,5]cyclo hepta[l,2- b]pyridine-9-carbonitrile

Zinc (50.0mg, 0.769mmol) and EXAMPLE 7 (lOOmg, 0.323mmol) were added to acetic acid (ImL) and the mixture was heated to reflux under nitrogen. After 24h, the acetic acid was removed in vacuo and sat. sodium bicarbonate was added to the remaining residue. The mixture was extracted with methylene chloride (3x) and the combined organic extracts were dried with sodium sulfate. The crude products were purified by silica gel chromatography (gradient, 100% hexane to hexane: ethyl acetate 40:60). Like fractions were combined and the solvent was removed in vacuo to give two white solids. Trituration of each with ether gave EXAMPLE 10 and EXAMPLE 11.

For EXAMPLE 10:

1H NMR (CDCI₃, 400MHz) δ 8.78 (d, IH); 7.82 (m, IH); 7.60 (m, 5H); 7.48 (m, 3H), 7.43 (m, 2H); 3.81 (s, 2H).

For EXAMPLE 11:

1H NMR (CDC1₃, 400MHz) δ 8.64 (m, IH); 7.66 (m, IH); 7.56 (m, 3H); 7.47-7.40 (m, 5H), 4.20 (s, 2H); 3.65 (m, 2H); 3.44 (m, 2H).

In another Example, 3-substituted-5-hydroxy-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitriles (Compounds 43) and 3- substituted-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitriles (Compounds 44) were prepared by Scheme 6 shown below:

Intermediate 6

Intermediate 9

In another Example, 3-(4-fluoro-phenyl)-5-hydroxy-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile Hydrochloride (EXAMPLE 13and 3-(4-Fluoro-phenyl)-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile Hydrochloride (EXAMPLE 14 were prepared by Scheme 7 shown below:

Intermediate 9

Compound 36: 5-Chloro-2-methyl-nicotinic acid methyl ester

Methyl acetoacetate (8.10mL, 75.0mol) and tetrahydrofuran (lOOmL) were combined under nitrogen and cooled to 0°C in an ice/salt bath. Potassium-t- butoxide solution (l.OM, 78.0mL, 78.0mmol) was added in a slow stream while maintaining the reaction temperature at 5°C. After complete addition, the mixture was stirred for 40min at 5°C. Compound 35 (24.0g, 78.0mmol), prepared similarly to Compound 11, was then added. The resulting mixture was transferred by canula into a stirred solution of acetic acid (30mL), trifluoroacetic acid (4.6mL) and tetrahydrofuran (lOOmL) and stirred for 45 min. Ammonium hydroxide (45mL) was added and the reaction mixture was heated to reflux for 45min. The reaction mixture was cooled and concentrated in vacuo. Water and sat. sodium bicarbonate were added and the mixture was extracted with methylene chloride (4x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to give a dark oil. Silica gel chromatography (hexane:ethyl acetate 90:10) followed by trituration with hexane gave Compound 36 as a yellow solid. ^XH NMR (CDC1₃, 400MHz) δ 8.59 (m, IH); 8.20 (m, IH); 3.92 (s, 3H); 2.80 (s, 3H).

Compound 37: 2-[2-(2-Bromo-phenyl)-vinyl]-5-chloro-nicotinic acid Hydrochloride

2-Bromobenzaldehyde (4.15mL, 35.8mmol) was added to a hexane (500mL) solution of Compound 36 (6.63g, 35.8mmol) under nitrogen. The reaction mixture was cooled in an ice bath and potassium-t-butoxide solution (l.OM, 71.6mL, 71.6mmol) was added. After 15min, tetrahydrofuran (150mL) was added and the reaction mixture was slowly warmed to room temperature. After 24h, the solvent was removed in vacuo and water (lOOmL) and 6N hydrochloric acid were added. Trituration of the resulting oil with ethanol gave Compound 37 as a yellow solid. H NMR (DMSO-ώ₆, 400MHz) δ 13.9 (s, br, IH); 8.85 (d, IH); 8.28 (d, IH); 8.18-8.00 (m, 2H), 7.80 (m, IH); 7.72 (m, IH); 7.48 (m, IH); 7.31 (m, IH).

Intermediate 6: 9-Bromo-3-chloro-benzo[4,5]cyclohepta[l,2-b]pyridin-5-one

Polyphosphoric acid (~200g) was added to Compound 37 (9.70g, 25.9mmol) and the resulting mixture was heated to 200°C for 24h. The reaction was cooled and poured onto ice with stirring. The pH of the suspension was adjusted to 7.0 using 5N sodium hydroxide and the mixture was extracted with methylene chloride (lOx). The combined organic extracts were dried with sodium sulfate and concentrated to a dark solid. The solid was triturated with hot methanol, cooled, and isolated by vacuum filtration to give Intermediate 6 as a brown-gray solid. H NMR (CDC1₃, 400MHz) δ 8.82 (d, IH); 8.12 (d, IH); 8.06 (m, IH); 7.98 (m, IH), 7.78 (m, IH); 7.42 (m, 2H).

Intermediate 7: 3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile

Copper (I) cyanide (16.4g,184mmol) was added to a dimethyl sulfoxide (200mL) solution of Intermediate 6 (11.8g, 36.9mmol) under nitrogen and the resulting mixture was heated to 150°C for 6h. The reaction was cooled, poured into water (IL) and ammonium hydroxide (500mL) was added. After 24h, the mixture was filtered. The isolated solid was added to ethanol (400mL) and water (30mL) and heated to reflux. After 30min. the mixture was cooled and filtered to give Intermediate 7 as a dark solid. MS m/z 267.48 (MH⁺)

Intermediate 8: 3-Chloro-5-hydroxy-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile

Sodium borohydride (2.10g, 55.4mmol) was added to an ethanol

(lOOmL) suspension of Intermediate 7 (9.8 lg, 36.9mmol) under nitrogen and the resulting mixture was heated to reflux for lOmin. The reaction mixture was cooled and the solvent removed in vacuo. Water was added and the mixture was extracted with ethyl acetate (6x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated to give Intermediate 8 as a brown-white solid. MS m/z 269.45 (MH⁺)

Intermediate 9: Acetic acid 3-chloro-9-cyano-5H-benzo[4,5]cycIohepta[l,2- b]pyridin-5-yl ester

Acetic acid (20mL), acetic anhydride( 4mL), and Intermediate 8 (8.60g, 32.1mmol) were combined under nitrogen and heated to reflux for 24h. The reaction was cooled and solvents were removed in vacuo. Water was added and the resulting mixture was extracted with ethyl acetate (2x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated. Flash column chromatography (hexane:ethyl acetate 70:30) gave a tan-white solid. Trituration with hexane/ether gave Intermediate 9 as a white solid. Η NMR (CDC1₃, 400MHz) δ 8.56 (s, IH); 7.84 (m, IH); 7.76 (d, IH); 7.72-7.64 (m, 2H), 7.56-7.44 (m, 2H); 6.35 (s, br, IH); 2.30 (s, br, 3H).

