Indazole compounds useful as protein kinase inhibitors Number:7,041,687 from the United States Patent and Trademark Office (PTO) owispatent

Title: Indazole compounds useful as protein kinase inhibitors

Abstract: The present invention provides compounds of formula I: ##STR00001## or a pharmaceutically acceptable derivative thereof, wherein R.sup.1, R.sup.2, V.sup.1, V.sup.2, and V.sup.3 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of AKT, PKA, PDK1, p70S6K, or ROCK kinase, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions in the treatment of various disorders.

Patent Number: 7,041,687 Issued on 05/09/2006 to Binch,   et al.

---

Inventors:	Binch; Hayley (Harwell, GB); Brenchley; Guy (Grove Wantage, GB); Golec; Julian M. C. (Swindon, GB); Knegtel; Ronald (Abingdon, GB); Mortimore; Michael (Burford, GB); Patel; Sanjay (Abingdon, GB); Rutherford; Alistair (Abingdon, GB)
Assignee:	Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Appl. No.:	350806
Filed:	January 23, 2003

---

Current U.S. Class:	514/359 ; 548/300.1; 548/358.1; 548/364.1
Current International Class:	A61K 31/41 (20060101)
Field of Search:	514/359 548/364.2,300.1,358.1

---

References Cited [Referenced By]

---

U.S. Patent Documents

	2002/0103229		August 2002		Bhagwat et al.

Foreign Patent Documents

	WO 00/71508		Nov., 2000		WO
	WO 00/76971		Dec., 2000		WO
	WO 01/56988		Aug., 2001		WO
	WO 01/85719		Nov., 2001		WO
	WO 02/10137		Feb., 2002		WO
	WO 02/083648		Oct., 2002		WO
	WO 02/100833		Dec., 2002		WO

Other References

Nicolaides, E.D., et al., "Potential antiviral agents," J. Med. Chem., 11(1):74-79 (1968). cited by other.

Primary Examiner: Wilson; James O.
Assistant Examiner: Johnsen; Jason H.
Attorney, Agent or Firm: Dixon; Lisa A. Vertex Pharmaceuticals Incorporated

---

Parent Case Text

---

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 60/351,597 filed Jan. 25, 2002, the contents of which are incorporated herein by reference.

---

Claims

---

We claim:

1. A compound of formula IIa: ##STR00428## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is selected from halogen, CN, N(R.sup.4).sub.2, or T-R; T is selected from a valence bond or a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; each R is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5 7 membered saturated, partially unsaturated, or aromatic ring having 1 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.2 is selected from Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C.sub.1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Ar.sup.1, Q-OR.sup.5, Q-OC(O)R.sup.5, Q-CONHR.sup.5, Q-OC(O)NHR.sup.5, Q-SR.sup.5, Q-N(R.sup.4).sub.2, N(R)(Q-Ar), N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; R' is an optionally substituted C.sub.1-6 aliphatic group; each R.sup.4 is independently selected from R, COR, CO.sub.2R, CON(R).sub.2, SO.sub.2R, SO.sub.2N(R).sub.2, or Ar.sup.1; each R.sup.5 is independently selected from R or Ar; V.sup.1, V.sup.2 and V.sup.3 are each independently C(R.sup.6); each R.sup.6 is independently selected from R, Ar.sup.1, halogen, CN, NO.sub.2, OR, SR, N(R.sup.4).sub.2, N(R)COR, N(R)CON(R.sup.4).sub.2, N(R)C(O)OR, CON(R.sup.4).sub.2, OC(O)N(R.sup.4).sub.2, CO.sub.2R, OC(O)R, N(R)SO.sub.2R, N(R)SO.sub.2N(R.sup.4).sub.2, SO.sub.2R, or SO.sub.2N(R.sup.4).sub.2; and each Ar.sup.1 is independently selected from an optionally substituted 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when V.sup.1, V.sup.2, and V.sup.3 are each CH and R.sup.1 is hydrogen then R.sup.3 is other than R', Q-OC(O)R.sup.5, or OCH.sub.2phenyl.

2. The compound according to claim 1, wherein: R.sup.1 is selected from halogen, N(R.sup.4).sub.2, or optionally substituted C.sub.1-6 aliphatic; and R.sup.2 is Q-C(R)(Q-Ar)R3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; and Ar is an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or all optionally substituted 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound according to claim 2, wherein: R.sup.1 is selected from chloro, bromo, fluoro, NH.sub.2, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, or d t-butyl; and R.sup.3 is selected from CH.sub.2OH, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, NHCO.sub.2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, or NHCH.sub.2-imidazol-4-yl.

4. The compound according to claim 1, wherein: R.sup.1 is hydrogen; and R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; and Ar is an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5. The compound according to claim 4, wherein: R.sup.3 is selected from OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, NHCO.sub.2t-butyl, phenyl, NH(CH.sub.2).sub.3NH.sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, or NHCH.sub.2-imidazol-4-yl.

