This invention relates to novel heterocycles which are useful as antagonists of the xcex1vxcex23 integrin, the xcex12bxcex23 integrin, and related cell surface adhesive protein receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.

This invention relates to novel heterocycles which are useful as antagonists of the xcex1vxcex23 integrin, the xcex12bxcex23 integrin, and related cell surface adhesive protein receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934; D""Amore and Thompson, Ann. Rev. Physiol. 1987, 49:453-464). However, angiogenesis also occurs pathologically, for example, in ocular neovascularization (leading to diabetic retinopathy, neovascular glaucoma, retinal vein occlusion and blindness), in rheumatoid arthritis and in solid tumors (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934; Blood and Zetter, Biochim. Biophys. Acta., 1990, 1032:118-128).
Tumor dissemination, or metastasis, involves several distinct and complementary components, including the penetration and transversion of tumor cells through basement membranes and the establishment of self-sustaining tumor foci in diverse organ systems. To this end, the development and proliferation of new blood vessels, or angiogenesis, is critical to tumor survival. Without neovascularization, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934).
Inhibition of angiogenesis in animal models of cancer has been shown to result in tumor growth suppression and prevention of metastatic growth (Herblin et al., Exp. Opin. Ther. Patents, 1994, 1-14). Many angiogenic inhibitors have been directed toward blocking initial cytokine-dependent induction of new vessel growth, e.g. antibodies to endothelial cell growth factors. However, these approaches are problematic because tumor and inflammatory cells can secrete multiple activators of angiogenesis (Brooks et al., Cell, 1994, 79:1157-1164). Therefore, a more general approach that would allow inhibition of angiogenesis due to a variety of stimuli would be of benefit.
The integrin xcex1vxcex23 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264:569-571; Enenstein and Kramer, J. Invest. Dermatol., 1994, 103:381-386). Integrin xcex1vxcex23 is the most promiscuous member of the integrin family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell, 1992, 69:11-25). These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues.
While integrin xcex1vxcex23 promotes adhesive events important for angiogenesis, this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley et al., J. Cell Biol., 1993, 121:163-170, 1993). For example, the interaction between the xcex1vxcex23 integrin and extracellular matrix components promotes a calcium signal required for cell motility.
During endothelium injury, the basement membrane zones of blood vessels express several adhesive proteins, including but not limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is xcex1vxcex23, the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
Recently, an antibody to the xcex1vxcex23 integrin has been developed that inhibits the interaction of this integrin with agonists such as vitronectin (Brooks et al., Science, 1994, 264:569-571). Application of this antibody has been shown to disrupt ongoing angiogenesis on the chick chorioallantoic membrane (CAM), leading to rapid regression of histologically distinct human tumor transplanted onto the CAM (Brooks et al., Cell, 1994, 79:1157-1164). In this model, antagonists of the xcex1vxcex23 integrin induced apoptosis of the proliferating angiogenic vascular cells, leaving pre-existing quiescent blood vessels unaffected. Thus, xcex1vxcex23 integrin antagonists have been shown to inhibit angiogenesis and are recognized as being useful as therapeutic agents for the treatment of human diseases such as cancer, restenosis, thromoembolic disorders, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934).
Increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell-cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing xcex1- and xcex2-subunits. Integrin subfamilies contain a common xcex2-subunit combined with different xcex1-subunits to form adhesion receptors with unique specificity. The genes for eight distinct xcex2-subunits have been cloned and sequenced to date.
The xcex1vxcex23 heterodimer is a member of the xcex23 integrin subfamily and has been described on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the xcex1vxcex23 receptor in this process and suggest that a selective xcex1vxcex23 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A2 synthetase inhibitors or receptor antagonists, which act against thromboxane A2; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. GPIIb/IIIa is a member of the integrin family, and is also referred to as the fibrinogen receptor or the xcex12bxcex23 integrin. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65:359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the RGD recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
Degrado, et al. in U.S. Pat. No. 5,563,158, disclose aromatic compounds containing basic and acidic termini of a general formula shown below:
useful as fibrinogen receptor antagonists
PCT Patent Application Publication Number WO95/14683, published Jun. 1, 1995 discloses isoxazoline and isoxazole fibrinogen receptor antagonists of general formula shown below:
Copending, commonly assigned U.S. patent application Ser. No. 08/455,768 filed May 31, 1995 discloses integrin inhibitors of the general formula shown below:
PCT Patent Application Publication Number WO95/32710, published Dec. 7, 1995 discloses compounds for inhibition of osteoclast-mediated bone resorption of general formula: X-Y-Z-Aryl-A-B ; wherein Aryl is a 6-membered aromatic ring system. Similarly, PCT Patent Application Publication Number WO94/08577, published Apr. 28, 1994, and PCT Patent Application Publication Number WO94/12181, published Jun. 9, 1994 disclose compounds as fibrinogen receptor antagonists of general formula: X-Y-Z-Aryl-A-B wherein Aryl is a 5 or 6-membered aromatic ring system such as phenyl, pyridyl, isoxozolyl, thiophenyl, and imidazolyl.
PCT Patent Application Publication Number WO96/00730, published Jan. 11, 1996 discloses relevant compounds as vitronectin receptor antagonists of general formulae shown below:
wherein W is a bridging group and A is a fibrinogen receptor antagonist template.
None of the above references discloses or suggests the pyrimidine/pyrimidone and triazine/triazinone compounds of the present invention which are described in detail below.
The present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of the present invention are useful for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
One aspect of this invention provides novel compounds of Formula (IA) (described below) which are useful as antagonists of the xcex1vxcex23 integrin, which is also referred to as the vitronectin receptor. The compounds of the present invention inhibit the binding of vitronectin or other RGD-containing ligands to xcex1vxcex23 and inhibit cell adhesion. The present invention also includes pharmaceutical compositions containing such compounds of Formula (IA), and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of disorders mediated by angiogenesis.
Another aspect of the present invention comprises agents that inhibit the binding of vitronectin to the xcex1vxcex23 receptor for the treatment (including prevention) of thrombosis which do not significantly alter hemostatic balance and do not significantly inhibit platelet aggregation and do not significantly inhibit coagulation. Also the compounds of the current invention can be used for the treatment or prevention of restenosis.
The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula (IA), for the therapeutic inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
Another aspect of the present invention comprises pharmaceutical compositions containing compounds of Formula (IA), and methods of using such compounds for the treatment (including prevention) of cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula (IA) alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.
The present invention provides novel nonpeptide compounds of Formula (IA) (described below) which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of the present invention are useful for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis, in a mammal.
One aspect of this invention provides novel compounds of Formula (IA) which are useful as antagonists of the xcex1vxcex23 integrin or GPIIb/IIIa. The compounds of the present invention inhibit the binding of vitronectin and other RGD-containing ligands to the xcex1vxcex23 integrin or GPIIb/IIIa and inhibit cell adhesion. The present invention also includes pharmaceutical compositions containing such compounds of Formula (IA) and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders, and/or for the inhibition or prevention of thrombosis, and/or for the treatment of thromboembolic disorders, and/or for the treatment of inflammation, bone degradation, cancer metastasis, diabetic retinopathy, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
As use herein the term xe2x80x9cintegrin antagonist templatexe2x80x9d means the core structure of an integrin receptor antagonist, said core including an acidic group. An integrin receptor antagonist is an agent which binds to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The present invention provides for an integrin receptor antagonist are preferably RGD peptidomimetic compounds comprising a guanidine mimic linked to an integrin antagonist template. Such integrin receptor antagonists preferably bind to the integrin receptors of the xcex1vxcex23 integrin, the xcex12xcex23 integrin, the integrin receptor GPIIb-IIIa, and related cell surface adhesive protein receptors.
[1] The present invention comprises compounds of Formula (I):
G-Txe2x80x83xe2x80x83(I)
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
T is an integrin antagonist template; and
G is a guanidine mimic selected from:
D1 is selected from:
H, NR2R4, OR3, SR3, F, Cl, Br, CF3, and C1-C4 alkyl;
R2 at each occurrence is independently selected from:
H, OR3, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, C3-C7 cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, C1-C6 alkylsulfonyl, aryl(C0-C6 alkyl)sulfonyl, heteroaryl(C0-C6 alkyl)sulfonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, C1, Br, CF3, and NO2;
R3 at each occurrence is independently selected from:
H, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl (C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R4 is selected from:
H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R2 and R4 when both substituents on the same nitrogen atom as in (xe2x80x94NR2R4) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl (C0-C5 alkyl)carbonyl, Cl-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl;
R5 is selected from:
H, NR2R4, OR3, NO2, NO, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2; alternatively, xe2x80x94NHR2 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and aryl, wherein said aryl group is substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R6 is selected from:
H, NR2R4, OR3, C1-C6 alkyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), CF3, F, Cl, and Br, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R5 and R6, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms or a 5-7 membered carbocyclic ring, said carbocyclic or heterocyclic ring being aromatic or nonaromatic, said carbocyclic or heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2 and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R7 is selected from:
H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R7, when substituents on adjacent atoms, are taken together with the atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
U1 is selected from:
xe2x80x94(CH2)n-,
xe2x80x94Q1-(CH2)m-,
xe2x80x94(CH2)m-Q2xe2x80x94,
xe2x80x94(CH2)t-Q2-CH2xe2x80x94,
xe2x80x94CH2-Q2-(CH2)t-,
xe2x80x94(CH2)t-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)t-S(xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)t-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-Q2-,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U2 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94Q1-(CH2)r-,
xe2x80x94(CH2)r-Q2-,
xe2x80x94(CH2)i-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)i-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-S(xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-Q2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2-Q2-(CH2)i-, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)i-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)2-Q2-,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)i-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U3 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)q-Q2-,
xe2x80x94(CH2)q-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94(R3)xe2x80x94,
xe2x80x94(CH2)q-S(O)2xe2x80x94N(R3),
xe2x80x94(CH2)q-N(R3)-S(O)2xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)q-O-CH2xe2x80x94,
xe2x80x94(CH2)h-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)-(CH2)p;
U4 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)2-Q2,
xe2x80x94(CH2) 2xe2x80x94Oxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)r-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)r;
Q1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or N(R4);
Q2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, or N(R3);
h is 0-4;
i is 0-2;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3;
t is 1-3; and
p is 0-2.
provided that when R6 is hydrogen then D1 is not hydrogen.
