AU2008325025A1 - Compounds for inhibiting KSP kinesin activity - Google Patents

Compounds for inhibiting KSP kinesin activity Download PDF

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Publication number
AU2008325025A1
AU2008325025A1 AU2008325025A AU2008325025A AU2008325025A1 AU 2008325025 A1 AU2008325025 A1 AU 2008325025A1 AU 2008325025 A AU2008325025 A AU 2008325025A AU 2008325025 A AU2008325025 A AU 2008325025A AU 2008325025 A1 AU2008325025 A1 AU 2008325025A1
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alkyl
group
aryl
ring
heteroaryl
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AU2008325025A
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Angie R. Angeles
Cliff Cheng
Chaoyang Dai
Xiaohua Huang
Umar Faruk Mansoor
Gerald W. Shipps Jr.
Arshad M. Siddiqui
Lalalnthi Dilrukshi Vitharana
Liping Yang
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Merck Sharp and Dohme LLC
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system

Description

WO 2009/061596 PCT/US2008/080176 COMPOUNDS FOR INHIBITING KSP KINESIN ACTIVITY Priority 5 This application claims the benefit of priority of U.S. Provisional Application No.: 60/986,799, filed, November 9, 2007, the contents of which are incorporated in their entirety herein by reference. FIELD OF THE INVENTION 10 The present invention relates to compounds and compositions that are useful for treating cellular proliferative diseases or disorders associated with Kinesin Spindle Protein ("KSP") kinesin activity and for inhibiting KSP kinesin activity. BACKGROUND OF THE INVENTION 15 Cancer is a leading cause of death in the United States and throughout the world. Cancer cells are often characterized by constitutive proliferative signals, defects in cell cycle checkpoints, as well as defects in apoptotic pathways. There is a great need for the development of new chemotherapeutic drugs that can block cell proliferation and enhance apoptosis of tumor cells. 20 Conventional therapeutic agents used to treat cancer include taxanes and vinca alkaloids, which target microtubules. Microtubules are an integral structural element of the mitotic spindle, which is responsible for the distribution of the duplicated sister chromatids to each of the daughter cells that result from cell division. Disruption of microtubules or interference with microtubule dynamics 25 can inhibit cell division and induce apoptosis. However, microtubules are also important structural elements in non proliferative cells. For example, they are required for organelle and vesicle transport within the cell or along axons. Since microtubule-targeted drugs do not discriminate between these different structures, they can have undesirable side 30 effects that limit usefulness and dosage. There is a need for chemotherapeutic agents with improved specificity to avoid side effects and improve efficacy.
WO 2009/061596 PCT/US2008/080176 -2 Microtubules rely on two classes of motor proteins, the kinesins and dyneins, for their function. Kinesins are motor proteins that generate motion along microtubules. They are characterized by a conserved motor domain, which is approximately 320 amino acids in length. The motor domain binds and 5 hydrolyses ATP as an energy source to drive directional movement of cellular cargo along microtubules and also contains the microtubule binding interface (Mandelkow and Mandelkow, Trends Cell Biol. 2002, 12:585-591). Kinesins exhibit a high degree of functional diversity, and several kinesins are specifically required during mitosis and cell division. Different mitotic kinesins 10 are involved in all aspects of mitosis, including the formation of a bipolar spindle, spindle dynamics, and chromosome movement. Thus, interference with the function of mitotic kinesins can disrupt normal mitosis and block cell division. Specifically, the mitotic kinesin KSP (also termed EGS), which is required for centrosome separation, was shown to have an essential function during mitosis. 15 Cells in which KSP function is inhibited arrest in mitosis with unseparated centrosomes (Blangy et al., Cell 1995, 83:1159-1169). This leads to the formation of a monoastral array of microtubules, at the end of which the duplicated chromatids are attached in a rosette-like configuration. Further, this mitotic arrest leads to growth inhibition of tumor cells (Kaiser et aL, J. Biol Chem. 20 1999, 274:18925-18931). Inhibitors of KSP would be desirable for the treatment of proliferative diseases, such as cancer. Kinesin inhibitors are known, and several molecules have recently been described in the literature. For example, adociasulfate-2 inhibits the microtubule stimulated ATPase activity of several kinesins, including CENP-E (Sakowicz et 25 al, Science 1998, 280:292-295). Rose Bengal lactone, another non-selective inhibitor, interferes with kinesin function by blocking the microtubule binding site (Hopkins et al., Biochemistry 2000, 39:2805-2814). Monastrol, a compound that has been isolated using a phenotypic screen, is a selective inhibitor of the KSP motor domain (Mayer et al., Science 1999, 286:971-974). Treatment of cells with 30 monastrol arrests cells in mitosis with monopolar spindles. KSP inhibitors have been disclosed in patents or publications, including: W02006/031348, W02006/110390, W02006/068933, W02006/023083, WO 2009/061596 PCT/US2008/080176 -3 W02006/007491, WQ20061086358, W02003/105855, W02006/023440, W02003/079973, W02004/087050, WQ2004/111193, W02004/112699, W02006/007497, WO2006/101761, W02006/007496, W02005/017190, W00224/037171, W02005/019205, W02005/019206, W02005/102996, 5 W02006/101780, W02006/007501, W02005/018547, W02004/058148, W02004/058700, W02005/018638, W02007/054138, W02006/133805, W02006/002726, W02006/133821, W02005/108355, W02006/094602, W02005/09201 1, W02006/031607, W02004/111023, W02006/137490, W02006/101102, W02006/101103, W02006/101104, W02006/101105, 10 W02004/092147, W02005/035512, W02006/044825, W02006/044825, W02006/119146, US2006/0247178, W02006/098961, W02006/098962, US2006/0258699, US2007/0213380, US2007/0112044, US2007/0155804, US2008/0194653, W02008/042928, US2007/0249636, US2007/0287703, US2008/0153854, and US2007/0037853. 15 KSP, as well as other mitotic kinesins, are attractive targets for the discovery of novel chemotherapeutics with anti-proliferative activity. There is a need for compounds useful in the inhibition of KSP, and in the treatment of proliferative diseases, such as cancer. SUMMARY OF THE INVENTION 20 In one embodiment, the present invention provides a compound, or pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compound, said compound having the general structure shown in Formula (1): R1 R 27 R 2 B N, A R P N R 2 (2) 25 WO 2009/061596 PCT/US2008/080176 -4 wherein R, R 2 W, p, R 27 , R 28 , E, ring A, and ring B are selected independently of each other and wherein: p is 0, 1, 2, 3, or 4; ring A (including E and the unsaturation shown) is a 4-8 membered cycloalkenyl 5 or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R 4
)(R
5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R'%))-, -C(O)-N(R)-, -N(R')-C(O)-, -S(0) 2
-N(R
1 )-, -N(R 1 )-S(0) 2 -, -C(Q)-Q-, -0-C(O)-, -0-N(R 6 )_,
-N(R
6 )-O-, -N(R3)-N(R 12 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R)=N-, -C(O)-N=N-, 10 -0-C(Y)-N(R")-, -N(R')-C(Y)-O-, -N(R 1
')-C(Y)-N(R
2 )-, -C(Y)-N(R'')-O-,
-C(Y)-N(R
1
)-N(R'
2 )-, -O-N(R')-C(Y)-, and -N(R' 2
)-N(R
1 )-C(Y)-, wherein each Y is independently selected from the group consisting of (=0), (=S), (=N(R 1 3 )), (=N(CN)), (=N(OR' 4 )), (=N(R' 5 )(R'6)), and (=C(R1)(R 1 8 )); 15 ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring, wherein said ring is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of 20 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
2 0 , -NR 2 1 R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 2 4 , -C(O)OR 2 0 , -SR's, -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 25 -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 ; R' is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said WO 2009/061596 PCT/US2008/080176 -5 heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 5 alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloakyl, heterocycloalkenyl, azido, -OR'9,
-OC(O)OR
20 , -NR 2 1
R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR23C(O)R 24 ,
-SO
2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR9, -S(O)R'9, -SO 2
R"
9 , -OC(O)R 24
-C(O)NR
2 sR 26 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 23
(O)NR
25
R
26 ; 10 R 2 is selected from the group consisting of -C(Z)R 7 , -C(Z)NR 9
R
0 , -C(Z)OR,
-SO
2
NR
9
R'
0 , alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each Z is independently selected from the group consisting of (=0), (=S), (=N(R 1 )), (=N(CN)), (=N(OR 1 4)), (=N(R' 5
)(R'
6 )), and 15 (=C(R 17 )(R')), and wherein each said alkyl, each said heteroalkyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which 20 can be the same or different, each substituent being independently selected from the group consisting of oxo (with the proviso that said aryl and said heteroaryl are not substituted with oxo), halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, 25 heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , -OC(O)OR 20 , -NR 2
'
2
-NR
2 3 S02R 24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -SO 2 N R 25
R
26 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR 19 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6
R
27 (when not joined with R 2 8) is independently selected from the group 30 consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, WO 2009/061596 PCT/US2008/080176 halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR 2 1 R 22 , -NR 23
SO
2 R24
-NRC
2 3
(O)OR
2 0 , -NR 23 C(O)R 24 , -SO 2
NR
2 5
R
2 3, -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R', -SO 2
R'
9 , -OC(O)R24, -C(O)NR 25
R
2 6 , -NR 2 3
C(N-CN)NR
25
R
2 6 and -NR 2 3 C(O)N R 2 5
R
2 6 , 5 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkeny, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more 10 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , 15 -NR 23
C(O)R
24 , -SO 2
NR
2
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR 9 , -S(O)R' 9 , -SO2R19, -OC(O)R 2 4 , -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
25
R
2 6 and -NR 23 C(O)NR 25
R
2 6 ;
R
28 (when not joined with R 27 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, 20 aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 2R 22 , -NR 23 SO2R 2 4 ,
-NR
23
C(O)OR
20 , -NR 23 C(O)R 24 , -SO 2 NR 25
R
2 6 , -C(O) R24, -C(O)OR 20 , -SR' ,
-S(O)R
9 , -SO 2
R
9 , -OC(O)R 24 , -C(O)NR 25
R
2 3, -NR 23
C(N-CN)N
25
R
2 and
-NR
2
C(O)NR
2 5
R
2 6 , 25 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more 30 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 -7 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2 R24, -NR 23
C()OR
20 ,
-NR
2
C(O)R
24 , -S0 2
NRR
2
R
2 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , 5 -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25 R2 6 , -NRC 2 3 (N-CN)N R 25
R
2 6 and
-NR
23
C(O)NR
2 5
R
2 ; or, alternatively, R 27 and R 28 , together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, 10 or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent 15 being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 ,
-OC(O)OR
2 0 , -NR 2 1 R2, -NR 23
SO
2
R
24 , -NRC 23
(O)OR
2 0 , -NR 23
C(O)R
24 , 20 -S0 2
NR
5
R
2 , -C(O)R 4 , -C(O)OR 20 , -SR', -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 4 , -C(0)NR 2
R
6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 23 C()N 25 R2 6 each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, 25 -NO 2 , -OR 19 , -OC(O)OR 20 , -NR 2 1 R 2 2 , -NR 23 S02R 24 , -NR 23
C(O)OR
20 ,
-NRC
23
(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R24, -C(S)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 ,
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 , -NR 2 3
C(N-CN)NR
2 5
R
26 , -NR 23 C(O)NR 25 26 , and -NR- 23
C(NH)-N(R
2 6
)
2 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each 30 said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, WO 2009/061596 PCT/US2008/080176 each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 5 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)OR 2 , -NR 2R 2 2 , -NR 23
SO
2
R
2 4 , -NR 23
C(O)OR
2 0 ,
-NR
23
C(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R 9 ,
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 6R 2 6 and 10 -NR 23
C(O)NR
2 5
R
26 , or, alternatively, when p is 2, 3, or 4, any two R 3 groups bound to the same ring carbon atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, or a spiroheterocycloalkyl ring containing from one to three ring heteroatoms 15 independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(O) 2 -, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-, or, alternatively, R 2 and R3, together with the atom to which they are 20 attached, are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms 25 independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(0)-, -S(0)2-, and -0-; each R4 (when not joined with R) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 30 halogen, -CN, -NO 2 , -OR'9, -OC(O)OR20, -NR 21
R
22 , -NR 23 S02R 24 , -NR 23C(O)OR20, -NR23C(O)R24, -SO 2
NR
25
R
2 6 , -C(O)R 2 4 , -C(O)OR 2 0 , -SR'9, WO 2009/061596 PCT/US2008/080176 -9
-S(O)R
19 , -SO2R' 9 , -OC()R24, -C(O)NR 2
R
2 6 , -NR 23
C(N-CN)NR
25 Rae and
-NR
2 3
C(O)NR
25
R
2 t wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 5 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 10 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
20 ,
-NR
23
C(O)R
24 , -S0 2
NR
2
-R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO2R 1 9, -OC(O)R 24 , -C(O)NR 2 5
R
2 3, -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 15 -NR 23
C(O)NR
25
R
26 each R 5 (when not joined with R 4 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR1 9 , -OC(O)OR 20 , -NR 1
R
22 , -NR 23 S0 2
R
24 , 20 -NR 2 3 C(0)OR 20 , -NR 23 C(O)R24, -S0 2
NR
25
R
2 3, -C(O)R24, -C(O)OR 2 0 , -SR' 9 ,
-S(O)R'
9 , -SO21 9 , -OC(O)R 2 4 , -C(O)NR 25
R
26 , -NR 23
C(N-CN)NR
2 5
R
2 6 and
-NR
23 C(O)N R 25
R
26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 25 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 30 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, WO 2009/061596 PCT/US2008/080176 -10 azido, -OR19, -OC(O)OR 2 0, -NR 21
R
22 , -NR 23 S0 2 R24, -NR 23
C(O)OR
2 0 ,
-NRC
23 (O)R24, -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR 1 9 , -S(O)R' 9 , -S0 2
R
1 9, -OC(O)R 24 , -C(O)NR 25
R
26 , -NR 23
C(N-CN)NR
2 R 26 and
-NR
2
C(O)NR
25
R
26 , 5 or, alternatively, R 4 and R5, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, 10 wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 15 haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR',
-OC(O)OR
20 , -NRR 2 'R 2 2 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , -NR23C(O)R 24 , -S0 2
NR
25
R
26 , -C(O)R 2 4 , -C(O)OR 2 0 , -SR 1 9 , -S(O)R' 9 , -S0 2
R
1 9 , -OC(O)R 2 4 ,
-C(O)NR
25
R
2 , -NR 23
C(N-CN)NR
2 5
R
26 and -NR 23
C(O)NR
2
R
2 6 ; 20 each R 6 is independently selected from the group consisting of H, alkyl, -C(O)R 2 4 ,
-C(O)OR
2 0 , -C(S)R 2 4 , heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 25 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 30 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, WO 2009/061596 PCT/US2008/080176 - 11 azido, -OR'9, -OC(O)OR 20 , -NR 2 1 R22, -NR 23
SO
2
R
24 , -NR 23
C(O)R
2 4,
-NR
23 C(O)R24, -SO 2
NR
2 5 R26, -C(O)R24, -C(S)R24, -C(O)OR20, -SR' 9 , -S(O)R'9, -S02R', -OC(O)R24, -C(O)NR 25R26, -NR 2 3
C(N-CN)NR
25
R
2 6 and
-NR
23 C(O)NR 25R2 5 each R7 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 10 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 15 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2, -NR 2 1
R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 ,
-NR
23
C(O)R
2 4 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR2o, -SR', -S(O)R'9, -SO2R'9, -OC(O)R24, -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 20 -NR 23 C(0)NR 25 2 each R8 is independently selected from the group consisting of H, alkyl, heteroalkyl. alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each 25 said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being 30 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 -12 heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalky, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 . -NR 21
R
2 2 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
20 ,
-NR
23 C(O)R 24 , -SO 2
NR
2 sR 2 6 , -C(O)R24, -C(O)OR 20 , -SR 1 , -S(O)R'9,
-SO
2 R1 9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 , -NRC 23
(N-CN)NR
2 5
R
2 5 and 5 -NR 2
C(O)NR
25
R
2 e each R 9 (when not joined with R 1 0 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each 10 said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being 15 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2 0 , -NR 2
R
22 , -NR 23
SO
2
R
2 4 , -NRC 23
(O)OR
20 ,
-NR
23
C(O)R
24 , -S0 2 NR2 5
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(0)R 9 , 20 -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR2R2 6 , -NR 23 C(N-CN)N R 25
R
26 and
-NRC(O)NR
52 6 R each R' 0 (when not joined with R 9 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 25 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more 30 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 13 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)ORao, -NR 2 ' R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 ,
-NR
23 C(O)R24, -S0 2
NR
25
R
2 3, -C(O)R24, -C(O)OR2 0 , -SR' 9 , -S(0)R 9 , 5 -SO2R' 9 , -OC(O)R 24 , -C(O)NR 25
R
2 t, -NR 2 3
C(N-CN)NR
2
R
2 6 and
-NR
2 3 C(O)N R 25
R
2 6 ; or, alternatively, R9 and R' 1 , together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, 10 wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 15 haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'",
-OC(O)OR
20 , -NR 2 1 R 22 , -NR 2 3S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 ,
-SO
2 N R 25
R
26 , -C(O) R 24 , -C(O)OR2 0 , -SR19, -S(O)R'9, -SO2R', -OC(O)R 2 4 ,
-C(O)NR
2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 20 each R" is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 25 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 30 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, WO 2009/061596 PCT/US2008/080176 - 14 azido, -OR' 9 , -OC(O)R 20 , -NR21R 2 2 , -NR 23
SO
2 R24, -NR 23
C(O)OR
2 0
-NR
23
C(O)R
24 , -S0 2
NR
2 5
R
2 , -C(O)R24, -C(O)OR 2 0 , -SR', -S(O)R' 9 ,
-SO
2 R9, -OC(O)R 24 , -C(O)N 25 R 26, -NR 23
C(N-CN)NR
25
R
2 6 and
-NR
2
C(O)NR
25 Re) 5 each R1 2 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said 10 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, 15 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido. -OR', -OC(O)OR 20 , -NR21R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)R
2 0 ,
-NRC
2 3
(O)R
2 4 , -SO 2
NR
2 5R 2 , -C(O)R 24 , -C(O)OR 2 0 , -SR 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 2 4 , -C(O)NRR 2 5 Rl 26 , -NR 2 3
C(N-CN)NRR
2 5
R
26 and 20 -NR 2
C(O)NR
2 RI each R 13 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each 25 said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being 30 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 - 15 heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalky, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NRR 21
R
22 , -NR 23
SO
2 R24, -NR 23
C(O)R
20 ,
-NR
23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)R 20 , -SR' 1 , -S(O)R' 9 , -S02R' 9 , -OC(O)R -C(O)NR 25 fR 2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 5 -NR 2 3
C(O)NR
2 5
R
2 F each R1 4 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloal kyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each 10 said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being 15 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroary, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR20, -NR 21
R
22 , -NR 23
SO
2 R24, -NR 23
C()R
20 ,
-NRC
23
(O)R
24 , -S0 2
NR
2 -8 2 6 , -C(O)R 24 , -C(O)R 20 , -SR 1 9 , -S(O)R' 9 , 20 -SO2R'9, -OC(O)R 24 , -C(O)NRR 25 f 26 , -NRC 23
(N-CN)NRR
25 f 26 and
-NR
2
C(O)NR
5
R
26 each R 5 (when not joined with R1 6 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 25 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more 30 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 16 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0, -NR 2 1 R 22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
20 ,
-NRC
23
(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , 5 -S0 2
R'
9 , -OC(O)R24, -C(O)NR 25
R
2 6 , -NR 2 3 C(N-CN)N 25
R
26 and
-NR
23
C(O)NR
25
R
2 each R' 6 (when not joined with R1 5 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 10 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more 15 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyi, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)OR2 0 , -NRE 1
R
22 , -NR 23 SO2R2 4 , -NRE 3 C(O)R20, 20 -NRE 3 C(O)R2 4 , -SO 2
NRE
5 R2 6 , -C(O)R2 4 , -C(O)OR2 0 , -SR'9, -S(O)R' 9 , -S02R 9 , -OC(O)R 24 , -C(O)NRE5R26, -NR 3
C(N-CN)NV
5
R
26 and
-NREC(O)NRE
5 R2. or, alternatively, R" and R'", together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from 25 one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, 30 -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, WO 2009/061596 PCT/US2008/080176 - 17 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR',
-OC(O)OR
2 0 , -NR 21
R
22 , -NR 23
SO
2 R24, -NRC 23 (O)OR2t, -NR 23
C(O)R
24 , -S0 2
NR
25 R2 6 , -C(0)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SQ 2
R'
9 , -OC(O)R 24 , -C(O)NR2 5
R
2 6 , -NR 2
C(N-CN)NR
25
R
26 and -NR 23
C(O)NR
2 5
H
2 6 ; 5 each R' 7 (when not joined with R 8 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(O)OR 20 , -OR' 9 , -NR 2
R
22 , -NR 23 SO2R 24 , -NR 23
C(O)OR
20 ,
-NR
23 C(O)R 2 4 , -SO 2 N R 25
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S02R 9 , 10 -OC(O)R 24 , -C(O)NR 25
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2
C(O)NR
2
R
2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is 15 unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 20 azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2
R
22 , -NR 23 SO2R 24 , -NR 23
C(O)OR
2 0 ,
-NR
23
C(O)R
24 , -S0 2 NR2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 ,
-SO
2 R', -OC(0)R 24 , -C(O)NR 25 R2 6 , -NR 23 C(N-CN)NR 25
R
2 6 and -NR 23 C(O)NR R 25
.