6. The compound according to claim 1, wherein said compound is selected from the group consisting of: ##STR00429## ##STR00430## ##STR00431## ##STR00432## ##STR00433## ##STR00434## ##STR00435## ##STR00436## ##STR00437## ##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442## ##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447## ##STR00448## ##STR00449## ##STR00450##

7. A compound of formula IIb: ##STR00451## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is T-Ar; T is selected from a valence bond or a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; each R is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5 7 membered saturated, partially unsaturated, or aromatic ring having 1 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C.sub.1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Ar.sup.1, Q-OR.sup.5, Q-OC(O)R.sup.5, Q-CONHR.sup.5, Q-OC(O)NHR.sup.5, Q-SR.sup.5, Q-N(R.sup.4).sub.2, N(R)(Q-Ar), N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; R' is an optionally substituted C.sub.1-6 aliphatic group; each R.sup.4 is independently selected from R, COR.sup.5, CO.sub.2R.sup.5, CON(R.sup.5).sub.2, SO.sub.2R.sup.5, SO.sub.2N(R.sup.5).sub.2, or Ar.sup.1; each R.sup.5 is independently selected from R or Ar; V.sup.1, V.sup.2 and V.sup.3 are each independently C(R.sup.6); each R.sup.6 is independently selected from R, Ar.sup.1, halogen, CN, NO.sub.2, OR, SR, N(R.sup.4).sub.2, N(R)COR, N(R)CON(R.sup.4).sub.2, N(R)C(O)OR, CON(R.sup.4).sub.2, OC(O)N(R.sup.4).sub.2, CO.sub.2R, OC(O)R, N(R)SO.sub.2R, N(R)SO.sub.2N(R.sup.4).sub.2, SO.sub.2R, or SO.sub.2N(R.sup.4).sub.2; and each Ar.sup.1 is independently selected from an optionally substituted 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when V.sup.1, V.sup.2, and V.sup.3 are each CH, T is a valence bond, and R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein Ar is an optionally substituted phenyl ring, then R.sup.3 is other than Q-OR.sup.5 or C(O)NH.sub.2.

8. The compound according to claim 7, wherein: R.sup.1 is T-Ar, wherein: T is selected from --NHC(O)--, --NH--, --NHCH.sub.2--, NHSO.sub.2--, --CH.sub.2NH--, --C.ident.--, --CH.sub.2-- or --CH.sub.2CH.sub.2--; and Ar is an optionally substituted 5 6 membered aryl ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9 10 membered aryl ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein: R.sup.3 is R', Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; each Q is independently selected from a valence bond, --CH.sub.2--, or --CH.sub.2CH.sub.2--; and Ar is an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9. The compound according to claim 8, wherein: R.sup.3 is CH.sub.2OH, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, NHCO.sub.2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

10. The compound according to claim 7, wherein: T is a valence bond; and R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; and Ar is an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

11. The compound according to claim 10, wherein: R.sup.3 is CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NHCO.sub.2(t butyl), phenyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

12. The compound according to claim 7, wherein said compound is selected from the group consisting of: ##STR00452## ##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485##

13. The compound according to claim 7, wherein said compound has the formula V: ##STR00486## or a pharmaceutically acceptable salt thereof.

14. A composition comprising a compound according to either of claim 1 or 7, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

15. The composition according to claim 13, additionally comprising a therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

16. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity comprising the step of contacting the kinase with a compound according to acyone of claims 1 through 13.

---

Description

---

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, the compounds are inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK kinases and are useful for treating diseases, such as cancer.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases.

Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H.sub.2O.sub.2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor .alpha. (TNF-.alpha.)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.

Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. A challenge has been to find protein kinase inhibitors that act in a selective manner. Since there are numerable protein kinases that are involved in a variety of cellular responses, non-selective inhibitors may lead to unwanted side effects.

AKT (also known as PKB or Rac-PK beta), a serine/threonine protein kinase, has been shown to be overexpressed in several types of cancer and is a mediator of normal cell functions [(Khwaja, A., Nature, 401, pp. 33 34, 1999); (Yuan, Z. Q., et al., Oncogene, 19, pp. 2324 2330, 2000); (Namikawa, K., et al., J. Neurosci., 20, pp. 2875 2886, 2000)]. AKT comprises an N-terminal pleckstrin homology (PH) domain, a kinase domain and a C-terminal "tail" region. Three isoforms of human AKT kinase (AKT-1, -2 and -3) have been reported so far [(Cheng, J. Q., Proc. Natl. Acad. Sci. USA, 89, pp. 9267 9271, 1992); (Brodbeck, D. et al., J. Biol. Chem. 274, pp. 9133 9136, 1999)]. The PH domain binds 3-phosphoinositides, which are synthesized by phosphatidyl inositol 3-kinase (PI3K) upon stimulation by growth factors such as platelet derived growth factor (PDGF), nerve growth factor (NGF) and insulin-like growth factor (IGF-1) [(Kulik et al., Mol. Cell. Biol., 17, pp. 1595 1606, 1997); (Hemmings, B. A., Science, 275, pp. 628 630, 1997)]. Lipid binding to the PH domain promotes translocation of AKT to the plasma membrane and facilitates phosphorylation by another PH-domain-containing protein kinases, PDK1 at Thr308, Thr309, and Thr305 for the AKT isoforms 1, 2 and 3, respectively. A second, as of yet unknown, kinase is required for the phosphorylation of Ser473, Ser474 or Ser472 in the C-terminal tails of AKT-1, -2 and -3 respectively, in order to yield a fully activated AKT enzyme.

Once localized to the membrane, AKT mediates several functions within the cell including the metabolic effects of insulin (Calera, M. R. et al., J. Biol. Chem., 273, pp. 7201 7204, 1998), induction of differentiation and/or proliferation, protein synthesisans stress responses (Alessi, D. R. et al., Curr. Opin. Genet. Dev., 8, pp. 55 62, 1998).