[2] The present invention preferably comprises compounds of Formula (IA), (IB), (IC), (ID), (IE), (IG) or (IH):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
A1 is selected from xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x80x94 or xe2x80x94Oxe2x80x94;
A is selected from xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
Cy is a spiro-fused 4-7 membered ring, including the spiro atom, containing 0-2 heteroatoms selected from O, S, or N, said ring system optionally being substituted on carbon with keto, or being substituted on carbon or nitrogen independently with 0-2 R8;
D1 is selected from:
NR2R4, OR3, SR3, F, Cl, Br, CF3, and C1-C4 alkyl;
R2 at each occurrence is independently selected from:
H, OR3, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, C3-C7 cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, C1-C6 alkylsulfonyl, aryl(C0-C6 alkyl)sulfonyl, heteroaryl(C0-C6 alkyl)sulfonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R3 at each occurrence is independently selected from:
H, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R4 is selected from:
H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl (C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R2 and R4 when both substituents on the same nitrogen atom as in (xe2x80x94NR2R4) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl;
R5 is selected from:
H, NR2R4, OR3, NO2, NO, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and aryl, wherein said aryl group is substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R6 is selected from:
H, NR2R4, OR3, C1-C6 alkyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), CF3, F, Cl, and Br, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R5 and R6, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms or a 5-7 membered carbocyclic ring, said carbocyclic or heterocyclic ring being aromatic or nonaromatic, said carbocyclic or heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2 and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R7 is selected from:
H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R7, when substituents on adjacent atoms, are taken together with the atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
U1 is selected from:
xe2x80x94(CH2)n-,
xe2x80x94Q1-(CH2)m-,
xe2x80x94(CH2)m-Q2xe2x80x94,
xe2x80x94(CH2)t-Q2-CH2xe2x80x94,
xe2x80x94CH2-Q2-(CH2)t-,
xe2x80x94(CH2)t-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)t-S(xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)t-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-Q2-,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U2 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94Q1-(CH2)r-,
xe2x80x94(CH2)r-Q2-,
xe2x80x94(CH2)i-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)i-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-S(xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-Q2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2-Q2-(CH2)i-, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)i-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)2-Q2-,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)i-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U3 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)q-Q2-,
xe2x80x94(CH2)q-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94(R3)xe2x80x94,
xe2x80x94(CH2)q-S(O)2xe2x80x94N(R3),
xe2x80x94(CH2)q-N(R3)-S(O)2xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)q-O-CH2xe2x80x94,
xe2x80x94(CH2)h-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)-(CH2)p;
U4 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)2-Q2,
xe2x80x94(CH2) 2xe2x80x94Oxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)r-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)r;
Q1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or N(R4);
Q2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, or N(R3);
R8 and R9 are independently selected from:
H, C1-C10 alkyl, NO2, CF3, F, Cl, Br, C1-C10 alkylcarbonyl, xe2x80x94NR2R4, OC(xe2x95x90O)R10, OC(xe2x95x90O)OR10, OR10, OC(xe2x95x90O)NR10R11, OCH2CO2R10, CO2CH2CO2R10, CO2R10, C(xe2x95x90O)R11, NR10C(xe2x95x90O)R11, NR7C(xe2x95x90O)OR10, NR7C(xe2x95x90O)NR10R11. NR7SO2NR10R11, NR7SO2R10, SR10, S(xe2x95x90O)R10, SO2R10, SO2NR10R11, SiMe3, R10OOC(C1-C6 alkyl), R2R4N(C2-C6 alkyl), R10OOC(C1-C6 alkoxy), R2R4N(C2-C6 alkoxy), C2-C6 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, aryl, and aryl(C1-C5 alkyl)-, wherein said aryl groups are substituted with 0-2 substituents independently selected from a group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R10 and R11 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R11 when both substituents on the same nitrogen atom as in (xe2x80x94-NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl (C1-C5 alkoxy) carbonyl, heteroaryl (C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl arylsulfonyl and heteroarylsulfonyl;
W is selected from:
C1-C4 alkylene,
xe2x80x94(C(R12)2)pO(C(R12)2)p-,
xe2x80x94(C(R12)2)pC(xe2x95x90O) (C(R12)2)p-,
xe2x80x94(C(R12)2)pC(xe2x95x90))N(R13)-, and
xe2x80x94(xe2x95x90O)xe2x80x94N(R13)-(C(R12)2)p-;
X is xe2x80x94(C(R12)2)pC(R12) (R14)xe2x80x94C(R12)2xe2x80x94 or
xe2x80x94(C(R12)2)p-C(R12) (R15)-;
alternatively, W and X can be taken together to be
R12 at each occurrence is independently selected from:
H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl(C0-C4 alkyl)-, (C1-C4 alkyl)carbonyl, aryl(C0-C6 alkyl), and heteroaryl(C0-C6 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R13 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C6 alkyl) , aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R14 is selected from:
H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(C1-C6 alkyl), aryl(C0-C6 alkoxy C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylsulfonyl(C1-C6 alkyl), aryl(C0-C6 alkylthio C1-C6 alkyl), aryl(C0-C6 alkylsulfonyl C1-C6 alkyl), C3-C10 cycloalkyl(C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), R17R20NC(xe2x95x90O) (C1-C4 alkyl), R10OC(xe2x95x90O)(C1-C4 alkyl), and R17R20N(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally be substituted independently with 0-1 R16 or 0-2 R8;
R15 is selected from:
H, R16, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl (C0-C6 alkyl), C1-C6 alkoxy(C1-C6 alkyl), C1-C6 alkylamino(C1-C6 alkyl), C2-C10 dialkylamino(C1-C6 alkyl), (C1-C10 alkyl)carbonyl, aryl(C0-C6 alkyl) carbonyl, heteroaryl (C0-C6 alkyl) carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), CO2R17, C(xe2x95x90O)R17, CONR17R2O, SO2R17, and SO2NR17R20, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
Y is selected from xe2x80x94C(xe2x95x90O)R19, xe2x80x94SO3H, and xe2x80x94PO3H;
R16 is selected from:
xe2x80x94N(R20)xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94N(R20)xe2x80x94C(xe2x95x90O)xe2x80x94R17,
xe2x80x94N(R20)xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R17,
xe2x80x94N(R20)SO2xe2x80x94R17, and
xe2x80x94N(R20)SO2xe2x80x94NR20R17;
R17 is selected from:
C1-C10 alkyl, C3-C10 cycloalkyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), arylaryl(C0-C6 alkyl), heteroarylaryl (C0-C6 alkyl), arylheteroaryl (C0-C6 alkyl), and heteroarylheteroaryl (C0-C6 alkyl), wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, CN, NH2, CF3, and NO2;
R18 is selected from:
H,
xe2x80x94C(xe2x95x90O)OR17,
xe2x80x94C(xe2x95x90O)R17,
xe2x80x94C(xe2x95x90O)NHR17,
xe2x80x94SO2R17,
xe2x80x94SO2NR20R17 ,
C1-C10 alkyl,
C3-C10 cycloalkyl (C0-C6 alkyl),
aryl(C0-C6 alkyl),and
heteroaryl (C0-C6 alkyl),
wherein said aryl group is optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CF3, and xe2x80x94NO2;
R19 is selected from:
hydroxy,
C1-C10 alkyloxy,
C3-C10 cycloalkyloxy,
aryloxy,
aryl(C1-C6 alkoxy),
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy,
aryloxycarbonyl(C1-C2 alkyl)oxy,
aryloxycarbonyloxy(C1-C2 alkyl)oxy,
arylcarbonyloxy(C1-C2 alkyl)oxy,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(R10)(R11)N-(C1-C10 alkoxy) and
xe2x80x94O(CH2)kN+(R21) (R22) (R23) Zxe2x88x92;
R20 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C6 alkyl)-, aryl, aryl(C0-C6 alkyl)-, and heteroaryl(C0-C6 alkyl), wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21, R22 and R23 are independently selected from:
H, C1-C9 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), aryl(C0-C6 alkyl), heteroaryl, and heteroaryl(C0-C6 alkyl), wherein said alkyl or aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, F, Cl, Br, CF3, and NO2;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic aromatic or non-aromatic ring system containing 1-3 heteroatoms selected from N, O and S and R23 is defined as above or R21, R22, and R23 can be taken together to form a heterobicyclic ring system containing 1-3 heteroatoms selected from N, O and S, wherein said heterocyclic or heterobicyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CF3, and xe2x80x94NO2;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3;
t is 1-3; and
p is 0-2;
provided that h, i, m, n, q, r, t, and p at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.