EXAMPLE 12: Acetic acid 9-cyano-3-(4-fluoro-phenyl)-5H-benzo[4,5]cyclohepta [l,2-b]pyridin-5-yl ester

4-Fluorophenylboronic acid (190mg, 1.35mmol), tris(dibenzylideneacetone)dipalladium(0) (24mg, 0.026mmol), cesium carbonate (505mg, 1.55mmol), tricyclohexylphosphine(14mg, 0.052mmol), Intermediate 9 (400mg, 1.29mmol), and dioxane were combined under nitrogen and heated at 100°C for 24h. The reaction mixture was cooled, concentrated and diluted with water and sat. sodium bicarbonate. The mixture was extracted with ethyl acetate (3x), dried with sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient, hexane:ethyl acetate 90:10 to 100% ethyl acetate). A yellow- white solid resulted which was triturated with hexane/ether to give EXAMPLE 12. Η NMR (CDC1₃, 400MHz) δ 8.80 (s, IH); 7.98 (s, IH); 7.80 (d, IH); 7.70 (m, 2H), 7.60-7.50 (m, 4H); 7.19 (m, 2H); 6.50 (s, br, IH); 2.30 (s, br, 3H).

EXAMPLE 13: 3-(4-Fluoro-phenvl)-5-hvdroxv-5H-benzor4,51cvcloheptari,2- b]pyridine-9-carbonitrile Hydrochloride

Aqueous lithium hydroxide (1M, 0.676mL, 0.676mmol) was added to a methanol (15mL) solution of EXAMPLE 12 (250mg, 0.676mmol) under nitrogen. After lh, the mixture was concentrated in vacuo and water was added. The mixture was extracted with methylene chloride (3x). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. A white solid remained which was added to ethyl acetate (lOOmL). To this was added IN hydrogen chloride/ether (4ml). After lOrnin the solvent was removed in vacuo and the remaining residue was triturated with ether to give EXAMPLE 13 as a white solid. Η NMR (DMSO-d₆, 400MHz) δ 8.95 (s, IH); 8.45 (s, IH); 8.11 (d, IH); 7.85 (m, 3H), 7.70 (m, 2H); 7.60 (m, IH); 7.39 (t, 2H); 5.45 (s, IH); 2.74 (d, IH).

EXAMPLE 14: 3-(4-Fluoro-phenvl)-10.11-dihvdro-5H-benzor4.51cvcloheptari.2- b]pyridine-9-carbonitrile Hydrochloride

Zinc (600mg, 9.23mmol) was added to an acetic acid (lOmL) solution of EXAMPLE 12 (357mg, 0.965mmol) under nitrogen and the resulting suspension was heated to reflux for 6h. The acetic acid was removed in vacuo and sat. sodium bicarbonate was added to the residue. The mixture was extracted with ethyl acetate (3x) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated. The crude product was purified y silica gel chromatography (gradient, hexane:ethyl acetate 90: 10 to 50:50) to afford a white foam. Addition of IN hydrogen chloride/ether (4ml) and concentration gave EXAMPLE 14 as a white solid. H NMR (DMSO-cZ₆, 400MHz) δ 8.96 (s, IH); 8.68 (s, IH); 7.94 (m, 2H); 7.76 (d, IH), 7.67 (d, IH); 7.42 (m, 3H); 4.48 (s, 2H); 3.52 (m, 4H).

Examples 15-24 and Intermediates 10-12 were prepared by procedures similar to that described above for Compounds 42 and EXAMPLE 12. These Examples are summarized in Table 3 below.

Table 3: Derivatives of Acetic acid 9-cyano-3-Substituted-5H- benzo[4,5]cyclohepta [l,2-b]pyridin-5-yl ester

Examples 15-24

Ex. R, -Metal R„ Salt MS m/z

Int. 10 OAc free base 458.3

Ex. R- -Metal R;, Salt MS m/z

Int. 11 OAc free base 458.3

Int. 12 8.3

(HO Cf^{° Ph} OAc TFA 45 )₂B^^

Ex. 15 OAc free base 371.25

Ex. 16 OAc free base 381.24

Ex. 17 (H0)₂B^^^Ph OAc free base 379.21

Ex. 18 JLJ OAc free base 383.6

Ex. 19 OAc free base 359.23

Ex. 20 OAc TFA 359.20 S^/^Sn(Bu)₃

Ex. 21 OAc free base 343.28 0^/^Sn(Bu)₃

Ex. 22 OH free base 301.26 0 Sn(Bu)₃ H₃

Ex. 23 (Bu)₃Srf OH free base 273.28

Ex. 24 OH free base 31.20 S^/^Sn(Bu)₃ EXAMPLE 26:

To a solution of Intermediate 9 (200mg, 0.64mmol) in dioxane (8mL) was added bis(pinacolato)diboron (490mg, 1.93mmol), cesium carbonate (630mg, 1.93mmol), tricyclohexylphosphine (36mg, 0.13mmol), and tris(dibenzylideneacetone)dipalladium(0) (59mg, 0.06mmol). The reaction mixture was heated to 80°C and stirred for lh. The reaction mixture was cooled, diluted with EtOAc and washed with aqueous NaHCO₃ and H₂O. The organic layer was dried over Na₂SO₄, filtered, concentrated and the resulting boronic ester was used with no further purification.

To a solution of the above crude boronic ester (50mg, 0.12mmol) in dioxane (3mL) was added 3-bromopyridine (39mg, 0.25mmol), cesium carbonate (121mg, 0.37mmol), tricyclohexylphosphine (14mg, 0.05mmol), and tris(dibenzylideneacetone)dipalladium(0) (23mg, 0.02mmol). The reaction mixture was heated to 80°C and stirred for 30min. The reaction mixture was cooled, diluted with EtOAc and washed with aqueous NaHCO₃ and H₂O. The organic layer was dried over Na₂SO₄, filtered, concentrated. The residue was purified on silica gel (gradient elution, 10:1 hexane:EtOAc to EtOAc) to give EXAMPLE 26 as an oil. MS (M+H) = 354.21.

Examples 25-29 and Intermediates 113-14 were prepared by procedures similar to that described above for EXAMPLE 26. These Examples are summarized in Table 4 below.