Manifestations of altered AKT regulation appear in both injury and disease, the most important role being in cancer. The first account of AKT was in association with human ovarian carcinomas where expression of AKT was found to be amplified in 15% of cases (Cheng, J. Q. et al., Prod. Natl. Acad. Sci. U.S.A., 89, pp. 9267 9271, 1992). It has also been found to be overexpressed in 12% of pancreatic cancers (Cheng, J. Q. et al., Proc. Natl. Acad. Sci. U.S.A., 93, pp. 3636 3641, 1996). It was demonstrated that AKT-2 was over-expressed in 12% of ovarian carcinomas and that amplification of AKT was especially frequent in 50% of undifferentiated tumours, suggesting that AKT may also be associated with tumour aggressiveness (Bellacosa, et al., Int. J. Cancer, 64, pp. 280 285, 1995).

PKA (also known as cAMP-dependent protein kinase) has been shown to regulate many vital functions including energy metabolism, gene transcription, proliferation, differentiation, reproductive function, secretion, neuronal activity, memory, contractility and motility (Beebe, S. J., Semin. Cancer Biol., 5, pp. 285 294, 1994). PKA is a tetrameric holoenzyme, which contains two catalytic subunits bound to a homo-dimeric regulatory subunit (which acts to inhibit the catalytic sub-units). On binding of cAMP (enzyme activation), the catalytic subunits dissociate from the regulatory subunits to yield the active serine/threonine kinase (McKnight, G. S. et al., Recent Prog. Horm. Res., 44, pp. 307, 1988). Three isoforms of the catalytic subunit (C-.alpha., C-.beta. and C-.gamma. have been reported to date (Beebe, S. J. et al., J. Biol. Chem., 267, pp. 25505 25512, 1992) with the C-.alpha. subunit being the most extensively studied, primarily because of its elevated expression in primary and metastatic melanomas (Becker, D. et al., Oncogene, 5, pp. 1133, 1990). To date, strategies to modulate the activity of the C-.alpha. subunit involve the use of antibodies, molecules that block PKA activity by targeting regulatory dimers and antisense oligonucleotides expression.

Rho-associated coiled-coil forming kinase (ROCK) (Ishizaki, T. et al., EMBO J., 15, pp. 1885 1893, 1996) is a 160 kDa serine/threonine kinase that activates the small G-protein RhoA. ROCK has been implicated in numerous diseases including hypertension [(Chitaley, et al., Curr. Hypertens. Rep. 2001 Apr., 3(2), pp.139 144); (Uehata, M. et al., Nature, 389, pp. 990 994, 1997)], erectile dysfunction (Chitaley, K. et al., Nature Medicine, 7, pp. 119 122, 2001), angiogenesis (Uchida, S. et al., Biochem. Biophys. Res. Commun., 269 (2), pp. 633 40, 2000), neuroregeneration (Bito, H. et al., Neuron, 26, pp. 431 441, 2000), metastasis [(Takamura, M. et al., Hepatology, 33, pp. 577 581, 2001); (Genda, T. et al., Hepatology, 30, pp. 1027 1036, 1999)], glaucoma (Rao, et al., Invest. Ophthalmol. Vis. Sci., 42, pp. 1029 37, 2001), inflammation (Ishizuka, T. et al., J. Immunol., 167, pp. 2298 2304, 2001), arteriosclerosis (Smimokawa, et al., Arterioscler. Thromb. Vasc. Biol., 11, pp. 2351 2358, 2000), immunosuppresion (Lou, Z. et al., J. Immunol., 167, pp. 5749 5757, 2001), restenosis (Seaholtz, et al., Circ. Res., 84, pp. 1186 1193, 1999), asthma (Yoshii, et al., Am. J. Respir. Cell Mol. Biol., 20, pp. 1190 1200, 1999), cardiac hypertrophy (Kuwahara, K. et al., FEBS Lett., 452, pp. 314 318, 1999).

The ribosomal protein kinases p70S6K-1 and -2 are members of the AGC sub-family of protein kinases that consists of, amongst others, PKB and MSK. The p70S6 kinases catalyze the phosphorylation and subsequent activation of the ribosomal protein S6, which has been implicated in the translational up-regulation of mRNAs coding for the components of protein synthetic apparatus.

These mRNAs contain an oligopyrimidine tract at their 5' transcriptional start site, termed a 5TOP, which has been shown to be essential for their regulation at the translational level (Volarevic, S. et al., Prog. Nucleic Acid Res. Mol. Biol. 65, pp 101 186, 2001). p70 S6K dependent S6 phosphorylation is stimulated in response to a variety of hormones and growth factors primarily via the P13K pathway (Coffer, P. J. et al., Biochem. Biophys. Res. Commun, 198, 7 pp 780 786, 1994), which maybe under the regulation of mTOR, since rapamycin acts to inhibit p70S6K activity and blocks protein synthesis, specifically as a result of a down-regulation of translation of these mRNA's encoding ribosomal proteins (Kuo, C. J. et al., Nature, 358, pp 70 73, 1992).

In vitro PDK1 catalyses the phosphorylation of Thr252 in the activation loop of the p70 catalytic domain, which is indispensable for p70 activity (Alessi, D. R., Curr. Biol., 8, pp 69 81, 1998). The use of rapamycin and gene deletion studies of dp70S6K from Drosophila and p70S6K1 from mouse have established the central role p70 plays in both cell growth and proliferation signaling.