2 6 ; each R8 (when not joined with R' 7 ) is independently selected from the group 25 consisting of H, alkyl, heteroalkyl, alkenyi, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(0)OR 20 , -OR' 9 , -NR 2
R
22 , -NR 23 S02R 24 , -NR 2
C(O)OR
20 , -NR 23 C(O)R 24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' , -S(O)R'9, -SO 2 R'9,
-OC(O)R
24 , -C(O)NR 25
R
26 , -NR 2 3 C(N-CN)NR2 5
R
2 6 and -NR 23
C(O)NR
25
R
2 6 , 30 wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said WO 2009/061596 PCT/US2008/080176 - 18 aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being 5 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9 , -OC(O)OR 20 , -NR 2 1
R
22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
20 ,
-NR
23
C(O)R
24 , -S0 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 2 0 , -SR 9 , -S(O)R 9 , 10 -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
25
R
2 3 and
-NRC
23
(O)NR
25
R
2 6 or, alternatively, R 17 and R 1 8 , together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, 15 or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent 20 being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' ,
-OC(O)OR
2 0 , -NR 2 ' R 22 , -NR 2 3
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NRC 23
(O)R
24 , 25 -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R 9 , -SO 2
R'
9 , -OC(O)R 24 ,
-C(O)NR
25
R
26 , -NR 23
C(N-CN)NR
5
R
26 and -NRC(O)NRR 2 ; each R 1 8 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 20 is independently selected from the group consisting of H, alkyl, 30 haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; WO 2009/061596 PCT/US2008/080176 -19 each R 21 (when not joined with R 22 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 22 (when not joined with R 21 ) is independently selected from the group 5 consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or, alternatively, R 21 and R 22 , together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S; 10 each R 23 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 24 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 25 (when not joined with R 26 ) is independently selected from the group 15 consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; and each R 26 (when not joined with R2 5 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; 20 or, alternatively, R and R23, together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. As explained in more detail below, it shall be understood that ring A can have unsaturation in addition to the unsaturation shown in the generic formulas 25 provided herein. Pharmaceutical formulations or compositions comprising a therapeutically effective amount of at least one of the inventive compounds, and/or WO 2009/061596 PCT/US2008/080176 - 20 pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers thereof and a pharmaceutically acceptable carrier also are provided. Pharmaceutical formulations or compositions comprising a therapeutically effective amount of at least one of the inventive compounds (and/or pharmaceutically acceptable salts, 5 solvates, esters, prodrugs, or isomers thereof) and a pharmaceutically acceptable carrier together with one or more additional active ingredients are also contemplated. Methods of treating cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject 10 comprising administering to a subject in need of such treatment an effective amount of at least one of the inventive compounds or formulations or compositions according to the invention are also are provided. The methods according to the invention may be used in a single agent regimen or as part of a multiple agent regimen as is determined appropriate by those skilled in the art. 15 Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." 20 DETAILED DESCRIPTION In one embodiment, the compounds of the invention have a structure shown in Formula (1) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds. As stated in Formula (1) (and in other formulas described herein depicting 25 various embodiments of the compounds of the invention), ring A is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring. It shall be understood that such cycloalkenyl or heterocycloalkenyl rings of ring A can have unsaturation that is in addition to the unsaturation shown in the generic formulas provided herein. For purposes of illustration only, non-limiting examples of such additional 30 unsaturation in ring A include: WO 2009/061596 PCT/US2008/080176 -21 R1I R27 R 28 N N A E
R
2
R
3 Additional non-limiting examples include: R1 R 28 R R 27 R 21 R27 R2 B BR R 27
R
2 Ft B a R4 I I I. NA O N A N~ 130 3 2 6 N
R
2 R R , and R? . In one embodiment, in Formula (1), ring A is a cycloalkenyl ring. 5 In one embodiment, in Formula (1), ring A is a heterocycloalkenyl ring. In one embodiment, in Formula (1), ring A is a 4-membered ring. In one embodiment, in Formula (1), ring A is a 5-membered ring. In one embodiment, in Formula (1), ring A is a 6-membered ring. 10 In one embodiment, in Formula (1), ring A is a 7-membered ring. In one embodiment, in Formula (1), ring A is an 8-membered ring. In one embodiment, in Formula (1), ring A (including the unsaturation shown) is mono-unsatu rated. 15 In one embodiment, in Formula (1), ring A (including the unsaturation shown) is poly-unsaturated. In one embodiment, in Formula (1), E is -C(R 4
)(R
5
)-.
WO 2009/061596 PCT/US2008/080176 -22 In one embodiment, in Formula (1), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R 6 )-, -N(C(Y)R 7 )_, -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R")-, -N(R')-S(0) 2 -, -C(0)-O-, -0-C(O)-, -0-N(R)-, -N(R 6 )-O-, -N(R6)-N(R 12 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, 5 -C(O)-N=N-, -O-C(Y)-N(R')-, -N(R')-C(Y)-O-, -N(R')-C(Y)-N(R 2 )-, -C(Y)-N(R")-O-, -C(Y)-N(R")-N(R1 2 )-, -0-N(R)-C(Y)-, and -N(R1 2 )-N(R)-C(Y)-. In one embodiment, in Formula (1), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R6)-. In one embodiment, in Formula (1), E is selected from the group consisting of -0-, 10 -S-, -S(0)-, -S(0)2-, and -N(Rr)-, wherein R6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR20, and -C(S)R 24 In one embodiment, in Formula (1), E is selected from the group consisting of -0 and -N(R 6 )-, wherein R6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR2, and -C(S)R24. 15 In one embodiment, in Formula (1), when E is -N(R 6 )-, then p is 0 and R 3 is absent. In such embodiments, non-limiting examples of R6 include H, alkyl, -C(O)R24, -C(O)OR2, and -C(S)R24 In one embodiment, in Formula (1), E is -0-. In one embodiment, in Formula (1), E is -S-. 20 In one embodiment, in Formula (1), E is -S(0)-. In one embodiment, in Formula (1), E is -S(0)2-. In one embodiment, in Formula (1), E is -CH 2 -. In one embodiment, in Formula (I), E is -CHR.4 In one embodiment, in Formula (1), E is -CRR 25 In one embodiment, in Formula (1), E is -N(R4)-. In one embodiment, in Formula (I), E is -N(C(Y))-. In one embodiment, in Formula (1), E is -N(C(Y)OR%).
WO 2009/061596 PCT/US2008/080176 - 23 In one embodiment, in Formula (1), E is -N(C(Y)N(R9)(R' 0 ))-. In one embodiment, in Formula (1), E is -C(O)-N(R")-. In one embodiment, in Formula (I), E is -N(R)-C(O)-. In one embodiment, in Formula (1), E is -S(O) 2 -N(R")-. 5 In one embodiment, in Formula (1), E is -N(R')-S(O) 2 -. In one embodiment, in Formula (1), E is -C(O)-O-. In one embodiment, in Formula (1), E is -0-C(O)-. In one embodiment, in Formula (1), E is -Q-N(R 6 )-. In one embodiment, in Formula (1), E is -N(R6)-0-. 10 In one embodiment, in Formula (1), E is -N(R 6 )-N(R1 2 )-. In one embodiment, in Formula (1), E is -N=N-. In one embodiment, in Formula (1), E is -C(R7)=N-. In one embodiment, in Formula (1), E is -C(O)-C(R 7 )=N-. In one embodiment, in Formula (1), E is -C(O)-N=N-. 15 In one embodiment, in Formula (1), E is -Q-C(Y)-N(R 1 )-. In one embodiment, in Formula (1), E is -N(R')-C(Y)-O-. In one embodiment, in Formula (I), E is -N(R)-C(Y)-N(R 2 )-. In one embodiment, in Formula (1), E is -C(Y)-N(R')-O-. In one embodiment, in Formula (1), E is -C(Y)-N(R 1
)-N(R
2 )-. 20 In one embodiment, in Formula (1), E is -0-N(R)-C(Y)-. In one embodiment, in Formula (1), E is -N(R' 2
)-N(R
1
)-C(Y)-.
WO 2009/061596 PCT/US2008/080176 -24 In one embodiment, in Formula (1), Y is (=0). In one embodiment, in Formula (1), Y is (=S). In one embodiment, in Formula (1), Y is (=N(R)). 5 In one embodiment, in Formula (1), Y is (=N(CN)). In one embodiment, in Formula (1), Y is (=N(OR1 4 )). In one embodiment, in Formula (1), Y is (=N(R 15
)(R'
6 )). In one embodiment, in Formula (1), Y is (=C(R1 7 )(R)). 10 In one embodiment, in Formula (1), ring A is a 4-7-membered cycloalkylene ring and E is -C(R4)(R 5 )-. In one embodiment, in Formula (1), ring A is a 5-7-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, 15 -N(R 6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R
10 ))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R')-, -N(R 1 )-S(0) 2 -, -C(0)-0-, -0-C(O)-, -0-N(R)-, -N(R6)-O-, -N(R6)-N(R 1)-, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -Q-C(Y)-N(R")-, -N(R')-C(Y)-O-, -N(R")-C(Y)-N(R1)-, -C(Y)-N(R)-O-, -C(Y)-N(R")-N(R1 2 )-, -0-N(R' 1 )-C(Y)-, and -N(R' 2 )-N(R%)-C(Y)-. 20 In one embodiment, in Formula (1), ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-,
-N(R
6 )-, -C(O)-N(R)-, and -N(R 1 )-C(O)-. 25 In one embodiment, in Formula (1), ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and WO 2009/061596 PCT/US2008/080176 - 25 -N(R)-. In one such embodiment, in Formula (1), R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and -C(S)R 24 In one embodiment, in Formula (1), ring A is a 5-6-membered heterocycloalkylene 5 ring and E is selected from the group consisting of -0- and -N(R 6 )-. In one such embodiment, in Formula (1), R 6 is selected from the group consisting of H, alkyl,
-C(O)R
24 , -C(O)OR 20 , and -C(S)R 24 . In one such embodiment, in Formula (I), ring A is a 5-membered heterocycloalkylene ring. In another such embodiment, in Formula (1), ring A is a 6-membered heterocycloalkylene ring. 10 In one embodiment, in Formula (1), ring A is a 4-membered ring and E is -C(R 4)(R 5)-. In one embodiment, in Formula (1), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -N(R)-, -N(C(Y)R 7 )-, 15 -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R')))-, -C(0)-N(R 1 )-, -N(R' 1 )-C(O)-, -S(0) 2 -N(R")-, -N(R")-S(0) 2 -, -C(O)-O-, -0-C(O)-, -0-N(R 6 )-, -N(R)-O-, -N(R)-N(R1)-, -N=N-,
-C(R
7 )=N-, -C(O)-C(R7)=N-, -C(O)-N=N-, -0-C(Y)-N(R)-, -N(R'')-C(Y)-O-, -N(R'l)-C(Y)-N(R' 2 )-, -C(Y)-N(R' 1 )-O-, -C(Y)-N(R")-N(R 2 )-, -0-N(R)-C(Y)-, and
-N(R
12 )-N(R)-C(Y)-. 20 In one embodiment, in Formula (I), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)-, and -N(R 6 )_ In one embodiment, in Formula (1), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(Q) 2 -, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and 25 -C(S)R 2 4 In one embodiment, in Formula (1), ring A is a 4-membered ring and E is selected from the group consisting of -0- and -N(R )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR 20 , and -C(S)R 2 4 WO 2009/061596 PCT/US2008/080176 -26 In one embodiment, in Formula (1), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R 6 )-,
-N(C(Y)R
7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R'))-. 5 in one embodiment, in Formula (1), A is a 4-membered ring and E is selected from the group consisting of -CH 2 -, -CH(R 4 )-, -C(R4)(R 5 )-, In one embodiment, in Formula (1), ring A is a 5-membered ring and E is -C(R 4)(R-5) 10 In one embodiment, in Formula (1), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 6 )-, -N(C(Y)R 7 )_, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R)-,
-N(R
1 )-S(0) 2 -, -C(0)-0-, -0-C(0)-, -0-N(R)-, -N(R)-O-, -N(R 6
)-N(R
12 )-, -N=N-, -C(R 7)=N-, -C(0)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R")-C(Y)-O-, 15 -N(R)-C(Y)-N(R 2 )-, -C(Y)-N(R)-O-, -C(Y)-N(R")-N(R 12 )-, -0-N(R")-C(Y)-, and
-N(R
12 )-N(R')-C(Y)-. In one embodiment, in Formula (1), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )_. In one embodiment, in Formula (1), ring A is a 5-membered ring and E is selected 20 from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R6)-, wherein R3 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 2 0 , and
-C(S)R
24 In one embodiment, in Formula (1), ring A is a 5-membered ring and E is selected from the group consisting of -0- and -N(R 6 )-, wherein R 6 is selected from the 25 group consisting of H, alkyl, -C(O)R24, -C(O)OR 2 0 , and -C(S)R24 In one embodiment, in Formula (1), ring A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R4)(R 5 )-, -N(R)-, WO 2009/061596 PCT/US2008/080176 -27 -N(C(Y)R 7 )-, -N(C(Y)OR")-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R)-, -N(R' 1 )-C(O)-, -S(0) 2 -N(R")-, -N(R")-S(0) 2 -, -C(0)-0-, -0-C(O)-, -O-N(R)-, -N(R)-O-,
-N(R)-N(R)
12 , -N=N-, and -C(R7)=N-. 5 In one embodiment, in Formula (1), A is a 5-membered ring and E is -0-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -S-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -S(O)-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -S(0)2-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -C(R4)(R 5 )-. 10 In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(R 6 )-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(C(Y)R 7 )-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(C(Y)OR)-. In one embodiment, in Formula (1), A is a 5-membered ring and E is 15 -N(C(Y)N(R")10. In one embodiment, in Formula (1), A is a 5-membered ring and E is
-C(O)-N(R
11 )-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(R")-C(O)-. 20 In one embodiment, in Formula (I), A is a 5-membered ring and E is -S(0) 2 -N(R1)-. In one embodiment, in Formula (I), A is a 5-membered ring and E is -N(Rem)-S(o)e. In one embodiment, in Formula (1), A is a 5-membered ring and E is -C(0)-O. 25 In one embodiment, in Formula (1), A is a 5-membered ring and E is -0-C(O)-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -O-N(R)-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(R6)-O_.
WO 2009/061596 PCT/US2008/080176 - 28 In one embodiment, in Formula (1), A is a 5-membered ring and E is -N(R)-N(R e)-. In one embodiment, in Formula (I), A is a 5-membered ring and E is -N=N-. In one embodiment, in Formula (1), A is a 5-membered ring and E is -C(R7)=N-. 5 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -C(R 4)(R5) In one embodiment, in Formula (1), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R 6 )-, -N(C(Y)R 7 )-, 10 -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R
0 ))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R)-,
-N(R'
1 )-S(0) 2 -, -C(O)-O-, -0-C(0)-, -0-N(R 6 )-, -N(R 6 )-O-, -N(R)-N(R' 2 )-, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R")-C(Y)-O-,
-N(R")-C(Y)-N(R'
2 )-, -C(Y)-N(R' 1 )-O-, -C(Y)-N(R)-N(R 12 )-, -O-N(R 1 )-C(Y)-, and
-N(R
12 )-N(R )-C(Y)-. 15 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and 204 20 -C(S)R2 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is selected from the group consisting of -0- and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and -C(S)R 2 4 . In one embodiment, in Formula (1), A is a 6-membered ring and E is selected 25 from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R 4 )(R5)-, -N(R 6 )-,
-N(C(Y)R
7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R'))-, -C(O)-N(R")-, -N(R')-C(O)-, -S(0) 2 -N(R')-, -N(R")-S(O)2-, -C(0)-O-, -0-C(O)-, -0-N(R6)-, -N(R6)-O-, -N(R6)-N(R12)-, -N=N-, -C(R7)=N-, -C(O)-C(R7)=N-, -C(O)-N=N-, WO 2009/061596 PCT/US2008/080176 -29 -O-C(Y)-N(R")-, -N(R")-C(Y)-0-, -N(R")-C(Y)-N(R 12)-, -C(Y)-N(R' )-O-,
-C(Y)-N(R')-N(R'
2 )-, -O-N(R')-C(Y)-, and -N(R 1 2 )-N(R")-C(Y)-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -0-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -S-. 5 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -S(O)-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -S(0) 2 -. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is
-C(R
4
)(R
5 )-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R6 10 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is
-N(C(Y)R
7 )_. In one embodiment, in Formula (I), ring A is a 6-membered ring and E is
-N(C(Y)OR
8 )_. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is 15 -N(C(Y)N(R9)(R'4))-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -C(O)-N(R1)-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R")-C(O)-. 20 In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -S(o)2-N(Rm)-, In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(Rll)-S(0)2-- WO 2009/061596 PCT/US2008/080176 -30 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -C(O) 0 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -O-C(O)-. 5 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -0
N(R
6 )-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R 6
)
0-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is 10 -N(R6)-N(R12)-. In one embodiment, in Formula (I), ring A is a 6-membered ring and E is -N=N-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -C(R7)=N-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is 15 -C(O)-C(R7)=N-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -C(O)-N=N-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -0-C(Y)-N(R")-. 20 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R)-C(Y)-O-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R")-C(Y)-N(R1 2 )-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is 25 -C(Y)-N(R' 1
)-O-.