Table 4: Derivatives of Acetic acid 9-cyano-3-Substituted-5H- benzo[4,5]cyclohepta [l,2-b]pyridin-5-yl ester 1) Pd₂(dba)₃

Cs₂C0₃, Cy₃P

Examples 25-29

R-Br or R-Otf Salt Form MS m/z (MET)

Ex. 26 ^o free base 354.21

Int. 13 Br-^^S TFA 360.25

Int. 14 μL .oτf TFA 384.34

Examples 30-55 were prepared using an approach similar to that described for EXAMPLE 13. These Examples are summarized in Table 5 below.

Table 5: Derivatives of 3-Substituted-5-hydroxy-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-

9-carbonitrile

Ex. R Salt Form MS m/z (MH⁺)

Ex. 30 A free base 329.49

Ex. 32 free base 325.53

Ex. 33 χO^m' free base 325.53

Ex. 34 "Co free base 325.54

Ex. 35 A free base 341.51

Ex. 37 x ³ free base 341.30

Ex. 38 free base 379.24

"&

Ex. R Salt Form MS m/z (MH⁺)

Ex. 50 A free base 315.29

Ex. 51 TFA 328.27 ^%> Ex. R Salt Form MS m/z (MH⁺)

Ex. 53 y free base 317.23

Ex. 54 A free base 342.27

EXAMPLE 56: 9-Cvano-3-(2-hvdroxvphenvl)-5H-benzor4,51cycIoheptari,2- b]pyridin-5-yl acetate

Intermediate 10 (216mg, 0.462mmol, -75% pure), 10% palladium on carbon (50mg) and ethanol (20mL) were combined and stirred under a balloon of hydrogen for 24h. The reaction mixture was filtered through celite and the filtrate was evaporated to give a residue which was purified by Gilson reverse phase preparative HPLC. Evaporation of the fractions containing the desired product gave a white solid which was triturated with ethyl acetate to give EXAMPLE 56. MS m/z 369.22 (MH⁺)

EXAMPLE 57: 9-Cyano-3-(3-hvdroxyphenvl)-5H-benzor4,51cycloheptari,2- b]pyridin-5-yl acetate

EXAMPLE 57 was prepared via the procedure for EXAMPLE 56 except using Intermediate 11 instead of Intermediate 10. MS m/z 369.22 (MET^1")

EXAMPLE 58: 9-Cvano-3-(4-hvdroxyphenyl)-5H-benzor4,51cvcloheptari,2- b]pyridin-5-yl acetate

EXAMPLE 58 was prepared via the procedure for EXAMPLE 56 except using Intermediate 12 instead of Intermediate 10. MS m/z 369.22 (MH0)

EXAMPLE 59: 5-Hydroxy-3-(2-hydroxyphenyl)-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile

EXAMPLE 59 was prepared from EXAMPLE 56 using an approach like that described for EXAMPLE 13. MS m/z 327.23 (ME0)

EXAMPLE 60: 5-Hvdroxv-3-(3-hvdroχyphenvl)-5H-benzor4.51cvcloheptari,2- b]pyridine-9-carbonitrile

EXAMPLE 60 was prepared from EXAMPLE 57 using an approach like that described for EXAMPLE 13. MS m/z 327.23 (MET^1")

EXAMPLE 61: 5-Hvdroxv-3-(4-hydroxyphenvl)-5H-benzor4,51cvcloheptari.2- b]pyridine-9-carbonitrile

EXAMPLE 61 was prepared from EXAMPLE 58 using an approach like that described for EXAMPLE 13.

MS m/z 327.23 (MH⁺)

Examples 62-82 were prepared using an approach similar to that described for EXAMPLE 14. These substances are summarized in Table 6 below.

Table 6: Derivatives of 3-Substituted-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile

Ex. R Salt Form MS m/z (MH )

64 AA_F free base 315.56

, ' free base 327.34

^H5D free base 313.26

°» TFA 331.21

_v O free base 323.33

Free base 327.34

82 A} 2 TFA 304.24

Scheme 8: General Synthesis of 5-Hydroxy-7-Alkylamino-l-yl-5H- dibenzo[a,d]cycloheptene-l-carbonitrile (Ex. 84)

NR-,R₂,

Intermediate 7 83

84

Scheme 9: Synthesis of 5-Hydroxy-7-piperidin-l-yl-5H- dibenzo[a,d]cycloheptene-l-carbonitrile

Intermediate 7 77% Intermediate 16

EXAMPLE 85: 5-Hvdroxv-7-piperidin-l-vl-5H-dihenzora.dlcycloheptene-1 - carbonitrile

Step 1:

Intermediate 16: 5-Oxo-7-piperidin-l-yl-5H- dibenzo[a,d]cycloheptene-l-carbonitri!e

Sodium-t-butoxide (81.0mg, 0.843mmol) was added to a suspension of Intermediate 7 (150mg, 0.562mmol), piperidine (0.115mL, 1.12mmol), tris(dibenzylideneacetone)dipalladium(0) (4mg, 0.004mmol) and (R,S)-2,2'- bis(diphenylphosphino)l,l'-binaphthyl (8mg, 0.013mmol) in toluene (ImL) and heated at 100°C under nitrogen for 24h. The solvent was removed in vacuo and water and sat. sodium bicarbonate were added to the residue. The mixture was extracted with methylene chloride (3x). The combined organic extracts were dried with sodium sulfate and the crude product was purified by silica gel chromatography (gradient, hexane:ethyl acetate 90:10 to 50:50) to give a yellow solid Intermediate 16. H NMR (CDC1₃, 400MHz) δ 8.65 (m, IH); 8.42 (d, IH); 8.00 (m, IH); 7.81 (m, IH), 7.62-7.51 (m, 3H); 3.44 (m, 4H); 1.78-1.66 (m, 6H).

Step 2:

EXAMPLE 85: 5-Hvdroxv-7-piperidin-l-vl-5H- dibenzo[a,d]cycloheptene-l-carbonitrile

Sodium borohydride (29.0mg, 0.762mmol) was added to a suspension of Intermediate 16 (120mg, 0.381mmol) in ethanol (lOmL) and the mixture was heated to reflux for 5min. The reaction was cooled and the solvent removed in vacuo. Water and sat. ammonium chloride were added and the resulting mixture was extracted with ethyl acetate (3x). The combined organic extracts were dried with sodium sulfate (anh.) and filtered. Removal of the filtrate in vacuo gave a solid. Trituration with ether/ethyl acetate afforded an off white solid, EXAMPLE 85,(71. lmg, 0.224mmol, 58.9%). Η NMR (CDC1₃, 400MHz) δ 8.19 (d, IH); 7.97 (d, IH); 7.60 (m, IH); 7.50-7.36 (m, 4H), 5.28 (s, IH); 3.29 (m, 4H); 3.05 (s, IH); 2.75-2.55 (m, 6H).