[3] Preferred compounds of the invention as described above are compounds of Formula (IA):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
D1 is selected from: NR2R4, OR3, SR3, F, Cl, Br, CF3, methyl, ethyl, propyl, and butyl;
R2 at each occurrence is independently selected from:
H, OR3, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, C3-C7 cycloalkyl (C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, C1-C6 alkylsulfonyl, aryl(C0-C6 alkyl)sulfonyl, heteroaryl(C0-C6 alkyl)sulfonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R3 at each occurrence is independently selected from:
H, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R4 is selected from:
H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl (C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl (C0-C6 alkyl) carbonyl, heteroaryl (C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R2 and R4 when both substituents on the same nitrogen atom as in (xe2x80x94NR2R4) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl;
R5 is selected from:
H, NR2R4, OR3, NO2, NO, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and phenyl, wherein said phenyl group is substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R6 is selected from:
H, NR2R4, OR3, C1-C6 alkyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), CF3, F, Cl, and Br, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R5 and R6, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms or a 5-7 membered carbocyclic ring, said carbocyclic or heterocyclic ring being aromatic or nonaromatic, said carbocyclic or heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2 and phenyl, wherein said phenyl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R7 is selected from:
H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R7, when substituents on adjacent atoms, are taken together with the atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and phenyl, wherein said phenyl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
U1 is selected from:
xe2x80x94(CH2)n-,
xe2x80x94Oxe2x80x94(CH2)m-,
xe2x80x94(CH2)m-Oxe2x80x94,
xe2x80x94(CH2)m-N(R3)xe2x80x94,
xe2x80x94Sxe2x80x94(CH2)m-,
xe2x80x94(CH2)m-Sxe2x80x94,
xe2x80x94(CH2)m-S(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)m-S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)t-S(xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)t-Oxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)t-Sxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)t-Sxe2x80x94(xe2x95x90O)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)t-S(xe2x95x90O)2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)t-,
xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)t-,
xe2x80x94CH2xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)t-,
xe2x80x94CH2xe2x80x94S(xe2x95x90O)2xe2x80x94(CH2)t-,
xe2x80x94CH2xe2x80x94N(R3)xe2x80x94(CH2)t-,
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)t-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)m-,
xe2x80x94N(R4)xe2x80x94(CH2)q-N(R3)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-Oxe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-Sxe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-S(O)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)q-S(O)2xe2x80x94,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U2 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94Oxe2x80x94(CH2)r-,
xe2x80x94(CH2)r-Oxe2x80x94,
xe2x80x94(CH2)r-N(R3)xe2x80x94,
xe2x80x94Sxe2x80x94(CH2)r-,
(CH2)r-Sxe2x80x94,
xe2x80x94(CH2)r-S(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)r-S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94S(xe2x95x90O)2xe2x80x94,
xe2x80x94(CH2)i-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-S (xe2x95x90O)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)i-Oxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-Sxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-S(xe2x95x90O)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-S(xe2x95x90O)2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)i-,
xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)i-,
xe2x80x94CH2xe2x80x94S(xe2x95x90O)xe2x80x94(CH2)i-,
xe2x80x94CH2xe2x80x94S(xe2x95x90O)2-(CH2)i-,
xe2x80x94CH2xe2x80x94N(R3)xe2x80x94(CH2)i,
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)i-,
xe2x80x94N(R4)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)r-,
xe2x80x94N(R4)xe2x80x94(CH2)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)2xe2x80x94Oxe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)2xe2x80x94Sxe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2 )2xe2x80x94S(O)xe2x80x94,
xe2x80x94N(R4)xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94,
xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)i-, and
xe2x80x94N(R4)xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94;
U3 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)q-Oxe2x80x94,
xe2x80x94(CH2)qN(R3)xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94C(xe2x95x90O)xe2x80x94,
xe2x80x94(CH2)t-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)q-Sxe2x80x94,
xe2x80x94(CH2)q-S(O)xe2x80x94,
xe2x80x94(CH2)q-S(O)2,
xe2x80x94(CH2)q-S(O)2xe2x80x94N(R3),
xe2x80x94(CH2)q-N(R3)xe2x80x94S(O)2xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)q-O-13 CH2xe2x80x94,
xe2x80x94(CH2)h-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r-, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)p;
U4 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)2xe2x80x94Oxe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(R3)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94Sxe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94,
xe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)r-C(xe2x95x90O)xe2x80x94,
xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)r, and
xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94(CH2)r;
R8 and R9 are independently selected from: H, C1-C4 alkyl, CF3, F, Cl, Br, and OR10;
R10 and R11 are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R11 when both substituents on the same nitrogen atom as in (xe2x80x94NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl arylsulfonyl and heteroarylsulfonyl;
W is xe2x80x94(CHR12)pC(xe2x95x90O)N(R13)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94N(R13)xe2x80x94(CHR12)p-;
X is xe2x80x94CH(R14)xe2x80x94CHR12xe2x80x94 or xe2x80x94CHR12xe2x80x94CH(R15)xe2x80x94;
R12 at each occurrence is independently selected from:
H, or C1-C6 alkyl;
R13 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C6 alkyl) , aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R14 is selected from:
H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(C1-C6 alkyl), aryl(C0-C6 alkoxy C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylsulfonyl(C1-C6 alkyl), aryl(C0-C6 alkylthio C1-C6 alkyl), aryl(C0-C6 alkylsulfonyl C1-C6 alkyl),C3-C10 cycloalkyl(C0-C6 alkyl), aryl (C0-C6 alkyl), heteroaryl (C0-C6 alkyl), R17R20NC(xe2x95x90O)(C1-C4 alkyl), R10OC(xe2x95x90O)(C1-C4 alkyl), and R17R20N(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R15 is selected from:
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R17,
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R17,
xe2x80x94NHSO2xe2x80x94R17, and
xe2x80x94NHSO2xe2x80x94NR20R17;
Y is xe2x80x94C(xe2x95x90O)R19;
R17 is selected from:
C1-C10 alkyl, C3-C10 cycloalkyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), arylaryl(C0-C6 alkyl), heteroarylaryl(C0-C6 alkyl), arylheteroaryl(C0-C6 alkyl), and heteroarylheteroaryl (C0-C6 alkyl), wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, CN, NH2, CF3, and NO2;
R19 is selected from:
hydroxy,
C1-C10 alkyloxy,
C3-C10 cycloalkyloxy,
aryloxy,
aryl (C1-C6 alkoxy)
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl (C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl) oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(R10) (R11)N-(C1-C10 alkoxy)- and
xe2x80x94O(CH2)kN+(R21) (R22) (R23)Zxe2x88x92;
R20 is selected from H, methyl, ethyl, propyl, and butyl;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21, R22 and R23 are independently selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, heteroaryl, and heteroaryl(C1-C6 alkyl)- wherein said alkyl or aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, F, Cl, Br, CF3, and NO2;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic aromatic or non-aromatic ring system containing 1-3 heteroatoms selected from N, 0 and S and R23 is defined as above or R21, R22, and R23 can be taken together to form a heterobicyclic ring system containing 1-3 heteroatoms selected from N, O and S, wherein said heterocyclic or heterobicyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CF3, and xe2x80x94NO2;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3;
t is 1-3; and
p is 0-2;
provided that h, i, m, n, q, r, t, and p at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.
[4] Further preferred compounds of the invention as described above are compounds of the Formula (IA):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
D1 is NR2R4 or OR3;
R2 at each occurrence is independently selected from:
H, methyl, ethyl, propyl, butyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy) carbonyl, C3-C7 cycloalkyl (C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, and C3-C7 cycloalkyl (C0-C4 alkoxy) carbonyl;
R3 is selected from: H, methyl, ethyl, propyl, and butyl;
R4 is selected from: H, methyl, ethyl, propyl, butyl cyclopropyl, and cyclopropylmethyl;
R5 is selected from H, NR2R4, methyl, ethyl, propyl, butyl, pentyl, and hexyl;
alternatively, xe2x80x94NHR2 and R5, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-6 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms, wherein xe2x80x94NHR2xe2x80x94R5- taken together are selected from the group xe2x80x94NHxe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94Nxe2x95x90Cxe2x80x94, xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, and xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94,
R6 is selected from:
H, NR2R4, OR3, methyl, ethyl, propyl, butyl, pentyl, hexyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), CF3, F, Cl, and Br, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94R5 and xe2x80x94R6, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 6 membered heterocyclic ring containing 1 or 2 nitrogen atoms or a 5-6 membered carbocyclic ring, wherein xe2x80x94R5xe2x80x94R6xe2x80x94 taken together are selected from the group xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94;
R7 is selected from:
H, methyl, ethyl, propyl, butyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, xe2x80x94NHR2 and R7, when substituents on adjacent atoms, are taken together with the atoms to which they are attached to form a 5-6 membered heterocyclic ring containing 2 or 3 nitrogen atoms, wherein xe2x80x94NHR2xe2x80x94R7xe2x80x94 taken together are selected from the group xe2x80x94NHxe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94Nxe2x95x90Cxe2x80x94, xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94;
U1 is selected from:
xe2x80x94(CH2)n-,
xe2x80x94O(CH2)m-,
xe2x80x94(CH2)m-Oxe2x80x94,
xe2x80x94(CH2)m-N(R3)xe2x80x94,
xe2x80x94(CH2)t-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)t-Oxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)t-,
xe2x80x94CH2xe2x80x94N(R3)xe2x80x94(CH2)t-, and
xe2x80x94N(R4)xe2x80x94(CH2)m-;
U2 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94Oxe2x80x94(CH2)r-,
xe2x80x94(CH2)r-Oxe2x80x94,
xe2x80x94(CH2)r-N(R3)xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-Oxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)i-,
xe2x80x94CH2xe2x80x94N(R3)xe2x80x94(CH2)i-, and
xe2x80x94N(R4)xe2x80x94(CH2)r-;
U3 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)qOxe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94CH2xe2x80x94, and
xe2x80x94(CH2)q-Oxe2x80x94CH2xe2x80x94;
R8 and R9 are independently selected from: H, methyl, ethyl, propyl, butyl, CF3, F, Cl, Br, and OR10;
R10 and R1l are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R11 when both substituents on the same nitrogen atom as in (xe2x80x94NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl arylsulfonyl and heteroarylsulfonyl;
W is xe2x80x94CH2C(xe2x95x90O)N(R13)xe2x80x94, xe2x80x94CH2CH2C(xe2x95x90O)N(R13)xe2x80x94, or xe2x80x94C(xe2x95x90O)N(R13)xe2x80x94;
X is xe2x80x94CH(R14)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R15)xe2x80x94;
R13 is H or methyl;
R14 is selected from:
H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(C1-C6 alkyl), aryl(C0-C6 alkoxy C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylsulfonyl(C1-C6 alkyl), aryl(C0-C6 alkylthio C1-C6 alkyl), aryl(C0-C6 alkylsulfonyl C1-C6 alkyl),C3-C10 cycloalkyl (C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), R17HNC(xe2x95x90O) (C1-C4 alkyl), R10OC(xe2x95x90O) (C1-C4 alkyl), and R17HN(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R15 is selected from:
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94R17,
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R17,
xe2x80x94NHSO2xe2x80x94R17, and
xe2x80x94NHSO2xe2x80x94NHR17;
Y is xe2x80x94C(xe2x95x90O)R19;
R17 is selected from:
C1-C10 alkyl, C3-C10 cycloalkyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), arylaryl(C0-C6 alkyl), heteroarylaryl(C0-C6 alkyl), arylheteroaryl(C0-C6 alkyl), and heteroarylheteroaryl (C0-C6 alkyl), wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, CN, NH2, CF3, and NO2;
R19 is selected from:
hydroxy,
C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5- (t-butyl) -1, 3-dioxacyclopenten-2-on-4-yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-, 1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-,
(R10)(R11)N-(C1-C10 alkoxy)-, and
xe2x80x94O (CH2)kN+(R21) (R22) (R23) Zxe2x88x92;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21 R22 and R23 are independently selected from:
H, methyl, ethyl, propyl, butyl, C3-C7 cycloalkyl (C0-C4 alkyl), phenyl, benzyl, wherein said phenyl group is substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, F, Cl, Br, CF3, and NO2;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic aromatic or non-aromatic ring system containing 1-2 heteroatoms selected from N, O and S and R23 is defined as above or R21, R22, and R23 can be taken together to form a heterobicyclic ring system containing 1-2 heteroatoms selected from N, O and S;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3; and
t is 1-3;
provided that h, i, m, n, q, r, and t, at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.
