AU734009B2 - Novel angiogenesis inhibitors - Google Patents

Description

WO 98/54093 PCT/US98/10590 -1- TITLE OF THE INVENTION NOVEL ANGIOGENESIS INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.

Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.

Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes.

For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to different aspects of angiogenesis.

KDR mediates the mitogenic function of VEGF whereas Flt-1 appears to modulate non-mitogenic functions such as those WO 98/54093 PCT/US98/10590 -2associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.

Vascular growth in the retina leads to visual degeneration culminating in blindness. VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy. Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased pO2 levels in mice that lead to neovascularization. Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.

Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities. These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells. Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors. Embryonic stem cells, which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors. Inhibition of KDR or Flt-1 is implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization. as well as various forms of cancer.

Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression. Examples of such cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach. larynx and lung. These include histiocvtic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating I oncogenes K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.

Summary of the Invention A compound is disclosed in accordance with formula I:

R

3

R

5

N

R

1 i5

I

or a pharmaceutically acceptable salt. hydrate or prodrug thereof, wherein SR is pyridyl, pyrimidyl, thienyl or pyrazinyl. optionally substituted with from one to three members selected from Ra:

R

2 is H or Ci- 6 alkyl;

R

3 and R 4 are selected from the group consisting of phenyl, pyridyl, pyrimidyl, *e thienyl or pyrazinyl, optionally substituted with from one to three members selected from R provided that only one of R 3 and R 4 is as defined above and the other is H or C-6, alkyl; Rs is H, CI-6 alkyl, OR, halo, NH 2 or NO 2 25 Ra is H, Cl-o 1 alkyl, halogen, OH, OCi 6 alkyl, NR 7

R

8 or phenyl, wherein OCI.6 alkyl is optionally substituted with NR 7

R

8 R is H or C 1 -6 alkyl; and

R

7 and R 8 are independently selected from: H, C- 1 lo alkyl, C 3 6 cycloalkyl, COR, COOR, C6- 10 aryl, and C 3 -6 heterocyclyl, or R 7 and Rg can be taken together with the nitrogen to which they are attached to form a Sheterocyclic 5-10 membered saturated or unsaturated ring optionally containing, in [I:\DAYLIB\L1BAA02595.doc:aak 4 addition to the nitrogen atomn, one to two additional heteroatoms selected from the group consisting of N, 0 and S.

Also disclosed is a pharmaceutical com-position which is comprised of a compound represented by the formula 1: I YI I .11 AB,\ 02 595 .dtoc aak WO 98/54093 PCT/US98/10590 R3 R4NN

R

5 N

R,

I

wherein R2, R 3

R

4 and R5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.

Also included is a method of treating a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.

Also included is a method of treating cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.

Also included in the present invention is a method of treating diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.

More particularly, a method of treating ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.

More particularly, a method of treating retinal vascularizationis included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or prodrug thereof in an amount which is effective for treatinal vascularization. Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overal disease etiology. Also included is a method of treating age-related macular cldegeneration.

The disclosure of the invention also includes the following: S A method of treating or preventing cancer in a mammalian patient, which Smethod is comprised of administering to said patient an anti-cancer effective amount of a compound of formula I: R3 R4

N

R2

I

R

5

N

R

1 or a pharmaceutically acceptable salt, hydrate or prodrug thereof, optionally combined 5 with a carrier in the form of a pharmaeutical composition wherein

RI

1 is 1-I, C 1 alkyl, C 3 .0 cycloalkyl. Cj-in aryl, halo, 01-. C3- 10 heterocyclyl, or li heleroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being opltionally substituted with from one to three members selected from Ra R2 and R 3 are independently I-I. Cl alkyl, C.io aryl, C 3 cycloalkyl. Ol-, NO 2 2' -N 1-12. or halogen: is I-1, CI-10 alkyl, C 3 -6 cycloalkyl, C 14 alkoxy C 2 alkeny C 2 -o alkynyl.

C-lo arYl. C3- 1 0 heterocyclyl. C -6 alkoxyNR 7 R, NO 2 01-i. -N- 2 or Ci 1 heteroaryl. said alkyl. alkenyl alkynyl aryl, heteroaryl and heterocyclyl being optionally substituted with Ironi one to three members selected from R' is i1H. or Cl alkyl, OR. halo, NHI- 2 or NO-): R' is I-1. CI- 1 alkyl. halogen. NO 2 OR. -NR, NR 7 Rs. R 7 Rs. aryl, C(I- h1Celeroaryl 01or C3- 10 heterocyclyl.

R is I-I. or C 1 -6 alkyl: and R7 and Rs are independently I-I. alkyl C 3 cycloalkyl, COR. COOR, COO-.

S C>l arvl. C 31 1 heterocyclyl. or C 5 o heteroaryl or NR 7 Rs can be taken together to form a hcterocyclic 5-10 membered saturated or unsaturated ring containing. in addition to the I [ADA Y1.1 MH It AA 102595,doc:aak 6a nitrogen atom, one to two additional heteroatoms selected from the group consisting ofN, O and S.

S A method of treating or preventing a disease in which neoangiogenesis is implicated, which method is comprised of administering to a mammalian patient a therapeutically effective amount of a compound of formula I: R3 R4 N N R 2

R

5

N

R1

I

or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein in RI is H, Cl-io alkyl, C3- 6 cycloalkyl, C5- 1 0 aryl, halo, OH, C3- 10 heterocyclyl, or 1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R';

R

2 and R 3 are independently H, Ci-6 alkyl, C5- 1 0 aryl, C3- 6 cycloalkyl, OH, NO 2

-NH

2 or halogen;

R

4 is H, C-o 1 0 alkyl, C 3 -6 cycloalkyl, Cl-6 alkoxy C2- 1 0 alkenyl, C2-1 0 alkynyl, Cs-lo aryl, C 3 1 0 heterocyclyl, CI-6 alkoxyNR 7 Rs, NO 2 OH, -NH 2 or C5- 1 0 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or C.-6 alkyl, OR, halo, NH 2 or NO 2 20 R" is H, Ci-lo alkyl, halogen, NO 2 OR, -NR, NR 7 Rs, R 7

R

8

C

5 -lo aryl, C.-lo heteroaryl or C 3 o heterocyclyl, R is H, or C.-6 alkyl; and

R

7 and Rg are independently H, Cl-lo alkyl, C 3 6 cycloalkyl, COR, COOR, COO-, SCj 5 1 lo aryl, C3- 1 0 heterocyclyl, or C 5 1 0 heteroaryl or NR 7

R

8 can be taken together to form a 25 heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.

A method of treating or preventing retinal vascularization which method is comprised of administering to a mammalian patient a therapeutically effective amount of a compound of formula I: [I:\DAYLIB\LIBAA]02595.doc:aak

R

3 R4

N

Rs N R2 R1

I

or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein Ri is H, Cl-io alkyl, C3- 6 cycloalkyl, C 5 1 o aryl, halo, OH, C3- 10 heterocyclyl, or Cs- 1 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R"; R2 and R 3 are independently H, Ci-6 alkyl, C-o 10 aryl, C3- 6 cycloalkyl, OH, NO 2

-NH

2 or halogen;

R

4 is H, CI-lo alkyl, C 3 6 cycloalkyl, Ci-6 alkoxy C 2 1 0 alkenyl, C2- 1 0 alkynyl, Cs-lo aryl, C 3 1 0 heterocyclyl, Ci-6 alkoxyNR 7 Rs, NO 2 OH, -NH 2 or Cs5 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or Ci-6 alkyl, OR, halo, NH 2 or NO 2 R" is H, Cl-io alkyl, halogen, NO 2 OR, -NR, NR 7

R

8

R

7 Rs, Cs-lo aryl, CS-o heteroaryl or C 3 1 0 heterocyclyl, R is H, or C 1 6 alkyl; and

R

7 and R 8 are independently H, CI.lo alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, C- .lo aryl, C 3 1 0 heterocyclyl, or C 5 sio heteroaryl or NR 7

R

8 can be taken together to form a 20 heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, 0 and S.

A method of treating or preventing diabetic retinopathy which method is comprised of administering to a mammalian patient a therapeutically effective amount of 25 a compound of formula I:

N

RI

or a pharmaceutically acceptable salt or hydrate thereof, wherein I :\DAYLIB\LIIBAA]02595.doc:aak 6c RI is H, C-o 1 0 alkyl, C3- 6 cycloalkyl, C-o 1 0 aryl, halo, OH, C3- 1 0 heterocyclyl, or 0 o heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

2 and R 3 are independently H, CI-6 alkyl, Cs- 1 0 aryl, C 3 -6 cycloalkyl, OH, NO 2

-NH

2 or halogen; R4 is H, Ci-io alkyl, C 3 6 cycloalkyl, CI-6 alkoxy C2- 1 0 alkenyl, C2- 10 alkynyl, Cs- 0 o aryl, C 3 1 0 heterocyclyl, Ci-6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C 5 1 0 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or CI- 6 alkyl, OR, halo, NH 2 or NO 2 R' is H, Ci.lo alkyl, halogen, NO 2 OR, -NR, NR 7 R, R 7

R

8 C5- 10 aryl, Cs- 1 0 heteroaryl or C 3 1 0 heterocyclyl, R is H, or Ci-6 alkyl; and

R

7 and Rs are independently H, C-.io alkyl, C3- 6 cycloalkyl, COR, COOR, COO-, Cs-io aryl, C3- 10 heterocyclyl, or Cs- 1 0 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.

A method of treating or preventing age-related macular degeneration which 20 method is comprised of administering to a mammalian patient a compound of formula I: **R4

NR

R

2

R

5 N_

R,

I

or a pharmaceutically acceptable salt or hydrate thereof, optionally conbined with a ,carrier in the form of a pharmaceutical composition, wherein 25 RI is H, Ci.io alkyl, C 3 -6 cycloalkyl, C 5 1 0 aryl, halo, OH, C 3 1 0 heterocyclyl, or C5-Io heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R";

R

2 and R 3 are independently H, Ci-6 alkyl, C-o 1 0 aryl, C 3 -6 cycloalkyl, OH, NO 2

-NH

2 or halogen; 3o R4 is H, C.-io alkyl, C 3 -6 cycloalkyl, CI-6 alkoxy C2- 10 alkenyl, C2- 10 alkynyl,

C

5 -Io aryl, C3- 1 o heterocyclyl, CI.

6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C5- 1 0 heteroaryl, said S O [l:\DAYII B\LIBAA]02595.doc:aak 6d alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or CI-6 alkyl, OR, halo, NH 2 or NO 2

R

a is H, C-o 1 0 alkyl, halogen, NOz, OR, -NR, NR 7 Rs, R 7 Rs, C5- 1 0 aryl,

C

5 .o 1 heteroaryl or C3- 10 heterocyclyl, R is H, or CI-6 alkyl; and

R

7 and Rg are independently H, Ci-.

0 alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, Cs.-o aryl, C3- 1 0 heterocyclyl, or Cs- 10 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the jo nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.

A method of treating or preventing an inflammatory disease which method is comprised of administering to a mammalian patient a therapeutically effective amount of a compound of formula I: R3 R4

N

R

R

5 N

R

I

15 R1 or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein RI is H, Ci-io alkyl, C 3 6 cycloalkyl, Cs.

1 0 aryl, halo, OH, C 3 1 0 heterocyclyl, or C5-o heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R';

R

2 and R3 are independently H, CI.

6 alkyl, C5- 1 o aryl, C 3 -6 cycloalkyl, OH, NO 2 -NH2, or halogen;

R

4 is H, C.-o 0 alkyl, C 3 -6 cycloalkyl, C.-6 alkoxy C2- 10 alkenyl, C2- 10 alkynyl, 25 C.s-o aryl, C 3 o heterocyclyl, CI- 6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C5.

