US 8,058,445 B2Grant

Substituted pyridinecarboxamides for the treatment of cancer

Issue Date:2011-11-15

•4 Claims

Abstract

Selected pyridine carboxamide compounds of Formula XI

are effective for treatment of diseases and other maladies or conditions involving, cancer and the like.

Metadata

Assignee

Amgen Inc.

Inventor

Andrew Tasker

Application Information

Application Number:US 11/234,713

Filing Date:2005-09-23

Priority Date:2001-01-12

Art Unit:1624

Classifications

IPC:

C07D213/00

Patent Drawings

This patent does not have any drawings.

Description

[0001] This application is a divisional of U.S. patent application Ser. No. 10/046,681 filed Jan. 10, 2002 now U.S. Pat. No. 6,995,162 which claims benefit of U.S. Provisional Application Nos. 60/261,339, filed Jan. 12, 2001, and 60/323,764 filed Sep. 19, 2001 which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer and angiogenesis-related disorders.

BACKGROUND OF THE INVENTION

[0003] Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes ab1, Atk, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an important therapeutic target.

[0004] Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).

[0005] At the center of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, and in a wide number of pathological anomalies and diseases, lies the angiogenic factor known as Vascular Endothelial Growth Factor”(VEGF; originally termed ‘Vascular Permeability Factor”, VPF), along with its cellular receptors (see G. Breier et al., Trends in Cell Biology, 6, 454-6 (1996)).

[0006] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to “Platelet-Derived Growth Factor” (PDGF); it is produced by normal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotactic for endothelial cells and monocytes; and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as “Placenta Growth Factor”(PlGF) and VEGF-C.

[0007] VEGF receptors (VEGFR) are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

[0008] A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in studies in which VEGF expression or VEGF activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis.

[0009] Angiogenesis is regarded as an absolute prerequisite for tumors which grow beyond a diameter of about 1-2 mm; up to this limit, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size.

[0010] Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) Inhibition of the growth of vessels, especially capillaries, into avascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11, 77-114 (2001).

[0011] VEGF's are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production.

[0012] Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF-mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. As such, regulators of angiogenesis have become an important therapeutic target.

[0013] Schipper U.S. Pat. No. 3,226,394, issued Dec. 28, 1965, describes anthranilamides as CNS depressants. Japanese patent JP2000256358 describes pyrazole derivatives that block the calcium release-activated calcium channel. EP application 9475000, published 6 Oct. 1999, describes compounds as PGE₂antagonists. PCT publication WO96/41795, published 27 Dec. 1996, describes benzamides as vasopressin antagonists. WO01/29009 describes aminopyridines as KDR inhibitors. WO01/30745 describes anthranilic acids as CGMP phosphodiesterase inhibitors. WO00/02851, published 20 Jan. 2000 describes arylsulfonylamnoaryl amides as guanylate cyclase activators. WO98/45268 describes nicotinamide derivatives as PDE4 inhibitors. WO98/24771 describes benzamides as vasopressin antagonists.