[5] Still further preferred compounds of the above invention as described above are compounds of the Formula (IA):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
U1 is selected from: xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94, and xe2x80x94NHxe2x80x94CH2CH2xe2x80x94;
U2 is selected from: xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH 2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94, and xe2x80x94NHxe2x80x94CH2CH2xe2x80x94;
U3 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2xe2x80x94;
R8 is selected from: H, methyl, ethyl, propyl, butyl, xe2x80x94OH, methoxy, ethoxy, F, Cl, Br, and CF3;
R9 is H,
R10 and R11 are independently selected from:
H, methyl, ethyl, propyl, butyl, C3-C6 alkenyl, C3-C4 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R11 when both substituents on the same nitrogen atom as in (xe2x80x94NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
W is xe2x80x94CH2C (xe2x95x90O) N(R13)xe2x80x94, xe2x80x94CH2CH2C(xe2x95x90O)N(R13)xe2x80x94, or xe2x80x94C(xe2x95x90O)N(R13)xe2x80x94;
X is xe2x80x94CH(R14)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R15)xe2x80x94;
R13 is H, methyl, ethyl, propyl, butyl, pentyl, or hexyl;
R14 is selected from:
C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl(C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl (C0-C6 alkyl), R17HNC (xe2x95x90O) (C1-C4 alkyl), and R17HN(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, CF3, and NO2;
R15 is selected from:
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94NHSO2xe2x80x94R17 and
xe2x80x94NHSO2xe2x80x94NHR17;
Y is xe2x80x94C(xe2x95x90O)R19;
R17 is selected from:
methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, heteroaryl(C1-C3 alkyl)-, arylaryl(C1-C3 alkyl)-, heteroarylaryl(C1-C3 alkyl)-, arylheteroaryl(C1-C3 alkyl)-, heteroarylheteroaryl(C1-C3 alkyl)-, heteroaryl, and aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenyl, F, Cl, Br, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CF3, and xe2x80x94NO2;
R19 is selected from:
hydroxy, methoxy, ethoxy, propoxy, butoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5- (t-butyl) -1, 3-dioxacyclopenten-2-on-4-yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-,
(R1O) (R11)N-(C1-C10 alkoxy)-, and
xe2x80x94O(CH2)kN+(R21) (R22) (R23)Zxe2x88x92;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21, R22 and R23 are independently selected from: H, methyl, ethyl, propyl and butyl;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic ring system containing 1-2 heteroatoms selected from N, O and S and R23 is defined as above;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3; and
t is 1-3;
provided that h, i, m, n, q, r, and t, at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.
[6] Specifically preferred compounds of the above invention are compounds including enantiomeric or
2-[(S)-((2,4,6-Trimethylphenyl)sulfonyl)amino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]-aminopropionic acid sodium salt,
2-[(S)-Phenylsulfonylamino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]aminopropionic acid sodium salt,
2-[(S)-i-Butylsulfonylamino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]aminopropionic acid sodium salt,
2-[(S)-n-Butylsulfonylamino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]aminopropionic acid sodium salt,
2-[ (S)-(i-Butyloxycarbonyl)amino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl) ethylphenylcarbonyl] aminopropionic acid sodium salt,
2-[(S)-(n-Butyloxycarbonyl)amino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]aminopropionic acid sodium salt,
2-[(S)-Benzyloxycarbonylamino]-3-[4-(2-(2-aminopyrimid-4-one-6-yl)ethylphenylcarbonyl]aminopropionic acid sodium salt,
2-[(S)-((2,4,6-Trimethylphenyl)sulfonyl)amino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl) ethylphenylcarbonyl]-aminopropionic acid trifluoroacetate salt,
2-[(S)-Phenylsulfonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]aminopropionic acid trifluoroacetate salt,
2-[(S)-i-Butylsulfonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]aminopropionic acid trifluoroacetate salt,
2-[(S)-n-Butylsulfonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]aminopropionic acid trifluoroacetate salt,
2-[(S)-i-Butyloxycarbonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]-aminopropionic acid trifluoroacetate salt,
2-[(S)-n-Butyloxycarbonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]-aminopropionic acid trifluoroacetate salt,
2-[(S)-Benzyloxycarbonylamino]-3-[4-(2-(2,4-diaminopyrimidin-6-yl)ethylphenylcarbonyl]-aminopropionic acid trifluoroacetate salt,
2-[(S)-((2,4,6-Trimethylphenyl)sulfonyl)amino]-3-[4-(2-(2,4-diaminotriazin-6-yl)ethylphenylcarbonyl]-aminopropionic acid,
2-[(S)-((2,4,6-Trimethylphenyl)sulfonyl)amino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]-aminopropionic acid,
2-[(S)-Phenylsulfonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]aminopropionic acid,
2-[(S)-i-Butylsulfonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]aminopropionic acid,
2-[(S)-n-Butylsulfonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]aminopropionic acid,
2-[(S)-i-Butyloxycarbonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]-aminopropionic acid,
2-[(S)-n-Butyloxycarbonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]-aminopropionic acid,
2-[(S)-Benzyloxycarbonylamino]-3-[4-(2-(4-aminoquinazolin-2-yl)aminomethylphenylcarbonyl]aminopropionic acid,
and ester forms thereof, said ester being selected from the group consisting of:
methyl,
ethyl,
isopropyl,
n-butyl,
isobutyl,
benzyl,
methylcarbonyloxymethyl,
ethylcarbonyloxymethyl,
tert-butylcarbonyloxyrmethyl,
cyclohexylcarbonyloxymethyl,
tert-butyloxycarbonyloxymethyl,
dimethylaminoethyl,
diethylaminoethyl,
morpholinoethyl,
pyrrolidinoethyl,
trimethylammonioethyl, and 2-(1-methylmorpholinium-1-yl)ethyl.
[7] In a second emodiment preferred compounds of the invention as described above are compounds of the Formula (IA):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
R2 at each occurrence is independently selected from:
H, methyl, ethyl, propyl, butyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, C3-c7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, and C3-C7 cycloalkyl(C0-C4 alkoxy)carbonyl;
R4 is selected from: H, methyl, ethyl, propyl, butyl cyclopropyl, and cyclopropylmethyl;
R5 is selected from H, NR2R4, methyl, ethyl, propyl, butyl, pentyl, and hexyl;
U2 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94Oxe2x80x94(CH2)r-,
xe2x80x94(CH2)r-Oxe2x80x94,
xe2x80x94(CH2)r-N(R3)xe2x80x94,
xe2x80x94(CH2)i-N(R3)xe2x80x94CH2xe2x80x94,
xe2x80x94(CH2)i-Oxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Oxe2x80x94(CH2)i-,
xe2x80x94CH2xe2x80x94N(R3)xe2x80x94(CH2)i-, and
xe2x80x94N(R4)xe2x80x94(CH2)r-;
U3 is selected from:
xe2x80x94(CH2)h-,
xe2x80x94(CH2)q-Oxe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94,
xe2x80x94(CH2)q-N(R3)xe2x80x94CH2xe2x80x94, and
xe2x80x94(CH2)q-Oxe2x80x94CH2xe2x80x94;
R8 and R9 are independently selected from: H, methyl, ethyl, propyl, butyl, CF3, F, Cl, Br, and OR10;
R10 and R1l are independently selected from:
H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R1l when both substituents on the same nitrogen atom as in (xe2x80x94NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C -C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl arylsulfonyl and heteroarylsulfonyl;
W is xe2x80x94CH2C(xe2x95x90O)N(R13)xe2x80x94, xe2x80x94CH2CH2C(xe2x95x90O)N(R13)xe2x80x94, or xe2x80x94C(xe2x95x90O)N(R13)xe2x80x94;
X is xe2x80x94CH(R14)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R15)xe2x80x94;
R13 is H or methyl;
R14 is selected from:
H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(C1-C6 alkyl), aryl(C0-C6 alkoxy C1-C6 alkyl), C1-C6 alkylthio (C1-C6 alkyl), C1-C6 alkylsulfonyl (C1-C6 alkyl), aryl(C0-C6 alkylthio C1-C6 alkyl), aryl(C0-C6 alkylsulfonyl C1-C6 alkyl),C3-C10 cycloalkyl (C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), R17HNC(xe2x95x90O)(C1-C4 alkyl), R10OC(xe2x95x90O)(C1-C4 alkyl), and R17HN(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
R15 is selected from:
xe2x80x94NHxe2x80x94C (xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94NHxe2x80x94C (xe2x95x90O)xe2x80x94R17,
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94R17,
xe2x80x94NHSO2xe2x80x94R17, and
xe2x80x94NHSO2xe2x80x94NHR17;
Y is xe2x80x94C(xe2x95x90O)R19;
R17 is selected from:
C1-C10 alkyl, C3-C10 cycloalkyl, aryl(C0-C6 alkyl), heteroaryl (C0-C6 alkyl), arylaryl (C0-C6 alkyl), heteroarylaryl (C0-C6 alkyl), arylheteroaryl (C0-C6 alkyl), and heteroarylheteroaryl (C0-C6 alkyl), wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, CN, NH2, CF3, and NO2;
R19 is selected from:
hydroxy,
C1-C10 alkoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-,
(R10) (R11)N-(C1-C10 alkoxy)-, and
xe2x80x94O(CH2)kN+(R21) (R22) (R23)Zxe2x88x92;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21, R22 and R23 are independently selected from:
H, methyl, ethyl, propyl, butyl, C3-C7 cycloalkyl(C0-C4 alkyl), phenyl, benzyl, wherein said phenyl group is substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, F, Cl, Br, CF3, and NO2;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic aromatic or non-aromatic ring system containing 1-2 heteroatoms selected from N, O and S and R23 is defined as above or R21, R22, and R23 can be taken together to form a heterobicyclic ring system containing 1-2 heteroatoms selected from N, O and S;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3; and
t is 1-3;
provided that h, i, m, n, q, r, and t, at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine or triazine of G is in the range of 8-12.