The 3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a key role in regulating the activity of a number of kinases belonging to the AGC subfamily of protein kinases (Alessi, D. et al., Biochem. Soc. Trans, 29, pp. 1, 2001). These include isoforms of protein kinase B (PKB, also known as AKT), p70 ribosomal S6 kinase (S6K) (Avruch, J. et al., prog. Mol. Subcell. Biol., 2001, 26, pp. 115, 2001), and p90 ribosomal S6 kinase (Frodin, M. et al., EMBO J., 19, pp. 2924 2934, 2000). PDK1 mediated signaling is activated in response to insulin and growth factors and as a consequence of attachment of the cell to the extracellular matrix (integrin signaling). Once activated these enzymes mediate many diverse cellular events by phosphorylating key regulatory proteins that play important roles controlling processes such as cell survival, growth, proliferation and glucose regulation [(Lawlor, M. A. et al., J. Cell Sci., 114, pp. 2903 2910, 2001), (Lawlor, M. A. et al., EMBO J., 21, pp. 3728 3738, 2002)]. PDK1 is a 556 amino acid protein, with an N-terminal catalytic domain and a C-terminal pleckstrin homology (PH) domain, which activates its substrates by phosphorylating these kinases at their activation loop (Belham, C. et al., Curr. Biol., 9, pp. R93 R96, 1999). Many human cancers including prostate and NSCL have elevated PDK1 signaling pathway function resulting from a number of distinct genetic events such as PTEN mutations or over-expression of certain key regulatory proteins [(Graff, J. R., Expert Opin. Ther. Targets, 6, pp. 103 113, 2002), (Brognard, J., et al., Cancer Res., 61, pp. 3986 3997, 2001)]. Inhibition of PDK1 as a potential mechanism to treat cancer was demonstrated by transfection of a PTEN negative human cancer cell line (U87MG) with antisense oligonucleotides directed against PDK1. The resulting decrease in PDK1 protein levels led to a reduction in cellular proliferation and survival (Flynn, P., et al., Curr. Biol., 10, pp. 1439 1442, 2000). Consequently the design of ATP binding site inhibitors of PDK1 offers, amongst other treatments, an attractive target for cancer chemotherapy.

The diverse range of cancer cell genotypes has been attributed to the manifestation of the following six essential alterations in cell physiology: self-sufficiency in growth signaling, evasion of apoptosis, insensitivity to growth-inhibitory signaling, limitless replicative potential, sustained angiogenesis, and tissue invasion leading to metastasis (Hanahan, D. et al., Cell, 100, pp. 57 70, 2000). PDK1 is a critical mediator of the P13K signalling pathway, which regulates a multitude of cellular function including growth, proliferation and survival. Consequently inhibition of this pathway could affect four or more of the six defining requirements for cancer progression, as such it is anticipated that a PDK1 inhibitor will have an effect on the growth of a very wide range of human cancers.

Specifically, increased levels of PI3K pathway activity has been directly associated with the development of a number of human caners, progression to an aggressive refractory state (acquired resistance to chemotherapies) and poor prognosis. This increased activity has been attributed to a series of key events including decreased activity of negative pathway regulators such as the phosphatase PTEN, activating mutations of positive pathway regulators such as Ras, and overexpression of components of the pathway itself such as PKB, examples include: brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, thyroid [(Teng, D. H. et al., Cancer Res., 57, pp. 5221 5225, 1997), (Brognard, J. et al., Cancer Res., 61, pp. 3986 3997, 2001), (Cheng, J. Q. et al., Proc. Natl. Acad. Sci., 93, pp. 3636 3641, 1996), Int. J. Cancer, 64, pp. 280, 1995), (Graff, J. R., Expert Opin. Ther. Targets, 6, pp. 103 113, 2002), Am. J. Pathol., 159, pp. 431, 2001)].

Additionally, decreased pathway function through gene knockout, gene knockdown, dominant negative studies and small molecule inhibitors of the pathway have been demonstrated to reverse many of the cancer phenotypes in vitro (some studies have also demonstrated a similar effect in vivo) such as block proliferation, reduce viability and sensitize cancer cells to known chemotherapies in a series of cell lines, representing the following cancers: pancreatic [(Cheng, J. Q. et al., Proc. Natl. Acad. Sci., 93, pp. 3636 3641, 1996), Neoplasia, 3, pp. 278, 2001)], lung [(Brognard, J. et al., Cancer Res., 61, pp. 3986 3997, 2001), Neoplasia, 3, pp. 278, 2001)], ovarian [(Hayakawa, J. et al., Cancer Res., 60, pp. 5988 5994, 2000), Neoplasia, 3, pp. 278, 2001)], breast (Mol. Cancer Ther., 1, pp. 707, 2002), colon [(Neoplasia, 3, pp. 278, 2001), (Arico, S. et al., J. Biol. Chem., 277, pp. 27613 27621, 2002)], cervical (Neoplasia, 3, pp. 278, 2001), prostate [(Endocrinology, 142, pp. 4795, 2001), (Thakkar, H. et al. J. Biol. Chem., 276, pp. 38361 38369, 2001), (Chen, X. et al., Oncogene, 20, pp. 6073 6083, 2001)] and brain (glioblastomas) [(Flynn, P. et al., Curr. Biol., 10, pp. 1439 1442, 2000)].

Accordingly, there is a great need to develop inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK protein kinases that are useful in treating various diseases or conditions associated with AKT, PKA, PDK1, p70S6K, and ROCK activation, particularly given the inadequate treatments currently available for the majority of these disorders.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of AKT, PKA, PDK1, p70S6K, and ROCK protein kinases. These compounds have the formula I:

##STR00002## or a pharmaceutically acceptable salt thereof, wherein V.sup.1, V.sup.2, V.sup.3, R.sup.1, and R.sup.2 are as defined below.