[0014] U.S. Pat. No. 5,532,358, issued Jul. 2, 1996, describes the preparation of 2-(cyclopropylamino)-N-(2-methoxy-4-methyl-3-pyridinyl)-3-pyridinecarboxamide as an intermediate for HIV inhibitors. Triazine-substituted amines are described for their aggregating ability (J. Amer. Chem. Soc., 115, 905-16 (1993). Substituted imidazolines were tested for their antidepressant activity in Ind. J. Het. Chem., 2, 129-32 (1992). N-(4-Pyridyl)anthranilic amides were described in Chem Abstr. 97:109837 (1981). PCT publication WO99/32477, published 1 Jul. 1999, describes anthranilamides as anti-coagulants. U.S. Pat. No. 6,140,351 describes anthranilamides as anti-coagulants. PCT publication WO99/62885, published 9 Dec. 1999, describes 1-(4-aminophenyl)pyrazoles as antiinflammatories. PCT publication WO00/39111, published 6 Jul. 2000, describes amides as factor Xa inhibitors. PCT publication WO00/39117, published 6 Jul. 2000, describes heteroaromatic amides as factor Xa inhibitors. PCT publication WO0/27819, published 18 May 2000, describes anthranilic acid amides as VEGF inhibitors. PCT publication WO00/27820 published 18 May 2000, describes N-aryl anthranilic acid amides as VEGF inhibitors. 7-Chloroquinolinylamines are described in FR2168227 as antiinflammatories. WO01/55114, published 2 Aug. 2001, describes nicotinamides for the treatment of cancer. WO01/55115, published 2 Aug. 2001, describes nicotinamides as inducers of apoptosis. WO01/85715, published 15 Nov. 2001, describes substituted pyridines and pyrimidines as anti-angiogenesis agents. PCT publication WO01/85691 published 15 Nov. 2001, describes anthranilic amides as VEGF inhibitors. PCT publication WO01/85671 published 15 Nov. 2001, describes anthranyl amides as VEGF inhibitors. PCT publication WO01/81311 published 1 Nov. 2001, describes anthranilic amides as VEGF inhibitors. However, compounds of the current invention have not been described as inhibitors of angiogenesis such as for the treatment of cancer.

DESCRIPTION OF THE INVENTION

[0015] A class of compounds useful in treating cancer and angiogenesis is defined by Formula I

[0016]

wherein each of A¹and A²is independently C, CH or N;

[0017] wherein ring A is selected from
- [0018] a) 5- or 6-membered partially saturated heterocyclyl,
  - [0019] preferably dihydropyran, dihydrothienyl, dihydrofuryl, oxo-dihydrofuryl, pyrrolinyl, dihydrothiazolyl, dihydro-oxazolyl, dihydro-isothiazolyl, dihydro-isoxazolyl, imidazolinyl and pyrazolinyl,
- [0020] b) 5- or 6-membered heteroaryl,
  - [0021] preferably
    - [0022] I) 5-membered heteroaryl selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl,
      - [0023] even more preferably 5-membered heteroaryl selected from

[0024]

- - - [0025] II) preferably 6-membered heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl,
      - [0026] even more preferably 6-membered heteroaryl selected from

[0027]

- - - - [0028] more specifically

[0029]

- [0030] c) 9-, 10- or 11-membered fused partially saturated heterocyclyl
  - [0031] preferably tetrahydroquinolinyl,
- [0032] d) 9- or 10-membered fused heteroaryl,
  - [0033] preferably
    - [0034] i) fused 9-membered fused heteroaryl selected from benzothienyl, benzothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuryl, indazolyl and isoindolyl, and
    - [0035] ii) fused 10-membered heteroaryl selected from quinolyl, isoquinolyl, naphthpyridinyl, quinoxalinyl and quinazolinyl,
- [0036] e) naphthyl, and
- [0037] f) 4-, 5- or 6-membered cycloalkenyl,
  - [0038] preferably 5-membered cycloalkenyl,
    - [0039] more preferably cyclopentadienyl or cyclopentenyl;
[0040] wherein X is selected from

[0041]

- [0042] preferably X is selected from

[0043]

- - [0044] more preferably X is

[0045]

[0046] wherein Z is oxygen or sulfur;
- [0047] wherein Y is selected from

[0048]

- [0049] preferably Y is selected from

[0050]

- - [0051] more preferably Y is selected from

[0052]