[8] Further preferred compounds of the above invention as described above are compounds of the Formula (IA):
including stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
G is a meta or para substituent with respect to W and is selected from:
U2 is selected from: xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94, and xe2x80x94NHxe2x80x94CH2CH2xe2x80x94;
U3 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2xe2x80x94;
R8 is selected from: H, methyl, ethyl, propyl, butyl, xe2x80x94OH, methoxy, ethoxy, F, Cl, Br, and CF3;
R9 is H,
R10 and R11 are independently selected from:
H, methyl, ethyl, propyl, butyl, C3-C6 alkenyl, C3-C4 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
alternatively, R10 and R11 when both substituents on the same nitrogen atom as in (-NR10R11) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
W is xe2x80x94CH2C(xe2x95x90O)N(R13)xe2x80x94, xe2x80x94CH2CH2C(xe2x95x90O)N(R13)xe2x80x94, or xe2x80x94C(xe2x95x90O)N(R13)xe2x80x94;
X is xe2x80x94CH(R14)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R15)xe2x80x94;
R13 is H, methyl, ethyl, propyl, butyl, pentyl, or hexyl;
R14 is selected from:
C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl(C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl (C0-C6 alkyl), R17HNC (xe2x95x90O) (C1-C4 alkyl), and R17HN(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, CF3, and NO2;
R15 is selected from:
xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R17,
xe2x80x94NHSO2xe2x80x94R17 and
xe2x80x94NHSO2xe2x80x94NHR17;
Y is xe2x80x94C(xe2x95x90O)R19;
R17 is selected from:
methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, heteroaryl (C1-C3 alkyl)-, arylaryl (C1-C3 alkyl)-, heteroarylaryl (C1-C3 alkyl)-, arylheteroaryl (C1-C3 alkyl)-, heteroarylheteroaryl (C1-C3 alkyl)-, heteroaryl, and aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of: methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenyl, F, Cl, Br, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CF3, and xe2x80x94NO2;
R19 is selected from:
hydroxy, methoxy, ethoxy, propoxy, butoxy,
methylcarbonyloxymethoxy-,
ethylcarbonyloxymethoxy-,
t-butylcarbonyloxymethoxy-,
cyclohexylcarbonyloxymethoxy-,
1-(methylcarbonyloxy)ethoxy-,
1-(ethylcarbonyloxy)ethoxy-,
1-(t-butylcarbonyloxy)ethoxy-,
1-(cyclohexylcarbonyloxy)ethoxy-,
i-propyloxycarbonyloxymethoxy-,
t-butyloxycarbonyloxymethoxy-,
1-(i-propyloxycarbonyloxy)ethoxy-,
1-(cyclohexyloxycarbonyloxy)ethoxy-,
1-(t-butyloxycarbonyloxy)ethoxy-,
dimethylaminoethoxy-,
diethylaminoethoxy-,
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-,
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-,
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-,
(R10) (R11)N-(C1-C10 alkoxy)-, and
xe2x80x94O(CH2)kN+ (R21) (R22) (R23)Zxe2x88x92;
Zxe2x88x92 is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfate, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and malonate;
R21, R22 and R23 are independently selected from: H, methyl, ethyl, propyl and butyl;
alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic ring system containing 1-2 heteroatoms selected from N, O and S and R23 is defined as above;
h is 0-4;
i is 0-2;
k is 2-6;
m is 1-4;
n is 0-5;
q is 2-3;
r is 0-3; and
t is 1-3;
provided that h, i, m, n, q, r, and t, at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.
[9] Specifically preferred compounds of the above invention are compounds including enantiomeric forms, diasteriomeric forms or mixtures of enantiomeric or diasteriomeric forms thereof, and pharmaceutically acceptable salt forms thereof, selected from:
2-[(S)-((2,4,6-Trimethylphenyl)sulfonyl)amino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]-aminopropionic acid,
2-[(S)-i-Butyloxycarbonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt,
2-[(S)-n-Butyloxycarbonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt,
2-[(S)-Benzyloxycarbonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt, and
2-[(S)-Phenylsulfonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt.
2-[(S)-i-Butylsulfonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt.
2-[(S)-n-Butylsulfonylamino]-3-[4-(2-(2-aminopyrimidin-4-yl)aminomethyl)phenylcarbonyl]aminopropionic acid trifluoroacetate salt.
Generally, the compounds of this invention are comprised of a guanidine mimic xe2x80x9cGxe2x80x9d and an integrin antagonist template xe2x80x9cTxe2x80x9d. The guanidine mimic comprises a substituted or unsubstituted pyrimidine, pyrimidone, triazinine or trizanone ring, optionally fused, and a linking group U. Preferably, the integrin antagonist template xe2x80x9cTxe2x80x9d is
as defined in the present invention. However, other integrin antagonist templates disclosed herein as T1 through T14 are included within the scope of the present invention and summarized below.
Template T1, disclosed in Bondinell, et al., WO 93/00095, published Jan. 7, 1993, is of the sub-formula (T1):
wherein, A1 to A5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized; D1 to D4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms; R, R*, and all substituents thereform are as defined in the Bondinell specification. Suitably, with reference to formula (T1); A1 is CR1R1, CR1, NR1, N, O or S(O)x; A2 is CR2R2xe2x80x2, CR2, NR2; A3 is CR3R3xe2x80x2, CR3, NR3, N. O or S(O)x; A4 is CR4R4, CR4, NR4, or N; A5 is CR5R5xe2x80x2, CR5, NR5, N, O or S(O)x; and D1-D4 are CR11, CR6 or N.
A preferred integrin antagonist template of sub-formula (T1) is defined by Bondinell wherein A1 equals N-R1, A2 equals CHCH2CO2H, A3 equals Cxe2x95x90O, A4 equals N-R4, A5 equals CH2, and D1 to D4 are carbon.
Another embodiment of a preferred integrin antagonist template of sub-formula (T1) is represented by the 1,4-benzodiazepine 2,5-dione of sub-formula (T2);
The preparation and the use of this sub-structure in preparing integrin antagonists of this sub-formula is detailed in Bondinell, et al., WO 93/00095 published Jan. 7, 1993 and Blackburn, et al., WO 93/08174, published Apr. 29, 1993.
Template T3, of sub-formulae:
is disclosed in Alig, et al., EP 0 381 033, published Aug. 8, 1990, wherein R21 or R22 provide for the acid terminus.
Template T4, of sub-formula:
is disclosed in Egbertson, et al., EP 0 478 328, published Apr. 1, 1992.
Template T5, of sub-formula:
is disclosed in Eldred, et al., EP 0542 363, published May 19, 1993.
Template T6, of sub-formula:
is disclosed in Porter, et al., EP 0537 980, published Apr. 21, 1993.
Template T7, of sub-formula:
is disclosed in Klinnick, et al., EP 0 635,492, published Jan. 25, 1995.
Template T8, of sub-formula:
is disclosed in Blackburn, et al., WO 95/04057, published Feb. 9, 1995.
Template T9, of sub-formula:
is disclosed in Hartman, et al., EP 0 540 331, published May 5, 1993.
Template T10, of sub-formula:
is disclosed in Sugihara, et al., EP 0 529, 858, published Mar. 3, 1993.
Template T11, of sub-formula:
is disclosed in Himmelsbach, et al., EP 0 483 667, published May 6, 1992.
Template T12, of sub-formula:
is disclosed in Linz, et al, EP 0 567 968, published Nov. 3, 1993.
Template T13, of sub-formula:
is disclosed in Bovy, et al., EP 0 539 343, published Apr. 28, 1993.
Template T14, of sub-formula:
is disclosed in Hartman, et al., WO97/26250, published Jul. 24, 1997.
The above description of integrin antagonist templates for use in the present invention were taken from pending published patent applications. Reference should be made to such patent applications for their full disclosures, including the methods of preparing said templates and specific compounds using said templates, the entire disclosure of such patent applications being incorporated herein by reference.
In the present invention it has been discovered that the compounds of Formula (IA) above are useful as inhibitors of cell-matrix and cell-cell adhesion processes. The present invention includes novel compounds of Formula (IA) and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formula (IA).
In the present invention it has also been discovered that the compounds of Formula (IA) above are useful as inhibitors of the xcex1vxcex23 integrin and/or the glycoprotein IIb/IIIa (GPIIbIIIa) integrin. The compounds of the present invention inhibit the binding of vitronectin and other RGD containing ligands to xcex1vxcex23 and/or to GPIIb/IIIa and inhibit cell adhesion.
The present invention also provides pharmaceutical compositions comprising a compound of Formula (IA) and a pharmaceutically acceptable carrier.
The compounds of Formula (IA) of the present invention are useful for the treatment (including prevention) of angiogenic disorders. The term xe2x80x9cangiogenic disordersxe2x80x9d as used herein includes conditions involving abnormal neovascularization, such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy, neovascular glaucoma, age-related macular degeneration, and retinal vein occlusion, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (IA) described above.
The compounds of Formula (IA) or the present invention may be useful for the treatment (including prevention) of thromboembolic disorders. The term xe2x80x9cthromboembolic disordersxe2x80x9d as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (IA) described above.
The compounds of Formula (IA) of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thromboembolic disorders, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula (IA) of the present invention may also be useful for wound healing.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor id desired. They are useful in surgery on peripheral arteries, (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemoli. The compounds of the present invention may be administered to these surgical patents to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.
Other applications for these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
The compounds of Formula (IA) of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
By xe2x80x9ctherapeutically effective amountxe2x80x9d it is meant an amount of a compound of Formula (IA) that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
By xe2x80x9cadministered in combinationxe2x80x9d it is meant that the compound of Formula (IA) and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as COUMADIN(copyright)) and heparin.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal xcex1-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Administration of the compounds of Formula (IA) of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of vitronectin or fibrinogen to xcex1vxcex23. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving xcex1vxcex23. The compounds of the present invention may also be used in diagnostic assays involving xcex1vxcex23.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example but not limited to, R2, R3, R4, R10, R11, R12, R17, h, i, n, m, r, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R4, then said group may optionally be substituted with up to two R4 and R4 at each occurrence is selected independently from the defined list of possible R4. Also, by way of example, for the group xe2x80x94N(R2)2, each of the two R2 substituents on N is independently selected from the defined list of possible R2. Similarly, by way of example, for the group xe2x80x94C(R12)2xe2x80x94, each of the two R12 substituents on C is independently selected from the defined list of possible R12.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula (IA), then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula (IA) via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, xe2x80x9cC0-C10 alkylxe2x80x9d denotes alkyl having 0 to 10 carbon atoms; thus, C0 denotes a direct bond between the groups linked by the C0 alkyl group. Similarly, xe2x80x9cC1-C6 alkylxe2x80x9d denotes methyl, ethyl, propyl, butyl, pentyl, hexyl; wherein, for example, butyl is intended to include n-butyl, i-butyl, s-butyl, and t-butyl.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -CvFw where v=1 to 3 and w=1 to (2v+1)). xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge (for example, xe2x80x9cC0-C10 alkoxyxe2x80x9d denotes alkoxy having 0 to 10 carbon atoms; thus, C0 denotes an oxygen atom between the groups linked by the C0 alkoxy group). xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, butenyl and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl and the like.