WO 2009/061596 PCT/US2008/080176 -31 In one embodiment, in Formula (1), ring A is a 6-membered ring and E is
-C(Y)-N(R
1
)-N(R
12 )-. In one embodiment, in Formula (1), ring A is a 6-membered ring and E is -0-N(R)-C(Y)-. 5 in one embodiment, in Formula (1), ring A is a 6-membered ring and E is -N(R )-N(Rm)-C(Y)-. In one embodiment, in Formula (1), ring A is a 7-membered ring and E is -C(R 4)(R-5)-. 10 In one embodiment, in Formula (1), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 6 )-, -N(C(Y)R 7 )_, -N(C(Y)OR')-, -N(C(Y)N(R 9
)(R'
1 ))-, -C(O)-N(R')-, -N(R 1 )-C(O)-, -S(0) 2
-N(R
1 )-, -N(Rl')-S(0) 2 -, -C(00)--, -0-C(0)-, -0-N(R 6 )-, -N(R 6 )-O-, -N(R)-N(R' 2 )-, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R'l)-C(Y)-O-, 15 -N(R 1
)-C(Y)-N(R
12 )-, -C(Y)-N(R")-O-, -C(Y)-N(R'")-N(R1 2 )-, -0-N(R 1 )-C(Y)-, and -N(R 1)-N(R")-C(Y)-. In one embodiment, in Formula (1), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )-. In one embodiment, in Formula (1), ring A is a 7-membered ring and E is selected 20 from the group consisting of -0-, -S-, -S(0)-, -S(0) 2 -, and -N(R 6 )-, wherein R6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR20, and -C(S)R24 In one embodiment, in Formula (1), ring A is a 7-membered ring and E is selected from the group consisting of -0- and -N(R3)-, wherein R6 is selected from the 25 group consisting of H, alkyl, -C(O)R24, -C(O)OR2, and -C(S)R 2 4 In one embodiment, in Formula (1), ring A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R4)(R5)-, -N(R6-, WO 2009/061596 PCT/US2008/080176 - 32 -N(C(Y)R 7 )-, -N(C(Y)OR8)-, -N(C(Y)N(R9)(R10))-, -C(O)-N(R1 1)-, -N(R11)-C(O)-, -S(O)2-N(R1 1)-, -N(R1 1)-S(O)2-, -C(O)-O-, -O-C(O)-, -O-N(R6)-, -N(R6)-O-, -N(R6)-N(Rl2)-, -N=N-, -C(R7)=N-, -C(O)-C(R7)=N-, -C(O)-N=N-, -O-C(Y)-N(R1 1)-, -N(R 1 1)-C(Y)-O-, -N(R1 1)-C(Y)-N(R1 2)-, -C(Y)-N(R 11)-O-, 5 -C(Y)-N(RI 1)-N(R1 2)-, -O-N(R1 1)-C(Y)-, and -N(R1 2)-N(R1 1)-C(Y)-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -0-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -S-. In one embodiment, in Formula (I), A is a 7-membered ring and E is -S(O)-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -S(0) 2 -. 10 In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(R6)-. In one embodiment, in Formula (I), A is a 7-membered ring and E is -N(C(Y)R 7 )-. In one embodiment, in Formula (1), A is a 7-membered ring and E is
-N(C(Y)OR
8 )-. 15 In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(C(Y)N(R)(R'o ))i In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(O)-N(R2)0 In one embodiment, in Formula (1), A is a 7-membered ring and E is 20 -N(R")-C(O)-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -S(0)R-N(R")-, In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(R")-S(O)r.- WO 2009/061596 PCT/US2008/080176 - 33 In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(O)-O-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -O-C(O)-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -Q-N(R 6 )-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(R 6 )-O-. 5 In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(R6)-N(R A). In one embodiment, in Formula (1), A is a 7-membered ring and E is -N=N-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(R7)=N, In one embodiment, in Formula (1), A is a 7-membered ring and E is 10 -C(O)-C(R7)=N-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(O)-N=N-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -O-C(Y)-N(R)-. In one embodiment, in Formula (I), A is a 7-membered ring and E is 15 -N(R")-C(Y)-O-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(R")-C(Y)-N(R 2)-. In one embodiment, in Formula (1), A is a 7-membered ring and E is -C(Y)-N(R)-O-. 20 In one embodiment, in Formula (1), A is a 7-membered ring and E is
-C(Y)-N(R")-N(R
12 )_. In one embodiment, in Formula (I), A is a 7-membered ring and E is -0
N(R)-C(Y)-.
WO 2009/061596 PCT/US2008/080176 - 34 In one embodiment, in Formula (1), A is a 7-membered ring and E is -N(R 12)-N(R")-C(Y)-. In one embodiment, in Formula (1), ring A is a 8-membered ring and E is 5 -C(R4)(R-)-. In one embodiment, in Formula (1), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R 6 )-, -N(C(Y)R 7 )_, -N(C(Y)ORa)-, -N(C(Y)N(R9)(R")))-, -C(O)-N(R")-, -N(R")-C(O)-, -S(O)r-N(R")-, -N(R")-S(0)2-, -C(O)-O-, -0-C(O)-, -0-N(R)-, -N(R 6 )-0-, -N(R 6
)-N(R
2 )-, -N=N-, 10 -C(R 7 )=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, -0-C(Y)-N(R)-, -N(R")-C(Y)-O-,
-N(R')-C(Y)-N(R
12 )-, -C(Y)-N(R')-O-, -C(Y)-N(R)-N(R 1 )-, -0-N(R)-C(Y)-, and
-N(R
12 )-N(R)-C(Y)-. In one embodiment, in Formula (1), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 0 )-. 15 In one embodiment, in Formula (1), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R6)-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and
-C(S)R
24 In one embodiment, in Formula (1), ring A is a 8-membered ring and E is selected 20 from the group consisting of -0- and -N(R 6 )_, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR20, and -C(S)R 24 . In one embodiment, in Formula (1), ring A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R 4
)(R
5 )-, -N(R 6 )-, 25 -N(C(Y)R 7 )-, -N(C(Y)OR")-, -N(C(Y)N(R 9 )(R'))-, -C(0)-N(R)-, -N(R")-C(O)-, -S(O)-N(R")-, -N(R")-S(0)r, -C(0)-03 -O-C(O)-, -0-N(R)-, -N(R)-NO- , -N(R'3)-N(R2)_, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, WO 2009/061596 PCT/US2008/080176 -35 -N(R')-C(Y)-O-, -N(R")-C(Y)-N(R1 2 )-, -C(Y)-N(R')-O-, -C(Y)-N(R)-N(R 12 )-, -0
N(R
1 )-C(Y)-, and -N(R' 2 )-N(R")-C(Y)-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -0-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -S-. 5 In one embodiment, in Formula (1), A is a 8-membered ring and E is -S(O)-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -S(0) 2 -, In one embodiment, in Formula (1), A is a 8-membered ring and E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -N(R3)-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -N(C(Y)R 7 )_ 10 In one embodiment, in Formula (I), A is a 8-membered ring and E is
-N(C(Y)OR
8 )_. In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(C(Y)N(R9)(R'4))-. In one embodiment, in Formula (1), A is a 8-membered ring and E is 15 -C(O)-N(R')-. In one embodiment, in Formula (I), A is a 8-membered ring and E is -N(R")-C(O)-. In one embodiment, in Formula (1), A is a 8-membered ring and E is
-S(O)
2 -N(R1), 20 In one embodiment, in Formula (1), A is a 8-membered ring and E is -N(R")-S(0) 2 -. In one embodiment, in Formula (1), A is a 8-membered ring and E is -C(O)-O-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -0-C(O)-.
WO 2009/061596 PCT/US2008/080176 - 36 In one embodiment, in Formula (1), A is a 8-membered ring and E is -O-N(R 6 )-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -N(R 6 )-O-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -N(R )-N(R e) , 5 In one embodiment, in Formula (1), A is a 8-membered ring and E is -N=N-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -C(R7)=N In one embodiment, in Formula (1), A is a 8-membered ring and E is
-C(O)-C(R
7 )=N-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -C(O)-N=N-. 10 In one embodiment, in Formula (1), A is a 8-membered ring and E is -O-C(Y)-N(R')-. In one embodiment, in Formula (1), A is a 8-membered ring and E is
-N(R
1 )-C(Y)-O-. In one embodiment, in Formula (1), A is a 8-membered ring and E is 15 -N(R')-C(Y)-N(Rl)-. In one embodiment, in Formula (1), A is a 8-membered ring and E is
-C(Y)-N(R
1 )-O-. In one embodiment, in Formula (1), A is a 8-membered ring and E is -C(Y)-N(R")-N(R 1)_ 20 In one embodiment, in Formula (I), A is a 8-membered ring and E is -0 N(R)-C(Y)-. In one embodiment, in Formula (I), A is a 8-membered ring and E is
-N(R
12 )-N(R )-C(Y)-.
WO 2009/061596 PCT/US2008/080176 -37 In one embodiment, in Formula (I), ring B is an unsubstituted or substituted benzo or an unsubstituted or substituted thiophenyl ring. In one embodiment, in Formula (1), ring B is an unsubstituted benzo or an unsubstituted thiophenyl ring. 5 In one embodiment, in Formula (1), ring B is an unsubstituted aromatic ring or an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, 10 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9,
-OC(O)OR
20 , -NR2'R 22 , -NR 23 S0 2
R
2 4 , -NR 23
C(O)OR
2 0 , -N R 23 C(O)R 24 -S0 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24
-C(O)NR
2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
25 2 6 . 15 In one embodiment, in Formula (1), ring B is an unsubstituted benzo ring or a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, 20 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9,
-OC(O)OR
2 0 , -NR 2
'R
22 , -NR 23 S02R 24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -S0 2
NR
25 R2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24
-C(O)NR
2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . 25 In one embodiment, in Formula (1), ring B is an unsubstituted or substituted heteroaromatic ring or a substituted heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , 30 alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 -38 heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2 'R 22 , -NR 23
SO
2
R
24 ,
-NR
2 3
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR 20 , -SR ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 5 NR23C(O)NR2R 2 6. In one such embodiment, in Formula (1), ring B is a 5-6 membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(0)2. 10 In one embodiment, in Formula (1), ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. 15 In one embodiment, in Formula (1), ring B is an unsubstituted aromatic ring. In one embodiment, in Formula (1), ring B is an unsubstituted benzo ring, and Formula (1) has the general structure: RR3 N I R 2 20 In one embodiment, in Formula (1), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 - 39 heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2
'R
2 2 , -NR 23
SO
2
R
24
-NR
23
C(O)OR
0 , -NRC 23
(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NV 5
R
2 6, -NR 3 C(N-CN)NR2R2E 6 and 5 NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (1), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, 10 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)ORE 0 , -NRE R 22 , -NREV 3 SO2R 24 , -NR 3 C(0)ORE 0 , -NR 23 C(O)R2 4 , -S0 2
NR
2 5 R2E, -C(O)R2 4 , -C(O)R2 0 , -SR 19 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NRE 3
C(N-CN)NR
2 5 R2 6 and 15 NR 2 3
C(O)NR
25
R
2 . In one embodiment, in Formula (1), B is an unsubstituted heteroaromatic ring. In one embodiment, in Formula (1), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or 20 different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(0)2. In one embodiment, in Formula (1), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each 25 substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR20, -NR 2 'R 22
-NREV
3
SO
2 R2 4 , -NR 3 C(O)ORE2 -NR 23 C(O)R 24 , -SO 2
NRE
5
R
2 6 , -C(O) R 24
,
WO 2009/061596 PCT/US2008/080176 - 40 -C(O)OR 20 , -SR' 9 , -S(O)R 9 , -S0 2
R
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6
-NR
2 3
C(N-CN)NR
2 5
R
26 and -NR 2 3C(O)NR 2 5
R
26 . In one embodiment, in Formula (1), B is a 5-6-membered heteroaromatic ring 5 having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 , which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, 10 heteroalkyl, haloalkyi, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR , -NR'R 22 , -NR 23 S0 2
R
24
-NR
23
C(O)OR
20 , -NR 2 3
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 , -NR 2 3
C(N-CN)NR
2
R
2 6 and 15 -NR 2 3
C(O)NR
2 5
R
26 . In one embodiment, in Formula (1), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group 20 consisting of N, S, and 0. In one embodiment, in Formula (1), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 25 and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalky, heterocycloalkenyl, 30 azido, -OR, -OC(O)OR 20 , -NR 21
R
2 2 , -NR 23 SO2R 24 , -NR 23 C(0)OR 20
,
WO 2009/061596 PCT/US2008/080176 - 41 -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24, -C(O)OR2, -SR 19 , -S(O)R' 9 , -S02R'9, -OC(O)R24, -C(0)NR 25R26, -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 23 C(O)NR25R 26. In one embodiment, in Formula (I), B is an unsubstituted 6-membered 5 heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0. In one embodiment, in Formula (1), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected 10 from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR 2 R22, -NR 23
SO
2
R
24
-NR
23 C(O)OR2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR20, -SRi9, -S(O)R'9, -S0 2
R
19 , -OC(O)R24, -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
25 sR 2 6 and
-NR
2 3 C(O)NR 25 R26, 20 In one embodiment, in Formula (1), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0. 25 In one embodiment, in Formula (1), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently 30 selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, WO 2009/061596 PCT/US2008/080176 -42 haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR 20 , -NR 2
R
2 2 , -NR 23
SO
2
R
24 , -NR 2 3
C(O)OR
20 -NR23C(O)R 24 , -SO 2
NR
2 5
R
2 6 -C(O)R 2 , -C(O)OR2), -SR 1 9 , -S(O)R 9 , -S0 2
R
1 9 , 5 -OC(O)R 2 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2
R
2 %. In one embodiment, in Formula (1), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0. 10 In one embodiment, in Formula (1), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 15 haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR2o, -NR R 22
-NR
23
SO
2
R
24 , -NR23C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2
NR
25
R
2 6 , -C(O)R24,
-C(O)OR
20 , -SR' 9 , -S(O)R 9 , -SO 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 ,
-NRC
23
(N-CN)NR
2 5
R
2 6 and -NRC 23
(O)NR
2 5
R
2 6 . 20 In one embodiment, in Formula (I), B is a 5-membered heteroaromatic ring having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , 25 alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR2, -NR 2 'R2 2 , -NR 2 3SO 2
R
24
-NRC
23
(O)OR
2 0 , -NRC 2 3
(O)R
24 , -SO 2
NR
2 5
R
2 , -C(O)R24, -C(O)OR 2 o, -SR 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 4 , -C(O)NR 25
R
26 , -NR 23
C(N-CN)NR
25
R
2 6 and 30 -NR 2 3
C(O)NR
2 6R 2 6
.
WO 2009/061596 PCT/US2008/080176 -43 In one embodiment, in Formula (1), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom. 5 In one embodiment, in Formula (1), B is a thiophenyl group. In one embodiment, in Formula (1), B is selected from the group consisting of R, and In one embodiment, in Formula (1), B is a pyridine. 10 In one embodiment, in Formula (1), B is a partially unsaturated alicyclic ring, which ring is unsubstituted. In one embodiment, in Formula (1), B is a partially unsaturated alicyclic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of 15 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , -OC(O)OR20, -NR 21
R
22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O) R 24, -SO 2 NR 25R26, -C(O)R 24, -C(O)OR2o, -SR' , -S(O)R'9, -SO 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 , 20 -NR 2 3
C(N-CN)NR
2 5
R
2 3 and -NR 23
C(O)NR
25
R
2 . In one embodiment, in Formula (1), B is a partially unsaturated heterocyclic ring, which ring is unsubstituted. In one embodiment, in Formula (I), B is a partially unsaturated heterocyclic ring 25 which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, WO 2009/061596 PCT/US2008/080176 -44 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR2
-NR
2 1 22 , -NR 2 3
SO
2
R
24 , -NR 2 3
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO2NR 25
R
2 6 , -C(O)R 2 4 -C(O)OR 20 , -SR 9 , -S(O)R'9, -S0 2
R
9 , -OC(O)R 24 5 -C(O)NR 2 5 R2 -NR 2 3
C(N-CN)NR
2 5
R
2 3 and -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (1), R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , 10 alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(0)OR 2 0 , -NR 2 1 R 22 , -NR 23
SO
2
R
24 ,
-NR
23
C(O)OR
20 , -NR 2 3C(O)R 24 , -SO 2
NR
25 R 2
-C(O)R
24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 15 -NR 2 3
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (1), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO 2 ,
-NR
2 R2 2 , and haloalkyl. 20 In one embodiment, in Formula (1), Ri' is unsubstituted aryl. In one embodiment, in Formula (1), R' is unsubstituted phenyl. In one embodiment, in Formula (1), R' is unsubstituted naphthyl. In one embodiment, in Formula (1), R' is substituted aryl. 25 In one embodiment, in Formula (1), R' is substituted phenyl. In one embodiment, in Formula (1), R' is substituted naphthyl. In one embodiment, in Formula (I), R' is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 45 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 0 , -NR R 22 , -NR 2
SO
2
R
2 ,
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR20 -SR' 9 , 5 -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 , -NR 23
C(N-CN)NR
2 5
R
26 and -NR 23 C(O)N R 25
R
26 In one embodiment, in Formula (1), R' is phenyl substituted with one or more substituents, which can be the same or different, each substituent being 10 independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR20, -NR 2 1 R 2 2 , -NR 23
SO
2
R
2 4
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 2 4 , -C(O)OR 2 0 , -SR'9, 15 -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
26 , -NRC 23
(N-CN)NR
2 5
R
2 6 and
-NR
23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (1), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being 20 independently selected from the group consisting of halo, -OH, -CN,--NQ 2 , -NR 2R 2 2 , and haloalkyl. In one embodiment, in Formula (1), R1 is selected from the group consisting of: halo NC cN halo halo halo halo alky haloalkyl halo halo 25 and WO 2009/061596 PCT/US2008/080176 -46 In one embodiment, in Formula (1), R 1 is: perfluoroalkyi halo In one embodiment, in Formula (1), R' is phenyl substituted with one to three fluoro groups. 5 In one embodiment, in Formula (1), R' is phenyl substituted with two fluoro groups. In one embodiment, in Formula (I), R' is phenyl substituted with one fluoro group. In one embodiment, in Formula (1), R 1 is: F : F 10 In one embodiment, in Formula (1), R 2 7 is H. In one embodiment, in Formula (1), R 27 is alkyl. In one embodiment, in Formula (1), R 28 is H. In one embodiment, in Formula (1), R 28 is alkyl. 15 In one embodiment, in Formula (1), R 27 and R 28 are each independently selected from the group consisting of H and alkyl. In one embodiment, in Formula (1), R 27 and R 28 , together with the carbon atom to 20 which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
WO 2009/061596 PCT/US2008/080176 - 47 In one embodiment, in Formula (1), R2 is selected from the group consisting of -C(O)R7, -C(O)NKR', and -C(O)ORK 5 In one embodiment, in Formula (1), R is -C(Z)R 7 . In one embodiment, in Formula (1), R 2 is -C(Z)NR 9
R'
0 . In one embodiment, in Formula (I), R2 is -C(Z)OR. In one embodiment, in Formula (1), R 2 is -SO 2 NR9R'. In one embodiment, in Formula (1), R2 is alkyl. 10 In one embodiment, in Formula (1), R2 is heteroalkyl. In one embodiment, in Formula (1), R2 is aryl. In one embodiment, in Formula (1), R2 is heteroaryl. In one embodiment, in Formula (1), R2 is cycloalkyl. In one embodiment, in Formula (1), R2 is cycloalkenyl. 15 In one embodiment, in Formula (1), R2 is heterocycloalkyl. In one embodiment, in Formula (I), R2 is heterocycloalkenyl. In one embodiment, in Formula (1), Z is (=0). In one embodiment, in Formula (1), Z is (=S). 20 In one embodiment, in Formula (1), Z is (=N(R')). In one embodiment, in Formula (1), Z is (=N(CN)). In one embodiment, in Formula (1), Z is (=N(OR 14 )). In one embodiment, in Formula (1), Z is (=N(R' 5
)(R'
6 )). In one embodiment, in Formula (1), Z is (=C(R1 7 )(R')). 25 WO 2009/061596 PCT/US2008/080176 -48 In one embodiment, in Formula (1), R 2 is -C(Z)R 7 , and Z is (=O). In one embodiment, in Formula (1), R 2 is -C(O)H. In one embodiment, in Formula (1), R2 is -C(O)alkyl. In one embodiment, in Formula (1), R 2 is -C(O)CH 3 . 5 In one embodiment, in Formula (1), R 2 is -C(O)R, wherein said R is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 10 heterocycloalkenyl, azido, -OR 1 9 , ~OC(O)OR 20 , -NR 2
R
22 , -NR 23 S0 2
R
24
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
2 4 , -S0 2
NR
2 5
R
2 , -C(O)R24, -C(O)OR 20 , -SR' 9 ,
-S(O)R
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and
-NR
2 3
C(O)NR
2 5
R
2 6 . 15 In one embodiment, in Formula (1), R2 is -C(O)R, wherein said R is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of
-OR
1 9 , -NR 21
R
22 , and cycloalkyl. 20 In one embodiment, in Formula (1), R 2 is -C(O)R 7 , wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In one embodiment, in Formula (1), R 2 is -C(O)R , wherein said R is alkyl substituted with one to three substituents, which can be the same or different, 25 each substituent being independently selected from the group consisting of -OH,
-NH
2 , and cyclopropyl. In one embodiment, in Formula (1), R 2 is -C(O)R, wherein said R is alkyl substituted with one to two substituents, which can be the same or different, each WO 2009/061596 PCT/US2008/080176 -49 substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. In one embodiment, in Formula (1), R 2 is -C(O)R, wherein said R 7 is alkyl 5 substituted with -OH. In one embodiment, in Formula (1), R 2 is -C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 10 In one embodiment, in Formula (1), R 2 is -C(O)R, wherein said R 7 is substituted heterocycloalkyl. In one embodiment, in Formula (1), R 2 is -C(O)R 7 , wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the 15 same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 20 , -NR 'R 22
-NR
23 S0 2
R
24 , -NR 2 3
C(O)R
20 , -NR 23
C(O)R
24 , -SO 2 NR 25
R
2 6 , -C(O)R 24 , 20 -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 sR 26
-NR
2 3
C(N-CN)NR
2 5
ER
2 6 and -NR 23
C(O)NR
25
ER
2 6 . In one embodiment, in Formula (1), R 2 is -C(O)R 7 , wherein said R 7 is selected from the group consisting of substituted piperidine, substituted piperazine, 25 substituted morpholine, substituted pyrrolidine, and substituted azetidine. In one embodiment, in Formula (I), R 2 is a moiety selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 -50 C_____ --- -- C -- __ HN ak N N ,y MN N NW N atkyl , and HN In one embodiment, in Formula (1), R 2 is -C(O)NR 9 R'1. In one embodiment, in Formula (1), R 2 is -C(O)NH 2 . 5 In one embodiment, in Formula (1), R 2 is -C(O)NR 9 R', wherein R 9 and R' 0 can be the same or different, each being independently selected from alkyl. In one embodiment, in Formula (1), R 2 is -C(O)NR 9
R'
0 , wherein R 9 is unsubstituted heterocycloalkyl and R 0 is selected from the group consisting of H and alkyl. 10 In one embodiment, in Formula (1), R 2 is -C(O)NR 9 R'4, wherein R 9 is substituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (1), R 2 is -C(O)NR 9
R'
0 , wherein R 9 is 15 heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R1 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (1), R 2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and 20 -C(O)NR 9
R'
0 . Non-limiting examples of R 2 include the following moieties: WO 2009/06 1596 PCT/US2008/080176 -51 K \--, \>ACF 3 , J CH F 2 F-NX\ H 0 AJ Jo 0 N 14 NH 2 N H 2 , NH 2 , NH, , ANH 0 0
NH
2 0 HN 0 HN NHHW- a 5 1-194 H 2 N H 2 NH N 00 HHH / , 2 N F 2 O 0 0 NHF NH NH NH HN NHNi 0 N N N 0rNH, Cs 11 and WO 2009/061596 PCT/US2008/080176 - 52 0 In one embodiment, in Formula (1), R 2 is \ CF 3 . 0 In one embodiment, in Formula (1), R 2 is \ 0 In one embodiment, in Formula (1), R 2 is 0 OH In one embodiment, in Formula (1), R 2 is 0 5 In one embodiment, in Formula (1), R2 is 0 0 In one embodiment, in Formula (1), R 2 is \ NH 2 0 In one embodiment, in Formula (1), R 2 is . 0 n Ne N In one embodiment, in Formula (1), R 2 is 3. 10 In one embodiment, in Formula (I), p isO0 and R3 is not present. In one embodiment, in Formula (1), p is 1. In one embodiment, in Formula (I), p is 2. In one embodiment, in Formula (I), p is 3. In one embodiment, in Formula (I), p is 4. 15 In one embodiment, in Formula (1), p is 2, 3, or 4, and at least two groups R 3 are attached to the same ring atom.