- - - [0053] even more preferably Y is —NH—CH₂—;
[0054] wherein R^aand R^bare independently selected from H, halo, cyano and C_1-4-alkyl substituted with R², or wherein R^aand R^btogether form C₃-C₄cycloalkyl,
- [0055] preferably H, halo, cyano and C_1-2-alkyl substituted with R², or wherein R^aand R^btogether form C₃-C₄cycloalkyl, more preferably H, halo and C_1-2-alkyl,
  - [0056] even more preferably H;
[0057] wherein R^zis selected from C₁-C₄alkylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an—NH—,
- [0058] preferably C₁-C₂alkylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—more preferably C₁-C₂alkylenyl;
[0059] wherein R^dis cycloalkyl,
- [0060] preferably C₃-C₆cycloalkyl;
[0061] wherein R is selected from
- [0062] a) substituted or unsubstituted 5-6 membered heterocyclyl,
  - [0063] preferably substituted or unsubstituted 5-6 membered heteroaryl comprising one or more nitrogen atoms,
    - [0064] more preferably 4-pyrazolyl, triazolyl, 4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 4-pyridazinyl, or 6-pyridazinyl,
      - [0065] even more preferably 4-pyridyl, 4-pyrimidinyl and 4-pyridazinyl,
      - [0066] even more preferably 4-pyridyl, and
- [0067] b) substituted or unsubstituted fused 9-, 10- or 11-membered heterocyclyl,
  - [0068] preferably substituted or unsubstituted 9-10 membered fused heteroaryl comprising one or more nitrogen atoms,
    - [0069] more preferably indazolyl, quinolinyl, isoquinolinyl, or quinazolinyl,
      - [0070] even more preferably indazolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 4-isoquinolyl, 5-isoquinolyl, and 6-isoquinolyl,
  - [0071] wherein substituted R is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R², cyano, nitro, lower alkenyl and lower alkynyl;
    - [0072] preferably halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³—NR³C(O)R³, —NR³C(O)NR³R³, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, nitro and C_1-2-haloalkyl;
[0073] wherein R¹is selected from
- [0074] a) substituted or unsubstituted 6-10 membered aryl,
  - [0075] preferably phenyl, naphthyl, indenyl, or
    - [0076] tetrahydronaphthyl,
    - [0077] more preferably phenyl,
- [0078] b) substituted or unsubstituted 5-6 membered heterocyclyl,
  - [0079] preferably 5-6 membered heteroaryl,
    - [0080] more preferably thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, or pyrrolyl,
- [0081] c) substituted or unsubstituted 9-10 membered fused heterocyclyl,
  - [0082] preferably 9-10 membered fused heteroaryl,
    - [0083] more preferably indazolyl, indolyl, 2,1,3-benzothiadiazolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, benzodioxanyl, or quinazolinyl,
- [0084] d) cycloalkyl, and
- [0085] e) cycloalkenyl
  - [0086] wherein substituted R¹is substituted with one or more substituents independently selected from halo, —OR³, —SR³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₄alkylenylR¹⁴), —SO₂R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, lower alkyl substituted with R², cyano, nitro, lower alkenyl and lower alkynyl,
    - [0087] preferably R¹is unsubstituted or substituted with one or more substituents independently selected from halo, —OR³, —SR³, —SO₂R³, —CO₂R³, —CONR³R³, —COR³, —NR³R³, —NH(C₁-C₂alkylenylR³), —(C₁-C₂alkylenyl)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, optionally substituted cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, optionally substituted phenyl-C_1-2-alkylenyl, optionally substituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, nitro and C_1-2-haloalkyl,