1 0 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R';

R

5 is H, or C.-6 alkyl, OR, halo, NH 2 or NO 2 R" is H, Ci.lo alkyl, halogen, NO 2 OR, -NR, NR 7 Rs, R 7

R

8 C5- 1 0 aryl, Cs- 1 0 heteroaryl or C3-o heterocyclyl, SR is H, or C-.

6 alkyl; and [I:\DAY LI B\LIBAA]02595.doc:aak 6e

R

7 and R 8 are independently H, Ci-lo alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, 1 0 aryl, C3- 10 heterocyclyl, or Cs-o 1 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.

A method for inhibiting tyrosine kinase which method comprises administering to a mammalian patient a therapeutically effective amount of a compound of formula I: R3 R4 N N R2

R

5 NR R1 l(

I

or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein R, is H, Cl-io alkyl, C 3 6 cycloalkyl, C-o 1 0 aryl, halo, OH, C 3 1 0 heterocyclyl, or Cs.-1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being 15 optionally substituted with from one to three members selected from R';

R

2 and R 3 are independently H, CI- 6 alkyl, C-o 1 0 aryl, C 3 -6 cycloalkyl, OH, NO 2

-NH

2 or halogen;

R

4 is H, Cl-lo alkyl, C3- 6 cycloalkyl, Ci-6 alkoxy C2- 1 0 alkenyl, C2- 1 0 alkynyl, Cs-lo aryl, C 3 1 0 heterocyclyl, Ci- 6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C 5 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or C1-6 alkyl, OR, halo, NH 2 or NO 2 R" is H, CI-lo alkyl, halogen, NO 2 OR, -NR, NR 7

R

8

R

7

R

8 C-o 10 aryl, C5- 10 heteroaryl or C3- 1 0 heterocyclyl, R is H, or CI-6 alkyl; and

R

7 and R 8 are independently H, Cl-io alkyl, C3- 6 cycloalkyl, COR, COOR, COO-, Cs-lo aryl, C3- 1 0 heterocyclyl, or Cso 10 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, 0 and S.

Use of an effective amount of a compound of formula I: cy [I:\DAYL11 \I,IBAA]O2595Sdoc:aak 6f R3 R4 N

R

5 N

R

R,

I

or a pharmaceutically acceptable salt or hydrate thereof, wherein R, is H, Ci-io alkyl, C3- 6 cycloalkyl, C 5 1 0 aryl, halo, OH, C 3 1 0 heterocyclyl, or S C5- 1 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R";

R

2 and R 3 are independently H, Ci-6 alkyl, Cs-lo aryl, C 3 -6 cycloalkyl, OH, NO 2

-NH

2 or halogen;

R

4 is H, Ci.io alkyl, C3- 6 cycloalkyl, Ci- 6 alkoxy C2-IO alkenyl, C2- 1 0 alkynyl, 1i Cs-io aryl, C 3 0 heterocyclyl, Ci- 6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C5- 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R";

R

5 is H, or Ci-6 alkyl, OR, halo, NH 2 or NO 2 Ra is H, C.-io alkyl, halogen, NO 2 OR, -NR, NR 7 Rs, R 7

R

8 Cs-io aryl, 0% 15is C.-o heteroaryl or C3- 1 0 heterocyclyl, R is H, or Ci- 6 alkyl; and

R

7 and R 8 are independently H, Cl-lo alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, C.s-io aryl, C 3 1 0 heterocyclyl, or C 5 1 0 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S, in the manufacture of a medicament for treating or preventing: cancer in a gyj mammalian patient, a disease in which neoangiogenesis is implicated, retinal vascularization, diabetic retinopathy, age-related macular degeneration or inflammatory 2 5 disease, or for inhibiting tyrosine kinase.

A compound of formula I: R3 RR2

R

5

N

R

SDAYLIB\LI A02595.doc:aak [l:\DAYLIB\LIBAA]02595.doc:aak 6g or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein RI is H, C- 10 o alkyl, C 3 6 cycloalkyl, C 5 1 o aryl, halo, OH, C 3 1 0 heterocyclyl, or

C-

1 0 o heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

2 and R 3 are independently H, CI-6 alkyl, C 5 1 0 aryl, C3- 6 cycloalkyl, OH, NO 2

-NH

2 or halogen;

R

4 is H, Ci lo alkyl, C 3 -6 cycloalkyl, CI- 6 alkoxy C 2 -o 1 alkenyl, C2- 10 alkynyl, Cs-lo aryl, C 3 1 0 heterocyclyl, C1- 6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C5- 1 0 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;

R

5 is H, or C 1 -6 alkyl, OR, halo, NH 2 or NO 2 R" is H, Ci-to alkyl, halogen, NO 2 OR, -NR, NR 7

R

8

R

7

R

8 C5- 1 0 aryl, Cs-o heteroaryl or C 3 1 0 heterocyclyl, R is H, or C 1 -6 alkyl; and

R

7 and R 8 are independently H, Cl-lo alkyl, C 3 6 cycloalkyl, COR, COOR, COO-,

C

5 1 o aryl, C 3 1 0 heterocyclyl, or C 5 1 0 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, 20 O and S, when used for treating or preventing: cancer in a mammalian patient, a disease in which neoangiogenesis is implicated, retinal vascularization, diabetic retinopathy, agerelated macular degeneration or inflammatory disease, or for inhibiting tyrosine kinase.

Detailed Description of the Invention 2: 5 The invention is described herein in detail using the terms defined below unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.

Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion.

S

[I:\DAYLIB\LIBAA]02595.doc:aak Examples include the following: and -(CH 2 -(CH 2 (CH2)x.--(CH2)ywherein: x plus y from 0-10; and w plus z from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.

[I:\DAYLIB\LIBAA]02595.doc:aak WO 98/54093 PCT/US98/10590 -7- When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of Ra, described herein.

The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four nonaromatic (non-resonating) carbon-carbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a when a substituted alkenyl group is provided.

The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carboncarbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a when a substituted alkynyl group is provided.

Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, naphthyl and the like. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 1-3 groups ofRa as defined herein.

Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.

The term heterocycle, heteroaryl or heterocyclic, as used herein except where noted, represents a stable 5- to 7membered mono- or bicyclic or stable 7- to 10-membered bicyclic WO 98/54093 PCT/US98/10590 -8heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of Ra. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. The term "alkoxy" refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.

The term "halogen" is intended to include the halogen atom fluorine, chlorine, bromine and iodine.

The term "prodrug" refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs include acyl amides of the amino compounds of this WO 98/54093 PCT/US98/10590 -9inventon such as amides of alkanoic(Ci.

6 )acids, amides_of aryl acids benzoic acid) and alkane(Ci6.)dioic acids.

Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis tumor growth, diabetic retinopathy), etc.

The compounds of the present invention are in accordance with formula I: or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein RI is optionally

R

2

&R

3 are

R

4 is alkenyl, H, C.- 10 alkyl, C 3 -6 cycloalkyl, C 5 1 0 aryl, halo, OH, C 3 -heterocyclyl, or C 5 1 0 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being substituted with from one to three members selected from Ra; independently H, C-.

6 alkyl, C 5 1 0 aryl, C3-6 cycloalkyl, OH, NO 2

-NH

2 or halogen; H, C.- 10 alkyl, C3-6 cycloalkyl,

C

1 -6 alkoxy C 2 10 C2- 10 alkynyl, C 5 10 aryl, C3- 10 heterocyclyl, CI-6 WO 98/54093 PCT/US98/10590 alkoxyNR 7 Rs, NO 2 OH, -NH 2 or C 5 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; H, or C 1 6 alkyl, OR, halo, NH 2 or NO 2 H, Ci.-o alkyl, halogen, NO 2 OR, -NR, NR 7

R

8

R

7

R

8

C

5 10 aryl, C 5 10 heteroaryl or C 3 1 0 heterocyclyl,

R

5 is Ra is R is H, or C 1 6 alkyl; and R7&R8 are independently H, alkyl, C3-6 cycloalkyl, COR, COOR, COO-, C 5 10 aryl, C 3 10 heterocyclyl, or C 5 1 0 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one two additional heteroatoms selected from the group consisting of N, O and S.

A preferred subset of compounds of the present realized when: H, C.- 1 0 alkyl, C 5 1 0 aryl, C 3 10 heterocyclyl, or C 5 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; invention is R, is

R

2

&R

3 are independently H, C-.

6 alkyl, C 3 6 cycloalkyl, OH, or halogen;

R

4 is H, CI.lo alkyl, C 3 -6 cycloalkyl, C 5 10 aryl, C 5 1 0 heteroaryl,

C

3 1 0 heterocyclyl,

CI.

6 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C 5 .10 heteroaryl, said alkyl, aryl, WO 98/54093 WO 9854093PCTIUS98/1 0590 11- heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described ab ove.

Examples of the compounds of this invention are: 3 -(4-fluorophenyl)-6-(4-pyridyl) pyrazolo( 3 -chlorophenyl)-6-(4-pyridyl) pyrazolo( 3 ,4-methylenedioxypheny)-6-(4-pyridyl) pyrazolo( A)pyrimidine, 3 -(phenyl)-6-(4-pyrimidyl) pyrazolo( 1,5 -A)pyrimidine, 3 -(4-fluorophenyl)-6- (4-pyrimidyl) pyrazolo( 3-(3 -chlorophenyl)-6-(4-pyrimidyl) pyrazolo( 1,5 -A)pyrimidine, 3 -thienyl)-6-(4-pyrimidyl) pyrazolo( 1, 3 -acetamidophenyl)-6-(4-methylphenyl) pyrazolo( A)pyrimidine, 3-(3 -thienyl)-6-(4-methylphenyl) pyrazolo( 1,5 -A)pyrimidine, 3-(phenyl)-6-(4-methoxyphenyl) pyrazolo( 1,5 -A)pyrimidine, 3 -acetamidophenyl)-6-(4-methoxyphenyl)pyrazolo( 1,5 A)pynimidine, 3-(3 -thienyl)-6-(4-methoxyphenyl) pyrazolo( 3 -(phenyl)-6-(4-methoxyphenyl) pyrazolo( 1,5 -A)pyrimidine, 3 4 -pyridyl)-6-(4-methoxyphenyl) pyrazolo( 3 -(phenyl)-6-(4-chlorophenyl) pyrazolo( 1,5 -A)pyrimidine.

3 4 -pyridyl)-6-(4-chlorophenyl) pyrazolo( 3 -(phenyl)-6-(4-methylphenyl) pyrazolo( 3 4 -pyridyl)-6-(4-methylphenyl) pyrazolo( 1,5 -A)pyrimidine, 3 -(phenyl)-6-(2-pyridyl) pyrazolo( 3 -(4-pyridyl)-6-(2-pyridyl) pyrazolo( 3-(phenyl)-6-(4-pyrimidyl) pyrazolo( 1,5 -A)pyrimidine, 3 4 -pyridyl)-6-(4-pyrimidyl) pyrazolo( 1 ,-A)pyrimidine, 3 -(phenyl)-6-(2-pyrazinyl) pyrazolo( 1,5 -A)pyrimidine, 3 -(4-pyridyl)-6-(2-pyrazinyl) pyrazolo( 3 -pyridyl)-6-(4-methoxyphenyl) pyrazolo( 3-(phenyl)-6-(4-pyridyl) pyrazolo( WO 98/54093 PCT/US98/10590 12- 3-(3-pyridyl)-6-(4-pyridyl) 3-(4 pyridyl)-6-(4-methoxyphenyl) 3-(3-thienyl)-6-(4-methoxyphenyl) 3-(3-thienyl)-6-(4-hydroxyphenyl)pyrazolo(1,5-A)pyrimidine, 3-(3-thienyl)-6-(4-(2-(4-morpholinyl)ethoxy)phenyl) A)pyrimidine, 3-(3-thienyl)-6-(cyclohexyl)pyrazolo 3-(bromo)-6-(4-methoxyphenyl) 3-(bromo)-6-(4-pyrimidyl) 3-(phenyl)-6-(2-(3-carboxy)pyridyl) and 3-(3-thienyl)-6-(4-pyridyl) Schemes 1-3 for preparing the novel compounds of this invention are presented below. The examples which follow the schemes illustrate the compounds that can be synthesized by Schemes 1-3, but Schemes 1-3 are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds.