WO 2009/061596 PCT/US2008/080176 -53 In one embodiment, in Formula (1), p is 1, 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 1 9 , -OC(O)OR2 0 , -NR 1 R2 2 , -C(O)R24, -C(S)R2 4 , -C(O)OR20, and
-C(O)NR
5
R
2 6 , 5 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 10 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)OR20, -NR 2 2
-NR
23 S0 2
R
24 , -NR 23 C(O)OR2 0 , -NR 23 C(O)R 2 4 , -SO 2 NR 25 R2 6 , -C(O)R 24 , -C(O)OR20, -SR 19 , -S(O)R' 9 , -S0 2
R
1 9 , -OC(O)R2 4 , -C(O)NR2 5 R2 6 ,
-NR
3
C(N-CN)NR
5
R
2 6 and -NR2 3
C(O)NR
5
R
2 6 . 15 In one embodiment, in Formula (1), p is 1 and R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR 19 , -OC(O)OR20, -NR 21 R22, -NR 23 S0 2
R
24 , -NR 3 C(O)OR20, -NR 3 C(O)R 24 , -S0 2 NR2R2 6 , -C(O)R 24 , 20 -C(O)OR20, -SR' 9 , -S(O)R'", -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR2 5 R2 6 ,
-NR
3
C(N-CN)NR
25 R2 6 and -NR 23 C(O)NR R 25 K In one embodiment, in Formula (1), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 25 heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR0, -NR 2 R,
-NR
23
SO
2
R
24 , -NR 2 3 C(O)OR20, -NR2C(O)R 24 , -S0 2
NR
2 5R26, -C(O)R24, -C(O)OR0, -SR 9 , -S(O)R 9 , -SO 2
R'
9 , -OC(O)R 4 , -C(O)NR 2 5 R
-NRC
2 3 (N-CN)NR 2
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 , In one embodiment, in Formula (1), p is 2, 3, or 4 and at least two groups R3 are 30 bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl, WO 2009/061596 PCT/US2008/080176 - 54 heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN,
-NO
2 , , -OR 19 , -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2 R24, -NR 2 3
C(O)OR
2 0 ,
-NR
23 C(O)R24, -SO 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2
R
9 , 5 -OC(O)R 2 4 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2
R
2 6 . In one embodiment, in Formula (1), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three 10 heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (1), each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 15 -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR 21
R
22 , -NR 2 3 S02R 24 , -NR 2 3
C(O)OR
20 ,
-NR
2 3
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(S)R 24 , -C(0)OR 20 , -SR 1 9 , -S(O)R' 9 ,
-SO
2
R
9 , -OC(O)R 24 , -C(O)NR2 5 R2 6 , -NR 2 3
C(N-CN)NR
2
R
26 , -NR 23
C(O)NR
25
R
2 6 and -NR 2 3
-C(NH)-NR
2 6
R
26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 20 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 25 heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9 , -OC(O)OR 20 , -NR 2
R
22
-NR
23 SO2R 24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -SO 2
NR
2 5
R
2 3, -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -S02R' 9 , -OC(O)R 24 , -C(O)N 2
R
2 ,
-NR
2 3 C(N-CN)NR 2 5 R 2 6 and -N R 23
C(O)NR
25 R2 6 . In one embodiment, in Formula (1), each R 3 (when present) is independently 30 selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, WO 2009/061596 PCT/US2008/080176 -55 -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 2
'R
2 2, -C(O)R24, -C(S)R24, -C(O)OR 20 , and -C(O)NR'6R , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 5 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR 2 0 , -NR 2
R
22 10 -NR 23 SO2R 24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5 R2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26 , -NR23C(N-CN)NR2R2 6 and -NR 23
C(O)NR
2 5
R
2 6 In one embodiment, in Formula (1), p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, 15 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 20 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR R 22 -NR 23
SO
2
R
24 , -NR 23 C(O)OR2, -NR 23 C(O)R 24 , -S0 2
NR
25 R2 6 , -C(O)R24,
-C(O)R
2 0 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25 2 6 ,
-NR
23
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
25
R
2 6 25 In one embodiment, in Formula (1), p is 2, 3, or 4, and any two R 3 groups bound to the same ring A atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, 30 -S(O) 2 -, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, WO 2009/061596 PCT/US2008/080176 - 56 -NR 6 -, -S-, -S(O)-, -S(O) 2 -, and -0-. Non-limiting examples of compounds of the invention in which two R 3 groups are thus taken together include: F Rz RA N'N F N N O ,and NH, 5 In one embodiment, in Formula (1), R 2 and R 3 are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0) 2 -, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms 10 independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0) 2 -, and -0-. Non-limiting examples of a compound of the invention in which
R
2 and R 3 are thus taken together include the following compound: F R27 NH F N 'N 15 In one embodiment, in Formula (1), R 3 is alkyl. In one embodiment, in Formula (1), R 3 is heteroalkyl. In one embodiment, in Formula (1), R 3 is alkenyl. In one embodiment, in Formula (1), R 3 is heteroalkenyl. In one embodiment, in Formula (1), R 3 is alkynyl. 20 In one embodiment, in Formula (1), R 3 is heteroalkynyl.
WO 2009/061596 PCT/US2008/080176 - 57 In one embodiment, in Formula (1), R 3 is aryl. In one embodiment, in Formula (1), R 3 is heteroaryl. In one embodiment, in Formula (1), R 3 is cycloalkyl. In one embodiment, in Formula (1), R 3 is cycloalkenyl. 5 In one embodiment, in Formula (1), R 3 is heterocycloalkylt In one embodiment, in Formula (1), R 3 is heterocycloalkenyl. In one embodiment, in Formula (1), R 3 is halogen. In one embodiment, in Formula (1), R 3 is -CN. In one embodiment, in Formula (1), R 3 is -NO 2 . 10 In one embodiment, in Formula (1), R 3 is -OR' 9 . In one embodiment, in Formula (1), R 3 is -OC(O)OR0. In one embodiment, in Formula (1), P 3 is -NP 21 22 In one embodiment, in Formula (I), R 3 is -NR 23
S
2
R
24 . In one embodiment, in Formula (1), R 3 is -NR 23 (O)0R 2 0 . 15 In one embodiment, in Formula (1), R 3 is -NR 23
C(O)R
2 In one embodiment, in Formula (I), P 3 is -S0 2
NR
25
PR
6 . In one embodiment, in Formula (1), R 3 is -C(O)R 24 . In one embodiment, in Formula (I), P 3 is -C(S)RP 24 . In one embodiment, in Formula (1), R 3 is -0(0)R2 0 . 20 In one embodiment, in Formula (I), R is -SR' 9 . In one embodiment, in Formula (1), R 3 is -S(O)R' 9 . In one embodiment, in Formula (2), R 3 is -S0 2
R'
9 . In one embodiment, in Formula (1), R 3 is -OC(O)R 24 In one embodiment, in Formula (2), P 3 is -C(O)NP 25
R
6 . 25 In one embodiment, in Formula (1), R is -NR 3
C(N-CN)NR
5 sR.
WO 2009/061596 PCT/US2008/080176 - 58 In one embodiment, in Formula (I), R 3 is -NR 23
C(O)NR
25
R
2 t Non-limiting examples of R 3 include the following: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl, N, N, NH 2 , H 2 N H 2 N OH, OH, HO, OH NH 2 HN 5 0, o o , O , - HN HN NH 0N 0 N,, OH , and H 2 N In one embodiment, in Formula (1), when E is -NR 6 -, R 3 is absent. In one embodiment, Formula (1) has the general structure shown in Formula (La): R1 R27 R2& B R3 Ny A P N 10 R2 (I.a). In one embodiment, Formula (1) has the general structure shown in Formula (Lb): WO 2009/061596 PCT/US2008/080176 -59 B R3 )
R
2 (L.b). In one embodiment, Formula (1) has the general structure shown in Formula (I.c): 5 R1 R7 R28 B R
R
2 R3 (.c), wherein p is 0, 1, 2, or 3. 10 In one embodiment, Formula (1) has the general structure shown in Formula (I.d): WO 2009/061596 PCT/US2008/080176 - 60 R1 R 27 28 B - RS N, A N R2 R 3 (Ld), wherein p is 0, 1, 2, or 3. 5 In one embodiment, Formula (1) has the general structure shown in Formula (Le): R1 R 2 R 28 B R3 NA /p N R 2 R 3 (I.e), wherein p is 0, 1, 2, or 3. 10 In one embodiment, Formula (1) has the general structure shown in Formula (I.f): WO 2009/061596 PCT/US2008/080176 -61 1 R R2 RIRRR B N A N R2 --3
R
2 R3 (1.f), wherein p is 0, 1, 2, or 3. In one embodiment, Formula (1) has the general structure shown in Formula (l.g): R1 R 2 R 28 B RR N 5~R 2 R 3 ('.g), wherein p is 0, 1, 2, or 3. In some embodiments, in each of formulas (I), (La), (Ib), (L.c), (Ld), (i.e), (.f), and F \/ F (I.g), R1 is and the compounds of the invention have the general 10 structure shown in Formula (L.h): WO 2009/061596 PCT/US2008/080176 -62 F B RRR3 (l.h), wherein p is 0, 1, 2, or 3. 5 In some embodiments, in each of Formulas (1), (La), (L.b), (l.c), (.d), (I.e), (l.f), (.g), and (I.h), p is 0. For the various embodiments of the present invention described herein, it shall be understood that any variable of a structural formula not explicitly defined therein is as defined in the formula to which the embodiment refers. It shall also be 10 understood that each R 3 , when present, is attached to a ring atom or ring heteroatom of ring A by replacement of an available hydrogen atom. In other embodiments, in each of Formulas (1), (La), (l.b), (l.c), (ld), (Le), (.f), (I.g), and (l.h): ring A is a 4-7 membered cycloalkenyl ring; 15 E is -C(R 4 )(R5)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of 20 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, WO 2009/061596 PCT/US2008/080176 - 63 alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
2 0 , -NR 2 1
R
22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 5 -C(O)N R 25
R
2 6 , -NRC 23 (N-CN)NR 25
R
26 and -NR 23 C(O)N R 25
R
26 . In other embodiments, in each of Formulas (1), (L.a), (I.b), (l.c), (.d), (L.e), (U.), and (l.g): ring A is a 4-7 membered cycloalkenyl ring; 10 E is -C(R 4 )(R)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of 15 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
2 0 , -NR 2 'R R 2 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , -NR 23 C(O)R24 -S0 2
NR
5
R
2 6 , -C(O)R 24 , -C(O)OR0, -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 20 -C(O)NR 25
R
2 6 , -NR 2 C(N-CN)NRa 5
R
26 and -NRC(O)NR 25 2 R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 ' R 2 , and haloalkyl;
R
2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, 25 heterohaloalkyl, -C(O)R 7 . -C(0)OR , and -C(O)NR 9
R
0 ; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 19 , -OC(0)OR0,
-N
2 1 R 2 2 , -NR 23 SO2R 24 , -NR 2 3
C(O)OR
20 , -NR 23 C(O)R 24 , -SO 2 NR25R 2 6 , -C(O)R 24
,
WO 2009/061596 PCT/US2008/080176 - 64
-C(S)R
24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R
9 , -OC(O)R 24 , -C(O)NR 2 5
R
26 ,
-NR
23
C(N-CN)NR
2 5
R
26 , -NR 2 3
C(O)NR
2 5
R
26 , and -NR 2 3
-C(NH)-NR
2
'R
2 3, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 5 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR 2 1
R
22 10 -NR 23
SO
2
R
24 , -NR 2 3
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R
1 , -OC(O)R 24 , -C(0)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 , In other embodiments, in each of Formulas (1), ([a), (Lb), (L.c), (.d), (Le), (U.), 15 and (l.g): ring A is a 4-7 membered cycloalkenyl ring; E is -C(R4)(R 5 )-; ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted 20 with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , 25 -OC(0)OR2 0 , -NR 21
R
22 , -NR 23 S0 2
R
2 4 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 ,
-SO
2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR0, -SR'9, -S(O)R , -SO 2
R'
9 , -OC(O)R2 4 -C(O)NR22 6 , -NR2 3 C(N-CN)NR2 5 R and -NR23C(O)N2 5 R2 6
;
WO 2009/061596 PCT/US2008/080176 - 65 R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 1
R
22 , and haloalkyl; R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, 5 heterohaloalkyl, -C(O)R 7 . -C(O)ORK, and -C(O)NR 9
R'
0 ; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR20 -NR2R 22 , -C(O)R 4 , -C(S)R 4 , -C(O)OR0 and -C(O)N 5
R
2 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 10 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 15 heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR20, -NR 2 ' R 22
-NR
2 3
SO
2
R
24 , -NR23C(O)OR 20 , -NR2 3
C(O)R
24 , -SO 2
NR
2 5R26, -C(O)R24, -C(O)OR20, -SR' 9 , -S(O)R 19 , -SO 2
R'
9 , -OC(O)R24, -C(O)NR2R2 6 ,
-NR
2 3
C(N-CN)NR
2 sR26 and -NR 23
C(O)NR
25 R26, 20 In other embodiments, in each of Formulas (I), (La), (1.b), (l.c), (.d), (Le), (l.f), and (Ikg): ring A is a 4-7 membered cycloalkenyl ring; E is -C(R 4 )(R5)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, 25 wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, WO 2009/061596 PCT/US2008/080176 - 66 alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
20 , -NR 2 R R22, -NR 23 S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 ,
-SO
2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR 9 , -S(O)R' 9 , -S02R' 9 , -OC(O)R 24 5 -C(O)NR 2 5
R
2 6 , -NR 23 C(N-CN)N R 25
R
2 6 and -NR 23 C(O)N R 2
R
26 .
R
1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 ' R 22 , and haloalkyl;
R
2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, 10 heterohaloalkyl, -C(O)R 7 . -C(O)OR , and -C(O)NR 9
R
10 ; and p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 15 substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(0)OR 20 , -NR 2 'R 22 20 -NR 23
SO
2
R
24 , -NR 23 C(0)OR 20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
H
2 6 ,
-NR
23
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . In other embodiments, in each of Formulas (I), (La), (1b), (l.c), (I.d), (i.e), (H.), 25 (l.g), and (l.h): ring A is a 5-6 membered heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R 6 )-,
-N(C(Y)R
7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R")-, -N(R)-C(O)-, -S(O)r-N(R")-, -N(R")-S(O)r-, -C(0)-0-, -O-C(O)-, -O-N(R6)-, -N(R6)-O-, -N(R 6) WO 2009/061596 PCT/US2008/080176 - 67 N(R1 2 )-, -N=N-, -C(R)=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R')-C(Y)-O-, -N(R')-C(Y)-N(R1)-, -C(Y)-N(R")-O-, -C(Y)-N(R' 1
)-N(R
1 )-, -o N(R")-C(Y)-, and -N(R' 2 )-N(R")-C(Y)-; and ring B is a benzo ring or a 5-6 membered heteroaromatic ring, 5 wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, 10 cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' ,
-OC(O)OR
20 , -NR 2 1 R 22 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 2 4
-C(O)NR
25
R
2 3, -NRC 2 3
(N-CN)NR
25
R
2 6 and -NRC 23
(O)NR
25
R
2 6 . 15 In other embodiments, in each of Formulas (I), (I.a), (Ib), (l.c), (.d), (Le), (I.f), and (1.g): ring A is a 5-6 membered heterocycloalkenyl ring; E is selected from the group consisting -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R24 20 -C(O)OR20, and -C(S)R 24 ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of 25 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, azido, -OR'9,
-OC(O)OR
2 0 , -NR 2
R
22 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
2 0 , -NR 23
C(O)R
24
,
WO 2009/061596 PCT/US2008/080176 - 68 -S0 2
NR
25 R, -C(O)R 2 , -C(O)OR, -SR' 9 , -S(O)R' 9 , -SO 2
R
9 , -OC(O)R 24
-C(O)NR
2 5 R2 -NR 23
C(N-CN)NR
2 5
R
2 and -NR 2 3
C(O)NR
2 5
R
2 6 1 R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group 5 consisting of halo, -OH, -CN,-N0 2 , -NR 21
R
2 2 , and haloalkyl; R 2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and -C(O)NR 9
R'
1 ; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 1 9 , -OC(O)OR 20 , 10 -NRE 21
R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)R
20 , -NR 23
C(O)R
24 , -SO 2 N R 25
R
2 6 , -C(O)R 24 ,
-C(S)R
24 , -C(O)OR 2 0 , -SR 1 9 , -S(O)R' 9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 25
R
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 , -NR 2 3
C(O)NR
25
R
2 6 , and -NR 23
-C(NH)-NR
2 6
R
2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 15 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR ER 20 -NR 23 S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NR 2 3
C(O)R
24 , -S0 2
NR
2
-R
2 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -S02R' 9 , -OC(O)R 24 , -C(O)NR 2 5
R
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
ER
2 6 . In other embodiments, in each of Formulas (1), (.a), (I.b), (I.c), (.d), (L.e), (If), 25 and (I.g): ring A is a 5-6 membered heterocycloalkenyl ring; E is selected from the group consisting -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )-, wherein R3 is selected from the group consisting of H, alkyl, -C(O)R 24
-C(O)OR
20 , and -C(S)R 24 WO 2009/061596 PCT/US2008/080176 - 69 ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group consisting of 5 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9,
-OC(O)OR
20 , -NR 2 'R 22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -S0 2
NRR
26 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 10 -C(O)NR 5 R, -NR 2
C(N-CN)NR
5
R
26 and -NRC(O)NRR;
R
1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 'R 22 , and haloalkyl;
R
2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, 15 heterohaloalkyl, -C(O)R 7 . -C(O)OR 8 , and -C(O)NR9R' 0 ; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR9, -OC(O)OR0 -NR 'R , -C(O)R 24 , -C(S)R 24 , -C(O)OR 20 , and -C(O)NR 25
R
2 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 20 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 25 heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR0, -NR 2 'R,
-NR
23 S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NR A 23 C(O)R 24 , -SO 2
NR
2 5
R
2 6, -C(O)R 24 ,
-C(O)OR
2 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 3 and -NR 23
C(O)NR
25
R
2 6
.