      - [0088] more preferably R¹is unsubstituted or substituted with one or more substituents selected from chloro, fluoro, bromo, methoxy, phenyloxy, benzyl, methylthio, methyl, ethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, hydroxymethyl, cyano, carboxy, aminocarbonyl, methylcarbonyl, amino, methylamino, cyclopropyl, cyclohexyl, piperidinyl, morpholinyl, N-methylpiperazinyl, N-ethylpiperazinyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, methylaminothiocarbonyl, N-methylamino-methylenyl, optionally substituted phenyl, N,N-diethylamino, or N,N-dimethylamino;
[0089] wherein R²is one or more substituents independently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —COR³, —CONR³R³, —NR³R³, —SO₂NR³R³—NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted phenylalkylenyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted heteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano, lower hydroxyalkyl, lower carboxyalkyl, nitro, lower alkenyl, lower alkynyl, lower aminoalkyl, lower alkylaminoalkyl and lower haloalkyl,
- [0090] preferably R²is one or more substituents independently selected from H, halo, —OR³, oxo, —SR³, —CO₂R³, —CONR³R³—COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substituted 5-6 membered heterocyclyl, optionally substituted phenyl, C_1-2-alkyl, cyano, C_1-2-hydroxyalkyl, C_1-3-carboxyalkyl, nitro, C_2-3-alkenyl, C_2-3-alkynyl and C_1-2-haloalkyl;
[0091] wherein R³is selected from H, lower alkyl, phenyl, 5-6 membered heterocyclyl, C₃-C₆cycloalkyl, and lower haloalkyl,
- [0092] preferably H, C_1-2-alkyl, phenyl, C₃-C₆cycloalkyl, and C_1-2-haloalkyl,
  - [0093] more preferably H, methyl, phenyl, cyclopropyl, cyclohexyl, and trifluoromethyl;
[0094] wherein R⁴is independently selected from C_2-4-alkylenyl, C_2-4-alkenylenyl and C_2-4-alkynylenyl, where one of the CH₂groups may be substituted with an oxygen atom or an —NH—,
- [0095] preferably C_2-3-alkylenyl where one of the CH₂groups may be substituted with an oxygen atom or an —NH—,
  - [0096] more preferably C₂-C₃alkylenyl;
[0097] wherein R⁵is selected from H, lower alkyl, phenyl and lower aralkyl,
- [0098] preferably H, methyl or ethyl;
[0099] wherein R⁶is selected from H or C_1-6-alkyl,
- [0100] preferably H or C_1-2alkyl; and
[0101] wherein R^cis selected from H, methyl and optionally
- [0102] substituted phenyl;
[0103] wherein R¹⁴is selected from H, phenyl, 5-6 membered
- [0104] heterocyclyl and C₃-C₆cycloalkyl;
[0105] wherein p is 0 to 2, preferably p is 2;
[0106] and pharmaceutically acceptable salts thereof;
[0107] provided A is not naphthyl when X is —C(O)NH— and when R¹is phenyl when Y is —NHCH₂— and when R is 4-pyridyl; further provided A is not pyridyl when X is —C(O)NH— and when R¹is 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is —N(CH₃)— and when R is 4-methylpiperidinyl; further provided A is not pyridyl when X is —C(O)NH— and when Y is —NHCH₂— and when R is 4-pyridylpiperidin-4-yl, 1-tertbutylpiperidin-4-yl, 1-isopropylpiperidin-4-yl or 1-cycloalkylpiperidin-4-yl; further provided A is not pyridyl when X is —C(O)NH— and when R¹is 4-[3-(3-pyridyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl when Y is —NHCH₂— and when R is 4-pyridyl; and further provided R is not unsubstituted 2-thienyl, 2-pyridyl or 3-pyridyl.