The terms xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula (IA). Such xe2x80x9calkylenexe2x80x9d, xe2x80x9c-alkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, may alternatively and equivalently be denoted herein as xe2x80x9c-(alkyl)-xe2x80x9d, xe2x80x9c-(alkyenyl)-xe2x80x9d and xe2x80x9c-(phenyl)-xe2x80x9d, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean phenyl or naphthyl; the term xe2x80x9carylalkylxe2x80x9d represents an aryl group attached through an alkyl bridge. For example, xe2x80x9caryl C1-C4 alkylxe2x80x9d represents phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic ringxe2x80x9d is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen 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 to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1, 2, 5-thiadiazinyl, 2H, 6H-1, 5, 2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
The term xe2x80x9cintegrinxe2x80x9d as used herein refers to any of the many cell surface receptor proteins, also referred to as adhesion protein receptors, which have been identified which bind to extracellular matrix ligands or other cell adhesion protein ligands thereby mediating cell-cell and cell-matrix adhesion processes. The integrins are encoded by genes belonging to a gene superfamily and are typically composed of heterodimeric transmembrane glycoproteins containing xcex1- and xcex2-subunits. Integrin subfamilies contain a common xcex2-subunit combined with different xcex1-subunits to form adhesion protein receptors with different specificities.
The integrin glycoprotein IIb/IIIa (referred to herein as GPIIb/IIIa or IIb/IIIa or the fibrinogen receptor) is the membrane protein mediating platelet aggregation. GPIIb/IIIa in activated platelets is known to bind four soluble RGD-containing adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. In addition to GPIIb/IIIa, a number of other integrin cell surface receptors have been identified, for example, xcex1vxcex23and
The term xe2x80x9cintegrin antagonistsxe2x80x9d as referred to herein (also referred to herein as integrin inhibitors) includes compounds (including peptidomimetic compounds and other small molecule compounds) which act as inhibitors of the binding of the integrin protein to endogenous protein ligands of such integrin. Preferred integrin inhibitors used in the present invention are RGD-peptidomimetic compounds. As used herein, the term xe2x80x9cRGD-peptidomimetic compoundsxe2x80x9d refers to chemical compounds which bind to the RGD-binding region of the integrin and which block RGD-mediated binding of one or more adhesive proteins to such integrin. Preferred in the present invention are antagonists of the xcex1vxcex23 nad GPIIb/IIIa integrin.
As used herein, xe2x80x9cprodrugsxe2x80x9d refer to any covalently bonded carriers which release the active parent drug according to Formula (IA) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula (IA) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula (IA) wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (IA), and the like.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of Formula (IA) is modified by making acid or base salts of the compound of Formula (IA). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
The pharmaceutically acceptable salts of the compounds of Formula (IA) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula (IA) formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula (IA) which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formula (IA) with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
Synthesis
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The templates of Formula (IB) and (IC) can be synthesized by methods disclosed in U.S. patent application Ser. No. 08/647132 filed May 9, 1996 or published in WO 96/37492 on Nov. 28, 1996. The templates of Formula (ID) and (IE) can be synthesized by methods disclosed in U.S. patent application Ser. No. 08/816580 filed Mar. 13, 1997 or published in WO 97/33887 on Sep. 18, 1997. The template of Formula (IG) can be synthesized by methods disclosed in U.S. patent application Ser. No. 08/770538 filed Dec. 20, 1996 or published in WO 97/23480 on Jul. 3, 1997. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The synthesis of compounds of formula I with various heterocycles represented by G may be prepared by many methods. For reviews on the synthesis of pyrimidines see Brown, D. J., in Comprehensive Heterocyclic Chemistry Vol. 3, pp. 57-157, (Katritzky A. R., and Rees, C. W ed""s) Pergamon Press Ltd., New York, 1984, and Brown, D. J., in The Pyrimidines Vol 16. with supplements I and II. in the series Chemistry of Heterocyclic Compounds (Weissberger A., and Taylor, E. C. ed""s) John Wiley and Sons, New York, 1970. For reviews on the synthesis of triazines see Quirke, J. M. E., in Comprehensive Heterocyclic Chemistry Vol. 3, pp. 457-531, (Katritzky A. R., and Rees, C. W ed""s) Pergamon Press Ltd., New York, 1984.
Some of the methods which may be used to prepare the heterocyclic moieties represented by G in formula I are illustrated below in schemes Ia through Id and IIa through IIh. In schemes Ia through Id and IIa through IIh the substituent J represents a group appropriate for eventual elaboration to a compound of formula I. Typical examples of such groups are represented by formulas J1 through J4. The examples J1 through J4 are for illustration purposes and do not represent a limitation on the scope of the invention.
One general method of synthesis of the G portion of the compounds of formula I involves the displacement of an activated halogen atom substituent on an electron deficient heterocycle with nucleophiles including but not limited to amines, hydroxide, alkoxide salts, mercaptan salts, alkylthio salts, or Grignard reagents as outlined in schemes Ia - Id. The examples shown in schemes Ia-Id are for illustration purposes and do not constitute a limitation on the scope of the invention. The halogen containing heterocycles are obtained from commercial sources or can be readily prepared by one skilled in the art of organic synthesis from several means including direct halogenation or by conversion of the available oxo precursors. The oxo derivative may be converted to the halide by treatment with a phosphorous halide, for example phosphorous oxychloride, at temperatures from room temperature to reflux, with or without addition of a co-solvent, and with or without the addition of a basic catalyst, for example N,N-dimethylaniline. Fluorine containing heterocycles may be produced by several methods including transhalogenation of the chloro derivatives by treatment with a fluoride salt such as sodium fluoride, potassium fluoride or silver fluoride at elevated temperatures.
The nucleophilic displacement of activated multiple halogen containing electron deficient heterocycles has been shown to be generally applicable to multistep substitution procedures. The level of substitution may be controlled by choice of the proper sequence of reactions and reaction conditions such as stochiometry, temperature, pressure and solvent. The choice of the proper conditions would be known to one skilled in the art of organic synthesis, for pyrimidines this process is outlined in Brown, D. J., in The Pyrimidines Vol 16 supplements II, pp.184-188 in the series Chemistry of Heterocyclic Compounds (Weissberger A., and Taylor, E. C. ed""s) John Wiley and Sons, New York, 1970. This iterative substitution process has also been illustrated for triazines starting from cyanuric chloride; for example, monosubstitution is depicted in Cambell, J. R., and Hatton, R. E., J. Org. Chem., 26, 2786, 1961, and for example, disubstitution is shown in Thurston, J. T., Dudley, J. R, Kaiser, D. W., Schaefer, F. C, et. al. J. Amer. Chem. Soc. 73, 2981, 1954, and for example, trisubstitution is shown in Controulis, J., Banks, C. K., J. Amer. Chem. Soc. 67, 1946, 1945. Other polyhalogenated heterocycles contained in this scope might be expected to behave in a similar manner.
Scheme Ia represents a means of sequentially introducing nucleophiles into the heterocyclic core. The starting heterocycles cyanuric chloride, 2,4,6 trifluoropyrimidine, 2,4,6-trichloropyrimidine and the intermediate 2-amino-4,6-dichloropyrimidine are commercially available. In this case the amine containing U3J is treated with the trihaloheterocycle first, although the sequence of addition may be altered. The reaction may be carried out in an alcoholic solvent or N,N-dimethylformamide, from 0xc2x0 C. to 100xc2x0 C. In the case where the heterocycle is a pyrimidine two isomers will generally be produced (Ia-2 and Ia-3) and may be separated by several methods including chromatography, crystallization or distillation. Scheme Ia depicts Ia-2 as being carried through the remainder of the reaction sequence although isomer Ia-3 may be carried through the same reaction sequence. Isomer Ia-2 is then allowed to react with a second amine, by heating the components in an alcoholic solvent or N,N-dimethylformamide, from 25xc2x0 C. to 140xc2x0 C. to provide Ia-4. The diaminoheterocycle may be treated with a third amine component be heating in a sealed tube at a temperature of 80xc2x0 C. to 210xc2x0 C. to provide Ia-5. Alternatively, Ia-4 may be treated with an alkoxide such as sodium benzylalkoxide possible with the addition of an inert solvent such as mesitylene at a temperature from 100xc2x0 C. to 160xc2x0 C. to provide Ia-6, or alternatively Ia-4 might be treated with a sodium alkylthio salt (not shown) by heating in an alcoholic solvent. The benzyl group in compound Ia-6 may be removed by hydrogenation in the presence of a suitable catalyst such as palladium on carbon at a pressure from atmospheric to 55 psi to provide Ia-7. The hydroxy substituted heterocycles may exist in either the hydroxy tautomer or the keto tautomer or may exist as a mixture of both tautomers.
In some pyrimidine cases produced in scheme Ia, the final nucleophilic addition may be difficult to achieve, the rate of the reaction can be accelerated by first adding an electron withdrawing substituent to the ring such as a nitro or bromo substituent as illustrated in scheme Ib.