WO 2009/061596 PCT/US2008/080176 - 70 In other embodiments, in each of Formulas (1), (La), (Lb), (Lc), (.d), (i.e), (U.), and (I g): ring A is a 5-6 membered heterocycloalkenyl ring; E is selected from the group consisting -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R-, 5 wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 2 4 -C(O)0R 20 , and -C(S)R 24 ring B is a benzo ring or a 5-6 membered heteroaromatic ring, wherein said ring is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each 10 substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 ,
-OC(O)OR
2 0 , -NR 2 1 R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , 15 -SO 2
NR
2 5
R
26 , -C(O)R 24 , -C(O)OR 2 0 , -SR 19 , -S(O)R' 9 , -SO 2
R
9 , -OC(O)R24
-C(O)NR
2
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 ; R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 1
R
2 2 , and haloalkyl; 20 R 27 and R 28 are each independently selected from the group consisting of H and alkyl;
R
2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and -C(O)NR 9
R'
0 ; and p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, 25 and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with from 1 to 3 substituents, which can be the same or different, each substituent being independently selected from the group of WO 2009/061596 PCT/US2008/080176 - 71 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -N R 2 1 R22,
-NR
23
SO
2 R24, -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2 NR 2 56 2, -C(O)R24, 5 -C(O)OR20, -SR'9, -S(O)R' 9 , -SO 2 R'9, -OC(O)R24, -C(O)NR 2 5
R
2 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
26 . In one embodiment, the compounds of the invention have a structure shown in Formula (11) and include pharmaceutically acceptable salts, solvates, esters, 10 prodrugs, or isomers of said compounds: R1 R 2 R 2 N, N E R2 (11) 15 wherein R', R 2 , R27, R 2 3, E, and ring B are selected independently of each other and wherein E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -C(R 4
)(R
5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-; and ring B, X, R1, R 2 , R 4 , R 5 , R6, R, R", R9, R 1 0 , R 27 , R28, Y, and the optional 20 substituents on ring B are as defined in any of the embodiments described above in Formula (1). In one embodiment, in Formula (11): WO 2009/061596 PCT/US2008/080176 - 72 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -C(R4)(R9)-, and -N(R)-, ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 5 pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
R
1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 1
R
2 2 , and haloalkyl; and 10 R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR9R' 0 , and -C(O)OR. In one embodiment, in Formula (11):
R
1 is: F F 15 In one embodiment, the compounds of the invention have a structure shown in Formula (II.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R 27 R 2 / B N () N E R 2 20 (11. a.) WO 2009/061596 PCT/US2008/080176 - 73 wherein R 1 , R 2 , R 27 , R 28 , E, and ring B are selected independently of each other and wherein: E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R4)(R 5 )-, 5 -N(R3)-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R)(R'4))-. ring B is a substituted or unsubstituted aromatic ring; and R 1 , R 2 , R 4 , R 5 , R 6 , R , R 8 , R 9 , R 10 , R2, R 2 3, Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I). 10 In one embodiment, Formula (Il.a.) has the general structure shown in Formula (ll.a.1): / B N E I R 2 (Il.a.1). 15 In one embodiment, Formula (ll.a.) has the general structure shown in Formula (Il.a.2): WO 2009/061596 PCT/US2008/080176 -74 R1 R 27 R 2 Ns N E R2 (II.a.2). In some embodiments, in each of Formulas (ll.a.), (I.a.1), and (Il.a.2), E is 5 -C(R4)(R5)-. In some embodiments, in each of Formulas (l.a.), (lI.a.1), and (ll.a.2), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )_. In some embodiments, in each of Formulas (lI.a.), (Il.a.1), and (I.a.2), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0) 2 -, and -N(R)-, 10 wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and
-C(S)R
2 4 . In some embodiments, in each of Formulas (lI.a.), (II,a.1), and (Il.a.2), E is selected from the group consisting of -0- and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 2 4 15 In some embodiments, in each of Formulas (II.a.), (ll.a.1), and (I.a.2), E is -0-. In some embodiments, in each of Formulas (ll a.), (Il.a.1), and (ll.a.2), E is -S-. In some embodiments, in each of Formulas (Hl.a.), (11.a.1), and (lI.a.2), E is -S(O)-. In some embodiments, in each of Formulas (Il.a.), (ll.a.1), and (I.a.2), E is 20 -S(0)2-- WO 2009/061596 PCT/US2008/080176 -75 In some embodiments, in each of Formulas (1l.a.), (II.a.1), and (Il.a.2), E is -C(R4)(R)-. In some embodiments, in each of Formulas (ll.a.), (lla.1), and (ll.a.2), E is -N(R)-. 5 In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), E is
-N(C(Y)R
7 )-. In some embodiments, in each of Formulas (Il.a.), (ll.a.1), and (ll.a.2), E is
-N(C(Y)OR
8 )-. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), E is 10 -N(C(Y)N(R9)(R'4))-. In some embodiments, in each of Formulas (ll.a.), (lI.a.1), and (ll.a.2), Y is (=0). In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), Y is (=S). In some embodiments, in each of Formulas (lI.a.), (ll.a.1), and (Il.a.2), Y is 15 (=N(R 13 )). In some embodiments, in each of Formulas (Ita.), (IL.a-1), and (ll.a.2), Y is (=N(CN)). In some embodiments, in each of Formulas (1I.a.), (ll.a.1), and (ll.a.2), Y is
(=N(OR'
4 )). 20 In some embodiments, in each of Formulas (1l a), (Il.a.1), and (ll.a.2), Y is
(=N(R
1 5)(R6)). In some embodiments, in each of Formulas (ll.a.), (I.a.1), and (II.a.2), Y is (=C(R 1 7)(R')). 25 In some embodiments, in each of Formulas (Il.a.), (Il.a.1), and (l1.a.2), B is an unsubstituted aromatic ring. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (II.a.2), B is an unsubstituted benzo ring, and Formula (ll.a.) has the general structure: WO 2009/061596 PCT/US2008/080176 -76 R -R27 R28 N E I R 2 in some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), B is an unsubstituted benzo ring, and Formula (ll.a.) has the general structure: R1 R 27 R 28 N N 5 R 2 In some embodiments, in each of Formulas (l.a.), (la.1), and (ll.a.2), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the 10 group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, azido, -OR 1 9,
-OC(O)OR
2 0 , -NR 21
R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R 24 ,
-SO
2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S02R 9 , -OC(O)R 24 , 15 -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5 R2 6 and -NR 2 3
C(O)NR
2 5
R
26
.
WO 2009/061596 PCT/US2008/080176 -77 In some embodiments, in each of Formulas (I.a.), (La.1), and (I.a.2), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, 5 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
2 0 , -NR 2 1
R
22 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , -NRC 23
(O)R
2 4,
-SO
2
NR
5
R
20 , -C(O) R 24 , -C(O)OR 2 0 , -SR'9, -S(O)R', -SO 2 R', -OC(O)R 24 ,
-C(O)NR
2 5
R
26 , -NRC 2 3
(N-CN)NR
25
R
2 c and -NR 23
C(O)NR
25
R
26 . 10 In some embodiments, in each of Formulas (1la.), (1I1a.1), and (l1.a.2), R' is unsubstituted aryl. In some embodiments, in each of Formulas (1l.a.), (ll.a.1), and (ll.a.2), R is unsubstituted phenyl. 15 In some embodiments, in each of Formulas (11.a.), (lI.a.1), and (Il.a.2), R1 is unsubstituted naphthyl. In some embodiments, in each of Formulas (ll.a.), (Ita.1), and (Ila.2), R' is substituted aryl. In some embodiments, in each of Formulas (lia.), (lI.a.1), and (1l1a.2), R' is 20 substituted phenyl. In some embodiments, in each of Formulas (I.a.), (lla.1), and (Il a.2), R1 is substituted naphthyl. In some embodiments, in each of Formulas ([I.a.), (Il a.1), and (Il.a.2), R' is aryl substituted with one or more substituents, which can be the same or different, 25 each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-aikyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 0 , -NR 2R,
-NR
23 SO2R 24 , -NR 2
C()OR
20 , -NRC 23 (O)R 24 , -SO 2 NR 2R26, -C(0)R 24
,
WO 2009/061596 PCT/US2008/080176 - 78 -C(O)OR 2 t, -SR' 9 , -S(O)R' 9 , -SO 2 R'9, -OC(O)R 24 , -C(O)NR 2 5
R
26
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 . In some embodiments, in each of Formulas (lL.a.), (ll.a.1), and (ll.a.2), R 1 is 5 phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 t 10 -NR 21
R
22 , -NR 23 S0 2
R
24 , -NR 23 C(0)OR 20 , -NR 23 C(O)R 24 , -SO 2 N R 2 5
R
2 6 , -C(O)R24,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26
-NR
2 3
C(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
25 26 . In some embodiments, in each of Formulas (lI.a.), (ll.a.1), and (Il.a.2), R' is 15 phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 , -NR 2 1 R 2 2 , and haloalkyl. In some embodiments, in each of Formulas (ll.a.), (II.a.1), and (ll.a.2), R' is selected from the group consisting of: halo HO -- NC 02N halo halo halo halo 20 alkyl haloalkyl halo halo and In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (Il.a.2), R' is: WO 2009/061596 PCT/US2008/080176 -79 halo perfiroa lky In some embodiments, in each of Formulas (II.a.), (ll.a.1), and (ll.a.2), R is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas (Il.a.), (II.a.1), and (i.a.2), R' is 5 phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (i.a.), (Il.a.1), and (Il.a.2), R' is phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (II.a.), (tl.a.1), and (Jl.a.2), R' is: F F 10 In some embodiments, in each of Formulas (Il a.), (II.a.1), and (II.a.2), R 27 and
R
28 are each independently selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (II.a.), (lI.a.1), and (II.a.2), R 2 is 15 -C(Z)R 7 . In some embodiments, in each of Formulas (I.a.), (l.a.1), and (l.a.2), R 2 is
-C(Z)NR
9 R"'. In some embodiments, in each of Formulas (ll.a.), (Il.a.1), and (Il.a.2), R2 is
-C(Z)OR
8 . 20 In some embodiments, in each of Formulas (II.a.), (ll.a.1), and (Il.a.2), R 2 is
-SO
2
NR
9 RO. In some embodiments, in each of Formulas (Il.a.), (Il.a.1), and (IL.a.2), R 2 is alkyl.
WO 2009/061596 PCT/US2008/080176 - 80 In some embodiments, in each of Formulas (Ita.), (lL.a.1), and (L.a.2), R 2 is heteroalkyl. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (Ita.2), R 2 is aryl. In some embodiments, in each of Formulas (11-a.), (Ita.1), and (I.a.2), R2 is 5 heteroaryl. In some embodiments, in each of Formulas (Il.a.), (Il.a.1), and (Il a.2), R2 is cycloalkyl. In some embodiments, in each of Formulas (I1a.), (ll.a.1), and (Illa.2), R 2 is cycloalkenyl. 10 In some embodiments, in each of Formulas (11la.), (1l.a.1), and (Il.a.2), R2 is heterocycloalkyl. In some embodiments, in each of Formulas (Il.a.), (Ita.1), and (lla.2), R 2 is heterocycloalkenyl. 15 In some embodiments, in each of Formulas (11.a.), (il a.1), and (Il.a.2), Z is (=0). In some embodiments, in each of Formulas (Il.a.), (ll.a.1), and (II.a.2), Z is (=S). In some embodiments, in each of Formulas (1Ia.), (l.a.1), and (I.a.2), Z is
(=N(R
3 )). In some embodiments, in each of Formulas (II.a.), (Il.a.1), and (1I.a.2), Z is 20 (=N(CN)). In some embodiments, in each of Formulas (ll.a.), (Il.a.1), and (ll.a.2), Z is (=N(OR1)). In some embodiments, in each of Formulas (II.a.), (1l.a.1), and (Il a.2), Z is (=N(R5)(R 16 )). 25 In some embodiments, in each of Formulas (Il.a.), (lI.a.1), and (II.a.2), Z is (=C(R17)(R18)).
WO 2009/061596 PCT/US2008/080176 - 81 In some embodiments, in each of Formulas (ll.a.), (II.a.1), and (Il.a.2), R 2 is -C(Z)R 7 , and Z is (=0). In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), R 2 is C(O)H. 5 In some embodiments, in each of Formulas (1l.a.), (ll.a.1), and (ll.a.2), R 2 is C(O)alkyl In some embodiments, in each of Formulas (la.), (Il.a.1), and (ll.a.2), R 2 is C(O)CH 3 . In some embodiments, in each of Formulas (Il a.), (ll.a.1), and (lI.a.2), R 2 is _ 10 C(0)R 7 , wherein said R is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 20 , -NR 2
R
22 15 -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24,
-C(O)OR
2 0 , -SR 1 9 , -S(O)R' 9 , -SO2R 19 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
25
R
2 6 . In some embodiments, in each of Formulas (II.a.), (1I.a.1), and (1lla.2), R 2 is 20 C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR' 9 , -NR 21
R
2 2 , and cycloalkyl. In some embodiments, in each of Formulas (1l.a.), (ll.a.1), and (IlI.a.2), R 2 is 25 C(O)R, wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In some embodiments, in each of Formulas (ll.a.), (lI.a.1), and (l.a.2), R 2 is _
C(O)R
7 , wherein said R is alkyl substituted with one to three substituents, which WO 2009/061596 PCT/US2008/080176 -82 can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH 2 , and cyclopropyl. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), R 2 is 5 C(O)R , wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), R 2 is 10 C(O)R 7 , wherein said R 7 is alkyl substituted with -OH. In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), R 2 is C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 15 In some embodiments, in each of Formulas (Il.a.), (ll.a.1), and (ll.a.2), R 2 is C(O)R 7 , wherein said R 7 is substituted heterocycloalkyl. In some embodiments, in each of Formulas (ll.a.), (lI.a.1), and (ll.a.2), R 2 is C(O)R 7 , wherein said R 7 is heterocycloalkyl substituted with one or more 20 substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido,
-OR
19 , -OC(O)OR 20 , -NR 21
R
22 , -NR 23 S0 2 R24, -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 25 -S0 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24
-C(O)NR
5 Re 26 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . In some embodiments, in each of Formulas (Il.a.), (ll.a.1), and (Il.a.2), R 2 is
C(O)R
7 , wherein said R 7 is selected from the group consisting of substituted WO 2009/061596 PCT/US2008/080176 - 83 piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. In some embodiments, in each of Formulas (ll.a.), (l.a.1), and (ll.a.2), R2 is 5 selected from: N N E~
--
C
H3C ,H 3 C , and H3c In some embodiments, in each of Formulas (ll.a.), (ll.a.1), and (ll.a.2), R2 is
-C(O)NR
9 R'4. 10 In some embodiments, in each of Formulas (ll a.), (Il.a.1), and (11.a.2), R 2 is _
C(O)NH
2 . In some embodiments, in each of Formulas (Il a.), (ILa.1), and (Ila.2), R2 is C(O)NR9R', wherein R9 and 1310 can be the same or different, each being independently selected from alkyl. 15 In some embodiments, in each of Formulas (ll.a.), (II.a.1), and (ll.a.2), R 2 is C(O)NR 9 R', wherein R 9 is unsubstituted heterocycloalkyl and R10 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (l.a.), (1l.a.1), and (I.a.2), R 2 is 20 C(O)NR 9 R'1, wherein R 9 is substituted heterocycloalkyl and R'1 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (11.a.), (Il.a.1), and (I.a.2), R 2 is C(O)NR9R', wherein R 9 is heterocycloalkyl substituted with from one to three 25 substituents, which can be the same or different, each substituent being independently selected from alkyl, and R' is selected from the group consisting of H and alkyl.
WO 2009/061596 PCT/US2008/080176 - 84 In some embodiments, in each of Formulas (Ila.), (lla.1), and (lI.a.2), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R . -C(O)OR3, and -C(O)NR 9 R(t Non-limiting examples of R2 include the following moieties: 0 5 ,
CF
3
CHF
2 S 0f 0 0 0 O 0 OH O 0 OH 0 /
NH
2
NH
2 , NH 2 0, A, OO 0 o "I o NH, HNtQ HNf NH C H N " H 10, HN H 2 N H 2 N 0 0 10 H HN NH 2 N H 2 N 0 0 o o§<cI O NH ( NH NH NH I H 2 N IH 2
N
WO 2009/061596 PCT/US2008/080176 - 85 tO 0 N H2 , H 2 N NH 2 , N , N, NH O o on 0 00 N 0H N jtS N 0, and I In some embodiments, in each of Formulas (Ilta.), (il.a.1), and (I.a.2), R2 is O CF3 5 In some embodiments, in each of Formulas (I1.a.), (l.a.1), and (Il.a.2), R 2 is 0 In some embodiments, in each of Formulas (I.a.), (Il.a.1), and (Il.a.2), R 2 is 0 In some embodiments, in each of Formulas (II.a.), (Il.a.1), and (Il.a.2), R 2 is 0 10 OH In some embodiments, in each of Formulas (l.a.), (ll.a.1), and (1L-a.2), R 2 is 0 In some embodiments, in each of Formulas (Il.a.), (Il.a.1), and (tl.a.2), R 2 is 0 N H WO 2009/061596 PCT/US2008/080176 -86 In some embodiments, in each of Formulas (1L.a.), (ll.a.1), and (ll.a.2), R 2 is 0 N I . In some embodiments, in each of Formulas (II.a.), (ll.a.1), and (ll.a.2), R 2 is 0 NK N 5 In one embodiment, the compounds of the invention have a structure shown in Formula (1I.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R 27 R 28 RB N , N E 10 R (lkb.) wherein R 1 , R 2 , E, R 27 , R 28 , and ring B are selected independently of each other and wherein: 15 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-,
-N(R
6 )-, -N(C(Y)R 7 )_, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-. ring B is a substituted or unsubstituted heteroaromatic ring; and R 1 , R 2 , R 4 , R 5 , R, R , R 8 , R 9 , R 1 0 , R, R 28 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula 20 (1).
WO 2009/061596 PCT/US2008/080176 -87 In one embodiment, Formula (ILL.b.) has the general structure shown in Formula (Il.b.1): R1 R 27 R 28 N E I R 2 (ll.b.1). 5 In one embodiment, Formula (IL.b.) has the general structure shown in Formula (fl.b.2): R1 R27 R 2 / B N , N E R 2 (11. b. 2). 10 In some embodiments, in each of Formulas (11.b), (l1.b.1), and (11.b.2), E is -C(R 4)(R5)-. In some embodiments, in each of Formulas (II.b), (IL.b.1), and (II.b.2), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6
)-.