Scheme 1 0 NAlr h N EtOHIHOAc rl

H

2

N

1 80 0 C Ar 2 Ar2 1 2 3 Generally, a method for the preparation of 3,6-diaryl comprises mixing a commercially available malondialdehyde compound with commercially available aminopyrazole in an alcohol, such as ethanol, methanol, isopropanol, butanol and the like, said alcohol containing catalytic quantities of an acid, such as acetic acid, to yield WO 98/54093 PCT/US98/10590 13wherein Arl and Ar2, respectively, are R4 and R1, as described above.

Scheme 2 o H Ar-O NN EtOH/HOAc Ar ,N

N

H2N q 800C SBr 80C N Br 1 7 8 Ar A N NN ArN i r Ar 2

-B(OH

2 d(PPh 3 4 Br Na 2

CO

3 Ar 2 0

C

8 9 Scheme 2 depicts a means for making 3,6-diaryl when the desired aminopyrazole is not commercially available. In a like manner to that described in scheme 1 compound is obtained. Treatment of with a boronic acid derivative in the presence of a palladium catalyst provides after workup the desired material Arl and Ar2 are as described above.

WO 98/54093 PCT/US98/10590 -14- Scheme 3 0 0 SArMe 2 N-OMe PhCH 3 Ar N OMe 115 0

C

16 17 CNMe PhCH 3 CN NH 2

NH

2 :HCI H 2

NH

oMe PhCH3 2 N Me 2 N M Ar2 Ar 2 OMe 15 0 C NM 2 EtOH reflux Ar 2 18 16 19 H2H O EtOH/HOAc Ar Ar 2 Arl N 80 0

C

Ar2 Ar 2 17 21 Scheme 3 ilustrates another method for the preparation of 3,7 diarylpyrazolo(1,5-A)pyrimidines. The comercially available ketone (15) and nitrile (18) are treated seperately with dimethylformamidedimethyl acetal (16) in refluxing toluene to give products (17) and (19) respectively. Compound (19) is then treated with hydrazinehydrochloride in refluxing ethanol to give the aminopyrazole Compounds (17) and (20) and then treated with catalytic amounts of acetic acid in ethanol as described previously giving the desired of 3,7 A)pyrimidines Arl and Ar2 are as described above.

The invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier. As used herein the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism WO 98/54093 PCT/US98/10590 and excretion. Other factors, more practical in nature, which are also important in the selection, are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.

When a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.

When the compound is negatively charged, it is balanced by a counterion, an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc. An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality. Likewise when the compound is positively charged, protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.

Pharmaceutically acceptable salts also include acid addition salts. Thus, the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and WO 98/54093 PCT/US98/10590 16magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

The compounds of the present invention, may have asymmetric centers-and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. When any variable aryl, heterocyle, R1, etc)occurs more than one time in any constituent or in Formula I, its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated.

The compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.

The compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.

Thus, the carrier employed may be, for example, either a solid or liquid. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier for oral use may include time delay material well known in WO 98/54093 PCT/US98/10590 -17the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.

Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Examples of injectable dosage forms include sterile injectable liquids, solutions, emulsions and suspensions.

Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.

In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.

For the methods of treatment disclosed herein, dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors. An example of a suitable oral dosage range is from about 0.1 to about mg/kg per day, in single or divided doses. An example of a suitable parenteral dosage range is from about 0.1 to about mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection. An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day. An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.

WO 98/54093 PCT/US98/10590 18- The compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.

EXAMPLE 1 MeO

N

3-(4 pyridyl)-6-(4-methoxyphenyl) A solution of commercially available dialdehyde (4, 12.9 mg, 0.0724 mmol) and aminopyrazole 10.4mg 0.0652mmol) in ethanol was heated at 80 0 C for 10 hours in a test tube containing catalytic amounts of acetic acid. The reaction was cooled to room temperature and the yellow solid was collected by filtration and the title compound was washed with cold ethanol and dried (11.7 mg, Mass Spec 303).

MeO A HNN gN-N H2 800C

N

H2N 4 EXAMPLE 2 3-(3-thienyl)-6-(4-methoxyphenyl) 3-(3-thienyl)-6-(4-methoxyphenyl) pyrazolo(1 WO 98/54093 PCT/US98/10590 -19- Step 1.

A solution of 4 (713 mg, 4.0 mmol) and commercially availaible 7 (648 mg, 4.0 mmol), discussed above in ethanol mL) was heated at 75 0 C for 4 h. The resulting white suspension was as decribed in example 1 for 4 hours, then cooled to filtered, and washed with methanol (3 x 5 mL) to provide 10 as a white powder (1.07 g, 88%, mp 168-170 0 1H NMR (CDC13) 6 8.79 1 H, J 2.2 Hz), 8.74 1 H, J 2.2 Hz), 8.12 1 7.51 2 H, J 8.8 Hz), 7.05 2 H, J 8.8 Hz), 3.88 (s, 3 H).

MeO OTO H2N EtOH/HOAc HOBr CBr 4 7 Step 2.

A suspension of (10) (250 mg, 0.82 mmol), thiophene-3-boronic acid (11) (158 mg, 1.24 mmol), and aqueous sodium carbonate (2 M, 1 mL) in dioxane (5 mL) was de-gassed by evacuating and backflushing with argon (3x).

Tetrakis(triphenyl-phosphine) palladium (20 mg, 0.017 mmol) was added and the reaction mixture was de-gassed again. The argon filled flask was then submerged in an oil bath pre-heated to 90 0

C

and was heated at that temperature for 16 h. After cooling to 0 C, the yellow precipitate which formed was collected by filtration and was washed with methanol (3 x 5 mL) to provide the title compound as a yellow powder (220 mg, 87%, mp 191-193 oC): IH NMR (CDCI 3 8 8.79 1 H, J 2.4 Hz), 8.76 1 H, J 2.2 Hz), 8.37 1 7.90 (dd, 1 H, J 2.9, 1.3 Hz), 7.70 (dd, 1 H, J 4.9, 1.2 Hz), 7.54 2 H, J 8.8 Hz), 7.43 1 H, J 4.9, 2.9 Hz), 7.06 2 H, J 8.8 Hz), 3.88 3H).

WO 98/54093 PCT/US98/10590 20 °N HQ N. N H BOH Pd(PPh3)4

N

N+ Na2CO3 Br Dioxane/ 90 0

C

11 EXAMPLE 3 H0O HU: Y

-NN

3-(3-thienyl)-6-(4-hydroxyphenyl)pyrazolo(1,5-A)pyrimidine Ethanethiol (30 mg, 36 uL) was added dropwise over 1 min to a suspension of sodium hydride (23 mg, 0.98 mmol) in dry DMF (2 mL) under argon. After 15 min, the compound of example 2 (50 mg, 0.16 mmol) was added and the reaction mixture was heated at 150 0 C for 1.5 h. The resulting brown solution was cooled, poured into water (25 mL) and washed with ethyl acetate (2 x 25 mL). The combined organics were dried (Na 2

SO

4 concentrated, and purified by flash chromatography EtOAc/Hexanes) to give the title compound as a yellow solid [11 mg, 23%, Rf 0.12 (40% EtOAc/Hexanes)]: 1H NMR (CD30D) 6 8.96 1 H, J= 2.4 Hz), 8.85 1 H, J= 2.2 Hz), 8.44 1 H), 7.94 (dd, 1 H, J 2.9, 1.2 Hz), 7.74 (dd, 1 H, J= 4.9, 1.2 Hz), 7.56 2 H, J 8.8 Hz), 7.46 (dd, 1 H, J 4.9, 2.9 Hz), 6.94 (d, 2 H, J= 8.6 Hz).

'NN NaH NN EtSH

DMF

V< o V^S N WO 98/54093 PCT/US98/10590 -21 EXAMPLE 4 3-(3-thienyl)-6-(4-(2-(4-morpholinyl)ethoxy)phenyl) A)pyrimidine A solution of example 3 (11 mg, 0.038 mmol), cesium carbonate (37 mg, 0.11 mmol), N-(2-chloroethyl)morpholine hydrochloride (7 mg, 0.11 mmol), and sodium iodide (0.013 mmol) in DMF (3 mL) was heated at 60 0 C under argon for 16 h. The reaction mixture was then poured into water (25 mL) and washed with ethyl acetate (2 x 25 mL). The combined organics were dried (Na 2

SO

4 concentrated, and purified by flash chromatography Hexanes/CHCl 3

(NH

3 to give the title compound as a yellow solid [10 mg, 65%, mp 149-151 0 C, Rf 0.39 (100% CHCl 3

(NH

3 IH NMR (CDCl 3 8 8.77 1 H, J 2.2 Hz), 8.75 1 H, J 2.2 Hz), 8.36 1 7.90 (dd, 1 H, J 2.9, 1.3 Hz), 7.69 (dd, 1 H, J 4.9, 1.3 Hz), 7.52 2 H, J 8.8 Hz), 7.43 1 H, J 4.9, 2.9 Hz), 7.06 2 H, J 8.8 Hz), 4.18 2 H, J= 5.7 Hz), 3.76 4 H, J= 4.6 Hz), 2.85 2 H, J= 5.7 Hz), 2.61 4 H, J 4.6 Hz); FAB MS Anal Calcd. for

C

22

H

22

N

4 0 2 S C, 65.00; H, 5.46; N, 13.78. Found C, 64.98; H, 5.55; N, 14.02.

H o N rNC rN~° HON 0Cs l N- N0 Cs 2

CO

3 Nal S DMF WO 98/54093 PCT/US98/10590 -22- EXAMPLE

N

S

3-(3-thiophenyl)-7-(4-pyridyl) pyrazolo( A 13 x 100 mm reaction tube was charged with aminopyrazole (22) (16.5 mg, 0.100 mmol) dissolved in 0.500 mL EtOH and vinylogous amide (23) (17.6 mg, 0.100 mmol) dissolved in 0.200 mL EtOH. Glacial acetic acid (1 drop) was added and the reaction was heated to 80 oC for 14 h. An additional 0.100 mL of glacial acetic acid was added and heating was continued for an additional 6 h. The sample was concentrated to dryness to provide the desired title compound. Analysis by mass spectrometry showed 279.2.

N

H2N o EtOH/HOAc S+ I 80 0

C

S

22 23 EXAMPLE 6 s s 3-(3-thienyl)-6-(cyclohexyl) WO 98/54093 PCT/US98/10590 -23- Step 1 Palladium on carbon 2 g) was added to a solution of 24 (5.62 g, 23.4 mmol) in ethanol (100 mL) under an argon atmosphere. After evacuating and backflushing the reaction vessel with H2 the black suspension was stirred vigorously under an H2 filled balloon for 16 h. The reaction mixture was then filtered through celite, washed with ethyl acetate (200 mL) and concentrated to provide 25 as a colorless oil (5.0 g, 1

H

NMR (CDC13) d 4.18 4 H, J 7.1 Hz), 3.13 1 H, J 9.2 Hz), 2.08 1 1.73 1.56 5 1.35 1.01 5 H), 1.26 6 H, J 7.0 Hz).

H

2 EtO OEt 10% Pd/C EtO OEt EtOH 0 0 0 0 O O O O 24 Step 2 A solution of 25 (2.0 g, 8.3 mmol) in dry THF (30 mL) at 0°C was treated with lithium aluminum hydride (1.0 M in THF, 16.5 mL, 16.5 mmol) over a 5 min period. The reaction mixture was warmed gradually to 15 0 C over 20 min and then was recooled to 0°C and quenched sequentially with water (630 uL), aqueous sodium hydroxide (1 N, 630 uL), and then water (3 x 630 uL). The resulting white suspension was stirred for 15 min, dried (Na2SO4), and filtered washing with THF (100 mL) and ethyl acetate (100 mL). The filtrate was concentrated to provide 26 as a white solid (1.35 g, 100%): 1 H NMR (CDC13) d 3.83 (ddd, 4 H), 1.77 1.62 5 1.57 1 1.42 1 1.30 0.96 (m,

H).