Examples 86-88 and Intermediates 17-22 were prepared using an approach similar to that described above for Intermediate 16. These Examples are summarized in Table 7 below.

Table 7: Derivatives of 5-Oxo-7-alkylamino-l-yl-5H-dibenzo[a,d]cycloheptene-

1-carbonitrile

NR.R, Salt Form MS m/z (MH )

1

Int. 17 free base 318.32

Int. 18 y free base 302.29

Int. 19 _{/ γ} free base 318.31

Int. 20 _y free base 330.32

Int. 21 free base 346.32

NR.R₉ Salt Form MS m/z (MH⁺)

Examples 89-97 were prepared using an approach similar to that described for EXAMPLE 85. These Examples are summarized in Table 8 below.

Table 8: Derivatives of 5-Hydroxy-7-alkylamino-l-yl-5H- dibenzo[a,d]cycloheptene-l-carbonitrile

Ex. NRaRb Salt Form MS m/z (MH⁺)

91 Free base 304.32

94 Free base 348.35

97 A_^^ free base 304.35

EXAMPLE 98: 9-Cvano-3-piperidin-l-vl-5H-benzor4,51cvcloheptari.2- b]pyridin-5-yl acetate

EXAMPLE 98 was prepared from EXAMPLE 85 using an approach like that described for EXAMPLE 9. MS m/z 360.36 (MH*)

EXAMPLE 99: 3-Piperidin-l-vl-5H-benzor4,51cvcloheptari,2-blpvridine-9- carbonitrile

EXAMPLE 99 was prepared from EXAMPLE 98 using an approach like that described for EXAMPLE 10. MS m/z 302.32 (MfT) EXAMPLE 100 to EXAMPLE 102 were prepared according to Scheme 10 below:

Example 102 INT. 19

Intermediate 18: 3-Phenyl-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile l-oxide

m-Chloroperoxybenzoic acid (39mg, 0.22mmol) was added to a stirred solution of EXAMPLE 11 (50mg, 0.17mmol) in 4mL of dichloromethane under nitrogen. After lh, aqueous sodium bicarbonate solution was added, the organic layer separated and the resulting aqueous layer was extracted with dichloromethane. The combined organic extracts were dried with Na₂SO₄, filtered, and concentrated. Purification by flash column chromatography (gradient elution, 1:1 hexane:ethyl acetate to ethyl acetate/5% methanol) and evaporation of solvents in vacuo yielded a white solid.

EXAMPLE 100: 9-Cvano-3-phenvl-10.ll-dihvdro-5H-benzor4.51cvcloheptari.2- b]pyridin-ll-yl acetate

A solution of Intermediate 18 (lOmg, 0.03mmol) in acetic anhydride (ImL) was heated to reflux for 15min. The reaction mixture was cooled and concentrated. The crude product was purified by silica gel chromatography (gradient elution, 10:1 hexanes:EtOAc to EtOAc) to give EXAMPLE 100. 1H NMR (300 MHz, CDC1₃) δ 8.75 (s, 1 H), 7.70 (s, 1 H), 7.55-7.05 (m, 8 H), 6.45 (m, 1 H), 4.40 (d, 1 H), 3.95 (d, 1 H), 3.79 (dd, 1 H), 3.64 (dd, 1 H), 2.15 (s, 3 H) ppm. Mass spectrum m/z 355.42 [(M+H)⁺,C₂₃H₁₉N₂O₂].

EXAMPLE 101: ll-Hvdroxy-3-phenvl-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile

To a solution of Intermediate 18 (lOmg, 0.03mmol) in MeOH (2mL) was added K₂CO₃ (7.7mg, 0.06mmol) and the reaction mixture was stirred for 3h at it. The mixture was partitioned between dichloromethane and aqueous NaHCO₃, the organic layer was dried over Na SO₄ and concentrated. The crude product was purified by silica gel chromatography (gradient elution, 10:1 hexanes:EtOAc to EtOAc) to give EXAMPLE 101. 1H NMR (300 MHz, CDC1₃) δ 8.70 (s, 1 H), 7.70 (s, 1 H), 7.55-7.20 (m, 8 H), 5.20 (m, 1 H), 4.23 (d, 1 H), 4.04 (d, 1 H), 3.80 (dd, 1 H), 3.41 (dd, 1 H) ppm. Mass spectrum m/z 313.39 [(M+H)⁺,C₂ιH₁₇N O].

EXAMPLE 102: 4-Chloro-3-phenvl-10.ll-dihvdro-5H-benzor4.51cvcloheptari.2- b]pyridine-9-carbonitrile

A solution of Intermediate 18 (10 mg, 0.03 mmol)in POCl₃ (1 mL) was heated to 90°C for 30 min. The reaction mixture was cooled and poured onto ice. The mixture was partitioned between dichloromethane and aqueous NaHCO₃, the organic layer was dried over Na₂SO and concentrated. The crude product was purified by silica gel chromatography (gradient elution, 10:1 hexanes:EtOAc to EtOAc) to give EXAMPLE 102. The 2-C1 pyridine isomer (Intermediate 19) is formed in an equal amount and elutes first.

EXAMPLE 102: 4-Chloro-3 -phenyl- 10, 1 l-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile: 1H NMR (300 MHz, CDC1₃) δ 8.30 (s, IH), 7.60-7.20 (m, 8 H), 4.42 (s, 2 H), 3.50 (m, 4 H) ppm. Mass spectrum m/z 331.34 [(M+H)⁺,C₂₁H₁₆N₂CTJ.

Intermediate 19: 2-Chloro-3-phenyl-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile: 1H NMR (300 MHz, CDC1₃) δ 7.60-7.20 (m, 9 H), 4.18 (s, 2 H), 3.41 (m, 4 H) ppm. Mass spectrum m/z 355.44 [(M+H)⁺, C₂₁H₁₆N₂C1].

EXAMPLE 103: 4-Phenyl-6,10b-dihydro-laH- benzo[4,5joxireno[6,7]cyclohepta[l,2-b]pyridine-10-carbonitrile.