WO 2009/061596 PCT/US2008/080176 -88 In some embodiments, in each of Formulas (Ib), (Ilb.1), and (11.b.2), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S) R 24 5 In some embodiments, in each of Formulas (II.b), (I.b.1), and (11.b.2), E is selected from the group consisting of -0- and -N(R6)-, wherein R 6 is selected from the group consisting of H, alkyl, -C(0)R 24 , and -C(S)R 2 4 In some embodiments, in each of Formulas (ib), (II.b.1), and (ILb.2), E is -0-, In some embodiments, in each of Formulas (11.b), (ILb.1), and (II.b.2), E is -S-. 10 In some embodiments, in each of Formulas (1.b), (1b.1), and (IL.b.2), E is -S(O)-. In some embodiments, in each of Formulas (ILb), (Il.b.1), and (11b.2), E is -S(0)2-. In some embodiments, in each of Formulas (11lb), (fl.b.1), and (ll.b.2), E is -C(R 4) (R)-. 15 In some embodiments, in each of Formulas (11 b), (Il.b.1), and (1lb.2), E is
-N(R
7 )-. In some embodiments, in each of Formulas (IL.b), (IL.b.1), and (11.b.2), E is -N(C(Y)R7). In some embodiments, in each of Formulas (11.b), (ll.b.1), and (II.b.2), E is 20 -N(C(Y)ORR)-. In some embodiments, in each of Formulas (11 b), (1l.b.1), and (ll.b.2), E is -N(C(Y)N(R9)(R*))-. In some embodiments, in each of Formulas (Il b), (H1 an (1.b2), Y is (=O). 25 In some embodiments, in each of Formulas (Il b), (il b.1), and (1l.b.2), Y is (=S). In some embodiments, in each of Formulas (11.b), (Il.b.1), and (1l.b.2), Y is (=N(R 1)).
WO 2009/061596 PCT/US2008/080176 - 89 In some embodiments, in each of Formulas (1l.b), (11.b.1), and (lI.b.2), Y is (=N(CN)). In some embodiments, in each of Formulas (Il b), (11 b.1), and (Il.b.2), Y is (=N(OR 4)). 5 In some embodiments, in each of Formulas (ll.b), (Il.b.1), and (11.b.2), Y is (=N(R' )(R' )). In some embodiments, in each of Formulas (11.b), (I1b.1), and (1l.b.2), Y is (=C(R h) (Rrn)). 10 In some embodiments, in each of Formulas (1l.b), (I1b.1), and (IIb.2), B is an unsubstituted heteroaromatic ring. In some embodiments, in each of Formulas (II.b), (IIb.1), and (11.b.2), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being 15 independently selected from the group consisting of N, S, 0, S(O), and S(0) 2 . In some embodiments, in each of Formulas (1l.b), (II.b.1), and (Ikb.2), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the 20 group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9,
-OC(O)OR
2 0 , -NR 2 R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6, -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R1 9 , -OC(O)R 24 25 -C(O)NR 2 5
R
2 6 , -NR 2 3C(N-CN)NR 25
R
2 6 and -NR 23
C(O)NR
25
R
2 6 . In some embodiments, in each of Formulas (11.b), (I1b.1), and (11.b.2), B is a 5-6 membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from WO 2009/061596 PCT/US2008/080176 -90 the group consisting of N, S, 0, S(O), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 5 haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NRR 22 , -NR 2 3
SO
2
R
24 , -NRC 23
(O)OR
20 , -NR 2 3
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
23
C(N-CN)NR
2 5
R
2 6 and -NRC 23
(O)NR
2 5
R
2 6 . 10 In some embodiments, in each of Formulas (I.b), (IL.b.1), and (Il.b.2), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently 15 selected from the group consisting of N, S, and 0. In some embodiments, in each of Formulas (1l.b), (I.b.1), and (Il-b.2), B is a 6 membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from 20 the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, 25 heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2
'R
2 2 , -NR 23
SO
2
R
24 ,
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -SO 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -S02R' 9 , -OC(O)R 24 , -C(O)NR 25
R
26 , -NRC 23
(N-CN)NR
2 5
R
2 and NR 23
C(O)NR
2 5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 -91 In some embodiments, in each of Formulas (l.b), (Il.b.1), and (ILb.2), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0. 5 In some embodiments, in each of Formulas (1I.b), (ll.b.1), and (l1.b.2), B is a 6 membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of 10 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR 'R, -C(O)R 24
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 2 , and -C(O)NR 25
B
2 . In some embodiments, in each of Formulas (Il.b), (Il b.1), and (lLb.2), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, 15 which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0. In some embodiments, in each of Formulas (l.b), (llb.1), and (Il.b.2), B is a 5 membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be 20 the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, 25 heteroaryl, aryl-alkyl-, heteroary-akyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2
R
22 , -NR 2 3 SO2R 24
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2
NR
2 5 R2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -SQ2R'9, -OC(O)R24 -C(O)NR 2 5 R2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and NR 2 3 C(O)NR 25
B
26 . 30 WO 2009/061596 PCT/US2008/080176 - 92 In some embodiments, in each of Formulas (ll.b), (II.b.1), and (1l.b,2), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0. 5 In some embodiments, in each of Formulas (II.b), (lL-b.1), and (Il.b.2), B is a 5 membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, 10 haloalkyl, -OR 1 9 , -NR R 22 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R', -SO 2
R'
9 ,
-OC(O)R
24 , and -C(O)NR 25
F
2 In some embodiments, in each of Formulas (11b), (Il.b.1), and (II.b.2), B is a 5 membered heteroaromatic ring having S as the ring heteroatom, which 15 heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR1 9 ,
-NR
21
R
22 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S02R 9 , -OC(O)R 24 , and
-C(O)NR
2 5
R
2 5 20 In some embodiments, in each of Formulas (lI.b), (1lb.1), and (Il.b.2), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom. In one embodiment, Formula (II.b.) has the general structure: WO 2009/061596 PCT/US2008/080176 -93 R 1 R 27 R 28 S R1 R27 R 28 N N E N N E I I R or R In one embodiment, Formula (11.b.) has the general structure: 1 R 27 R 28 1 R27 R 28 RSR N N N N
R
2 or R 2 5 In some embodiments, in each of Formulas (1l.b), (ILb.1), and (II.b.2), R' is unsubstituted aryl. In some embodiments, in each of Formulas (II.b), (ll.b.1), and (Il.b.2), R' is unsubstituted phenyl. In some embodiments, in each of Formulas (11.b), (ll.b.1), and (I.b.2), R' is 10 unsubstituted naphthyl. In some embodiments, in each of Formulas (11.b), (Il.b.1), and (iI.b.2), R' is substituted aryl. In some embodiments, in each of Formulas (11.b), (lI.b.1), and (ll.b.2), R' is substituted phenyl.
WO 2009/061596 PCT/US2008/080176 - 94 In some embodiments, in each of Formulas (II~b), (Il.b.1), and (II.b.2), R' is substituted naphthyl. In some embodiments, in each of Formulas (1I.b), (11.b.1), and (1l.b.2), R' is aryl substituted with one or more substituents, which can be the same or different, 5 each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR0, -NR 'R 22
-NR
23
SO
2 R24, -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 2 4 , 10 -C(O)OR , -SR' 9 , -S(O)R' 9 , -SO 2 R1 9 , -OC(O)R 4 , -C(O)NR 5 R
-NR
23
C(N-CN)NR
2 5R26 and -NR 23
C(O)NR
2 R2 6 . In some embodiments, in each of Formulas (ll.b), (II.b.1), and (lI.b.2), R 1 is phenyl substituted with one or more substituents, which can be the same or 15 different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 2 0 ,
-NR
2 R2 2 , -NR2 3 S0 2
R
24 , -NR2 3
C(O)OR
2 0 , -NR 23 C(O)R2 4 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, 20 -C(0)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 4 , -C(O)NR 25
R
6
-NR
2 3 C(N-CN)NR25R2 6 and -NR 23
C(O)NR
2 5R 26 , In some embodiments, in each of Formulas (li.b), (II.b.1), and (lI.b.2), R' is phenyl substituted with one to four substituents, which can be the same or 25 different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 , -NR R22 , and haloalkyl. In some embodiments, in each of Formulas (1.b), (l1.b.1), and (II.b.2), R' is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 -95 halo -- 0 2 N halo halo halo halo alkyl haloalkyt$ halo halo and In some embodiments, in each of Formulas (l.b), (li.b.1), and (lI.b.2), R' is: perfluoroalkyl -halo 5 In some embodiments, in each of Formulas (II.b), (Il.b.1), and (I1.b.2), R 1 is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas (11.b), (II.b.1), and (II.b.2), R' is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (llb), (ILb.1), and (I.b.2), R' is 10 phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (11.b), (II.b.1), and (Il.b,2), R' is: F F In some embodiments, in each of Formulas (1l.b), (II.b.1), and (I.b.2), R 27 and R28 15 are each independently selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (11.b), (IlI.b.1), and (11.b.2), R 2 is
-C(Z)R
7 WO 2009/061596 PCT/US2008/080176 - 96 In some embodiments, in each of Formulas (I.b), (II.b.1), and (ll-b.2), R 2 is
-C(Z)NR
9
R
0 . In some embodiments, in each of Formulas (II.b), (Il.b.1), and (11.b.2), R2 is -C(Z)OR. 5 In some embodiments, in each of Formulas (Itb), (ILb.1), and (IL.b.2), R2 is -S0 2
NR
9
R
0 . In some embodiments, in each of Formulas (Ikb), (lI.b.1), and (II.b.2), R2 is alkyl. In some embodiments, in each of Formulas (i.b), (ll.b.1), and (II.b.2), R2 is heteroalkyl. 10 In some embodiments, in each of Formulas (ll.b), (1l b.1), and (Il.b.2), R2 is aryl. In some embodiments, in each of Formulas (1l.b), (11.b.1), and (ll.b.2), R2 is heteroaryl. In some embodiments, in each of Formulas (lI.b), (II.b.1), and (II.b.2), R2 is cycloalkyl. 15 In some embodiments, in each of Formulas (ib), (IL.b.1), and (IL.b.2), R2 is cycloalkenyl. In some embodiments, in each of Formulas (1Ib), (Ikb.1), and (11.b.2), R2 is heterocycloalkyl. In some embodiments, in each of Formulas (II.b), (IL.b.1), and (ll.b.2), R2 is 20 heterocycloalkenyl. In some embodiments, in each of Formulas (1lb), (il.b.1), and (1I.b.2), Z is (=0). In some embodiments, in each of Formulas (ll-b), (II.b.1), and (lI.b.2), Z is (=S), In some embodiments, in each of Formulas (Ikb), (Il b.1), and (ll.b.2), Z is 25 (=N(R 3 )). In some embodiments, in each of Formulas (il b), (il.b,1), and (1I.b.2), Z is
(=N(CN)).
WO 2009/061596 PCT/US2008/080176 -97 In some embodiments, in each of Formulas (11.b), (Il.b.1), and (1.b,2), Z is (=N(OR'4)). In some embodiments, in each of Formulas (Ikb), (1l1b.1), and (lI.b.2), Z is (=N(Re)(R'e( a 5 In some embodiments, in each of Formulas (11b), (Il.b.1), and (ll.b.2), Z is (=C(R 1 7 ) (R Z ()). In some embodiments, in each of Formulas (11b), (Il.b.1), and (11b.2), R 2 is -C(Z)R, and Z is (=O). 10 In some embodiments, in each of Formulas (Ikb), (11.b.1), and (IL.b.2), R 2 is _ C(O)H. In some embodiments, in each of Formulas (1.b), (ll.b.1), and (ll.b.2), R 2 is _ C(O)alkyl. In some embodiments, in each of Formulas (11lb), (Ikb.1), and (Ilb.2), R 2 is 15 C(OCH3. In some embodiments, in each of Formulas (II~b), (ILb.1), and (1l.b.2), R2 is C(O)R, wherein said R 7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, 20 alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR , -NR 2
'R
22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5R2 6 , -C(O)R24
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
H
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
26 and -NR 23
C(O)NR
2 5
R
26 , 25 In some embodiments, in each of Formulas (Ilib), (lI.b.1), and (Ilb.2), R 2 is
C(O)R
7 , wherein said R is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR 1 9 , -NR 21
R
22 , and cycloalkyl.
WO 2009/061596 PCT/US2008/080176 - 98 In some embodiments, in each of Formulas (11.b), (I1.b.1), and (Il.b.2), R 2 is _
C(O)R
7 , wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. 5 In some embodiments, in each of Formulas (I.b), (lL.b.1), and (1l.b.2), R 2 is _
C(O)R
7 , wherein said R7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH 2 , and cyclopropyl. 10 In some embodiments, in each of Formulas (Ib), (II.b.1), and (l.b.2), R 2 is C(O)R, wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. 15 In some embodiments, in each of Formulas (ilIb), (Il.b.1), and (l1.b.2), R2 is _
C(O)R
7 , wherein said R7 is alkyl substituted with -OH. In some embodiments, in each of Formulas (11 b), (ll.b.1), and (II.b.2), R 2 is 20 C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. In some embodiments, in each of Formulas (11.b), (1l.b.1), and (I1.b.2), R 2 is C(O)R , wherein said R is substituted heterocycloalkyl. 25 In some embodiments, in each of Formulas (11.b), (I1.b.1), and (II.b.2), R 2 is C(O)R, wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 - 99 heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'S, -OC(O)OR20, -NR 2 1
R
22 , -NR 2 3 S0 2
R
24 , -NR 23
C(O)OR
2 0, -NR 23 C(O)R24,
-SO
2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR 2 0 , -SR'9, -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24
-C(O)NR
2 5
R
2 6, -NR 23
C(N-CN)NR
2
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 . 5 In some embodiments, in each of Formulas (1l b), (1lb.1), and (1l.b.2), R 2 is
C(O)R
7 , wherein said R 7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 10 In some embodiments, in each of Formulas (Il.b), (Il.b.1), and (l1.b.2), R 2 is selected from: 0 0 NN NEl
H
3 C
,H
3 C , and H 3 C 15 In some embodiments, in each of Formulas (Ikb), (IL.b.1), and (11.b.2), R 2 is
-C(O)NR
9 R'. In some embodiments, in each of Formulas (i b), (Il.b.1), and (IL.b.2), R 2 is _
C(O)NH
2 . In some embodiments, in each of Formulas (ILb), (11b.l), and (I.b.2), R 2 is _ 20 C(O)NR 9
R'
0 , wherein R 9 and R' can be the same or different, each being independently selected from alkyl. In some embodiments, in each of Formulas (II.b), (1l.b.1), and (Ilb.2), R 2 is C(O)NR9R' 0 , wherein R9 is unsubstituted heterocycloalkyl and R 0 is selected from the group consisting of H and alkyl. 25 WO 2009/061596 PCT/US2008/080176 - 100 In some embodiments, in each of Formulas (11.b), (11.b.1)., and (l1b.2), R2 is C(O)NRR'4, wherein R9 is substituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. 5 In some embodiments, in each of Formulas (l.b), (1l.b.1), and (ILb.2), R2 is C(O)NR 9
R
1 4, wherein R 9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R14 is selected from the group consisting of H and alkyl. 10 In some embodiments, in each of Formulas (II.b), (Il b.1), and (II.b.2), R 2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and -C(O)NR 9 R'. Non-limiting examples of R2 include the following moieties: , \ CF 3 ) CHF2 0 o 0 0 0 O OH OO 15 ,N, HO O N OH OH 0 >NP0 00
NH
2
NH
2 NH, NH 2 'NH o 0 0 H HNro H N TNH H0HN' 0 H 1 H 2 N H 2 N H 2
NI
WO 2009/061596 PCT/US2008/080176 -101 HN H 2 N H 2 NO NH NH NH NH H 2 a~o oPJo NHNH ,N d N N 0 N N0
N
0,IN, .! H, and I 5 In some embodiments, in each of Formulas (l.b), (II.b.1), and (1.b.2), R 2 is In some embodiments, in each of Formulas (II.b), ([Lb.1), and (tl.b.2), A 2 is 0 In some emnbodiments, in each of Formulas (1l.b), ([Lb.I), and (II.b.2), R is 0 10 v In some embodiments, in each of Formulas (l.b), (I.b.1), and (11.b.2), R 2 is 0
OH
WO 2009/061596 PCT/US2008/080176 - 102 In some embodiments, in each of Formulas (I.b), (I.b.1), and (11.b.2), R 2 is 0 In some embodiments, in each of Formulas (11.b), (II.b.1), and (lI.b.2), R 2 is 0
NH
2 5 In some embodiments, in each of Formulas (ll.b), (I.b.1), and (lI.b.2), R 2 is 0 N In some embodiments, in each of Formulas (II.b), (l1.b.1), and (ll.b2), R 2 is 0
N-CN
10 In one embodiment, the compounds of the invention have a structure shown in Formula (111.1) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R27 R 2 N R 2R 3 72 15 (1l.1) wherein R 1 , R 2 , R 3 , R 2 R, p, E, and ring B are selected independently of each other and wherein: WO 2009/061596 PCT/US2008/080176 - 103 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -C(R4)(R 5 )-,
-N(R
6 )-, -N(C(Y)R')-, -N(C(Y)OR)-, and -N(C(Y)N(R 9
)(R'
0 ))-; and p is 0, 1, or 2; and ring B, R', R 2 , R4, R 5 , R 6 , R, R", R9, R' 0 , Ra 2 , R 2 , Y, and the optional 5 substituents on ring B are as defined in any of the embodiments described above in Formula (1). In one embodiment, in Formula (Il1): E is selected from the group consisting of -C(R4)(R 5 )-, -0-, -S-, -S(O)-, -S(O) 2 -, 10 and -N(R6_ ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 , 15 said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN,
-NO
2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR , -OC(O)OR 2 0 , -NR 'R 22 , -NR 23
SO
2 R24 20 -NR 23 C(0)OR 2 0 , -NR 23
C(O)R
24 , -SO 2
NR
2 5R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR 19 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR23C(N-CN)NR 2 5 R2 and NR 23
C(O)NR
2 5
R
2 6 ;
R
1 is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from 25 the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 ,
-OC(O)OR
2 0 , -NR 21
R
22 , -NR 23
SO
2
R
24 , -NR 2 3 C(O)OR2 0 , -NR 23
C(O)R
24
,
WO 2009/061596 PCT/US2008/080176 -104 -S0 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R't -S0 2 R'9 -OC(O)R 24
-C(O)NR
2 5
R
2 6 , -NR 23
C(N-CN)NR
25
R
26 and -NR 23C(O)NR 25
R
2 t R2 is selected from the group consisting of -C(O)R7, -C(O)NR 9 R', and -C(O)ORI; p is 0 or 1; and 5 each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR's, -OC(O)OR20, -NR 'R 22 , -C()R 2 4, -C(S)R 24 , -C(O)OR2, and -C(O)NR 25 Re, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 10 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR's, -OC(O)OR2, -NR2R22, 15 -NR 23 S0 2
R
24 , -NR 23C(O)OR20, -NR23C(O)R24, -SO 2 N R 25
R
26 , -C(O)R24, -C(O)OR2o, -SR 1 9 , -S(O)R 9 , -SO 2 R'9 -OC(O)R24, -C(O)N 25
R
2
-NR
2 3
C(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (111.1): 20 ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
R
1 is phenyl substituted with one to four substituents, which can be the same or 25 different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 'R 22 , and haloalkyl; R27 and R2" are each independently selected from the group consisting of H and alkyl;
R
2 is selected from the group consisting of -C(O)R7, -C(O)NR*R' 0 , and -C(O)ORB; WO 2009/061596 PCT/US2008/080176 - 105 p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 5 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 10 heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 20 , -NR R 22
-NR
23 S0 2
R
24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR 25
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR 9 , -S(O)R' 9 , -SO2R' 9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
26 and -NR 2 3
C(O)NR
2 5
R
2 6 . 15 In one such embodiment, in Formula (111.1): R' is: F F : and
R
6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and
-C(S)R
24 20 In one embodiment, the compounds of the invention have a structure shown in Formula (111.2) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: WO 2009/061596 PCT/US2008/080176 -106 R1 R27 R 28 B N E R2R (11.2) wherein R', R 2 , R 3 , R 2 , R 28 , p, E, and ring B are selected independently of each 5 other and wherein: E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)-, -C(R 4
)(R
5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, and -N(C(Y)N(R 9 )(R'))-; and p is 0, 1, or 2, and ring B, R 1 , R 2 , R 4 , R5, R 6 , R 7 , R 8 , R 9 , Ri', R 27 , R 28 , Y, and the optional 10 substituents on ring B are as defined in any of the embodiments described above in Formula (1). In one embodiment, in Formula (111.2): E is selected from the group consisting of -C(R 4 )(R9)-, -0-, -S-, -S(O)-, -S(0)2-, 15 and -N(R6 ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(O), and S(0)2, 20 said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN,
-NO
2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(0)OR20, -NR 2 1
R
22 , -NR 23 S02R 24 , 25 -NR 23
C(O)R
20 , -NR 23 C(O)R 24 , -S0 2 NR2 5
R
2 6 , -C(O)R 24 , -C(O)OR2 0 , -SR' 9
,
WO 2009/061596 PCT/US2008/080176 -107 -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 , -NRC 23
(N-CN)NR
2 5
R
2 6 and NR 2 3
C(O)NR
2 5
R
2 6 ; R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from 5 the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR20, -NR 2
R
2 2 , -NR 23 SO2R 24 , -NRC 23
(O)OR
20 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR', -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 10 -C(O)NR 2 5
R
26 , -NR 23 C(N-CN)NR2R 2 6 and -NR 23
C(O)NR
25
R
2 6 ;
R
2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9
R'
0 , and -C(O)OR; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 19 , -OC(O)OR 2 0 , 15 -NR R 2 , -C(O)R 24 , -C(S)R 24 , -C(O)OR , and -C(O)NRR 26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 20 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR 'R
-NR
2 3
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 2 3 C(O)R 24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)R
20 , -SR 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 , 25 -NR 23
C(N-CN)NR
2 5
R
2 6 and -NRC 23
(O)NR
25
R
2 t In one embodiment, in Formula (111.2): ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, WO 2009/061596 PCT/US2008/080176 -108 pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group 5 consisting of halo, -OH, -CN,-N0 2 , -NR 2 1 R 22, and haloalkyl; R" and R 2 ' are each independently selected from the group consisting of H and alkyl;
R
2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R'%, and -C(O)OR; p is 0 or 1; and 10 each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or 15 different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 20 , -NR 21
R
22
-NR
23 S0 2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R 24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , 20 -C(O)OR20, -SR 19 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 In one such embodiment, in Formula (Ill.2): R' is: F F 25 ;and WO 2009/061596 PCT/US2008/080176 -109
R
6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and
-C(S)R
24 In one embodiment, the compounds of the invention have a structure 5 shown in Formula (Il.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1I R2 R 28 Ny A P N E R2 (II.a.) 10 wherein R, R 2 , R 3 , R 27 , R 2 , p, E, ring A, and ring B are selected independently of each other and wherein: ring A (including E and the unsaturation shown) is a 5-membered cycloalkenyl or heterocycloalkenyl ring; 15 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R6)-, -N(C(Y)R 7 )-, -N(C(Y)OR")-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R)-, -N(R 11 )-S(0) 2 -, -C(0)-0-, -0-C(0)-, -O-N(R 6 )-, -N(R)-O-, -N(R 6 )-N(R1 2 )-, -N=N-, and -C(R7)=N-; ring B is a substituted or unsubstituted aromatic ring; 20 p, R 1 , R 2 , R 3 R 4, R 5 , R 6 , R 7 , R 8 , R 9 , R 1 0 , R", R R 2 , 27 , R 28 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (1). In one embodiment, Formula (ll.a) has the general structure: WO 2009/061596 PCT/US2008/080176 -110 B RR N A P N R2 In one embodiment, Formula (Ill.a) has the general structure: R1 R27 R28 B 5 R 2 In one embodiment, in Formula (lItIa.), p is 0, 1, or 2; In one embodiment, in Formula (illa.), ring A is a cycloalkenyl ring and E is 10 -C(R4)(R), In one embodiment, in Formula (Ilil.a.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -C(O)-N(R 1 )-, -N(R)-C(0)-, -S(0)-N(R'l)-, -N(R')-S(0)2-, -C(O)-O-, -0-C(O)-, -0-N(R 6 )-, -N(R 6 )-0-, -N(R3 N(R1 2 )-, -N=N-, and -C(R 7 )=N-. By way of non-limiting illustration, an example of WO 2009/061596 PCT/US2008/080176 - 111 a compound of Formula (1ILa.) wherein E is -C(O)-N(R) F F N-N NH includes: o In one embodiment, in Formula (1ll.a.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-. 5 In one embodiment, in Formula (Ill.a.), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-, wherein R3 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 24 In one embodiment, in Formula (1ll1a.), E is selected from the group consisting of -0- and -N(R3)-, wherein R 6 is selected from the group consisting of H, alkyl, 10 -C(O)R 24 , and -C(S)R 2 4 In one embodiment, in Formula (Ill.a.), E is -0 In one embodiment, in Formula (lll.a.), E is -S-. In one embodiment, in Formula (Ill.a.), E is -S(O)-. In one embodiment, in Formula (Ill.a.), E is -S(0) 2 -. 15 In one embodiment, in Formula (Illa.), E is -C(R4)(R5)-. In one embodiment, in Formula (llI.a.), E is -N(R 6 )-. In one embodiment, in Formula (Ill.a.), E is -N(C(Y)R 7 )_. In one embodiment, in Formula (Ill.a.), E is -N(C(Y)OR)-. In one embodiment, in Formula (Ilila.), E is -N(C(Y)N(R 9
)(R
1 4))-. 20 In one embodiment, in Formula (Ill a.), E is -C(O)-N(R 1 )-. In one embodiment, in Formula (Ill.a.), E is -N(R")-C(O)-. In one embodiment, in Formula (Ill.a.), E is -S(O) 2
-N(R
1 )-. In one embodiment, in Formula (Ill a.), E is -N(R' 1 )-S(0) 2
-.