Nitration or halogenation of the 5-position of pyrimidine Ib-1 which contain one or two amino substituents or hydroxy or alkoxy substituents occurs readily as described in Brown, D. J., in The Pyrimidines Vol 16 supplements II, pp.135-39 and suppliment I pp. 119-122, the series Chemistry of Heterocyclic Compounds (Weissberger A., and Taylor, E. C. ed""s) John Wiley and Sons, New York, 1970. Nitration occurs in a temperature range from 0xc2x0 C. to 50xc2x0 C. with a variety of nitrating reagents such as fuming nitric acid in acetic acid or sodium nitrate in sulfuric acid to provide Ib-5. Alternatively, the pyrimidines may be halogenated for example with bromine in acetic acid to provide Ib-2. After addition of the electron withdrawing substituent treatment with an amine can proceed at an acceptable rate at elevated temperature to produce either Ib-3 or Ib-6. In the case of Ib-2 nucleophilic attack usually only occurs at the 6-position and does not displace the 5-bromo substituent. The bromine atom in Ib-3 may be removed by catalytic hydrogenation for example by using palladium or platinum on carbon as the catalyst. In the case of a 5-nitro substituent Ib-6, reduction with palladium on carbon, or use of a metal such as zinc, provides the 5-amino substituent Ib-7.
In scheme Ic the dihaloheterocycle Ic-1 is reacted with a nucleophilic amine in an alcoholic solvent or a solvent such as N,N-dimethylacetamide. Isolation of the product Ic-2 may also require the separation of isomers. Each isomer may be carried through the reaction sequence. Reaction of Ic-2 with a second amine substituent usually requires elevated temperatures and in some cases high pressure to provide Ic-3. Alternatively, the monohalo derivative Ic-2 may be treated with an alkoxide or alkylthio salt to provide Ic-4. Removal of the alkyl group may be accomplished by treatment with reagents such as hydrobromic acid, or AlCl3 or BBr3. If a benzylalkoxide is used the benzyl group may be remove by hydrogenolysis using a catalyst such as Pd/C, or Pt/C, in the presence or absence of an added base such as NaOH, or a tertiary amine base. The oxygen or sulfur sustituent may exist in either the enol (Ic-5a) or keto(Ic-5b) form or a mixture of both.
A second general method of synthesis of the G portion of compounds of formula I, involves ring forming reactions. The many ring forming reactions for pyrimidines, triazines, and other heterocycles which can be used to prepare the compounds in this invention, are outlined in the reviews cited above. The examples shown in schemes IIa through IIg are for illustration purposes and do not constitute a limitation on the scope of the invention.
Scheme IIa shows a general condensation route to pyrimidines based on the method of Taylor, E. C., Harrington, P. M., and Shih, C., in Heterocycles, 28, 1169, 1989. Taylor starts with an alcohol which can be obtained by a variety of methods well known to one skilled in the art of organic chemistry some examples are shown in schemes IIIa-IIIc, other precursors such as an aklylhalide is also permissible, which may be readily prepared from the alcohols. The group U2J is used in this general method, but for this synthetic scheme, U2J is meant to include only those cases in which the terminal methylene group is an alcohol. For example U2J is a compound like IIIa-6. In this case the alcohol is reacted with a sulfonyl chloride such as mesyl chloride or tosyl chloride in the presence of a tertiary amine, such as triethylamine, or a base such pyridine, in a suitable solvent, such as methylene chloride or N,N-dimethylformamide to prepare the activated sulfonate IIa-2.
Activated methylene compounds are either, commercially available, or are readily prepared by methods known to one skilled in the art of organic synthesis, for example preparation by acylation of an ester enolate. Alkylation of active methylene compounds are well known in organic chemistry for example, see xe2x80x9cThe alkylation of active methylene compoundsxe2x80x9d in Modern Synthetic Reactions 2nd ed. House, H. O., Chapter 9, Benjamin/Cummings Publishing Co, Menlo Park, Calif., 1972. Briefly alkylation may be accomplished by treatment of an activated methylene compound with a suitable base such as sodium hydride, in a suitable solvent such as anhydrous tetrahydrofuran, or anhydrous dioxane at a temperature ranging from xe2x88x925xc2x0 C. to solvent reflux will form an anion. This is accompanied by the evolution of hydrogen gas (caution). A solution of the anion is generally cooled to xe2x88x9210xc2x0 C. -0xc2x0 C. and the alkylsulfonate ester is added. The reaction mixture is allowed to stir at a temperature ranging from 0xc2x0 C. to solvent reflux, until the reaction is deemed to have progressed to completion or as far as practical.
In scheme IIa method I, the intermediate cyanoacetate IIa-3 is heated with a guanidine to provide pyrimidine IIa-4. In scheme IIa method 2 the intermediate malononitrile IIa-5 is heated with a guanidine provides pyrimidine IIa-6, and in scheme IIa method 3, the intermediate ketoester IIa-7 is heated with a guanidine to provide pyrimide IIa-8.
Scheme IIb methods 1-3 utilize guanidines which are either commercially available or are readily prepared by methods known to one skilled in the art of organic synthesis, for example as illustrated in scheme IIId. It has been suggested in the method of Taylor that guanidine salts should first be treated with sodium alkoxide/alcohol and filtered to prepare a xe2x80x9csalt freexe2x80x9d solution of the guanidine base. At this point the solvent may be removed and the gaunidine redissolved in a appropriate solvent, the choice of which is determined by by considerations such as desired reaction temperature and solubility of the reactants, and includes alcohols, N,N-dimethylformamide, and N,N-dimethylacetamide and would be known to one skilled in the art of organic synthesis. Reaction of the guanidine base with the active methylene compounds in methods 1-3, at a temperature from room temperature to solvent reflux provides the desired pyrimidines.
In cases where there is a single alkyl group on the guanidine base it can be envisioned that there will be two possible condensation products, one the desired pyrimidine and one which is the ring nitrogen substituted iminopyrimidine. These products may be separated to provide the desired product. In some cases the ring nitrogen substituted iminopyrimidine may undergo the Dimroth rearragement to provide the desired aminosubstituted pyrimidine (for a discussion of the Dimroth rearrangement see Brown, D. J., in The Pyrimidines Vol 16 supplements I, pp.287-294 in the series Chemistry of Heterocyclic Compounds (Weissberger A., and Taylor, E. C. ed""s) John Wiley and Sons, New York, 1970. Alternatively, iminopyrimidines may be hydrolyzed to the pyrimidone (or hydroxypyrimidine tautomer) by treatment with aqueous acid.
Scheme IIb illustrates the use of activated methylene compounds to generate the isomeric pyrimidines which are also within the scope of this invention. In scheme IIb method 1 the guanidine is condensed with a xcex2-ester nitrile in a ethanolic solvent or N,N-dimethylformamide, at 40xc2x0 c. to 120xc2x0 C. to give the pyrimidine. In scheme IIb method 2 a malononitrile derivative is condenesed with a guanidine derivative to produce the desired pyrimidine. Scheme IIb method 3 illustrates the condensation of a xcex2-ketoester with a guanidine to produce the desired pyrimidine.
Amidines are either commercially available or readily prepared by one skilled in the art of organic chemistry from readily available nitriles by several methods including a method commonly refered to as the Pinner synthesis of amidines which involves treatment of the nitrile with methanol and anhydrous HCl either with or without an added solvent such as methylene chloride or chloroform followed by the addition of an amine. Amidines readily condense with a variety of activated methylene groups to form pyrimidines. Scheme IIc ilustrates the condensation of an amidine with and active methylene group. In scheme IIc method 1, a malonic ester is heated in a ethanolic solvent or N,N-dimethylformamide, at 40xc2x0 c. to 120xc2x0 C. with an amidine to provide pyrimidine IIc-2. In scheme IIc method 2, a malonitrile is heated in a ethanolic solvent or N,N-dimethylformamide, at 40xc2x0 c. to 120xc2x0 C. with an amidine to provide pyrimidine IIc-4. In a similar manner intermediate IIc-6 may be treated with phosphourous oxychloride at reflux either with ot without a cosolvent to produce the intermediate dichloropyrimidine IIc-7, which is a useful intermediate, capable of reacting with a variety of nucleophiles in a manner similar to those depicted in schemes Ia through Ic.
Scheme IId illustrates the synthesis of b-ketoesters from a carboxylic acid which is available by many routes known to one skilled in the art of organic chemistry, for example hydrolysis of an ester. An illustration of a carboxylic acid intermediate useful in the preparation of compounds of formula I is shown in scheme IIIc. A convenient preparation of xcex2-ketoester and xcex2-ketonitriles, from N-methoxy-N-methylamides has been reported by Turner, J. A., and Jacks, W. S in J. Org. Chem., 54, 4229-31, 1989. The carboxylic acid may be converted to the acid chloride by many methods for example treatment with oxalyl chloride in an inert solvent such a methylene chloride with a catalytic amount of N,N-dimethylformamide. Alternatively, the carboxylic acid may be activated by reaction with many available reagents such as BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or a a carbodiimide reagent such as dicyclohexylcarbodiimide with the addition of 1-hydroxybenzotriazole.
Once the carboxylic acid has been activated reaction can occur with N,O-dimethylhydroxylamine hydrochloride or and a suitable base such as triethylamine or pyridine to produce N-methoxy-N-methylamide IId-2. A suitable ester which is either commercially available or readily prepared by a variety of methods known to one skilled in the art of organic synthesis is dissolved in a dry solvent such as tetrahydrofuran and cooled to a temperature in the range of xe2x88x9278xc2x0 C. to xe2x88x9220xc2x0 C., and is added to a precooled solution of a suitable base is added such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Addition of the N-methoxy-N-methylamide to the enolate solution at low temperature for a sufficient amount of time then allowing the reaction mixture to reach room temperature, and quenching with dilute aqueous acid to provide the ketoester IId-3. There are many other means of preparing 5-keto esters, for example, a synthesis of ketoesters from the acid chloride and meldrums acid followed by treatment with alcohol has been reported by Oikawa, Y., Sugano, K., Yonemitsu, O., J. Org. Chem, 43, 2087, 1978.
The ketoester IId-3 is treated with guanidine free base, prepared as described previously, or guanidine carbonate in an alcholic solvent or N,N-dimethylformamide from room temperature to 120xc2x0 C., until the reaction is deemed to have progressed by an analytical method such as TLC or HPLC, to provide the pyrimidone IId-4. Additionally the pyrimidone IId-4 may be treated with phosphorous oxychloride to provide intermediate IId-5. As illustrated in schemes Ia-Ic, the chloropyrimidine is a useful intermediate in the synthesis of additional compounds via a nucleophilic displacement.