NaOCI

Example 103

To a solution of EXAMPLE 10 (150mg, 0.51mmol) in dichloromethane (lOmL) was added bleach (NaOCI solution, ImL). Tetrabutylammonium sulfate (173mg, 0.51mmol) was added and the reaction mixture was stirred for 2h at RT. The reaction mixture was partitioned between dichloromethane and water, the organic layer was dried over Na₂SO and concentrated. The crude product was purified by silica gel chromatography (gradient elution, 10:1 to 1:1 hexanes:EtOAc) to give EXAMPLE 103. 1H NMR (300 MHz, CDC1₃) δ 8.70 (s, 1 H), 7.66 (s, 1 H), 7.65-7.25 (m, 8 H) 5.28 (d, 1 H), 4.96 (d, 1 H), 4.74 (d, 1 H), 3.41 (d, 1 H) ppm. Mass spectrum m/z 311.44 [(M+H)⁺,C₂₁Hι₅N₂O] . POCI

Example 105

EXAMPLE 104: 3-Phenvl-5H-benzor4,51cycloheptari,2-blpyridine-9- carbonitrile 1-oxide

N-oxide EXAMPLE 104 was prepared via the procedure for Intermediate 18 except starting with EXAMPLE 10 instead of EXAMPLE 11.

EXAMPLE 105: 4-Chloro-3-phenvl-5H-benzor4,51cvcloheptari,2-blpyridine-9- carbonitrile

EXAMPLE 105and Intermediate 20 were prepared via a similar procedure used for EXAMPLE 102 and Intermediate 19 except staring with EXAMPLE 104 instead of Intermediate 18.

EXAMPLE 105: 4-Chloro-3-phenyl-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile: 1H NMR (300 MHz, CDC1₃) δ 8.40 (s, IH), 7.70-7.40 (m, 10 H), 4.01 (s, 2 H) ppm. Mass spectrum m/z 329.42 [(M+H)⁺,C₂₁Hi₄N₂Cl]. Intermediate 20: 2-Chloro-3-phenyl-5H-benzo[4,5]cyclohepta[l,2-b]pyridine-9- carbonitrile: 1H NMR (300 MHz, CDC1₃) δ 7.60-7.35 (m, 11 H), 3.75 (s, 2 H) ppm. Mass spectrum m/z 329.42 [(M+H)⁺, C₂ιHι₄N₂Cl].

Intermediate 5

Intermediate 23 Example 106

EXAMPLE 106: 4-[(2-Phenylethyl)amino]-10,ll-dihydro-5H- benzo[4,5jcyclohepta[l,2-b]pyridine-9-carbonitrile

Step 1:

Intermediate 21: 10,ll-Dihydro-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile

Intermediate 21 was prepared from Intermediate 5 following the same reaction sequence used to convert Intermediate 1 to EXAMPLE 11. Step 2:

Intermediate 22: l-Oxy-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

m-Chloroperoxybenzoic acid (627mg, 3.63mmol) was added to a stirred solution of pyridine Intermediate 21 (400mg, 1.82mmol) in 70mL of dichloromethane under nitrogen. After lh, lOOmL of sat'd sodium bicarbonate solution was added, the organic layer separated and the resulting aqueous layer was extracted 2x75mL dichloromethane. The combined organic extracts were dried with magnesium sulfate (anh.), filtered, and evaporated in vacuo to yield a white solid. Purification by flash column chromatography (ethyl acetate to ethyl acetate:methanol:ammonium hydroxide, 95:4.5:0.5) and evaporation of solvents in vacuo yielded a white solid, Intermediate 22. MS: 237.24 m/z 1H NMR (CDC1₃, 400MHz) δ 8.19 (t, IH); 7.59 (d, IH); 7.48 (d, IH); 7.30 (t, IH); 7.19 (m, 2H); 4.18 (s, 2H); 3.52 (t, 2H); 3.35 (t, 2H).

Step 3:

Intermediate 23: 4-Chloro-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

N-oxide Intermediate 22 (309mg, 1.31mmol) was added to phosphorous oxychloride (15mL) and heated at 90°C under nitrogen for 2h, and 18h at 25°C. Ice and 500mL sat'd sodium bicarbonate solution were slowly added and the solution was extracted with 2x200mL of dichloromethane. The combined organic extracts were dried with magnesium sulfate (anh.), filtered and evaporated in vacuo to yield a white solid. The product was pre-absorbed on silica and purified by flash column chromatography (ethyl acetate:hexanes 1:20 to 1:1), yielding a white solid of desired product Intermediate 23 and the 2-chloro isomer as a minor product. MS: 255.25 m z. 1H NMR (CDC1₃, 400MHz) δ 8.60 (d, IH); 7.67 (d, IH); 7.61 (d, IH); 7.55 (d, IH); 7.34 (t, IH); 4.51 (s, 2H); 3.73 (t, 2H); 3.56 (t, 2H).

Step 4 EXAMPLE 106: 4-Phenethylamino-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

A solution of chloropyridine Intermediate 23 (15mg, 0.059mmol) in 2mL of toluene was flushed well with nitrogen. Phenethylamine (22.2μL, 0.18mmol), Pd₂(dba)₃ (21.6mg, 0.02mmol), BINAP (14.7mg, 0.02mmol) and sodium t-butoxide (14.2mg, 0.15mmol) were added, forming a dark orange suspension After 2h, the mixture was evaporated in vacuo. Dichloromethane (20mL) was added, followed by 20mL brine. The organic layer was separated and the aqueous layer was extracted with 2x50mL dichloromethane. The combined organic extracts were dried with magnesium sulfat, filtered and evaporated to an orange oil. Purification on reversed phase HPLC yielded EXAMPLE 106 as a white solid. MS: 340.34 m/z 1H NMR (CD₃OD, 400MHz) δ 7.91 (d, IH); 7.65 (d, IH); 7.51 (d, IH); 7.36 (t, IH); 7.21 (m, 5H); 6.82 (d, IH); 4.10 (s, 2H); 3.71 (t, 2H); 3.48 (t, 2H), 3.39 (t, 2H), 2.99 (t, 2H).

EXAMPLE 107: 4-(3-Phenyl-propylamino)-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

Reaction of the chloropyridine 213 (15mg, 0.059mmol) 3- phenylpropylamine (25.1μL, O.lδmmol), Pd₂(dba)₃ (27.0mg, 0.03mmol), BINAP (18.3mg, 0.03mmol) and sodium t-butoxide (14.2mg, 0.15mmol), as above provided EXAMPLE 107 as a yellow oil after reversed phase HPLC purification. MS: 354.22m/z. 1HNMR (CD₃OD, 400MHz) δ 7.92 (d, IH); 7.64 (d, 2H); 7.34 (t, IH); 7.28 (m, 2H); 7.19 (m, 3H); 6.79 (d, IH); 4.14 (s, 2H); 3.48 (m, 4H); 3.37 (t, 2H) 2.75 (t, 2H); 2.02 (quintuplet, 2H).

EXAMPLE 108: 4-Benzylamino-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile.