[0108] The invention also relates to compounds of Formula II

[0109]

wherein R^aand R^bare independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,

- [0110] preferably H;
[0111] wherein n is 0-2;
- [0112] preferably 1-2;
[0113] wherein R is selected from
- [0114] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
- [0115] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
  - [0116] preferably 4-pyridyl, pyrimidinyl, triazolyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
- [0117] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
  - [0118] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
[0119] wherein R¹is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
- [0120] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
  - [0121] wherein R¹is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
    - [0122] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
[0123] wherein R²is one or more substituents independently selected from
- [0124] H,
- [0125] halo,
- [0126] C_1-6-alkyl,
- [0127] C_1-6-haloalkyl,
- [0128] C_1-6-alkoxy,
- [0129] C_1-6-haloalkoxy,
- [0130] C_1-6-carboxyalkyl,
- [0131] unsubstituted or substituted aryl and
- [0132] unsubstituted or substituted 5-6 membered heteroaryl;
[0133] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected
- [0134] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
[0135] wherein R⁶is H or C_1-2-alkyl;
[0136] and pharmaceutically acceptable isomers and salts thereof.

[0137] The invention also relates to compounds of Formula III

[0138]

wherein R^aand R^bare independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,

- [0139] preferably H;
[0140] wherein n is 0-2;
- [0141] preferably 1-2;
[0142] wherein R is selected from
- [0143] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
- [0144] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
  - [0145] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
- [0146] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy, preferably substituted with one or more
  - [0147] substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
[0148] wherein R¹is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
- [0149] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
  - [0150] wherein R¹is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-C_1-2-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
    - [0151] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
[0152] wherein R²is one or more substituents independently selected from
- [0153] H,
- [0154] halo,
- [0155] C_1-6-alkyl,
- [0156] C_1-6-haloalkyl,
- [0157] C_1-6-alkoxy,
- [0158] C_1-6-haloalkoxy,
- [0159] C_1-6-carboxyalkyl,
- [0160] unsubstituted or substituted aryl and
- [0161] unsubstituted or substituted 5-6 membered heteroaryl;
- [0162] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
[0163] wherein R⁶is H or C_1-2-alkyl;
[0164] and pharmaceutically acceptable isomers and salts thereof.

[0165] The invention also relates to compounds of Formula IV

[0166]

wherein A³is selected from CR²and N;

[0167] wherein A⁴is selected from CR²and N; provided one of A³and A⁴is not CR²;
[0168] wherein R^aand R^bare independently selected from H, halo, C_1-4-alkyl and —N(R⁶)₂,
- [0169] preferably H;
[0170] wherein n is 0-2;
- [0171] preferably 1-2;
[0172] wherein R is selected from
- [0173] a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
- [0174] b) unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
  - [0175] preferably 4-pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl or quinozalinyl,
- [0176] where R is substituted with one or more substituents selected from halo, amino, hydroxy, C_1-6-alkyl, C_1-6-haloalkyl and C_1-6-alkoxy,
  - [0177] preferably substituted with one or more substituents selected from chloro, fluoro, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy and ethoxy;
[0178] wherein R¹is selected from unsubstituted or substituted aryl, 5-6-membered heteroaryl and 9-10 membered fused heteroaryl,
- [0179] preferably unsubstituted or substituted phenyl, tetrahydronaphthyl, naphthyl, isoquinolyl, quinolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, naphthyridinyl, quinozalinyl, tetrahydroquinolinyl, indazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, or benzthiazolyl,
  - [0180] wherein R¹is substituted with one or more substituents selected from halo, C_1-6-alkyl, optionally substituted C_3-6-cycloalkyl, optionally substituted phenyl, C_1-6-haloalkoxy, optionally substituted phenyloxy, benzyl, optionally substituted 5-6 membered heterocyclyl-C₁-C₂-alkylenyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, C_1-6-haloalkyl, and C_1-6-alkoxy,
    - [0181] preferably chloro, fluoro, amino, hydroxy, cyclohexyl, phenylmethyl, morpholinylmethyl, methylpiperdinylmethyl, methylpiperazinylmethyl, ethyl, propyl, trifluoromethyl, phenyloxy, methoxy and ethoxy;
[0182] wherein R²is one or more substituents independently selected from
- [0183] H,
- [0184] halo,
- [0185] C_1-6-alkyl,
- [0186] C_1-6-haloalkyl,
- [0187] C_1-6-alkoxy,
- [0188] C_1-6-haloalkoxy,
- [0189] C_1-6-carboxyalkyl,
- [0190] unsubstituted or substituted aryl and
- [0191] unsubstituted or substituted 5-6 membered heteroaryl;
- [0192] preferably one or more substituents independently selected from H, chloro, fluoro, bromo, amino, hydroxy, methyl, ethyl, propyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, carboxymethyl, unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl selected
- [0193] from thienyl, furanyl, pyridyl, imidazolyl, and pyrazolyl; and
[0194] wherein R⁶is H or C_1-2-alkyl;
[0195] and pharmaceutically acceptable isomers and salts thereof.

[0196] The invention also relates to compounds of Formula V

[0197]