These compounds, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of disorders, including allergic disorders such as asthma, inflammatory disease, proliferative disorders, and neurological disorders.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula I:

##STR00003## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is selected from halogen, CN, N(R.sup.4).sub.2, T-R, or T-Ar; each T is independently selected from a valence bond or a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; each R is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5 7 membered saturated, partially unsaturated, or aromatic ring having 1 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.2 is selected from Q-Ar, Q-N(R.sup.5).sub.2, or Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C.sub.1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Ar.sup.1, Q-OR.sup.5, Q-OC(O)R.sup.5, Q-CONHR.sup.5, Q-OC(O)NHR.sup.5, Q-SR.sup.5, Q-N(R.sup.4).sub.2, N(R)(Q-Ar), N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; R' is an optionally substituted C.sub.1-6 aliphatic group; each R.sup.4 is independently selected from R, COR.sup.5, CO.sub.2R.sup.5, CON(R.sup.5).sub.2, SO.sub.2R.sup.5, SO.sub.2N(R.sup.5).sub.2, or Ar.sup.1; each R.sup.5 is independently selected from R or Ar; V.sup.1, V.sup.2 and V.sup.3 are each independently selected from nitrogen or C(R.sup.6); each R.sup.6 is independently selected from R, Ar.sup.1, halogen, CN, NO.sub.2, OR, SR, N(R.sup.4).sub.2, N(R)COR, N(R)CON(R.sup.4).sub.2, N(R)C(O)OR, CON(R.sup.4).sub.2, OC(O)N(R.sup.4).sub.2, CO.sub.2R, OC(O)R, N(R)SO.sub.2R, N(R)SO.sub.2N(R.sup.4).sub.2, SO.sub.2R, or SO.sub.2N(R.sup.4).sub.2; and each Ar.sup.1 is independently selected from an optionally substituted 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that: when V.sup.1, V.sup.2, and V.sup.3 are each CH, T is a valence bond, and R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein Ar is an optionally substituted phenyl ring, then R.sup.3 is other than Q-OR.sup.5 or C(O)NH.sub.2; and when V.sup.1, V.sup.2, and V.sup.3 are each CH and R.sup.1 is hydrogen then R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein R.sup.3 is other than R', Q-OC(O)R.sup.5, or OCH.sub.2phenyl.

As used herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

The term "aliphatic" or "aliphatic group" as used herein means a straight-chain or branched C.sub.1 C.sub.12 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C.sub.3 C.sub.8 hydrocarbon or bicyclic C.sub.8 C.sub.12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, hut which is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3 7 members. For example, suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I.

The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0 4 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR.sup.+ (as in N-substituted pyrrolidinyl).

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members.

The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group are selected from halogen, oxo, N.sub.3, --R.degree., --OR.degree., --SR.degree., 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), Ph substituted with R.degree., --O(Ph), O--(Ph) substituted with R.degree., --CH.sub.2(Ph), --CH.sub.2(Ph) substituted with R.degree., --CH.sub.2CH.sub.2(Ph), --CH.sub.2CH.sub.2(Ph) substituted with R.degree., --NO.sub.2, --CN, --N(R.degree.).sub.2, --NR.degree.C(O)R.degree., --NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.CO.sub.2R.degree., --NR.degree.NR.degree.C(O)R.degree., --NR.degree.NR.degree.C(O)N(R.degree.).sub.2, --NR.degree.NR.degree.CO.sub.2R.degree., --C(O)C(O)R.degree., --C(O)CH.sub.2C(O)R.degree., --CO.sub.2R.degree., --C(O)R.degree., --C(O)N(R.degree.).sub.2, --OC(O)N(R.degree.).sub.2, --S(O).sub.2R.degree., --SO.sub.2N(R.degree.).sub.2, --S(O)R.degree., --NR.degree.SO.sub.2N(R.degree.).sub.2, --NR.degree.SO.sub.2R.degree., --C(.dbd.S)N(R.degree.).sub.2, --C(.dbd.NH)--N(R.degree.).sub.2, or --(CH.sub.2).sub.yNHC(O)R.degree., wherein y is 0 4, each R.degree. is independently selected from hydrogen, optionally substituted C.sub.1-6 aliphatic, an unsubstituted 5 6 membered heteroaryl or heterocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl (Ph), --O(Ph), or --CH.sub.2(Ph)--CH.sub.2(Ph). Substituents on the aliphatic group of R.degree. are selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O--(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), --O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic.

An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: .dbd.O, .dbd.S, .dbd.NNHR*, .dbd.NN(R*).sub.2, .dbd.N--, .dbd.NNHC(O)R*, .dbd.NNHCO.sub.2(alkyl), .dbd.NNHSO.sub.2(alkyl), or .dbd.NR*, where each R* is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic. Substituents on the aliphatic group of R* are selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O--(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), --O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic.

Substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from --R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --CO.sub.2R.sup.+, --C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --SO.sub.2R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --C(.dbd.S)N(R.sup.+).sub.2, --C(.dbd.NH)--N(R.sup.+).sub.2, or --NR.sup.+SO.sub.2R.sup.+; wherein R.sup.+ is hydrogen, an optionally substituted C.sub.1-6 aliphatic, optionally substituted phenyl (Ph), optionally substituted --O(Ph), optionally substituted --CH.sub.2(Ph), optionally substituted --CH.sub.2CH.sub.2(Ph), or an unsubstituted 5 6 membered heteroaryl or heterocyclic ring. Substituents on the aliphatic group or the phenyl ring of R.sup.+ are selected from NH.sub.2, NH(C.sub.1-4 aliphatic), N(C.sub.1-4 aliphatic).sub.2, halogen, C.sub.1-4 aliphatic, OH, O--(C.sub.1-4 aliphatic), NO.sub.2, CN, CO.sub.2H, CO.sub.2(C.sub.1-4 aliphatic), --O(halo C.sub.1-4 aliphatic), or halo C.sub.1-4 aliphatic.