EtOROEt

HF

O 0 OH OH 26 WO 98/54093 PCT/US98/10590 -24- Step 3 A solution of oxalyl chloride (2.39 g, 1.64 mL, 18.8 mmol) in CH2C12 (50 mL) at -60 0 C was treated with DMSO (2.94 g, 2.67 mL, 37.6 mmol) in CH2C12 (10 mL) over 2 min. After 5 min, a solution of 26 (1.35 g, 8.5 mmol) in CH2C12 (20 mL) was added and the resulting suspension was maintained at -60 0 C for 15 min.

Triethylamine (8.6 g, 11.8 mL, 85 mmol) was then added and the reaction mixture was allowed to warm to 20 0 C. The quenched reaction was poured into water (200 mL) and washed with CH2C12 (2 x 100 mL). The combined organics were dried (Na2SO4), concentrated, and purified by flash chromatography Hexane/EtOAc) to provide 27 as a viscous oil [135 mg, 10%, Rf= 0.34 (40% Hexane/EtOAc)]: 1 H NMR (CDC13) d 8.26 2 H), 2.09 (tt, 1 1.85 1.68 6 1.39 1.13 5 H).

oxalyl chlQride

DMSO

NEt3 d OH OH CH 2

C

2 0 0 26 27 Step 4 A solution of 27 (50 mg, 0.30 mmol) and 22 (47 mg, 0.30 mmol) in ethanol (5 mL) was heated at 75°C for 16 h. After cooling, the reaction mixture was concentrated, and the crude product was purified by flash chromatography EtOAc/Hexane) to provide 6 as a yellow solid [54 mg, 63%, Rf 0.33 (25% EtOAc/Hexanes)]: 1 H NMR (CDC13) d 8.48 1 H, J 2.2 Hz), 8.44 1 H, J 1.5 Hz), 8.30 1 7.86 (dd, 1 H, J 2.9, 1.1 Hz), 7.66 (dd, 1 H, J 4.9, 1.2 Hz), 7.41 (dd, 1 H, J 4.9, 2.9 Hz), 2.64 1 2.03 1.80 5 1.52 1.27 (m, FAB MS calcd. for 284, found 284; Anal Calcd. for C16H17N3S (0.05 H20): C, 67.59; H, 6.06; N, 14.78. Found C, 67.66; H, 6.12; N, 15.14.

WO 98/54093 PCT/US98/10590 25 HN-

N

EtOH

N

22 27 Kinase inhibition is demonstrated in accordance with the following protocol.

VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate. The phosphorylated pEY product is trapped onto a filter membrane and the incoporation of radiolabeled phosphate quantified by scintillation counting.

MATERIALS

VEGF receptor kinase The intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519- 524) were cloned as glutathione S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene. Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).

Lysis buffer mM Tris pH 7.4, 0.5 M NaC1, 5 mM DTT, 1 mM EDTA, 0.5% triton X-100, 10 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride (all Sigma).

WO 98/54093 PCT/US98/10590 -26- Wash buffer mM Tris pH 7.4, 0.5 M NaC1, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100, 10 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.

Dialysis buffer mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100, 50 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsuflonyl fluoride X reaction buffer 200 mM Tris, pH 7.4, 1.0 M NaCI, 50 mM MnC12, mM DTT and 5 mg/ml bovine serum albumin (Sigma).

Enzyme dilution buffer mM Tris, pH 7.4, 0.1 M NaC1, 1 mM DTT, 10 glycerol, 100 mg/ml BSA.

X Substrate 750 pg/ml poly (glutamic acid, tyrosine; 4:1) (Sigma).

Stop solution 30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher).

Wash solution trichloroacetic acid, 0.2 M sodium pyrophosphate.

Filter plates Millipore #MAFC NOB, GF/C glass fiber 96 well plate.

WO 98/54093 PCT/US98/10590 -27-

METHOD

A. Protein purification 1. Sf21 cells were infected with recombinant virus at a multiplicity of infection of 5 virus particles/ cell and grown at 27 °C for 48 hours.

2. All steps were performed at 4 0 C. Infected cells were harvested by centrifugation at 1000 X g and lysed at 4 OC for minutes with 1/10 volume of lysis buffer followed by centrifugation at 100,000Xg for 1 hour. The supernatant was then passed over a glutathione Sepharose column (Pharmacia) equilibrated in lysis buffer and washed with 5 volumes of the same buffer followed by 5 volumes of wash buffer. Recombinant GST- KDR protein was eluted with wash buffer/10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer.

B. VEGF receptor kinase assay 1. Add 5 pl of inhibitor or control to the assay in

DMSO.

2. Add 35 ll of reaction mix containing 5 pl of 10 X reaction buffer, 5 pl 25 mM ATP/10 gCi 33 P]ATP (Amersham), and 5 pl 10 X substrate.

3. Start the reaction by the addition of 10 gl of KDR nM) in enzyme dilution buffer.

4. Mix and incubate at room temperature for minutes.

Stop by the addition of 50 pl stop solution.

6. Incubate for 15 minutes at 4 0

C.

7. Transfer a 90 ptl aliquot to filter plate.

8. Aspirate and wash 3 times with wash solution.

9. Add 30 pl of scintillation cocktail, seal plate and count in a Wallac Microbeta scintillation counter.

WO 98/54093 PCT/US98/10590 -28- Human Umbilical Vein Endothelial Cell Mitogenesis Assay Expression of VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation. In the assay described, quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF). The mitogenic response to VEGF or bFGF is determined by measuring the incorporation of 3 H]thymidine into cellular DNA.

Materials HUVECs HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages 3-7.

Culture Plates NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

Assay Medium Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine serum (Clonetics).

Test Compounds Working stocks of test compounds are diluted serially in 100% dimethylsulfoxide (DMSO) to 400-fold greater than their desired final concentrations. Final dilutions to IX concentration are WO 98/54093 PCT/US98/10590 -29made directly into Assay Medium immediately prior to addition to cells.

Growth factors Solutions of human VEGF 65 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.

['HIThymidine [Methyl- 3 H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 uCi/ml in low-glucose DMEM.

Cell Wash Medium Hank's balanced salt solution (Mediatech) containing 1 mg/ml bovine serum albumin (Boehringer-Mannheim).

Cell Lysis Solution 1 N NaOH, 2% Na 2

CO

3 Method 1. HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per 100 ul Assay Medium per well in 96-well plates. Cells are growtharrested for 24 hours at 37°C in a humidified atmosphere containing 5% CO 2 2. Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37C/5%

CO

2 for 2 hours to allow test compounds to enter cells.

3. After the 2-hour pretreatment period, cells are stimulated by addition of 10 ul/well of either Assay Medium, WO 98/54093 PCT/US98/10590 VEGF solution or 10X bFGF solution. Cells are then incubated at 37°C/5% CO 2 4. After 24 hours in the presence of growth factors, 3 H]Thymidine (10 ul/well) is added.

5. Three days after addition of 3 H]thymidine, medium is removed by aspiration, and cells are washed twice with Cell Wash Medium (400 ul/well followed by 200 ul/well). The washed, adherent cells are then solubilized by addition of Cell Lysis Solution (100 ul/well) and warming to 37C for 30 minutes. Cell lysates are transferred to 7-ml glass scintillation vials containing 150 ul of water. Scintillation cocktail (5 ml/vial) is added, and cell-associated radioactivity is determined by liquid scintillation spectroscopy.

Based upon the foregoing assays the compounds of formula I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, diabetic retinopathy and in the treatment of cancers, solid tumors. The instant compounds inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with IC 50 values between 150-650 nM. These compounds also show selectivity over related tyrosine kinases FGFR1 and the Src family).

Claims (22)

1. A compound in accordance with formula I: R3 R4 ,NN 2 R 5 y N R, I or a pharmaceutically acceptable salt or hydrate thereof, wherein RI is pyridyl, pyrimidyl, thienyl or pyrazinyl, optionally substituted with from one to three members selected from R; R2 is H or CI- 6 alkyl; R 3 and R 4 are selected from the group consisting of phenyl, pyridyl, pyrimidyl, i. thienyl or pyrazinyl, optionally substituted with from one to three members selected from provided that only one of R 3 and R 4 is as defined above and the other is H or CI-, alkyl; Ri is HI-, CI-( alkyl, OR, halo, NHI- or NO2; R' is I-H, Cl-io alkyl, halogen, OH, OC-A, alkyl. NR 7 Rs or phenyl, wherein OCir,.alkyl is optionally substituted with NR 7 Ra; R is H or Ci-, alkyl; and 1R 7 and Rs are independently selected from: Ci- 1 alkyl, cycloalkyl, COR, COOR. Ch-1) aryl, and C3. 6 heterocyclyl, r or 1R 7 and Rx can be taken together with the nitrogen to which they are attached to 20 Irm a heterocyclic 5-10 membered saturated or unsaturated ring optionally containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of'N, O and S.

2. A- compound in accordance with claim I wherein R 7 and Rs are independently selected from: 1-1, Cl-io alkyl, C3- 6 cycloalkyl, COR, COOR. aryl. and heterocyclyl. or R 7 and Rx can be taken together with the nitrogen to which they are attached to oIbrm a heterocyclic 5 or 6 membered saturated or unsaturated ring optionally containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N. and S. o 3. A compound according to claim I selected from: S 3-( 3 -thienyl)-6-(4-pyrimidyl) pyrazolo( 3 3 -thienyl)-6-(4-methylphenyl) pyrazolo( 1101, 1 BA A 102579.doc:aak 32 3 -(3'-thienyl)-6-(4-methoxyphenyl) pyrazolo( 1,5 -A)pyrirniidine, 3 4 -pyridyl)-6-(4-methoxyphenyl pyrazolo( 1,5 -A)pyrirnidine,

3-(4-pyridyl)-6-(4-chlorophenyl) 3 4 -pyridyl)-6-(4-methylphenyl) 3 -(4-pyridyl)-6-(2-pyridyl) 3 4 -pyridyl)-6-(4-pyrirnidyl) 3 4 -pyridyl)-6-(2-pyrazinyl) 3 3 )-pyridyl)-6-(4-miethoxyphienyl) 3 -(3)-pyridyl)-6-(4-pyridyl) Io 3 4 -pyridyl)-6-(4-i-ethoxypheniyl) pyrazolo( 1,5 -A)pyri midinle, 3 -(3)-tliienyl)-6-(4-hiydroxyphienyl) pyrazolo(1I,5 -A)pyri midinle, 3 3 -thiieniyl)-6-(4-(2-(4-miorphol i nyl)ethioxy)phieny I) pyrazolo- (I 3 -(3)-tienyl)-6-(cyclohiexyl) is 3-(3-thienyl)-6-(4-pyridyl) 3-(3)-thienyl)-7-(4-pyridyl) pyrazolo(lI,5-A)pyrimid1Ine. or a pharmaceu-tically acceptable salt thereof.

4. A process of preparing a comIpoundIC which iscapable of iniiigtyrosine kinase enzyme, which process IS substantially as hereinibefore described with reference to 2' any one of Schemres I to 3. A process of' preparing a com1pound which is capable of inhibitino tyrosinle *kinaZse enIzymeIs. which Process IS substantially as hecreinbefore described with reference to any one of 'Examples I to 4 or 6.