WO 2009/061596 PCT/US2008/080176 -112 In one embodiment, in Formula (lll.a.), E is -C(O)-O-. In one embodiment, in Formula (IILa.), E is -0-C(O)-. In one embodiment, in Formula (1lla.), E is -0-N(R)-. In one embodiment, in Formula (Ill a.), E is -N(R 6 )-O-. 5 In one embodiment, in Formula (ilI.a.), E is -N(R 6 )-N(R1 2 )-. In one embodiment, in Formula (lll.a.), E is -N=N-. In one embodiment, in Formula (llta.), E is -C(R 7 )=N-. In one embodiment, in Formula (Ill a.), Y is (=O). 10 In one embodiment, in Formula (Il.a.), Y is (=S). In one embodiment, in Formula (Ill.a.), Y is (=N(R 13 )). In one embodiment, in Formula (Ill.a.), Y is (=N(CN)). In one embodiment, in Formula (Illa.), Y is (=N(OR1 4 )). In one embodiment, in Formula (Il.a.), Y is (=N(R 1
)(R
16 )). 15 In one embodiment, in Formula (Ill.a.), Y is (=C(R 17
)(R
18 )). In one embodiment, in Formula (Il.a.), B is an unsubstituted aromatic ring. In one embodiment, in Formula (lIta.), B is an unsubstituted benzo ring, and Formula (illa.) has the general structure: R 1 2R R B8 R N A N 20 R2 WO 2009/061596 PCT/US2008/080176 -113 In one embodiment, in Formula (Ill.a.), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, 5 -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR R 22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
26 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R'9, -SO 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 , 10 -NR 23 C(N-CN)NR 25
R
2 6 and -NR 23
C(O)NR
25
R
2 6 . In one embodiment, in Formula (Ill.a.), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , 15 alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR's, -OC(O)OR 20 , -NR 2
'R
22 , -NR 23
SO
2
R
24 ,
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -SO 2 R', -OC(O)R24, -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and 20 -NR 2 3
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (IlIa.), R' is unsubstituted aryl. In one embodiment, in Formula (lita.), R' is unsubstituted phenyl. In one embodiment, in Formula (Ill.a.), R' is unsubstituted naphthyl. 25 In one embodiment, in Formula (I1a.), R' is substituted aryl. In one embodiment, in Formula (1lla.), R' is substituted phenyl. In one embodiment, in Formula (ILa.), R' is substituted naphthyl. In one embodiment, in Formula (Ill.a.), R' is aryl substituted with one or more substituents, which can be the same or different, each substituent being WO 2009/061596 PCT/US2008/080176 -114 independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 2 , -NR R 22 , -NR 23
SO
2
R
2 4 5 -NR 2 3
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SQ 2
NR
2 5
R
2 3, -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R', -S0 2 R1 9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and
-NR
23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (IlI.a.), R' is phenyl substituted with one or more 10 substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR1 9 , -OC(O)OR 20 , -NR 2 'R 22 , -NR 23 S0 2
R
24 15 -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SQ 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR 19 ,
-S(O)R'
9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and
-NR
2 3 C(O)NR 2 5
R
2 6. In one embodiment, in Formula (IlIla.), R' is phenyl substituted with one to four 20 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 ,
-NR
21
R
22 , and haloalkyl. In one embodiment, in Formula (Ill.a.), R' is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 -115 halo HO NC - 02N halo halo halo halo alkyl - haloalkyl halo halo and In one embodiment, in Formula (Illa), R' is: perfluoroalkyl halo 5 In one embodiment, in Formula (IlIl.a.), R' is phenyl substituted with one to three fluoro groups. In one embodiment, in Formula (IlLa.), R 1 is phenyl substituted with two fluoro groups. In one embodiment, in Formula (Illa.), R' is phenyl substituted with one fluoro 10 group. In one embodiment, in Formula (Ill.a.), R' is: F F In one embodiment, in Formula (Illa.), R 27 and RA are each independently 15 selected from the group consisting of H and alkyl. In one embodiment, in Formula (lita.), A 2 is -C(Z)R7. In one embodiment, in Formula (lIl.a.), R 2 is -C(Z)NRR.
WO 2009/061596 PCT/US2008/080176 -116 In one embodiment, in Formula (Ill.a.), R 2 is -C(Z)OR. In one embodiment, in Formula (Ill.a.), R 2 is -SO 2 NR'R1. In one embodiment, in Formula (lila.), R 2 is alkyl. In one embodiment, in Formula (lila.), R 2 is heteroalkyl. 5 In one embodiment, in Formula (Illa.), R 2 is aryl. In one embodiment, in Formula (1lla.), R 2 is heteroaryl. In one embodiment, in Formula (Ill a.), R 2 is cycloalkyl. In one embodiment, in Formula (II.a.), R 2 is cycloalkenyl. In one embodiment, in Formula (1lla.), R 2 is heterocycloalkyl. 10 In one embodiment, in Formula (Ili.a.), R 2 is heterocycloalkenyl. In one embodiment, in Formula (lll.a.), Z is (=0). In one embodiment, in Formula (Ill.a.), Z is (=S). In one embodiment, in Formula (Ill.a.), Z is (=N(R 3 )). 15 In one embodiment, in Formula (1I11a.), Z is (=N(CN)). In one embodiment, in Formula (Il.a.), Z is (=N(OR')). In one embodiment, in Formula (Ill.a.), Z is (=N(R' 5 )(R'6). In one embodiment, in Formula (Ill a.), Z is (=C(R' 7 )(R')). 20 In one embodiment, in Formula (lIla.), R 2 is -C(Z)R 7 , and Z is (=0). In one embodiment, in Formula (Ill.a.), R 2 is -C(O)H. In one embodiment, in Formula (Ill a.), R 2 is -C(0)alkyl. In one embodiment, in Formula (1lIIa.), R 2 is -C(O)CH 3 . In one embodiment, in Formula (Ill.a.), R 2 is -C(O)R, wherein said R is alkyl 25 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, WO 2009/061596 PCT/US2008/080176 -117 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2
R
22 , -NR 23
SO
2
R
2 4
-NR
23 C(0)OR 20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 4, -SR' 9 , 5 -S(O)R' 9 , -S0 2 R9 , -OC(O)R 24 , -C(O)N R 25
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
26 and
-NR
23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (III.a.), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, 10 each substituent being independently selected from the group consisting of
-OR'
9 , -NR 21
R
22 , and cycloalkyl. In one embodiment, in Formula (Ilta.), R 2 is -C(O)R, wherein said R is alkyl, wherein said alkyl is substituted with alkyl and -OH. 15 In one embodiment, in Formula (llila.), R 2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH,
-NH
2 , and cyclopropyl. 20 In one embodiment, in Formula (1Ila.), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. 25 In one embodiment, in Formula (Il.a.), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with -OH.
WO 2009/061596 PCT/US2008/080176 -118 In one embodiment, in Formula (lll.a.), R 2 is -C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. In one embodiment, in Formula (Ill.a.), R 2 is -C(O)R , wherein said R 7 is 5 substituted heterocycloalkyl. In one embodiment, in Formula (IlI.a.), R2 is -C(O)R 7 , wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group 10 consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR21, -NR 2 1R22 -NR 23
SO
2
R
24 , -NR 23C(O)OR1)20, -NR 2C(O)R 24, -S0 2 NR2 5 R2 6 , -C(O)R24,
-C(O)OR
2 0, -SR 1 9 , -S(O)R' 9 , -SO 2 R1', -OC(O)R24, -C(O)NR 2 5
R
2 6, 15 -NR 2 3
C(N-CN)NR
25 R2 6 and -NR 2 3
C(O)NR
25 1R 26 . In one embodiment, in Formula (IlI.a.), R2 is -C(O)R , wherein said R is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 20 In one embodiment, in Formula (Ila.), R2 is selected from: 0 0 0 N N N
H
3 C ,H 3 C , and H 3 C In one embodiment, in Formula (IlI.a.), R2 is -C(O)NR 9
R'
0 . 25 In one embodiment, in Formula (Ill.a.), R2 is -C(O)NH 2 In one embodiment, in Formula (ll.a.), R2 is -C(O)NRR , wherein R9 and RI0 can be the same or different, each being independently selected from alkyl.
WO 2009/061596 PCT/US2008/080176 -119 In one embodiment, in Formula (Ill.a.), R 2 is -C(O)NR 9 R'4, wherein R 9 is unsubstituted heterocycloalkyl and R 1 0 is selected from the group consisting of H and alkyl. 5 In one embodiment, in Formula (Ill.a.), R 2 is -C(O)NR 9 R', wherein R 9 is substituted heterocycloalkyl and R 1 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (Ill.a.), R 2 is -C(O)NR 9
R'
0 , wherein R 9 is 10 heterocycloakyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and
R
1 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (Ill.a.), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and 15 -C(O)NR 9
R
0 . In one embodiment, in Formula (Ill a.), R 2 is selected from the group consisting of K , 0- , CF 3 0 02 jJ 0 0 OH 0 HO ,0 '-o 01NOH OH 0 0 2 , 2 20 N H 2 N H 2 , N H 2 , NH 2 ~ N WO 2009/061596 PCT/US2008/080176 - 120 oHN HN -NH 0 0a
NH
2 o O NH
H
2 4 H 2 N H2N HN H 2 N 14 2 N NH ON H HH O NH NH NH NH H 2 N H -2R KtOo oO o N 5 NH ari \ NN
H
2 n o 2 n NHl, N is N NH 0O 0n o 0 N 0NNO - N 5 0 Q NH, 0H ,and 0 In one embodiment, in Formula (lIl.a.), R 2 is 0 OH 10 In one embodiment, in Formula (Ili.a.), R 2 is WO 2009/061596 PCT/US2008/080176 - 121 0 In one embodiment, in Formula (I1a.), R 2 is 0 In one embodiment, in Formula (Ill.a.), R2 is 2. O N In one embodiment, in Formula (Ill.a.), R 2 is 0 \t N--
N
In one embodiment, in Formula (Ill.a.), R 2 is|. 5 In one embodiment, in Formula (Ill.a.), p is 0 and R3 is not present. In one embodiment, in Formula (Ill.a.), p is 1. In one embodiment, in Formula (lila.), p is 2. In one embodiment, in Formula (1l.a.), p is 3. 10 In one embodiment, in Formula (llia.), p is 4. In one embodiment, in Formula (IllIa.), p is > 2 and at least two groups R 3 are attached to the same ring atom. In one embodiment, in Formula (ilI.a.), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, 15 heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR 1 9 , -OC(O)OR 20 , -NR R 22
-NR
23
SO
2
R
24 , -NR 2 3
C(O)OR
20 , -NR 23 C(O) R 24 , -SO 2 N R 2
SR
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR 1 9 , -S(O)R', -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5 R26
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
25 Rl 2 6 . 20 In one embodiment, in Formula (lIl.a.), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR'9, -OC(O)OR 20
,
WO 2009/061596 PCT/US2008/080176 - 122 -NR 21
R
2 2 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
20 , -NRC 2 3
(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24
-C(O)OR
20 , -SR 9 , -S(O)R 9 , -S0 2
R
19 , -OC(O)R2, -C(O)NR 5
R
2 6 ,
-NRC
23
(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
2 5 fR 2 6 , In one embodiment, in Formula (lila.), p is 2, 3, or 4 and at least two groups R3 5 are bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN,
-NO
2 , , -OR' 9 , -OC(O)OR 2 0 , -NR 2R 2 2 , -NR 23 S0 2
R
24 , -NRC 23
(O)OR
20 , 10 -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 ,
-OC(O)R
24 , -C(O)N R 25
R
26 , -NRC 23
(N-CN)NR
25
R
2 6 and -NRC 23
(O)NR
25
R
2 6 . In one embodiment, in Formula (llI.a.), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, 15 form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (lIl.a.), p is 1 or 2 and each R 3 is independently 20 selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 9 , -OC(O)OR 2 , -NR 21
R
22 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
2 ),
-NR
23
C(O)R
24 , -SO 2
NR
25 R, -C(O)R 24 , -C(S)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 ,
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NRC 23
(N-CN)NR
2 5
R
2 6 , -NRC 23
(O)NR
2 5
R
2 6 , and -NR 23
-C(NH)-NR
26
R
2 6 , 25 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 30 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR, -NR 1
R
2
,
WO 2009/061596 PCT/US2008/080176 -123 -NR2 3
SO
2 R2 4 , -NR2 3 C(O)OR2 0 , -NR2 3 C(O)R2 4 , -SO 2 NR 2 5 R2 6 , -C(O)R24 -C(O)OR0, -SR, -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R24 -C(O)NR5R
-NR
2 3 C(N-CN)NR2 5 R2 6 and -NR 2 3C(O)NR2R2 6 . In one embodiment, in Formula (ill.a.), p is I and R3 is selected from the group 5 consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 10 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR20, -NR 21
R
22 -NR2 3
SO
2 R2 4 , -NR23C(O)OR2 0 , -NR 2 3 C(O) B 24 , -S0 2 NR2 5
R
2 6 , -C(O)R24, -C(O)OR0, -SR' 9 , -S(O)R 9 , -SO 2
R'
9 , -OC(O)R 4 , -C(O)NRR, 15 -NR2 3 C(N-CN)NR2 5 R2 6 and -NR2 3
C(O)NR
25 R2 6 . In one embodiment, in Formula (lIla.), p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In one embodiment, in Formula (lIl.a.), p is 2 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having 20 from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, 0, S, S(O), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-,
-NR
6 -, 0, S, S(O), and S(0)2 25 In one embodiment, in Formula (Ilila.), R3 is alkyl. In one embodiment, in Formula (Ill.a.), R 3 is heteroalkyl. In one embodiment, in Formula (Il.a.), R is alkenyl. In one embodiment, in Formula (Ill.a.), R3 is heteroalkenyl. In one embodiment, in Formula (Ill.a.), R 3 is alkynyl.