The term "alkylidene chain" refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of connection to the rest of the molecule.

The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40.degree. C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a .sup.13C- or .sup.14C-enriched carbon are within the scope of this invention.

Compounds of this invention may exist in alternative tautomeric forms. Unless otherwise indicated, the representation of either tautomer is meant to include the other.

One embodiment of the present invention relates to a compound of formula Ia:

##STR00004## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 are as defined above for compounds of formula I.

According to one preferred embodiment, the present invention relates to a compound of formula I wherein V.sup.1 is N, V.sup.2 is CH, and V.sup.3 is CH.

Preferred compounds of formula I include those wherein V.sup.1 is C--R.sup.6, V.sup.2 is CH, and V.sup.3 is CH or N.

Another preferred embodiment of the present invention relates to a compound of formula I wherein V.sup.1 is C--R.sup.6, V.sup.2 is CH, and V.sup.3 is N.

Another preferred embodiment of the present invention relates to a compound of formula I wherein V.sup.1 is C--R.sup.6, V.sup.2 is CH, and V.sup.3 is CH.

According to another preferred embodiment, the present invention relates to a compound of formula Ia wherein V.sup.2 is CH and V.sup.3 is N.

According to another preferred embodiment, the present invention relates to a compound of formula Ia wherein V.sup.2 and V.sup.3 are each N.

Preferred R.sup.1 groups of formula I or Ia include hydrogen, halogen, CN, N(R.sup.4).sub.2, and optionally substituted C.sub.1-6 aliphatic. Examples of such R.sup.1 groups include chloro, bromo, fluoro, NH.sub.2, NHME, NHEt, NH--(optionally substituted phenyl), NH-cyclohexyl, NHCH.sub.2(optionally substituted phenyl), NHC(O)(optionally substituted phenyl), NHC(O)NH(optionally substituted phenyl), NHC(O)CH.sub.2(optionally substituted phenyl), NHC(O)CH.sub.2CH.sub.2(optionally substituted phenyl), N(R)C(O)(optionally substituted phenyl), NHC(O)naphthyl, NHC(O)thienyl, NRC(O)thienyl, SC(O)thienyl, CH.sub.2C(O)thienyl, NHC(O)pyridyl, NHC(O)furanyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, and t-butyl.

The optional substituents of the phenyl rings of R.sup.1 of formula I or Ia, when present, are optionally substituted R.degree., halogen, nitro, CN, OR.degree., SR.degree., N(R.degree.).sub.2, SO.sub.2R.degree., C(O)R.degree., C(O)OR, and C(O)N(R.degree.).sub.2, wherein each R.degree. is as defined supra. Examples of such groups include chloro, bromo, fluoro, CN, nitro, OMe, OPh, OCF.sub.3, OCH.sub.2Ph, OEt, SCHF.sub.2, methyl, ethyl, isopropyl, propyl, vinyl, CF.sub.3, acetylenyl, CH.sub.2Ph, CH.sub.2NH.sub.2, CH.sub.2N(Et).sub.2, CH.sub.2morpholin-4-yl, CH.sub.2piperidin-1-yl, CH.sub.2imidazol-1-yl, CH.sub.2piperazin-1-yl, C(O)NH.sub.2, C(O)Me, SO.sub.2Me, NHEt, and NHMe.

When R.sup.1 of formula I or Ia is T-Ar, preferred Ar groups are selected from an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such Ar rings include optionally substituted phenyl, thienyl, furan, and pyridyl rings. Preferred T moieties of the T-Ar group of R.sup.1 are selected from a valence bond, --N(R)C(O)--, --NH--, --NHCH.sub.2--, --NHSO.sub.2--, --CH.sub.2NH--, --SC(O)--, --CH.sub.2C(O)--, --C.ident.C--, --CH.sub.2-- or --CH.sub.2CH.sub.2--. More preferred T moieties of the T-Ar group of R.sup.1 are selected from --NHC(O)--, --NH--, --NHCH.sub.2--, --CH.sub.2--, --C.ident.C--, or --CH.sub.2CH.sub.2--. Most preferred T moieties of the T-Ar group of R.sup.1 are selected from --N(R)C(O)--, --NH--, or --NHCH.sub.2--. Preferred substituents on the Ar group, when present, include fluoro and CF.sub.3, Me, Et, iPr, vinyl, acetylene, Ar, Cl, CF.sub.3, nitro, CN, OMe, OPh, OCF.sub.3, SO.sub.2NH2, C(O)OEt, C(O)OH, CH.sub.2CO.sub.2H, CH.sub.2CH.sub.2CO.sub.2H, CH.sub.2NH.sub.2 and C(O)NH.sub.2, thienyl, oxazolyl, isoxazolyl, and tetrazolyl.

Preferred Q groups of formula I or Ia are selected from a valence bond, --CH.sub.2--, or --CH.sub.2CH.sub.2--.

When R.sup.2 of formula I or Ia is Q-Ar, preferred Ar groups are an optionally substituted ring selected from a 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, pyrimidinyl, pyridonyl, furanyl, tetrazolyl, thienyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, indan-1-onyl, naphthyl, benzothiophenyl, 2,3-dihydro-1H-isoindolyl, indanyl, benzofuranyl, and indolyl.