6. A compIIound prepared by the pr~ocess of claim 4 or claim

7. A pharmaceu-tical composition whlich is comprised of' a comlpoundC InI accordance with any one of claims I to 3) or 6 in1 combination with a carrier. S. A method of treatingl or preventing cancer inI a mamrmal ian patient. which method is comprised of administering to said patient anI anti-can1cer- e ffctve amIounIt Of a COInpIoundIC of' 1-1rm1.a 1: -R2 R 5 N R 1 I I A\A 1025 79).doc :aak 33 or a pharmaceutically acceptable salt, hydrate or prodrug thereof, optionally combined with a carrier in the form of a pharmaeutical composition wherein RI 1 is H, Cl-lo alkyl, C 3 6 cycloalkyl, C 5 1 -o aryl, halo, OH, C 3 1 o heterocyclyl, or C 1 lo heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R; R 2 and R 3 are independently H, C 14 6 alkyl, CsIo() aryl, C 34 cycloalkyl, OHI, NO 2 -NI- 2 or halogen; RI 4 is i-I, alkyl, C 3 6 cycloalkyl, CI-6 alkoxy C2-Io alkenyl, C 2 alkynyl, C-lo) aryl. C 3 1 o heterocyclyl, CI-6 alkoxyNR 7 Rs, NO 2 01-1, -NI-H2 or C 5 -lo heteroaryl, said S alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R" R 5 is 1-I, or C 1 alkyl, OR, halo, NH 2 or NO 2 R' is I-I, Cij-o alkyl, halogen, NO 2 OR, -NR, NR 7 Rs, R 7 Rs, C 5 1 o aryl, 1 lo heteroaryl or C3-. 10 o heterocyclyl, I R is Il. or C 1 alkyl; and RI 7 and RN are independently H, Ci 1 o alkyl, C3-6 cycloalkyl, COR, COOR, COO-, Ci.lo aryl C 3 heterocyclyl, or Cso 10 heteroaryl or NR 7 Rs can be taken together to form a helerocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrooen atom, one to two additional heteroatoms selected fiom the group consisting ofN, and S. method of treating or preventing cancer in a mammalian patient, which Imethod is comprised of administering to said patient an anti-cancer effective amount of a compound of any one of claims 1 to 4 or 6 or of a composition of claim 7. method in accordance with claim 8 or claim 9, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system. stomach. larynx Mianl lune. I 1. A method in accordance with claim 8 or claim 9, wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma. small cell lung cancers, pauncreatic cancer, gioblastomas and breast carcinoma. 1: 2. A method of treating or preventing a disease in which neoangogenesis is implicated. w\vhich method is comprised of administering to a mammalian patient a therapeutically effective amount of a compound of formula 1: 1101 111 AA 102579.docaaik R 3 R4 N-N R 5 N or a phiarmaceutically acceptable salt or hydrate thereof" optionally combined with a carrier in the form of a pharmaceutical composition, wherein 3 is I-1, C 1 1 alkyl, C 3 6 cycloalkyl, C 5 1 aryl, halo. 011, C 3 1 0 heterocyclyl, or C5_10) heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected f-rm RW; R, and R 3 are independently C 1 6 alkyl, C 5 10 aryl, C 3 6 cycloalkyl, OH, NO 2 or- halogen; is I-1, 0 alkyl, C 3 -6 cycloalkyl, C 1 alkoxy 10 alkenyl. alkynyl, C 5 10 aryl. C 3 1 0 heterocyclyl, C 1 6 alkoxyNR 7 Rg. 017I. -NI or Ci. 10 heteroaryl, said alkyl. alkenyl, alkynyl, aryl, hieteroaryl and heterocyclyl being optionally substituted with from one to three members selected from W'. R 5 is 1-1, or C 14 alkyl, OR, halo, NH- or NO,); W1' is I-1, CI- 10 alkyl, halogen, OR. -NR. NR 7 Rs. R 7 R4, C 5 10 aryl. C 5 .1 Ichteroaryl or' C 3 1 0 1 heterocyclyl. R IS orC 1 6 alkyl; and R 7 and Rg are indepen-dently 1-1. C 1 10 alkyl, C 3 6 cycloalkyl, COR. COOR, COO-, CS. 1 1 1 Ma\yL C 3 10 heterocyclyl. Or C 5 1 0 1 heteroaryl or NIR 7 1Z cnbSaknt.ehe ofr 2)heterocyclic 5-10 membered saturated Or unsatrated rim, containinw. inaddition to thle ilnitrogeii atom. one to two additional heteroatoms selected From11 thle gr'oupJ consisting of N, (and S.

13. A method of treating or Pre\'entin2 ai disease In whi1ch necoangio-enesis Is Implicated. \vhich method is comprised of administering1 to ai mnammlalian patient a 23 IherapCLuCAllv Lffective am1ounIt OF a compound ofMI any C oeof clims I to 4 or 6 or of a composition of'claimn 7 in ant amou1-nt w~hich is eflbctivefor01 r-edCInIC.I neoang.logenesis.

14. A- mnethod in accordance with claim 12 Or claim 13. wherein the disease is an ocular diseaIse. A. method of treating or lpreventim, retinal VaIscLarization which method Is comprised of administering to a mammalian patienlt a1 theraIpeuticlly1 effective amoLInt Of' aI Com1pound Of formu1Lla 1: AU3. R 3 R 5 N or a phiarmaceultically acceptable salt or hydrate thereof, Optionally combined with a carrier in the form of. 'a pharmaceutical composition, wherein R, is 1-11 C 110 o alkyl, C 3 -6 cycloalkyl, Cj 5 0 aryl, halo, 01-1, C 3 -1 0 heterocyclyl, or 1 hieteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected froml W~; R? and R 3 are independently C, 4 alkyl, Ci-, 0 aryl, C 3 -6 cycloalkyl, OH, NO 2 -N l+l, or halogen; I R4 is 1-1. C,, 1 alkyl, C 3 6 cycloalkyl, C1- 6 alkoxy alkenyl. C 2 -1 0 alkynyl, C 1 0 rl C3-10 heterocyclyl, C,. 6 alkoxyNR 7 R 8 NO 2 01-1, -NIH) or C 10 heteroaryl, said alkvl. alk enil. alkynyl, aryl, heteroaryl and heterocyclyl being optionally suibstituted with frlom one to three members selected from IS 1-I. Or C, 4 alkyl, OR, halo, NI-I 2 or NO 2 W' is I-1, Cl., 1 1 alkyl, halogen, OR, -NR. NR-,Rs, R 7 Rg, C5_1( aryl, C 5 hteroarvl or' C 3 1 0 1 heterocyclyl. R IS I-IL Or C 1-6 alkyl and R 7 and Rs are independently 1-I, Cl. 11 1 alkyl, C 3 -6 cycloalkyl, COR. COOk. COO-, Cs 111 arl- 3 1 eeoyll rC. 1 eeoaryl or NR 7 1RS canl be taken together to torm a .0 10 m hterocyclic 5-10 membered saturated or' unsaturated rim). containline. inl addition to the nlitroiuen atom, one to two additional hieteroatomIS Selected fl-om1 the ('rotip con1sistin"( of N, 0 arld S.

16. A\ method of treating or preventing retinal VaIscularization vich mnethlod is comprised of adminlister in(, to a mammial ian patient a thierapeuLtically e ffective amlount Of Ot I la C01)Onipoud of any oneC Of claims I to 4 or 6 or of ai composition of claim 7 in anl amonOL~t *wich is cl'l'ctiv;e f'or treating~ retinal vascularizationl. so*: 17. A methiod of treating or pre\'entine diabetic retinopathyv whlich mecthod is *Comp~rised of admninisterine to a mammalian patient a the~rapeuLtical ly eff'ective amlount Of. al Coml)Oun1d of' formul.a I: I R .111 A A 112570 .doc:aak 36 R 3 R4 N R2 R 5 N R, or a pharmaceUtically acceptable salt or hydrate thereof, wherein R, is 1-1, C 11 alkyl, C 3 6 cycloalkyl, aryl, halo, OH-, C 3 10 heterocyclyl, or C5_ 1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with fromn one to three members selected from W'; and R 3 are independently H, C 14 alkyl, C5- 1 aryl, C 3 -6 cycloalkyl, OH, NO 2 -NI-I 2 or halogen; R 4 is 1-1- C 111 1 alkyl, C 3 6 cycloalkyl, C 14 alkoxy alkenyl, C 2 10 alkynyl, I C5_ 1 0 aryl, C3-10 heterocyclyl, C 1 6 alkoxyNR 7 Rg, 01-I, -NI-b- or C 5 1 heteroaryl, said alkyl, alkenyl. alkynyl, aryl, heteroaryl and heterocyclyl being optionally suibstituted with frlom one to three members selected from IS I-I. Or C 1 6 alkyl, OR, halo, NI- or NO-,: IRI is 1-1. CI- 0 alkyl, halogen, OR, -NR. NR 7 RS, RAK. Ci- 11 aryl, C heteroaryl or C 3 10 hieterocyclyl. R is 1-I. or C 14 alkyl; and RZ 7 and Rs are independently I1I, Cjj() alkyl, C 3 -6 cycloalkyl. COR, COOR, COO-, 1 alryl. C 3 1 0, heterocyclyl, or C 5 10 heteroaryl or NR 7 Rx, cani be taken together to form a *heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the m nitrogen atomn, one to two additional heteroatomns selected from the gopcniting of N, (0 aind S. 1 8. A method of. treating or preventino diabetic retinopathy which method is comiprised of 'administerino to a mammalian patient a therapeuLticaIl ye liVe amou0Lnt Of aI c01Iompond ol'any one of claims I to 4 or 6 or of a composition of claim 7 in an amounIt which is efetive lbr treatino diabetic retinopathy. *19. A method of treating or preventini, aue-relatec i acLar dCleICenerationI whIich mekthod is comprised of 'administeringL to a mammal ian patient a compound of lornla 1: R 3 R4 N- R 5 N I R:\I 10257 t )d(oc:aa~k 37 or a pharmaceutically acceptable, salt or hydrate thereof, optionally conbined with a carrier in the form of a pharmaceutical composition, wherein R, is FlI, Cr- 10 alkyl, C 3 6 cycloalkyl, C 5 10 aryl, halo, 01-I, C- 1 0 heterocyclyl, or C 5 1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from W;' and R 3 are independently 1-1, C,. 6 alkyl, C 5 1 ar) 1l, C 3 -6 cycloalkyl, 01H, NO 2 -NI-b. or halogen, R 4 is 1-I, CI- 111 alkyl, C 3 6 cycloalkyl, C 1 6 alkoxy, alkenyl. C 2 alkynyl, C- 1 0 1 arl C3-10 heterocyclyl, CI- 6 alkoxyNR 7 R 8 NO?, 01-I. -NI- 2 or C5_1( heteroaryl, said III alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with fromn one to three members selected from W~; is I-I, or C 14 alkyl, OR, halo, NH 2 or NO 2 W' is 1-1, CI- 1 alkyl, halogen, NO 2 OR, -NR. NR 7 RS, R 7 R 8 C5_ 10 aryl, (51)heteroaryl or C 3 1 0 heterocyclyl, R is I-I, or C, 4 alkyl; and R7, anid Rx aire independently 1-1, alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, ar510WW, C3- 1 0 heterocyclyl, or heteroaryl or NR 7 R, 8 can be taken together to form a heterocyclic 5-1 0 membered saturated or unsaturated rino containing. in addition to the flitrogen atom,. one to two additional heteroatomns selected From11 the gr-oupI consisting of N, 2 )and S. 2( 0.-A method of treating or preventing age-related miacular degeneration which 0 Ce inC ethod is copie oi administering to a mammalian patient a therapeutically effective m1oun1t o'l acomp)ound of any one of clalims I to 4 or 6 or a pharmaceutically acceptable SaIlt. prIOCIlug or hydrate thereof.' or of' a composition of' claim 7 in1 an1 am1ount Which is 25 c11lctivc f'or inflammiationl. 2 1 A method of treating or pr1eventing ani inflammiatory disease which method is comprised of administering~ to a miammnalian patient a therap~eutically effective amiount Of ZI .acoin poLlild Of formul1,1a I: R 3 *so* R4 N_ R 5 N R, or: a1 phaMa11ceutical ly acceptable salt Or hydrate thereof,. optional lv combined with a f\US! carrier in the formn of a phiarmaceutical composition. \vhlerei n I RAI. I I'\MA f02i7 t ).dic:aak 38 R 1 is 1-I, CjI-o( alkyl, C 3 6 cycloalkyl, C 5 1 0) aryl, halo, OH, C 3 1 0 heterocyclyl, or C 5 1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Wi; R, anid R 3 are independently H, C,. 6 alkyl, C5-1() aryl, C 3 6 cycloalkyl, OH, NO 2 -NH 2 or halogen; R 4 is 1-1, C 1 10 alkyl, C 3 cycloalkyl, C 1 6 alkoxy C)_ 11 alkenyl, alkynyl, C 5 10 a~ryl, C 3 -1 0 heterocyclyl, C 1 6 alkoxyNR 7 Rg, NO 2 01-, -NI- 2 or Ci- 1 0 heteroaryl, said alkyl, alkeniyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally Substituted with from one to three members selected from RW; III R 5 is or C 1 6 alkyl, OR, halo, NH 2 or NO 2 W1' is 1-1, C 111 alkyl, halogen, NO 2 OR. -NR, NR 7 R,4, R 7 Rx, C 5 10 aryl, C 5 1 heteroaryl or C 3 -10 heterocyclyl, R is 1-I, or C 1 6 alkyl;- and R 7 anid Rs are independently 1-1, CI. 11 alkyl, C 3 6 cycloalkyl, COR, COOR, COO-, C 5 10 arYl. C 3 1 0 heterocyclyl, or C 510 heteroaryl or NR 7 Rs can be takeni together to form a lieterocyclic 5-1 0 membered saturated or unsaturated ring containing2, in addition to the n1itrogen aitomn, one to two additional heteroatomns selected from the grIouIp consisting of N, (an-d S.