Similarly as above, using the following starting materials: chloropyridine, Intermediate 23, (lOmg, 0.039mmol) in 5mL of toluene, benzylamine (12.7μL, 0.12mmol), Pd₂(dba)₃ (7.3mg, 0.008mmol), BINAP (4.9mg, 0.008mmol) and sodium t-butoxide (7.5mg, 0.008mmol) yielded as a yellow oil EXAMPLE 108. MS: 326.32 m/z. 1H NMR (CDC1₃, 400MHz) 6 8.18 (d, IH); 7.53 (d, IH); 7.37 (m, 6H); 7.18 (t, IH); 6.38 (d, IH); 4.55 (br. s, IH); 4.39 (d, 2H); 3.94 (s, 2H); 3.39 (m, 2H).

Example 109

Example 110 Example 111

EXAMPLE 109: 2-Indol-l-yl-3-phenyl-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

A solution of chloropyridine, EXAMPLE 103, (15mg, 0.059mmol) in 2mL of toluene was flushed well with nitrogen. Phenethylamine (11.3μL, 0.09mmol), Pd₂(dba)₃ (8.2mg, O.Olmmol), BINAP (5.6mg, O.Olmmol) and sodium t-butoxide (8.6mg, 0.09mmol) were added to form a dark orange suspension. After 2h, the mixture was evaporated in vacuo. Ethyl acetate (20mL) was added, followed by 20mL sat'd sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3x50mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to an orange oil. Purification by reversed phase HPLC yielded EXAMPLE 109 as an oil. MS: 416.41 m/z

1H NMR (CDC1-₃, 400MHz) δ 7.92 (s, IH); 7.60 (d, IH); 7.51 (m, 5H); 7.25 (m, 3H); 7.16 (d, 2H); 6.91 (m, 2H); 3.99 (s, 2H); 3.51 (t, 2H); 3.46 (m, 6H).

EXAMPLE 110: 4-(2.6-Dimethoxv-benzvIamino)-3-phenvl-10,ll-dihvdro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile.

A solution of chloropyridine, EXAMPLE 103, (60mg, 0.059mmol) in lOmL of toluene was flushed well with nitrogen. 2,4-Dimethoxybenzylamine (81.6μL, 0.54mmol), Pd₂(dba)₃ (70mg, 0.076mmol), BINAP 53.8mg, 0.086mmol) and sodium t-butoxide (43.5mg, 0.45mmol) were added to form a dark orange suspension. After 3d, the mixture was evaporated in vacuo. Ethyl acetate (20mL) was added, followed by 20mL sat'd sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3x50mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated to an orange oil. Purification by flash column chromatography (dichloromethane to dichloromthane:methanol: ammonium hydroxide, 90:10:1) and evaporation of solvents in vacuo yielded an oily solid, EXAMPLE 110. MS: 462.34 m/z. 1H NMR (CDC1₃, 400MHz) δ 8.06 (s, IH); 7.54 (d, IH); 7.38 (m, 5H); 7.17 (m, 3H); 6.75 (d, IH); 6.32 (t, IH); 4.23 (s, 2H); 4.04 (s, H); 3.79 (s, 3H); 3.57 (s, 3H); 3.47 (m, 4H).

EXAMPLE 111: 4-Amino-3-phenyl-10,ll-dihydro-5H-benzo[4,5]cyclohepta[l,2- b]pyridine-9-carbonitrile.

To a stirring solution of EXAMPLE 110 in 5mL of dichloromethane was added trifloroacetic acid. The solution was stirred 30min then basified with sat'd sodium bicarbonate, the organic layer was separated, dried with magnesium sulfate, filtered and evaporated to a yellow oil. Purification by flash column chromatography (dichloromethane to dichloromethane:methanol:ammonium hydroxide, 80:20:1) and evaporation of solvents in vacuo yielded EXAMPLE 111 as a yellow solid. MS: 312.35 m/z. 1H NMR (CDCI₃, 400MHz) δ 8.01 (d, IH); 7.54 (d, IH); 7.35-7.50 (m, 5H); 7.22 (m, 2H); 4.32 (s, 2H); 4.04 (s, 2H); 3.44 (m, 4H).

EXAMPLE 112: 5-hvdroxv-3-phenvl-5H-benzor4.51cvcloheptari.2-blpvridine-9- carbaldehyde

Lithium aluminum hydride solution (l.OM in THF, 0.81mL, 0.81 mmol) was added in a slow stream to a THF solution of EXAMPLE 6 (50mg, 0.16 mmol) at -78°C under a nitrogen atmosphere. After 0.5h the reaction flask was warmed to 0°C and aged 18h. The contents of the reaction flask were quenched with water and extracted with methylene chloride (3 x 50mL). The combined organic extracts were washed with brine and dried with sodium sulfate. Flash column chromatography (methylene chloride:methanol:ammonium hydroxide 98:2:0.2) gave after trituration with methanol EXAMPLE 112 as a yellow solid. 1H NMR (CDC1₃, 400MHz) δ 10.38 (s, IH); 8.75 (m, IH); 8.26 (m, 2H); 8.10 (m, IH); (7.80, m, IH); 7.60 (m, 3H); 7.50 (m, 4H); 5.40 (m, IH); 2.77 (m, IH).

EXAMPLE 113: 9-({r2-(dimethvlamino)ethvllamino>methvl)-3-phenvl-5H- benzo[4,5]cyclohepta[l,2-b]pyridin-5-ol

EXAMPLE 112 (4.3mg, 0.014mmol), sodium cyanoborohydride solution (1.0M in THF, 0.027mL, 0.027 mmol), N,N-dimethylethylenediamine

(0.003mL, 0.027mmol) and methanol were combined under nitrogen and heated to 80°C for 24h. Removal of the solvent in vacuo followed by Gilson reverse phase preparative HPLC gave EXAMPLE 113 as a white solid. MS ESI m/z [M+H]⁺ 386.35

EXAMPLE 114: 9-{r2-(dimethylaπuno)ethvl1amino}-3-phenyl-5H- benzo[4,5]cyclohepta[l,2-b]pyridin-5-one

A toluene (5mL) solution of Intermediate 1 (lOOmg, 0.276mmol), NN-dimethyl-ethylenediamine (0.080mL, 0.730mmol), tris(dibenzylideneacetone)dipalladium (0) (5mg, 0.005mmol), 2,2'- bis(diphenylphophino)-l,l'-binaphthyl (lOmg, 0.016mmol) and sodium-t-butoxide (80mg, 0.833mmol) was heated at 80°C for 24h. The contents of the reaction flask were quenched with water and extracted with methylene chloride (3 x 50mL). The combined organic extracts were washed with brine and dried with sodium sulfate (anh.). Flash column chromatography (methylene chloride:methanol:ammonium hydroxide 97:3:0.3) gave after trituration with methanol a yellow oil which was treated with EtOAc and IN HCl/Et₂O to give EXAMPLE 114 as a red solid. 1H NMR CDMSO-d_d, 400MHz) δ 10.35 (s, br, IH); 9.25 (m, IH); 8.49 (m, IH); 7.88 (d, 2H); 7.68 (d, IH); 7.50 (m, 4H); 7.25-7.35 (m, 2H); 7.15 (d, IH); 3.60 (m, 2H); 3.37 (m, 2H); 2.50 (m, 6H).