When present, preferred substituents on the Ar ring of R.sup.2 include R.degree., halogen, oxo, OR.degree., phenyl, optionally substituted dialkylamino, haloalkyl, C(O)R.degree., NHC(O)R, or SR.degree.. Examples of such preferred substituents include chloro, bromo, fluoro, OH, OMe, NHC(O)CH.sub.3, OEt, C(O)phenyl, Ophenyl, N(CH.sub.2CH.sub.2Cl).sub.2, N(Me).sub.2, CF.sub.3, and SCF.sub.3. Other examples of preferred Ar groups of formula I or Ia also include those shown in Table 1 below.

When the R.sup.2 group of formula I or Ia is Q-C(R)(Q-Ar)R.sup.3, preferred R.sup.3 groups include R', Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, and N(R)Q-N(R.sup.4).sub.2. Examples of such R.sup.3 groups include CH.sub.2OH, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NHCO.sub.2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

More preferably, the R.sup.3 group of formula I or Ia is selected from OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NHCO.sub.2t-butyl, phenyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

Most preferably, the R.sup.3 group of formula I or Ia is selected from CH.sub.2CH.sub.2NH.sub.2.

Preferred rings formed by the R and R.sup.3 moieties of the Q-C(R)(Q-Ar)R.sup.3 group of R.sup.2 are selected from a 5 6 membered saturated ring having 0 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R.sup.3 include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

When the R.sup.2 group of formula I or Ia is Q-C(R)(Q-Ar)R.sup.3, preferred Ar groups of the Q-C(R)(Q-Ar)R.sup.3 moiety are selected from an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, furanyl, pyridone, and thienyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, naphthyl, indanyl, and indolyl. When present, preferred substituents on the Ar ring of the Q-C(R)(Q-Ar)R.sup.3 group of R.sup.2 include R.degree., halogen, OR.degree., phenyl, N(R.degree.).sub.2, NHC(O)R.degree., or SR.degree.. Examples of such groups include fluoro, chloro, bromo, CF.sub.3, OH, OMe, OPh, OCH.sub.2Ph, SMe, NH.sub.2, NHC(O)Me, methyl, ethyl, isopropyl, isobutyl, and cyclopropyl.

Preferred R.sup.6 groups of formula I or Ia, when present, are selected from halogen, R, and Ar.sup.1. More preferred R.sup.6 groups of formula I or Ia, when present, are selected from halogen, optionally substituted C.sub.1-4 aliphatic, or an optionally substituted 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such groups include chloro, bromo, methyl, ethyl, t-butyl, cyclopropyl, isopropyl, phenyl, and pyridyl.

According to another embodiment, the present invention relates to a compound of formula I':

##STR00005## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is selected from halogen, CN, N(R.sup.4).sub.2, T-R, or T'-Ar; T is selected from a valence bond or a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; T' is a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T' are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; each R is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5 7 membered saturated, partially unsaturated, or aromatic ring having 1 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.2 is selected from Q-Ar, Q-N(R.sup.5).sub.2, or Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C.sub.1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Ar.sup.1, Q-OR.sup.5, Q-OC(O)R.sup.5, Q-CONHR.sup.5, Q-OC(O)NHR.sup.5, Q-SR.sup.5, Q-N(R.sup.4).sub.2, N(R)(Q-Ar), N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; R' is an optionally substituted C.sub.1-6 aliphatic group; each R.sup.4 is independently selected from R, COR.sup.5 CO.sub.2R.sup.5 CON(R.sup.5).sub.2, SO.sub.2R.sup.5, SO.sub.2N(R.sup.5).sub.2, or Ar.sup.1; each R.sup.5 is independently selected from R or Ar; V.sup.1, V.sup.2 and V.sup.3 are each independently selected from nitrogen or C(R.sup.6); each R.sup.6 is independently selected from R, Ar.sup.1, halogen, CN, NO.sub.2, OR, SR, N(R.sup.4).sub.2, N(R)COR, N(R)CON(R.sup.4).sub.2, N(R)C(O)OR, CON(R.sup.4).sub.2, OC(O)N(R.sup.4).sub.2, CO.sub.2R, OC(O)R, N(R)SO.sub.2R, N(R)SO.sub.2N(R.sup.4).sub.2, SO.sub.2R, or SO.sub.2N(R.sup.4).sub.2; and each Ar.sup.1 is independently selected from an optionally substituted 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that: when V.sup.1, V.sup.2, and V.sup.3 are each CH and R.sup.1 is hydrogen, then R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein R.sup.3 is other than R', Q-OC(O)R.sup.5, or OCH.sub.2phenyl.

Preferred R.sup.1 and R.sup.2 groups of formula I' are those described above for compounds of formulae I and Ia. When R.sup.1 is T'-Ar, preferred T' groups of formula I' are selected from --NHC(O)--, --NH--, --NHCH.sub.2--, --NHSO.sub.2--, --CH.sub.2NH--, --CH.sub.2--, --C.ident.C--, or --CH.sub.2CH.sub.2--. More preferred T' groups of formula I' are selected from --NHC(O)--, --NH--, --NHCH.sub.2--, --NHSO.sub.2--, or --CH.sub.2NH--.

According to another embodiment, the present invention relates to a compound of formula Ib:

##STR00006## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.3, Q, and Ar are as defined above for compounds of formula I.

Preferred R.sup.1 groups of formula Ib include those described above for compounds of formula I and Ia.

Preferred V.sup.1, V.sup.2, and V.sup.3 groups of formula Ib are the preferred V.sup.1, V.sup.2, and V.sup.3 groups set forth for compounds of formula I, supra.