22. A method of treating or- preveniting ain inflammatory disease which method is 2 comprisedl ofadiisei1 to a mammnalian patient a therapeuLtically effective amount Of' a1 c01)onioud of anx' one of claims I to 4 or a pharmaceutically acceptable salt, prodrUg or Il. ydrate thiereof or of a compositioni of claim 7 in1 an1 amoun111t wh11Ih is eff-ective for in haniniation. 3.A- method according to claimn 21 or cla'im 22 \vhere'il the infl1amrmatory 23 CLS Iic Se isslcteI.d From11 the grIouIp c0InSISting) of' rhe1Cumatoid arthritis. psoriasis. contact derimatitis aind delayed hypertensitivity reactions.

24. A- method for inhibitingo tyrosine kinase which method comprises -vi adni ini1sterine to a mammall i patienit a therapeutically ef~ective aMount111 of'L acompound R, I I(H I 1:\A 11125 7().doc:a:ak 39 or a pharmaceutically acceptable. salt or hydrate thereof, optionally combined with a carrier in the form of a pharmaceutical composition, wherein R, is C 1 1 0 alkyl, C 3 6 cycloalkyl, C 5 1 aryl, halo, OK, C3-10 heterocyclyl, or C.,i_ 11 heteroaryl; said alkyl, alkenyl, alkynyl, __aryl, heteroaryl and heterocyclyl being optionally Substituted with fromn one to three members selected f-rm R; R? and R3 are independently Hl, C 1 6 alkyl, C 5 1 aryl, C3- 6 cycloalkyl, 01-1, NO 2 -N or halogen; R 4 is I-1, C~I- 0 alkyl, C 3 6 cycloalkyl, C 1 6 alkoxy alkenyl, C%10( alkynyl, ary'l. C 3 1 0 1 heterocyclyl, C 1 6 alkoxyNR 7 Rs, NO?, 01-1, -NI-I 2 or- Ci- 1 1 1 heteroaryl, said l0 alkyl. alkenyl, alkynyl, aryl, heteroaryl and hieterocyclyl being optionally Substituted with fr'Iom one to three members selected from W; IS I-1, or C 1 -6 alkyl, OR, halo, NH 9 or NO-); R" is 1-1, C 111 1 alkyl, halogen, NO?. OR, -NR, NR 7 R 8 R 7 R8, aryl, Ci_, 0 heteroaryl or' C 3 10 heterocyclyl, I R IS I-1- Or- C 1 -6 alkyl. and R7 and Rs are Independently I-1, Cj. 111 alkyl, C 3 -6 cycloalkyl. COR, COOR, COO-, arV I. C 3 heterocyclyl, or C 5 10 heteroaryl or NR 7 RN can be taken togyether to form a hecterocNvclic 5-10 membered saturated or uinsaturated ring~ containing, in addition to thle nlitrooten atom,. one to two additional hieteroatomis selected from11 thle grIoup consisting of N, Li nd S. A- methiod for inhibiting tyrosine kinase wich method comprises admini11stering, to a mnammial ian patient a thierapeu-tically effctive amou1-nt of 'a com1pound of any, one of claimis I to 4 or 6 or of a con-pjosition of claimi 7.

26. Use of an anti-cancer effectiVe amou1-nt ol a c01)opond of* formul-a 1: 3 R4 N-N R 5 N 255 Mr a phama-1Zceutical ly acceptable salt or hydrate thiereofl' whierein1 Ri is 1-1. Ci-n alkyl. C3-6 cvcloal kv'l. C 5 aryl hialo. 01-I. C 3 heter'ocyc or- (.lu eteroaryl: said alky'l. alkenyl. alkynvl, aryl. hietemoaryl anid hieterocyclyl being o)pt1ional lvsubstituted withl from one to three mnembers selected fr'iom W', P2, and 1Z are independently I-1. C1-6 alkvl. C 5 -1a0 l C 3 6 cvcloalkyl. 01-I. NO,. NII- or hialog-cnl: I RAIA I 3AA 1025 79.dolc:aak R 4 is H, CI- 1 0 alkyl, C 3 6 cycloalkyl, C 1 6 alkoxy alkenyl, C 2 10 alkynyl, CS. 1 1 1 aryl, C 3 1 heterocyclyl, C 1 6 alkoxyNR 7 R 8 NO 2 OH, -NH 2 or C5- 1 0 heteroaryl, said alkyl, alkeniyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally Substituted with fromn one to three memnbers selected from R'; Rj is 1-1, or C 1 6 alkyl, OR, halo, NH 2 or NO 2 W' is 1-1, C 111 alkyl, halogen, OR, -NR, NR 7 R 8 R 7 RX, C 5 10 aryl, 1 0 1 heteroaryl or C 3 10 heterocyclyl, R is FlI, or C 1 6 alkyl; and R 7 an-d Rx are independently C 11 alkyl, C 3 6 cycloalkyl. COR, COOR, COO-, In C.. 111 aryl, C 3 10 heterocyclyl, or C5- 1 heteroaryl or NR 7 Rx cani be taken together to form a hieter-ocvclic 5-10 mnembered saturated or unsaturated ring containing, in addition to the 113itrogen atomn, one to two additional hieteroatomrs selected fromn the group consisting of N, 0 anld S. in the mnuf1.1actUre of a mnedicarnent for treating or preventing cancer in a miammialian patient.

27. Use of 'a com1pou~nd of any one of claimns I to 4 or 6 ini the mnanufacture of a *inedicamnen-t for treating or preventing cancer ini a mnammialian patient. 2 8. Use in accordance with claimn 26 or- claimi 27, whereini the cancer is selected f'romi cancers of' the brain, enitouinnary tract. lymiphatic system, stomrach, larynx and

29. Use in accordance withi claimn 26 or claimi 97, whiereini the cancer is selected mmii I-i stiocytic lymnphoria. lung adenocarina. smiall cell lung11 cancers, pancreatic cancer, ioblastomas and breast carcinoma. Use of a therapeu-tically effective amountI ol'Z ac0)oound off'01brmLLI 1: R 3 R~N ()rZ a pharma71Zceu~tically) acceptable salt or- hydrate thiereof. whlereinl 1 is 1-1. C 1 alkyl. C 3 6 cycloalkyl. C 5 aryl. hialo. 01-1. C 3 .1 I heteocyclyl, Or Csm( hieteroairvl: said alkyl. alkeniyl. alkvniyL aryl, hieteroaryl and hieterocyclyl being 0ptionally su~bstituted with fromn onie to three memibers selected fromn R: an-d R, are Independently 1-1. C 1 6 alkyl. C 511 1 aryl, C 3 cycloalkyl. 01-I. NO-?. 01r lialo('en: .1A I1,A' 1o2579.doc .uik 41 R 4 is Fl, C 1 1 o alkyl, C 3 6 cycloalkyl, C 14 alkoxy C 210 alkenyl, C 2 10 alkynyl, C _jo aryl, C3-10 heterocyclyl, C 1 6 alkoxyNR 7 R 8 01-, -NH 2 or C5-1( heteroaryl, said alkyl. alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with From one to three members selected from W~; is 1-I, Or C 1 alkyl, OR, halo, NH,) or NO-); is 1-1, C 1111 alkyl, halogen, NO 2 OR, -NR, NR 7 Rx. R 7 Rs, C 5111 aryl, 1 heteroaryl or C3-10 heterocyclyl, R IS 1-1, Or C 14 alkyl; and R 7 and R 8 are independently H, Cj 11 alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, inC3_ 1 aryl, C 3 10 heterocyclyl, or C5_I 1 heteroaryl or NR 7 Rg can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the n1itrogen atomn, one to two additional heteroatomrs selected from the group consisting of N, 0 and S. in the mianufatl~ure of a medicament for treating or preventing a disease in which 13 coanigiogenesis is implicated. 31 Use of a com1pound of any one of claims I to 4 or 6 in the manufaEcIture of a mredicamrent for treating or preventing a disease in wich neoangiogenesis is implicated. 3- s i codance with claimn 30 or claimn 3 1. \vhierein the disease is an ocular disease. Use of a Compound of formu11Lla 1: R 3 R 5 N a phar-Maceutically acceptable salt or- hyNdrate thereolC \vhcretii IS 0 a!lkyl. C 3 cycloalk L. C5_1(0 aryl, hialo. 01-1. 0 heterocyc ly I or 23 cteroaryl: said alkyl. alkenyl. a! kynv I. arv-l. hieteroarvI and hcteriocvc Iv! being( otionally' Substitulted Wvith from11 One to three mcmbers sclected fromi W': and R 3 are Independently 1-1. C 1 -6 alkyl, C5. 10 arvL. cvcloalk\ I. O1-. NO 2 -IN H'I or hialogen:. is 1-I. C 1 -10 al kyl, C 3 cycloal ky I, CI-6 alkoxN/ C 2 0( al keny I. C 2 o alkynyl. 10 arvl CI. et"C"CY1 C1-6 a! koxvN R 7 1Z NO). 01-1. -N 1-12 or C 5 10 heteroaryl, said ailkv I. a Ikeniv 1. a! kvnyl. aryl. heteroarvl and hieterocyclyl beingI- optional1 lvSubstituted with n ,to three m em bers selected fromn W I R:,.IA1 0 279.doc:aiak 42 Ri is H, or C 1 6 alkyl, OR, halo, NH 2 or NO-); W~ is 1, C 110 o alkyl, halogen, NO,, OR, -NR, NR 7 R 8 R 7 R 8 C 5 10 aryl, C heteroaryl or C 3 10 heterocyclyl, R is FlI, or C 1 alkyl; and R 7 and R8 are indlependenitly H, C 1 _I 0 alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, 1 0 ar'yl, C3- 1 0 heterocyclyl, or C5-10 heteroaryl or NR 7 R8 can be taken together to form a heterocyclic 5-10 membered safturated or unisaturated ring containing, in addition to the n1itrooeni atom. one to two additional heteroatomns selected fiom11 the grouIp consisting of N, 0 anld S. in the manUfacture of a medicamnent for treating or preventing retinal \'aSCUlarization.