EXAMPLE 115: 3-phenvl-ll-piperidin-l-vl-10αi-dihvdro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile

A solution of EXAMPLE 101 (63.0mg, 0.202mmol), methanesulfonyl chloride (0.017mL, 0.222mmol), N,N-diisopropylethylamine (0.039mL, 0.222mmol) and methylene chloride (2mL) was stirred lh at room temperature under Nitrogen. To this was added a piperidine (0.025mL, 0.253mmol). After 24h methylene chloride was added and the contents of the reaction flask were washed with sat. ammonium chloride. Dried the organic layer with sodium sulfate, filtered, and removed the solvent in vacuo. Gilson reverse phase preparative HPLC gave EXAMPLE 115 as a white foam. 1H NMR (CD₃OD, 500MHz) δ 8.87 (d, IH); 8.16 (m, IH); 7.73 (m, 4H); 7.53 (m, 2H); 7.46 (m, 2H); 4.83-4.70 (m, 2H); 4.18 (d, IH); 3.94 (m, 2H); 3.70 (m, 2H); 3.25 (m, 2H); 2.20-1.60 (m, 6H).

EXAMPLE 116: ll-azido-3-phenvl-10.11-dihvdro-5H-benzor4,51cycloheptari,2- b]pyridine-9-carbonitrile

A solution of EXAMPLE 101 (50.0mg, O.lόOmmol), diethyl azodicarboxylate (0.025mL, 0.160mmol), triphenylphosphine (46mg, 0.176mmol), diphenylphosphoryl azide (0.038mL, 0.176mmol) and THF (ImL) was stirred 24h under Nitrogen. The contents of the reaction flask were poured into water. Extracted with methylene chloride (4x); dried with sodium sulfate, filtered. Removal of the solvent in vacuo followed by Gilson reverse phase preparative HPLC gave EXAMPLE 116 as a white foam. 1H NMR (CD₃OD, 500MHz) δ 8.80 (d, IH); 8.20 (d, IH); 7.73 (m, 2H); 7.66 (m, 2H); 7.52 (m, 2H); 7.46 (m, IH); 7.39 (m, IH); 5.23 (m, IH); 4.51 (m, IH); 4.19 (m, IH); 3.86 (m, IH); 3.70 (m, IH).

EXAMPLE 117: ll-amino-3-phenvI-10,ll-dihvdro-5H-benzor4,51cycloheptari,2- b]pyridine-9-carbonitrile

A solution of EXAMPLE 116 (lO.Omg, 0.029mmol), triphenylphosphine (9.0mg, 0.032mmol), THF (0.5mL) and water (0.5mL) were combined under Nitrogen and stirred at rt 48h. To this was added aqueous sodium hydroxide and methanol. After 2h the contents of the reaction flask were evaporated in vacuo and the remaining residue was subjected to Gilson reverse phase preparative HPLC to give EXAMPLE 117 as a white solid. MS ESI m/z [M+H]⁺ 312.25

EXAMPLE 118: 3-Phenvl-10.ll-dihvdro-5H-benzor4.51cvcloheptari.2- b]pyridine-9-carbaldehyde

To a solution of EXAMPLE 11 (0.5g, 1.69mmol) in toluene (lOmL) at -60°C and under nitrogen was slowly added over lh l.OM diisobutylaluminium hydride in dichloromethane (3.4mL, 3.38mmol). The reaction mixture was allowed to stir at -60°C for lh and additional charge of l.OM diisobutylaluminum hydride in dichloromethane (3.4mL, 3.38mol) added. The reaction was aged an additional hour at -60°C and quenched by addition of acetic acid (5mL). The reaction was diluted with water (20mL) and ethyl acetate (50mL) and mixed well. The ethyl acetate extract was dried over sodium sulfate, filtered, concentrated and chromatographed on silica using 20-50% ethyl acetate/hexane to give EXAMPLE 118 as a foam. M.S.(M+1): 300.

EXAMPLE 119: 9-(1.3-Oxazol-5-vl)-3-phenyl-10qi-dihvdro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine

EXAMPLE 118 (50 mg, 0.167 mmole) was dissolved in 0.5 M sodium methoxide (l.lmL) and allowed to stir at rt for 5min. 4- Toluenesulfonylmethylisocyanide (40mg, 0.20mmole) was added and the mixture stirred at 40°C for 3h. The reaction was diluted with water (20mL) and extracted with ethyl acetate (30mL). The ethyl acetate extract was dried over sodium sulfate, filtered, concentrated and chromatographed on silica using 30-100% ethyl acetate/hexane to give EXAMPLE 119 as a foam. M.S.(M+1): 339.

EXAMPLE 120: 2,2-Dimethyl-propionic acid 9-cyano-3-phenyl-5H- benzo[4,5]cyclohepta[l,2-b]pyridin-5-yl ester.

To a stirred solution of EXAMPLE 7 (25mg, 0.081mmol) in methylene chloride (2mL) was added DMAP (19.8mg, 0.162mmol) and trimethyacetyl chloride (21 μL, 0.17 mmol), forming a white suspension that was stirred under N₂ for 18h. The reaction mixture was evaporated in vacuo to provide

60mg of a white solid. The solid was purified by silica gel chromatography (gradient elution, 10% to 50% ethyl acetate in hexanes), yielding a white solid, which was triturated in 5mL hexanes to obtain EXAMPLE 120 as a white solid. MS: M+l=395.3 EXAMPLE 121: Acetic acid 9-cyano-3-(3-hydroxymethyl-phenyl)-5H- benzo[4,5]cyclohepta[l,2-b]pyridin-5-yl ester.

To a stirring solution of EXAMPLE 16 (20mg, 0.053mmol) in THF (2mL) was added sodium cyanoborohydride (1M/THF, 50μL, 0.05mmol). The solution was stirred for 2h, followed by addition of 4 drops 6N HCI. The resulting mixture was evaporated in vacuo to a white solid. The solid was dissolved in ImL DMSO and 1 drop TFA and purified on reversed-phase HPLC, affording EXAMPLE 121 as a white solid. MS: M+l=383.2

EXAMPLE 122: 6-Chloro-5-hvdroxv-3-phenvl-5H-benzor4,51cycloheptan,2- b]pyridine-9-carbonitrile.