Preferred Q groups of formula Ib include those described above for compounds of formula I and Ia.

Preferred Ar groups of formula Ib include an optionally substituted ring selected from a 5 6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such monocyclic rings include phenyl, pyridyl, thienyl, furanyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such bicyclic rings include benzo[1,3]dioxolyl, indan-1-onyl, naphthyl, benzothiophenyl, 2,3-dihydro-1H-isoindolyl, indanyl, benzofuranyl, and indolyl. When present, preferred substituents on the Ar group of formula Ib include R.degree., halogen, OR.degree., phenyl, optionally substituted dialkylamino, haloalkyl, C(O)R.degree., or SR.degree.. Examples of such preferred substituents include tetrazolyl, oxazolyl, isoxazolyl, chloro, bromo, fluoro, OH, OMe, OEt, C(O)phenyl, Ophenyl, N(CH.sub.2CH.sub.2Cl).sub.2, N(Me).sub.2, CF.sub.3, and SCF.sub.3.

Preferred R.sup.3 groups of formula Ib include R', Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, and N(R)Q-N(R.sup.4).sub.2. Examples of such R.sup.3 groups include CH.sub.2OH, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, NHCO.sub.2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

More preferably, the R.sup.3 group of formula Ib is selected from OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH.sub.2CH.sub.2N(Me).sub.2, CH.sub.2C(Me).sub.2NH.sub.2, CH.sub.2C(Me).sub.2CHMe, NHCO.sub.2t-butyl, phenyl, NH(CH.sub.2).sub.3NH.sub.2, NH(CH.sub.2).sub.2NH.sub.2, NH(CH.sub.2).sub.2NHEt, NHCH.sub.2pyridyl, NHSO.sub.2phenyl, NHC(O)CH.sub.2C(O)Ot-butyl, NHC(O)CH.sub.2NH.sub.3, and NHCH.sub.2-imidazol-4-yl.

Most preferably, the R.sup.3 group of formula Ib is selected from CH.sub.2CH.sub.2NH.sub.2.

Preferred rings formed by the R and R.sup.3 moieties of the Q-C(R)(Q-Ar)R.sup.3 group of formula Ib are selected from a 5 6 membered saturated ring having 0 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of such rings formed by R and R.sup.3 include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

Another embodiment of the present invention relates to a compound of formula IIa:

##STR00007## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is selected from halogen, CN, N(R.sup.4).sub.2, or T-R; T is selected from a valence bond or a C.sub.1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by --O--, --N(R)--, --S--, --N(R)C(O)--, --C(O)N(R)--, --C(O)--, or --SO.sub.2--; each R is independently selected from hydrogen or an optionally substituted C.sub.1-6 aliphatic group, or: two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5 7 membered saturated, partially unsaturated, or aromatic ring having 1 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.2 is Q-C(R)(Q-Ar)R.sup.3, wherein: R and R.sup.3 optionally form a 5 7 membered saturated or partially unsaturated ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C.sub.1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8 10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R.sup.3 is selected from R', Ar.sup.1, Q-OR.sup.5, Q-OC(O)R.sup.5, Q-CONHR.sup.5, Q-OC(O)NHR.sup.5, Q-SR.sup.5, Q-N(R.sup.4).sub.2, N(R)(Q-Ar), N(R)C(O)Q-N(R.sup.4).sub.2, or N(R)Q-N(R.sup.4).sub.2; R' is an optionally substituted C.sub.1-6 aliphatic group; each R.sup.4 is independently selected from R, COR, CO.sub.2R, CON(R).sub.2, SO.sub.2R, SO.sub.2N(R).sub.2, or Ar.sup.1; each R.sup.5 is independently selected from R or Ar; V.sup.1, V.sup.2 and V.sup.2 are each independently selected from nitrogen or C(R.sup.6); each R.sup.6 is independently selected from R, Ar.sup.1, halogen CN, NO.sub.2, OR, SR, N(R.sup.4).sub.2, N(R)COR, N(R)CON(R.sup.4).sub.2, N(R)C(O)OR, CON(R.sup.4).sub.2, OC(O)N(R.sup.4).sub.2, CO.sub.2R, OC(O)R, N(R)SO.sub.2R, N(R)SO.sub.2N(R.sup.4).sub.2, SO.sub.2R, or SO.sub.2N(R.sup.4).sub.2; and each Ar.sup.1 is independently selected from an optionally substituted 5 7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when R.sup.1 is hydrogen then R.sup.3 is other than R', Q-OC(O)R.sup.5, or OCH.sub.2phenyl.

Preferred R.sup.1 groups of formula IIa include halogen, N(R.sup.4).sub.2, and optionally substituted C.sub.1-6 aliphatic. Examples of such groups include chloro, bromo, fluoro, NH.sub.2, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, and t-butyl.

Preferred V.sup.1, V.sup.2, and V.sup.3 groups of formula IIa are the preferred V.sup.1, V.sup.2, and V.sup.3 groups set forth for compounds of formula I, supra.

Preferred Q groups of formula IIa are selected from a valence bond, --CH.sub.2--, or --CH.sub.2CH.sub.2--.

Preferred R.sup.3 groups of formula IIa include R', Q-OR.sup.5, Q-N(R.sup.4).sub.2, Ar.sup.1, N(R)C(O)Q-N(R.sup.4).sub.2, and N(R)Q-N(R.sup.4).sub.2. Examples of such R.sup.3 groups include CH.sub.2OH, OH, NH.sub.2, CH.sub.2NH.sub.2, CH.sub.2NHMe, CH.sub.2N(Me).sub.2, CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NHMe, CH