34. Use of a com1pouind of any one of claims I to 4 or 6 in the manufacture of a medicament f*or treating or preventing retinal vascularization Use of a compound of formlula 1: R 3 R 5 N *R, or a pharmaceutiCallyN acceptable salt or hydrate thereof' wherein R, is I-1, CjI 0 alkyl, C 3 -6 cycloalkyl, Ci- 1 aryl. halo. 01-1, C 3 1 0 heterocyclyl, or *Ci-j licteroaryl, said alkyl. alkenyl. alkyinIL. aryl. heteroaryl and heterocyclyl being 2 optionalk Slv bstituted With From one to three members selected From Rz 9 R2 andu R 3 are- independenitly 1-1. C 1 6 alkyl. C 5 1 arv1l. C-6c cycloalkyl., O1-, NO-), -N 12. or halogeni: R 4 is I-I. CII) alkyl I, cycloalkyl. C 14, alkoxy alkeinyl. alkynyl, ('5-1o ai-v I1. C 3 1 0 heter0cyclyl Crc, alkoxyNR 7 R 01-I. -NI-I 1 or' C5_ 1 heteroaryl, said lkvl. al kenyl, alkvNv'l. ary'l, heteroaryl and heterocyclyl being optinally suibstituted With I'rom one to three members selected from Wi: IS is1-I. or Cl- 6 alkyl. OR. halo, NI-I or NO-,: W1 is I-I. CI. 111 alkyl, hialogen. NO 2 OR. -NR. NR 7 RX. R 7 RS. Cs. 111 aryl, heteroarl-V or C 3 11 1 heter-ocyclyl. RIS is I- CI-6 alkyl; anid I R AL I 102 57 9 .tloc aak 4 3 R 7 and P. 8 are independently Cjj() alkyl, C3-6 cycloalkyl. COR, COOR, COO-, 1 1 1 aryl, C 3 10 heterocyclyl, or C5-10 heteroaryl or NR 7 R 8 can be taken together to form a hieterocyclic 5-10 mnembered saturated or unsaturated ring containing, in addition to the nitrogen atomn, one to two additional heteroatomns selected fromn the group consisting of N, 0 and S. in the manufacture of a medicament for treating or preventing diabetic retinopathy.

36. Use of a compound of any one of claimrs I to 4 or 6 in the manufacture of a mnedicamient for treating diabetic retinopathy.

37. Use of a compound of formula I R 3 N N or a phiarmaceutically acceptable salt or hydrate thereof, wherein R, 1 is 1-1, Cj 11 alkyl, C3- 6 cycloalkyl. C 1 aryll. halo. 01-1. C3- 1 0 heterocyclyl, or 1 0 heteroaryl: said alkyl, alkenyl, alkynyl. aryl, hieteroaryl and hecterocyclyl being 13 optionally, substituted with fromn one to three miembers selected frim W', and R. 3 are independently I-I, C -6 alkvl. C5-10 aryVL C3-6 cycloalkyl, 01-I. NO 2 -NI-V2. or hialogen; 1 is I-1. C 11 I( alkyl, C3-6 cycloalkyl. C -6 alkoxy alkenyl. alkylnyl, ('X 10 arylV. C3-10 hleterocyclyl. C 1 -6 alkoxyNR 7 R 8 NO%. 01-1. or C 5111 heteroaryl, said -1 al kyl. al kenvil. alkynyl aryl. hieteroaryl and hieteroeveclyl being optionally Substituted with Irlomi one to three memnbers selected from RW: IS II or01 alkyl, OP., halo. NI-I or- NO,: P is 1-1. Cj. 1 11 alkyl. hialogen. OR. -NlP.. NP. 7 1 P 7 RS C5-10 aryl. 1o 0 eeravI- C3-1 heterocvcCl\ 1 P.i1-1. or- C 1-6 alkvlI- and P.\ 7 and P.s are Independently v CI-j)) alkyl. cvcloalkvl. COP.. COOP.. COO-. C'> 1 MW L. C3- 10 heCteroCVclyl. or Ci_ 5 w heteroar\ I or NP. 7 P 8 can be taken together to formi a hectcrocvclic 5-I10 memnbered satura ted Or unsaturatedl iino containinp. in addition to the 1itlrooen atoni, one to two adiditional heteroatonis selected fr-om thle grup-1, consistino of. 'N. ci 0and S. uS In thle manufacture of a iinedicanment Ior treLating or pre-ventin ag-etd )acu4a deceneration jR Al IBAAj1125 79.doc:aak 44

38. Use of a compound of any one of claims I to 4 or 6 or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in the manufacture of a medicament for treating or preventing age-related macular degeneration.

39. Use of a compound of formula 1: or a pharmaceutically acceptable salt or hydrate thereof, wherein R, is IFl, CI-1 0 alkyl, C 3 6 cycloalkyl, C 5 aryl, halo, OH, C 3 -10, heterocyclyl, or heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being I optionally suibstituted with fromi one to three members selected from RW; R) and R 3 are independently 1-I, CI- alkyl, C 5 aryl. C-6 cycloalkyl, OH, NO 2 -N or halogen; R, is I-1. CI_. 10 alkyl. C3-6 cycloalkyl, C, 4 alkoxy alkenyl. C, 0 alkynyl, C. .,,aryl C3-10 heterocyclyl, C, 4 alkoxyNR 7 Rx, NO), 01-1, -NH-I or heteroaryl, said I alkyl. alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally Substituted With f'rom one to three members selected from RZ; R i I Or C I-6 alkyl, OR, halo. NF1-1 or NO,: *R i C.,,ak0,hlgn OR. -NR. NR 7 R 5 R 7 Rs,, Ci-, 0 aryl, 0C ,M heteroary 01orC3-1 0 heterocyclyl. 2 R IS I-I. Or C -6 alkyl.- and 0 R 7 and R8 are independently Cl.j,, alk L. C 3 cycloalkyI. COR. COOR. COO-. ,o aryl. heterocyclyl, or Ci- 1 heteroaryl or NR 7 R 8 can be taken topether to f'orm a hleterocyclic 5-10 membered saturated Or u~nsatuIRatedl rine containing, in addition to the 0 1nitrogen atom. one to two additional hieteroatoms selected from11 thle grIouIp con1sistling of N, 0. an S. *Inl theC m1anLhfLcture of' a medicament for1 treating or 1preventine Inflammatory Use of a compou~nd of any one of' claimis I to 4 or 6 or a pharmiaceutically accepitable Salt. prodrug,11 or hydrate thereof in the nmanlactUi-e of' a medicament for treating or p~reventing I nflammatory disease. 41 Use of a compound off lbrmuLla 1: IlI IAAA 112579 .doc i'ik R3 R 1 4 ora hamaeuicll acetalesat r ydat terot werN Cora phatroaryl;icsaid alkyltaley altrynyate ahrl, heeryindetoclybin optionally suibstituted with from one to three members selected fr~oml Wi: R? and R 3 are independently C,. 6 alkyl, C 0 aryl. C-6 cycloalkyl, 0H-, NO 2 -N H?1, or halogen; R 4 is 1-1, alkyl, C 3 6 cycloalkyl, C1- 6 alkoxy alkenyl, C2-10 alkynyl, In aryl, C 3 -10, heterocyclyl, C1- 6 alkoxyNR 7 RS, 01-1 -Nil 9 or C 5 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with frlom one to three members selected from R". R3 is 1-1, or C,- 6 alkyl, OR, halo, NI-b or NO?; R" is 1-1, alkyl, halogen. NO?, OR. -NR. NR 7 RZ,. R 7 Rs. C 5 aryl, 53 heeoaryl or C3-10 heterocyclyl. R is 1-I, or alkyl; and R7 aind R,4 are independently 1-I, alkyl, C3-6 cycloalkyl. COR, COOR, COO-. C 5 1 0 aryl. heterocyclyl, or- heteroaryl or NR 7 R can be taken tooether to form a heterocy'clic 5-10 membered saturated Or unsaturated inu containing. in addition to the 2o itrouen atom. one to two additional heteroatomns selected from the grouLp consistino of'N, 0 and S. In theC m1anuf.1acture1- of a medicament I'mr inhibiting~ tyrosine kinlase.

42. Use of a com1pound of any one of claims I to 4 or 6 in the manuf11acture of a medicament for inhibiting tyrosine ki nase.

43. A- com1pound of formula3 R, or a pharmIaceutically acceptable salt or hydrate thereol' optionally combined wVith a cailriCr_1 in1 th' form1 ofa phar-macUtical com1position. Wherevin I RAi~iii,\~\