EXAMPLE 122 was prepared by following the reaction sequence described for the conversion of Compound 14 to EXAMPLE 7 except using 2- bromo-5-chlorobenzaldehyde instead of 2-bromobenzaldehyde. MS: M+l = 345.

EXAMPLE 123: 9-Cvano-2-phenvl-5H-benzor4,51cvcloheptari.2-b1pvridin-5-vl acetate

Intermediate 24 Intermediate 25

Intermediate 24 was prepared according to the procedure for preparing EXAMPLE 9 except using Intermediate 5 instead of Example 2.

Intermediate 25 was prepared according to the procedure for preparing Intermediate 19 except using Intermediate 24 instead of Intermediate 18.

EXAMPLE 123 was prepared according to the procedure for preparing EXAMPLE 12 except using Intermediate 25 instead of Example 23. MS m/z 311.3 (Mtf)

EXAMPLE 124: ll-Hydroxy-3-phenyl-10,ll-dihydro-5H- benzo[4,5]cyclohepta[l,2-b]pyridine-9-carbonitrile

EXAMPLE 124 was prepared from EXAMPLE 101 using an approach like that described for EXAMPLE 13. MS m/z 313.28 (MH⁺)

EXAMPLE 125: ll-Hvdroχy-3-phenyl-5H-benζor4,51cycloheptan,2-blpvridine- 9-carbonitrile

Oxalyl chloride (31μL, 0.353mmol) was added to methylene chloride (4mL) and cooled under nitrogen to -70°C. To this was added a solution of DMSO (60μL, 0.847mmol) in methylene chloride. After lOmin. a solution of EXAMPLE 124 (lOOmg, 0.321mmol) in methylene chloride was added. After lOmin. triethylamine (223μL, l.όlmmol) was added and the reaction was warmed to it. Water and 5% potassium bisulfate were added and the layers were separated. The aqueous layer was extracted with methylene chloride and the combined organic portions were dried with anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by Gilson reverse phase preparative HPLC then ISCO chromatography (methylene chloride to methylene chloride:methanol:ammounium hydroxide 98:2:0.2 to give a yellow solid which was triturated with ether to afford EXAMPLE 125: MS m/z 311.29 (Mtf)

EXAMPLE 126: ll-Methoxv-3-phenvl-5H-benζor4.51cvcloheptan.2-b1pyridine- 9-carbonitrile

EXAMPLE 125 (5rng, O.Olόrnrnol), methanol (50μL) and (trimethylsilyl)diazomethane (2.0M in hexane, lOOμL) were combined and stirred 24h under nitrogen. The contents of the reaction flask were quenched with 6N hydrochloric acid, evaporated and subjected to Gilson reverse phase preparative HPLC to give EXAMPLE 126 as a yellow solid. MS m/z 325.25 (MH ^")

Claims

WHAT IS CLAIMED IS:

1. A compound represented by Formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein

Rl is hydrogen, CI, or Cι_6alkyl group, C2-6alkenyl group, C2-6*alkynyl group, C3_8cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, or NR9R10 group; each group optionally substituted with one to five substituents, each substituent independently being halogen, -CN, Cι_6alkyl, hydroxyCi_6alkyl, haloCi_6alkyl, Cι_6alkoxy, -CHO, C3_6cycloalkenyl, Ci-βalkyl- S-, -NH2, -C(O)NH2, phenyl, halophenyl, phenylCι_6alkyl, phenylC ι_6alkyl-O-, phenylC i _6alkyl-O-C 1 -6alkyl ;

R2, R3, R6₅ and R7 are each independently hydrogen, OH, -O-Ci-βalkyl group, -O-acyl group, -O-aryl group, -NH2_> -NH(Ci-6alkyl) group, -N(Ci-6alkyl)(Cι_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci-6alkyl; R77 is hydrogen; optionally R2 and R3 together form =O; optionally R and R7 together form =O; optionally R7 and R77 together form a bond; optionally R7 and R77 together form -X-;

R4, R41_; 42_? and R43 are each independently -CN, hydrogen, bromo, chloro, fluoro, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, amino, nitro, Ci-6alkyl, aryl, R8SO2NH-, or -CHO;

R-5 and R55 are each independently hydrogen, chloro, amino, Ci-6alkylamino, Ci_6alkyl(Ci-6alkyl)amino, or arylamino; R8 is Cι_6alkyl, phenyl, or heterocyclic; R9 and RlO are each independently hydrogen, Ci_6alkyl group, C3-7cycloalkyl group, aryl group, or heterocylic group each group optionally substituted with one to five substituents, each substituent independently being Cι_ 6alkoxy, -N(Cθ-6alkyl)(Cθ-6alkyl), or C3_7cycloalkyl; and

X is O or CH2; but excluding compounds represented by the following table wherein other R are H:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R77 is hydrogen.

3. The compound of claim 1 represented by:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 represented by:

wnerem R K*l is

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently hydrogen, OH, -O-Ci-βalkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Cι_

6alkyl)(Ci_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Cι_6alkyl.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form =O.

7. The compound of claim 1 represented by Formula (II):

(H) or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 represented by

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 represented by:

wherein Rl and R2 are according to the following table:

Rl R2

x^ OAc

V^^Ph OAc

f\ OH

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 represented by:

wherein Rl is:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 represented by:

w Herei mn R Kl is

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 represented by:

wherein NR9R10 i_s:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently hydrogen, OH, -O-Ci-βalkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Cι_6alkyl) group, -N(Ci_

6alkyl)(Cι_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci-βalkyl.

14. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 and R together form =O.

15. The compound of claim 1 represented by:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 represented by:

wherein NR9R10 is

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 represented by Formula (DI):

(HI) or pharmaceutically acceptable salts thereof.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2, and R3 are each independently hydrogen, OH, -O-Cι_6alkyl group, -O-acyl group, -O-aryl group, -NH2, -NH(Ci-6alkyl) group, -N(Cι_ 6alkyl)(Cι_6alkyl) group, -NH(aryl) group, each group optionally substituted with one to five substituents, each substituent independently being Ci_6alkyl.

19. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together form =O.

20. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein X is O.

21. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein X is CH2-

22. A compound represented by

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1.

24. The pharmaceutical composition according to claim 23 effective in the treatment of pain.

25. The pharmaceutical composition according to claim 23 effective in the treatment of migraine, depression, anxiety, schizophrenia, Parkinson's disease, or stroke.

26. A method of treating pain comprising a step of administering to one in need of such treatment an effective amount of a compound according to claim 1.

27. A method of treating migraine, depression, anxiety, schizophrenia,

Parkinson's disease, or stroke comprising a step of administering to one in need of such treatment an effective amount of a compound according to claim 1.