Scheme IIe illustrates the preparation of a pyrimidine from a xcex2-ketonitrile. The intermediate IId-2 is reacted with the anion of a nitrile to produce IIe-1. Reaction of IIe-1 with either diazomethane or trimethylsilyldiazomethane in the presence of a suitable base such as triethylamine provides the xcex2-methoxyacrylate derivative IIe-2. Treatment of intermediate IIe-2 with a guanidine at temperatures ranging from 100xc2x0 C. to 200xc2x0 C. in a sealed tube generally provides the desired pyrimidine derivative IIe-3.
Another synthetic route to pyrimidines is also useful for the preparation of compounds in this invention, and is depicted in scheme IIf. For a review of this approach to the synthesis of pyrimidines see Brown, D. J., in Comprehensive Heterocyclic Chemistry Vol. 3, pp. 107-108, (Katritzky A. R., and Rees, C. W ed""s) Pergamon Press Ltd., New York, 1984. Malondiamidine and substituted malondiamidines are readily prepared by one skilled in the art of organic synthesis from the readily available malononitriles by the Pinner reaction (for example see Meyer, H., Kurz, J., in Justus Liebigs Ann. Chem. (9) 1491-1504, 1978). Malonamamidine, the mixed amide amidine, is commercially available. Malondiamidine IIf-1 is heated with an appropriate ester IIf-2 in a suitable solvent such as an alcohol or N,N-dimethylformamidine to provide the desired pyrimidines IIf-3. In a similar manner malonamamidine IIf-4 may be heated with an ester to provide pyrimidine IIf-5.
In Scheme IIg, a triazine IIg-2 is prepared from a carboxylic ester by heating with biguanide IIg-1, (Karipides, D. and Fernelius, W. C., in Inorganic Synthesis 7, pp 56-59, 1962, John Wiley and Sons, New York.) in either an alcoholic solvent or N,N-dimethylformamide at a temperature ranging from 25xc2x0 C. to 80xc2x0 C.
Another synthetic route to pyrimidines is also useful for the preparation of compounds in this invention, and is depicted in scheme IIh. Compounds which contain an aryl or heteroaryl ring with an ortho-aminocarboxamides (IIh-1) are either commercially available or readily available by methods known to one skilled in the art of organic chemistry. Reaction of IIh-1 with either an acid chloride in the presence of a base such as pyridine or an acid group in the presence of a suitable coupling agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, provide intermediate IIh-3. Intermediates of type IIh-3 are readily cyclized to the pyrimidines IIh-4 under a wide variety of conditions which are known to one skilled in the art of organic chemistry, including heating in the presence of pyridine followed by treatment with acid.
The synthesis of additional intermediates useful in the preparation of compounds of formula I is shown in schemes IIIa-IIId.
Scheme IIIa illustrates one method for the preparation of esters useful as intermediates in the preparation of compounds of formula I it should be noted that these and similar compounds including the meta substituted analogs can be prepared by a wide variety of methods known to one skilled in the art of organic synthesis.
Aminomethylbenzoic acid (IIIa-1) and hydroxyaminobenzoic acid (IIIa-6) are commercially available. Aminomethylbenzoic acid (IIIa-1) is reacted with benzylchloroformate in the presence of sodium hydroxide with or without a cosolvent such as dioxane. Acidification of the reaction mixture provides IIIa-2. Treatment of the acid with isobutylene and catalytic sulfuric acid in dioxane in a sealed pressure vessel provides IIIa-3. Hydrogenation in an alcoholic solvent with palladium on carbon provides the intermediate IIIa-4. Arndt-Eistert homologation of IIIa-2 followed by removal of the benzylcarbamate by hydrogenation in the presence of palladium on carbon provides the intermediate IIIa-5.
Hydroxyaminobenzoic acid (IIIa-6) is reacted with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole in a solvent such as tetrahydrofuran. Treatment of the the reaction mixture with dilute base followed by acidification provides the acid IIIa-7. Reaction of the acid with oxalyl chloride in a suitable solvent such as methylenechloride with a catalytic amount of N,N-dimethylformamide provides the acid chloride. The acid chloride is reacted with t-butanol in the presence of pyridine to provide IIIa-8. Treatment of IIIa-8 with tetrabutylammonium fluoride (TBAF) provides the intermediate alcohol IIIa-6.Arndt-Eistert homologation of IIIa-2 followed by removal of the TBDMS group to provide intermediate IIIa-10.
Scheme IIIb illustrates one method for the preparation of additional esters useful as intermediates in the preparation of compounds of formula I it should be noted that these and similar compounds including the meta substituted analogs can be prepared by a wide variety of methods known to one skilled in the art of organic synthesis.
4-Bromophenethylamine (IIIb-1) is commercially available. Reaction with benzyl chloroformate in dioxane in the presence of sodium hydroxide, followed by aryl coupling with commercially available 2-furanboronic acid in the presence of a suitable catalyst such as tetrakistriphenylphosphine palladium (0) to provide IIIb-2. The furan may be converted to the carboxylic acid IIIb-3 by several method including treatment with nitric acid and a vanadium salt (see Carbateas, P. M., and Williams, G. L., in J. Heterocycl. Chem. 11, 819-821, 1974) or by ozonolysis (see, Tsukamoto, T., Yoshiyama, T., Kitazume, T., in Tetrahedron: Asymmetry 2(8), 759-62, 1991). Treatment of the acid with isobutylene in dioxane with a catalytic amount of sulfuric acid followed by catalytic hydrogenation in the presence of palladium on carbon provides intermediate IIIb-4. Alternatively, the acid IIIb-3 may be be subjected to an Arndt-Eistert homologation followed by catalytic hydrogenation to provide intermediate IIIb-5.
4-Bromophenethylalcohol (IIIb-6) is commercially available. Treatment with TBDMSCl and imidazole, followed by aryl coupling with commercially available 2-furanboronic acid in the presence of a suitable catalyst such as tetrakistriphenylphosphine palladium (0) to provide IIIb-7. Oxidation of furan in a manner similar for IIIb-2, provides the acid IIIb-8. The acid can be converted to the acid chloride with oxalyl chloride in methylene chloride with a catalytic amount of N,N-dimethylformamide. Treatment of the acid chloride with t-butanol and pyridine, followed by treatment with tetrabutylammonium fluoride solution provides the intermediate IIIb-9. Alternatively, the acid IIIb-8 may be be subjected to an Arndt-Eistert homologation followed by catalytic hydrogenation to provide intermediate IIIb-10.
Scheme IIIc illustrates one method for the preparation of additional esters useful as intermediates in the preparation of compounds of formula I. It should be noted that these and similar compounds including the meta substituted analogs can be prepared by a wide variety of methods known to one skilled in the art of organic synthesis.illustrates the synthesis of some esters and acids useful as intermediates in the preparation of compounds of formula I.
4-Iodobenzoic acid (IIIc-1) and 3-iodobenzoic acid are commercially available. The preparation of t-Butyl esters can be accomplished by many methods, for example treatment of the the acid with isobutylene in the presence of an acid such as sulfuric acid. The 4-iodoester is subjected to a Heck reaction with methyl acrylate in the presence of palladium acetate according to the method of Jeffrey (Jeffrey, T., J. Chem. Soc., Chem. Commun. 1287-89, 1984.) to provide IIIc-2. Reduction of the double bond can be accomplished under a variety of catalytic hydrogenation conditions for example, palladium on carbon with ammonium formate in methanol at reflux (Tam, S., Spicer, L. D. Syn. Comm. 22(18), 2683-2690, 1992) to provide intermediate IIIc-3. Hydrolysis of the methyl ester in the presence of the t-butyl ester usually requires basic conditions such as lithium or sodium hydroxide, followed by acidification with dilute to provide the mono-acid IIIc-4. The carboxylic acid may be reduced with borane in THF (see Yoon, N. M., Pak, C. S., Brown, H. C., Krishnamurthy, S., Stocky, T. P., in J.Org. Chem. 38, 2786-92, 1973.) to provide the alcohol IIIc-5. Treatment of the alcohol with methansulfonyl chloride and triethylamine to provide the mesylate, which may be reacted with sodium azide in N,N-dimethylformamide, to provide the alkylazide. Reduction of the azide to the intermediate amine IIIc-6 can be accomplished by several methods including hydrogenation with palladium on carbon as the catalyst, or by the Staudinger reaction which involves treatment of the azide with triphenylphosphine followed by treatment with water.
Alternatively the amines prepared in schemes IIIa-c may be converted to the guanidine by several methods including treatment with the commercially available 2-3,5-dimethylpyrazole-1-carboxamidine nitrate.
Scheme IIIe illustrates the synthesis of amidines useful as intermediates in this invention. Alcohols IIIe-1 for example such as IIIa-6, and IIIb-6 are readily converted to the corresponding nitrile IIIe-2 by formation of the sulfate ester followed by treatment with sodium or potassium cyanide. Amidines IIIc-3 are readily prepared by one skilled in the art of organic chemistry by several methods including a method commonly refered to as the Pinner synthesis of amidines which involves treatment of the nitrile with methanol and anhydrous HCl, either with or without, an added solvent such as methylene chloride or chloroform followed by the addition of an amine.
The appropriately substituted racemic xcex2-amino acids may be purchased commercially or, as is shown in Scheme IV, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299). Racemic xcex2-substituted-xcex2-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol Scheme IV, Method 2,or by reductive amination of xcex2-keto esters as is described in published PCT patent application WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58, 7948-51.) Enantiomerically pure xcex2-substituted-xcex2-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding xcex1-amino acids as shown in Scheme IV, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Enal. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme IV, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive treatise on the preparation of xcex2-amino acid derivatives may be found in published PCT patent application WO 9307867, the disclosure of which is hereby incorporated by reference. The synthesis of N2-substituted diaminopropionic acid derivatives as shown in Scheme IV method 5 can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981).
Scheme V depicts the coupling acids prepared in Schemes IIIa and IIIb with the amines prepared in sheme IV Coupling of the resulting acids to appropriately substituted xcex1- or xcex2-amino esters affords an intermediate which can be deprotected to give compounds of Formula (IA). The coupling is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding acid chloride, or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole.
The detailed processes for preparing the compounds of Formula (IA) are illustrated by the following Examples. It is, however, understood that this invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) were measured in chloroform-d (CDCl3) unless otherwise specified and the peaks are reported in parts per million (ppm) downfield from tetramethylsilane (TMS). The coupling patterns are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; m, multiplet.