1112579.dnc:aak 46 R, is Cl- 10 alkyl, C 3 6 cycloalkyl, C 5 1 aryl, halo, OH-, C3- 10 heterocyclyl, or Ci()o heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from W;' and R 3 are independently H, C 1 6 alkyl, Ciio( aryl, C 3 -6 cycloalkyl, OH, NO 2 or halogen; KZ is 1-1, C 11 alkyl, C 3 6 cycloalkyl, C 14 alkoxy alkenyl, alkynlyl, C3- 1 0 arylI. C 3 10 heterocyclyl, C 1 6 alkoxy-NR 7 R 8 01-1, -NI-I- 2 or C 510 heteroaryl, said alkyl. alkenyl, alkynyl, aryl, heteroaryl and hieterocyclyl being optionally Substituted with f'romn one to three members selected from W~; I RK is or C 14 alkyl, OR, halo, NI-) or NO?; RW is I-I, C 11 alkyl, halogen, NO 2 OR, -NR. NR 7 R8, R 7 Rg, C 5 -lo aryl, 1 heteroaryl or C3-10 heterocyclyl, R IS orC 1 6 alkyl; and R 7 and Rs are independently Hl, Cjl-() alkyl, C 3 -6 cycloalkyl, COR. COOR, COO-, is C 10 aryl, C 3 10 heterocyclyl, or C5- 10 heteroaryl or NR 7 Rx canl be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitroglen atomn, one to two additional heteroatomns selected Ilom the 01-o.up consisting of N, :Do0 andi S. *W11en used for treating or preventino cancer in a mammrralian patient. _1o* 44. A Compound of' any one of claimrs 1 to 4 or 6 or a composition of claim 7 WhenI uIsed l'or treating or preventing cancer In a1 mamm111al ian patient. A Compound of formul.a I: R 3 "N Or ZI pharmaI ceutically acceptable salt or hlydrate thlereo optional ly combined with a carrier in the lborm of a pharmaceutical composition wheirein R 1 I is I-I. C 1 II alkyl. C 3 -6 cycloal kNl. aryl. halo. 01-I. I hterocyclyl. or Ci_.1 heteroarvl: said al kyl. alkenyl. al kynvl. ar\'l. hecteroaryl and heterocyclyl being(- optionaLlly Substituted with from" one to three members selected fromn R": 3'Kand IZ 3 are independently I-I. C 1 al ky I. C5-1 Z arvL. C 3 -6 cvcloal kvl 01-1. NO-, -NILk or hialouien: I RA;L I I02579.doc:aak R4 is C 1 10 alkyl, C 3 6 cycloalkyl, C 14 alkoxy C 2 10 alkenyl, C 2 10 alkynyl, C' 5 1 0 aryl, C 3 1 0 heterocyclyl, C 1 6 alkoxyNR 7 R 8 NO 2 OH, -NH 2 or C 5 10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with From one to three members selected from Wi; R5 is IFI, or C 1 6 alkyl, OR, halo, NH 2 or NO 2 R" is 1-1, C 1 1 0 alkyl, halogen, NO 2 OR, -NR. NR 7 R R 7 Rs, C 5 1 aryl, Ci_. 1 hieteroaryl or C3-10o heterocyclyl, R is 1-1, or C 1 6 alkyl; and R 7 and R8 are independently 1-1, C 1 10 alkyl, C 3 -6 cycloalkyl. COR, COOR, COO-, I aryl, C 3 1 0 heterocyclyl, or Ci-.io heteroaryl or NR 7 R 8 can be taken together to form a hecterocyclic 5-10 m~embered saturated or Unsaturated ring containing, in addition to the niitrogen atomn, one to two additional heteroatorns selected from the griouip consisting of N, 0 anld S. wh~en Used For treating or preventing a disease in whiich neoanigiogenesis is implicated. 46. A compou~nd of any one of claims I to 4 or 6 or a composition of claim 7 whenCI Used for treating or preventing a disease in wich neoangiogenesis is Implicated. 47. A compound of formula 1: F 3 -4 orI ai phiarmaceutically acceptable salt or hiydrate thlereoF' optionlally combined \vith a ca1rIer Mn the Form oF a phar-MaceUtical compositioni \vhereinl R, Is I-1. C 1 alkyl. C 3 6 cycloalkyl. CS.. 1 ary, alo. 01-I. heterocyclyl, or C 5 i eteroaryl; said alkyl, alkenivl. alkyniyl, arvl. heteroaryl anid hecterocvclvl being0 option1alk SLv bstituted with Fromn one to three members Selected Frlom W': and R 3 are independently 1-I. C 1 alkyl. C 5 1 aryl. cycloalkyl. 01-1, NO), -N1-12. or halogen:; RK. is CI.. 0 al kyl. C 3 6 cyclbalkN/I. C 1 -6 al koxy 1 alkeInyl. alkynyl, C 5 1 arlI. C 3 10 hieterocyclyl, C 1 6 alkoxyNR 7 R 5 01-1.. -NI-I 2 or C 5 1 hieteroaryl, said alk enyL. alkynyl, aryl, heteroaryl anld hieteroc\clvl he inc optionally substi*tuted With Frlom oneL to three members selected from W~: 4Iis IS-I. Or C 1 6 alkvl. OR, halo. NI-I 2 or NO-,: 48 is Ci. 10 alkyl, halogen, NO 2 OR, -NR, NR 7 Rg, R 7 R 8 C 5 10 aryl, Ci- 111 heteroaryl or C 3 10 heterocyclyl, R is 1-1, or CI- 6 alkyl; and R7, and R 8 are independently FlI, Ci-io alkyl, C 3 -6 cycloalkyl, COR, COOR, COO-, C 10 aryl, C 3 -10) heterocyclyl. or C5-1( heteroaryl or NR 7 RX can be taken together to form a hecterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nlitrogen atomn, one to two additional heteroatorns selected F1,o1m thle grouIp consisting of N, Uand S, when1 Used for treating or preventing retinal vascularization. 48. A compound of any one of claims I to 4 or 6 or a composition of claimn 7 for treating~ or preventing retinal vascularization 49. A compound of formula 1: a a a a a a a.. a a a -A Or aI phar-MaCeutically acceptable salt or hydrate thiereof, optionally combined with a carrier in the f1orm of a phiarmaceutical comp11ositin whereli R, is I-1, C 1 1 alkyl. C 3 -6 cycloalkyl. C 5 10 hialo. 01-I, C- 1 0 heterocyclyl, or 1 heteroaryl; said alkyl. alkenyl, alkynyl. aryl, heteroarvl and hieterocv clyl being optionally1 substituted withl from one to three members selected From R': 2 R- and R 3 are independently 1-1. C I-6 alkyl. Ci- 10 arNiL C 3 -6 cvcloalk\l. 01-1. NO-), or halogen: R4 IS 1-1. C 1 -10 aIl kVl C 3 -6 c\'cl oail CI-6 al koxy 10 al kei-Id. alkynyl, C 1IN rL C- 10 heterocyclvl. CI- alkoxyNR 7 R 5 NO?. 01-1. -NI-b? or- C 5 1 hecteroaryl. said a 1k vI. alk enyl, alkynN 1. arN 1. heteroarylI and heterocy I benopIonl sbtttdwt f'rom one to three members selected f'rom W': I'\ 5 IS I-I. Or CI1.6 alkyl. OR. hialo. NH)-1 or NO?: Rd is 1-I. C 1 1 11 alkyl. hialogeni. OR. -NR. NR 7 R 5 R 7 RX. C 5 1 0 aryl, C 5 _10 hecteroaryl or 1 o heterocNIclyl. R IS I-I. Or C 14 alkyl: and R7 and RX are_ indCeendently I-I. C 11 alkyl. C--6 C cvcloalkVl COR. COOR. COO-, aVL.C3-10 heCterocyclvl. or C 5 1 11 heteroaryl 'or N R 7 1Z can be taken togethier to form a licterocycl ic 5-10 membered saturated orI ulnsatu~rated rinii, containin, in addition to thle nlitrogen atomn, one to two additional heteroatoms selected from the group consisting of N, o anid S, whenl used for treating or preventing diabetic retinopathy. A compound of any one of claim-s I to 4 or 6 or a composition of claim 7 When) used for treating diabetic retinopathy. 1. A com1pounid of formula I R 3 or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a I carrier Mn the fo 0rm of a pharmaceutical comrpositioni, whereinl R 1 I is 1-1, C 1 alkyl, C 3 6 cycloalkyl, C 5 aryl, halo, 01-1, C 3 heterocyclyl, or ('5_10 heteroaryl; said alkyl, alkenyl, alkyniyl, aryl, hieteroaryl anid heterocyclyl being optionally Substituted with from one to three memibers selected from W.: IZ? anid R 3 are independently 1-1, C 14 alkyl, C5-1() aryl. C 3 -6 cycloalkyl, 01-I, NO-), -N H?1. or halogen; IZ. is 1-1. C, 111 alkyl, C3-6( cycloalkyl, C 14 alkoxy C 2 1 1 alkenyl.I C 2 alkyniyl, MW;j, arL C- 1 0 heterocyclyl, C 1 -6 alkoxyNR 7 Rg, 01-1, -NI- 2 or heteroaryl, said alkvl. alk eniv. alkyniyl, aryl, heteroaryl and heterocyclyl beingo optionially Substituted with I'rom one to three members selected From W~: InR Is Or C 14 alkyl, OR, halo, NI-I, or NO 2 R' is I-I. alkyl, halogen., O1Z. -NRZ. NR 7 RZX. R 7 RZS. C5- 1 0,ar C heteroarl or01 C 3 -10, heterocyclyl. 'S is1 I-I.o C 14 zilkyl: and 1\) 7 andc R8 are independently I-1, C 1 1 1 alkyL. C3-0, cycloalkyl. COP.. COOP.. COO-. 5 11 hleter-ocyclyl, or Ci 1 heteroaryl or NR 7 P.S cani be takeni tocethier to form a hecterocvclic 5-10 membered saturated o1 risaturatedl rineo containin. 'in aditin to the Iaitr~o-en atom, onie to two additional hetero0atomIs selectedI from1 the grIoupJ conIsisting( of N, (and S. whenCI Used for treatingo or preveniting age-relatedt miaclar cenierationl. 52 A c01Iompound of any onie of'claims I to 4 or 6 or a phamaIceutCiclly acceptable SR Salit. pr1odrugII or hydrate thereof' or a compositioni of' claimi 7 whenCI Used f'or treatino or' pre\'cnlti ae-elated 1MacLar degenierationl. I RAI 1 I A A 102 5 79.doc :aak 53. A compound of formula 1: R 3 R, or a pharmaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the form of a pharmnaceutical comnposition, wherein R, is 1-1, Cj~ 1 alkyl, C 3 6 cycloalkyl, C5- 1 aryl, halo, 01-1, heterocyclyl, or C._ 1 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three mnembers selected from R"; and R 3 are independently I-l, C 1 6 alkyl, C 51 aryl, C 3 -6 cycloalkyl, 01H, NO 2 -NI-I 2 or halogen; R4 IS 1-1, Cj_ 1 alkyl. C 4 cycloalkyl. 1 alkoxy alkenyl. C 2 alkynlyl, 1 aryl, C 3 -1 0 heterocyclyl, C,- 6 alkoxyN\R 7 R 8 01-1., -NJI- 2 or Ci-,o) heteroaryl, said alkyl. alkenyl. alkynyl, aryl, heteroaryl and heterocyclyl being, optionally Substituted with 0:06 IFromi one to three members selected from R", R 5 IS I-1- Or- C 1 alkyl, OR, halo, NI-I 2 or NO); R:'i I-I alkyl, halogen, NO,, OR. -NR, NR 7 R 8 R 7 C 51 aryl, C heteroaryl or' C 3 -1 0 heterocyclyl, R.i I1-I. o0r C 1-6 alIkyl1; and R. 7 aind Kx are independently 1-1. CI0 alkyl, C 3 cycloalkyl. COW. COOR, COO-, 21 C 5 arl'N C 3 1 heterocyclyl, or C 5 0 heteroaryl or NR 7 Rs can be taken together to formi a .heterocvclic 5-10 membered saturated or' unsaturated rino. containing. in addition to the 1nitro(,en atom, one to twvo additional heteroatom~s selcteI.d I'rom1 the grIoupJ conIsisting' of N. ()and S. \hIcn uIsed Imr treating or preventing in llammiatory disease. 54. A compIIoundI of any one of clais I to 4 or 6 or a phar-maceutically acceptable salt. prodrug' or hydrate thereof. or a comlposito of cli 7wenuedIr treatin* o preventing i ntlanimatory disease. 5T. A- compound of frl.1a I: I I: UI I IAA' 102 79.doc: a R 3 R 5 N R R, 6 6666 0 6600 S 600 S 060@ 0006 @6 0O *0 9 6@ 00 6 0e 6 666 6 @6 4 .~6 6 6 @66066 6 6460 6 6 @646 6666 0 0 *SeS S 6660 S 00666* 6 or a pharmnaceutically acceptable salt or hydrate thereof, optionally combined with a carrier in the fo6rm of a pharmnaceutical composition, wherein R, is 1-1, Cj_ 1 alkyl, C 3 -6 cycloalkyl, C5- 1 aryl, halo, OH, C3-10 heterocyclyl, or (C 5 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being option01ally' substituted with from one to three members selected fromn and R 3 are independently IH, C 14 alkyl, C5- 1 aryl, C 3 -6 cycloalkyl, 01-, NO 2 -N 1-12 oi halogen; R 4 is I-1, Cj_ 1 1 alkyl, C 3 6 cycloalkyl, C 1 6 alkoxy alkenyl, alkynyl, C2 51 1 aryl, C 3 -1 0 heterocyclyl, C 1 6 alkoxyNR 7 Rg, OH, -NI1I 2 Oi C 5 -1 0 heteroaryl, said alkyl. alk enyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with f-rm one to three members selected from W; R 5 IS 1-1. Or C 14 alkyl, OR, hialo, NI-? or NO?; W' Is I-I. C 11 alkyl, halogen. NO?, OR, -NR, NR 7 Rs,, R-,R 8 C 5 1 aryl, Csheteroaryl or C 3 1 0) heterocyclyl, R I S I-1 o 0r C 1 -6 alIkyl1; and R7, and Rg are independently 1-1, C 1 alkyl, C 3 cycloalkyl. COR. COOR, COO-, (i- 1 1 arl.C 3 1 heterocyclyl, or Ci_. 10 heteroaryl or NR 7 Rs can be taken to(,ether to form a _1 lcterocyclic 5-10 memberedl saturated Or unsaturated ring containino. in addition to the ilitro~len atom,. one to twvo additional heteroatoms selected from11 the g-oupJ con1sisting of N, (and S. .VhCen uIsed for iniiigtyrosine kinase. 56. A* com1pound of' any one of claims I to 4 or 6 or a composition of claim 7 1. whenI uIsed for- inhibiting tyrosine kinase. Dated 12 March, 2001 Merck Co., Inc. Patent Attorneys for the Applicant/Nominatcd Person SPRUSON FERGUSON I RAL I I IA\A 11)2579.doc:aak