WO 2009/061596 PCT/US2008/080176 - 124 In one embodiment, in Formula (llIa.), R 3 is heteroalkynyl. In one embodiment, in Formula (Ill.a.), R 3 is aryl. In one embodiment, in Formula (Ill.a.), R 3 is heteroaryl. In one embodiment, in Formula (Ill a.), R 3 is cycloalkyl. 5 In one embodiment, in Formula (lila.), R 3 is cycloalkenyl. In one embodiment, in Formula (Ill.a.), R 3 is heterocycloalkyl. In one embodiment, in Formula (Illa.), R 3 is heterocycloalkenyl. In one embodiment, in Formula (Il.a.), R 3 is halogen. In one embodiment, in Formula (Ill.a.), R 3 is -CN. 10 In one embodiment, in Formula (Ill a.), R 3 is -NO 2 . In one embodiment, in Formula (Ill.a.), R 3 is -OR' 9 . In one embodiment, in Formula (lILa.), R 3 is -OC(O)0R 20 In one embodiment, in Formula (lll.a.), R 3 is -NR 2
'R
22 In one embodiment, in Formula (llIa.), R 3 is -NR 23 S0 2
R
2 4 . 15 In one embodiment, in Formula (Ill.a.), R 3 is -NR 23 (O)0R 2 0 . In one embodiment, in Formula (lIIa.), R 3 is -NR 23
C(O)R
2 4 . In one embodiment, in Formula (Ill.a.), R 3 is -S0 2
NR
5
R
2 . In one embodiment, in Formula (llta.), R 3 is -C(Q)R 2 4 In one embodiment, in Formula (Ill.a.), R 3 is -O()0R 20 20 In one embodiment, in Formula (Illla.), P 3 is -SR 1 9 . In one embodiment, in Formula (Ill.a.), R 3 is -S(O)R 9 . In one embodiment, in Formula (Ill.a.), R 3 is -SO 2 R', In one embodiment, in Formula (Ill.a.), R 3 is -O(O)R 24 . In one embodiment, in Formula (lll.a.), R 3 is -C(O)NR 2
R
2 t. 25 In one embodiment, in Formula (Ill.a.), R 3 is -NR 23
C(N-CN)NR
2 5
R
2
.
WO 2009/061596 PCT/US2008/080176 - 125 In one embodiment, in Formula (Ill.a.), R 3 is -NR 23 C(O)NRaR 2 6 . In one embodiment, in Formula (Ill.a.), R 3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl, N, N, NH 2 , H 2 N H 2 N OH 5 OH, OH, HO, 0, O NH2 HN HN HN NH2 NN OH ") H N H N Nf-H 0) 0 , 0 N, OH , and
H
2 N In one embodiment, in Formula (Ill.a.), when E is -NR 6 -, R 3 is absent. 10 In one embodiment, Formula (Ill.a.) has the general structure (Ill.a.1): WO 2009/061596 PCT/US2008/080176 - 126 R 1 R 27 R 28 B N NE 2 R) R (2ll.a.1) wherein R, R , R 3 , R R, p, E, and ring B are selected independently of each other and wherein: 5 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R)-, -N(C(Y)R7)-, -N(C(Y)OR 8 )-, and -N(C(Y)N(R 9
)(R
1 ))-; and p, R 1 , R 2 , R 3 , R 4 , R 5 , R6, R, R 8 , R, R 0 , RN , R 2 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (Ill.a.). 10 In one embodiment, Formula (Ill.a.1) has the general structure shown in Formula (Ill.a.1.1): 27 28 RR R N NE 2 ~ R 3), R2 (Ill.a.1.1). 15 WO 2009/061596 PCT/US2008/080176 - 127 In one embodiment, Formula (Ill.a.) has the general structure Ill.a.2: R1 R 27 R 28 B N, N E R2(R3 p (Ill.a.2) wherein R', R 2 , R 3 , R 27 , R 2 8 , p, E, and ring B are selected independently of each 5 other and wherein: E is selected from the group consisting of -0-, -S-, -S(O)-, -S(Q) 2 -, -C(R 4
)(R
5 )-, -N(R6)-, -N(C(Y)R 7 )-, -N(C(Y)ORs)-, and -N(C(Y)N(R 9 )(R'%))-; and p, R', R , R 3 , R 4 , R 5 , R , R 7 , R 8 , R9, R, R 27 , R 28 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above 10 in Formula (lil.a.). In one embodiment, Formula (Il.a.2) has the general structure shown in Formula (lIl.a.2.1): R1 R27 R28 RB N,, N R2 (R3 ) R 15 WO 2009/061596 PCT/US2008/080176 - 128 In one embodiment, Formula (Illa.2) has the general structure shown in Formula (Ill.a.2.2): 1 R27 R 28 B N E
R
2 (R 3) (Ill.a.2.2). 5 In one embodiment, Formula (Ill.a.2) has the general structure shown in Formula (IlI.a.2.3): 27 R R R N E
R
2 R 3 (Ill .a.2.3). 10 WO 2009/061596 PCT/US2008/080176 - 129 In one embodiment, Formula (Il a.2) has the general structure shown in Formula (Ill.a.2.4): 1 R2
R
28 B N NH R2 (R E (Ill.a.2.4). 5 In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (1ll.a.2), (Ill.a.2.1), (ll.a.2.2), (1ll.a.2.3), and (Ill.a.2.4), p is 0. In some embodiments, in each of Formulas (lil.a.1), (Illa.1.1), (IlI.a.2), (Ill.a.2.1), (Ill.a.2.2), (Illa.2.3), and (lita.2.4), p is 1. 10 In some embodiments, in each of Formulas (lIl.a.1), (lll.a.1.1), (lila.2), (Ill.a.2.1), (1ll.a.2.2), (IlI.a.2.3), and (illa.2.4), p is 2. In some embodiments, in each of Formulas (Ill.a.1), (1ll.a.1.1), (IlI.a.2), (ill.a.2.1), (Il.a.2.2), (III.a.2.3), and (ll.a.2.4),E is -C(R 4
)(R
5 )-. 15 In some embodiments, in each of Formulas (11I.a.1), (lI a.1.1), (ll.a.2), (Ill.a.2.1), (ill.a.2.2), (llta.2.3), and (1ll.a.2.4),E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (lita.2), (Ill.a.2.1), (lita.2.2), (111.a.2.3), and (Ill.a.2.4),E is selected from the group consisting of -0-, 20 -S-, -S(O)-, -S(0)2-, and -N(R 0 )-, wherein R3 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 24 WO 2009/061596 PCT/US2008/080176 - 130 In some embodiments, in each of Formulas (IllI.a.1), (Ill.a.1.1), (llla.2), (lIta.2.1), (111a.2.2), (Ill.a.2.3), and (ilLa.2.4),E is selected from the group consisting of -0 and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl,
-C(O)R
24 , and -C(S)R 2 4 5 In some embodiments, in each of Formulas (llI.a.1), (Ill.a.1.1), (1ll.a.2), (Ill.a.2.1), (Ill.a.2.2), (Ill.a.2.3), and (lll.a.2.4),E is -0-. In some embodiments, in each of Formulas (IllI.a.1), (IllI.a.1.1), (lll.a.2), (III.a.2.1), (Ill.a.2.2), (lll.a.2.3), and (Ill.a.2.4),E is -S-. In some embodiments, in each of Formulas (lll.a.1), (Il.a.1.1), (llta.2), (Ill.a.2.1), 10 (Il.a.2.2), (ltl.a.2.3), and (Ill.a.2.4),E is -S(O)-. In some embodiments, in each of Formulas (Ill a.1), (II~a.1.1), (Il.a.2), (Ill.a.2.1), (ill.a,2.2), (Ill.a.2.3), and (Ill.a.2.4),E is -S(0) 2 -. In some embodiments, in each of Formulas (Ill.a.1), (IlIl.a.1.1), (Ill.a.2), (llI.a.2.1), (Ill.a.2.2), (li.a.2.3), and (Ill a.2.4),E is -C(R4)(R 5 )-. 15 In some embodiments, in each of Formulas (lIi a.1), (Ill.a.1.1), (II.a.2), (Ill.a.2.1), (llI.a.2.2), (Ill.a.2.3), and (lll.a.2.4),E is -N(R 6 )_. In some embodiments, in each of Formulas (Il.a.1), (lIi a.1.1), (Il.a.2), (Il.a.2.1), (IlLa.2.2), (Il.a.2.3), and (Ill.a.2.4),E is -N(C(Y)R 7 )_. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (1ll.a.2), (lla.2.1), 20 (lll.a.2.2), (lIl.a.2.3), and (Lta.2.4),E is -N(C(Y)OR 8 )_ In some embodiments, in each of Formulas (Ill.a.1), (IIi.a.1.1), (ll.a.2), (Ill.a.2.1), (Ill.a.2.2), (ll.a.2.3), and (illta,2.4),E is -N(C(Y)N(R 9
)(R
0 ))-. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (lIL a.2), (lla.2.1), 25 (Illa.2.2), (Ill.a.2.3), and (lII.a.2.4),Y is (=0). In some embodiments, in each of Formulas (ll1a.1), (IlL.a.1.1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (Ill.a.2.3), and (Ill.a.2.4),Y is (=S).
WO 2009/061596 PCT/US2008/080176 - 131 In some embodiments, in each of Formulas (Ill.a.1), (llL.a.1.1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (Ill.a.2.3), and (ill.a.2.4),Y is (=N(R' 3 )). In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (Ill.a.2.3), and (Ill.a.2.4),Y is (=N(CN)). 5 In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1 .1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (Ill.a.2.3), and (Ill.a.2.4),Y is (=N(OR1)). In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (Ill.a.2.1), (lll.a.2.2), (Ill.a.2.3), and (Illa.2.4),Y is (=N(R 1 5 )(R')). In some embodiments, in each of Formulas (lll.a.1), (Ill.a.1.1), (Ill.a.2), (Illa.2.1), 10 (Ill.a.2.2), (llL.a.2.3), and (Ill.a.2.4),Y is (=C(R')(R 1 8 )). In some embodiments, in each of Formulas (Ill.a.1), (llLa.1.1), (ll.a.2), (Ill.a.2.1), (111a.2.2), (Ill.a.2.3), and (Ill.a.2.4),R is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , 15 -NR 2R 2 2 , and haloalkyl. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (Il.a.2.1), (lli.a.2.2), (lll.a.2.3), and (Ill.a.2.4),R' is selected from the group consisting of: halo -- HO N- NC -ON halo halo halo halo alkyl - - haloalkyl halo halo 20 , and In one embodiment, in Formula (1), R' is: WO 2009/061596 PCT/US2008/080176 -132 perfluoroalkyl - haso In some embodiments, in each of Formulas (tIl.a.1), (Il.a.1.1), (iI.a.2), (11L.a.2.1), (Ill.a.2.2), (111a.2.3), and (1lLa.2.4),R is phenyl substituted with one to three fluoro groups. 5 In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (1il.a.2.3), and (1ll.a.2.4),R' is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (IlI.a.1), (Ill.a.1.1), (ll.a.2), (Il.a.2.1), (lIl.a.2.2), (lll.a.2.3), and (11l.a.2.4),R' is phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (lil.a.2.1), 10 (lhl.a.2.2), (Ill.a.2.3), and (Ill.a.2.4),R' is: F F In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (1I.a.2.1), (Il.a.2.2), (1l1.a.2.3), and (Ill.a.2.4), R 27 and R2 8 are each independently selected from the group consisting of H and alkyl. 15 In some embodiments, in each of Formulas (Ill.a.1), (1ll.a.1.1), (ll.a.2), (Ill.a.2.1), (Ill.a.2.2), (1ll.a.2.3), and (1I1.a.2.4), R 2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R". -C(O)OR 8 , and
-C(O)NR
9
R'
0 . 20 In some embodiments, in each of Formulas (lll.a.1), (IlL.a.1.1), (Ill.a.2), (1ll.a.2.1), (Ill.a.2.2), (III.a.2.3), and (II.a.2.4),R 2 is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 - 133 o- NK~CF 3 , 0
CHF
2 F 0 0 N OH o H,, HO 0 W 0 0 NH OH OH , OO O too O 2
NH
2 , HNH N H 0 \ N, N 5 01TH 2 N H 2 N H 2 N H H -0 G 0 D" ' tiN H 2 N , 2 0 0 0 00 NH NH NH NH HNH 2 0 00 0 0 -N
H
2 N H 2 N NH, NH7 0i 0 0 00 O N N' NI NN 0, 0 Nnand WO 2009/061596 PCT/US2008/080176 -134 In some embodiments, in each of Formulas (llI.a.1), (lll.a.1.1), (Ill.a.2), (Ill.a.2.1), (Ill.a.2.2), (lIl.a.2.3), and (IllIa.2.4),p is 1 or 2 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 19 , -OC(O)OR 20 , -NR 2
'R
22 , -NR 23
SO
2 R24, -NR 23
C(O)OR
20 , 5 -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(S)R 2 4, -C(O)OR 20 , -SR' 9 , -S(O)R 1 9,
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 , -NR 23
C(O)NR
2 5
R
2 6 , and -NR 2 3
-C(NH)-NR
2 6
R
26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 10 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0, -NR R 2 2 , 15 -NR 23
SO
2
R
24 , -NR 2 3
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
26 and -NR 23
C(O)NR
2 5
R
2 6 . In some embodiments, in each of Formulas (llI.a.1), (Illa.1.1), (Ill.a.2), (Ill.a.2.1), (ill.a.2.2), (Ill.a.2.3), and (ill.a.2.4),p is 1 and R 3 is selected from the group 20 consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 25 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 , -N R 2
'
2 -N R 23 SO2R 24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , 30 -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 -135 In some embodiments, in each of Formulas (lll.a.1), (Ill.a.1.1), (Ill.a.2), (lILa.2.1), (lll.a.2.2), (lll.a.2.3), and (Ill.a.2.4),p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In some embodiments, in each of Formulas (Ill.a.1), (Ill.a.1.1), (Ill.a.2), (1ll.a.2.1), 5 (lll.a.2.2), (lll.a.2.3), and (llL.a.2.4),p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, 0, S, S(O), and S(0) 2 , or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, 10 -NR 6 -, 0, S, S(O), and S(0) 2 . In one embodiment, the compounds of the invention have a structure shown in Formula (Ill.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R27 R28 B RR Nq, A R P HN E 15 R 2 (111.b.) wherein R 1 , R 2 , R 3 , R 27 , R 2 , p, E, ring A, and ring B are selected independently of each other and wherein: 20 ring A (including E and the unsaturation shown) is a 5-membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R4)(R 5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R)-, -N(R")-C(O)-, -S(0) 2 -N(R)-, -N(R 1 )-S(0) 2 -, -C(Q)-0-, -0-C(O)-, -0-N(R 6 )-, 25 -N(R)-O-, -N(R 6
)-N(R
12 )-, -N=N-, and -C(R7)=N-; WO 2009/061596 PCT/US2008/080176 -136 ring B is a substituted or unsubstituted heteroaromatic ring; and p, R', R 2 , R 3 , R 4 , R5, R 6 , R, R, R 9 , R 1 0 , R", R 12 , R 27 , R 2 Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (1). 5 In one embodiment, Formula (lil.b) has the general structure: R1 R2' R28 B IN A R)P N
R
2 In one embodiment, Formula (I1.b) has the general structure: 10 R1 R2' R28 B R3 Ns A R 2 In one embodiment, in Formula (Ill.b.), p is 0, 1, or 2. In one embodiment, in Formula (Ill.b.), ring A is a cycloalkenyl ring and E is 15 -C(R4)(R5)_ WO 2009/061596 PCT/US2008/080176 - 137 In one embodiment, in Formula (Il.b.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -C(O)-N(R 1 )-, -N(R")-C(O)-, -S(0) 2 -N(R)-, -N(R 11
)-S(O)
2 -, -C(O)-O-, -0-C(O)-, -0-N(R 6 )-, -N(R 6 )-O-, -N(R 6
)
N(R1 2 )-, -N=N-, and -C(R )=N-, By way of non-limiting illustration, an example of 5 a compound of Formula (Ill.a.) wherein E is -C(O)-N(R") F S N-N N includes: 0 In one embodiment, in Formula (I.b.), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-. 10 In one embodiment, in Formula (Illb.), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(0)R 24 , and -C(S)R 24 In one embodiment, in Formula (11.b.), E is selected from the group consisting of -0- and -N(R )-, wherein R 6 is selected from the group consisting of H, alkyl, 15 -C(O)R 24 , and -C(S)R 24 In one embodiment, in Formula (ll.b.), E is -0-. In one embodiment, in Formula (llI.b.), E is -S-. In one embodiment, in Formula (ILkb.), E is -S(O)-. In one embodiment, in Formula (1lLb.), E is -S(0) 2 -. 20 In one embodiment, in Formula (llIb.), E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (lli.b.), E is -N(R 6 )-. In one embodiment, in Formula (llb.), E is -N(C(Y)R 7 )_. In one embodiment, in Formula (111 b.), E is -N(C(Y)OR )-. In one embodiment, in Formula (Ill.b.), E is -N(C(Y)N(R 9
)(R'))-.
WO 2009/061596 PCT/US2008/080176 -138 In one embodiment, in Formula (lil.b.), E is -C(O)-N(R)-. In one embodiment, in Formula (llb.), E is -N(R')-C(O)-. In one embodiment, in Formula (lii.b.), E is -S(O) 2 -N(R")-, In one embodiment, in Formula (il.b.), E is -N(R")-S(0) 2 -. 5 In one embodiment, in Formula (Ill.b.), E is -C(00)--. In one embodiment, in Formula (Ill.b.), E is -0-C(O)-. In one embodiment, in Formula (Iil.b.), E is -0-N(R 6 )-. In one embodiment, in Formula (Ilb.), E is -N(R)-O-. In one embodiment, in Formula (ll.b.), E is -N(R 6 )-N(R1 2 )-. 10 In one embodiment, in Formula (Ill.b.), E is -N=N-. In one embodiment, in Formula (ill.b.), E is -C(R 7 )=N-. In one embodiment, in Formula (Illi.b.), Y is (=0). In one embodiment, in Formula (Ill.b.), Y is (=S). 15 In one embodiment, in Formula (Ill.b.), Y is (=N(R' 3 )). In one embodiment, in Formula (IlIlb.), Y is (=N(CN)). In one embodiment, in Formula (lll.b.), Y is (=N(OR 14 )). In one embodiment, in Formula (lilb.), Y is (=N(R 5
)(R'
6 )). in one embodiment, in Formula (lll.b.), Y is (=C(R 1 7
)(R
8 )). 20 In one embodiment, in Formula (Il.b.), B is an unsubstituted heteroaromatic ring, In one embodiment, in Formula (Ill.b.), B is an unsubstituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group 25 consisting of N, S, 0, S(O), and S(0) 2
.
WO 2009/061596 PCT/US2008/080176 - 139 In one embodiment, in Formula (ill-b.), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 5 haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2 1
R
22 ,
-NR
23 SO2R 24 , -NR 23 C()OR2 0 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R24
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26 ,
-NRC
23
(N-CN)NR
25
R
2 6 and -NRC 23
(O)NR
2 5
R
2 6 . 10 In one embodiment, in Formula (Ill-b.), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(0) 2 , which heteroaromatic ring is substituted with one or more 15 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR , -OC(O)OR 2 0 , -NR 2 1
R
22 , -NR 23
SO
2
R
24 , 20 -NRC 23
(O)OR
2 0 , -NRC 23
(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR2o, -SR 1 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
25
R
2 6 and NR 23 C(O)NR 2
R
2 6 . In one embodiment, in Formula (ll.b.), B is an unsubstituted 6-membered 25 heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0. In one embodiment, in Formula (llI.b.), B is a 6-membered heteroaromatic ring 30 having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, WO 2009/061596 PCT/US2008/080176 - 140 and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, 5 heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 0 , -NR 2
'R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 ,
-NR
23
C(O)R
24 , -S0 2
NR
25
R
2 , -C(O)R 2 4, -C(0)OR 2 0 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)N R 25
R
2 6 , -NR 23 C(N-CN)NR R 2 9R 26 and -NR 23
C(O)NR
25 R2 6 . 10 In one embodiment, in Formula (Ill.b.), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0. In one embodiment, in Formula (lll.b.), B is a 6-membered heteroaromatic ring 15 having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NRR 21 22 , -C(O)R 24 , -C(O)R 2 , -SR' 9 , -S(O)R' 9 , 20 -SO 2
R'
9 , -OC(O)R 24 , and -C(O)NRR 2 . In one embodiment, in Formula (ll1.b.), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group 25 consisting of N, S, and 0. In one embodiment, in Formula (ll.b.), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 30 and 0, which heteroaromatic ring is substituted with one or more substituents, WO 2009/061596 PCT/US2008/080176 -141 which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 5 azido, -OR' , -OC(O)OR 2 4, -NR 2
'R
2 2 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 ,
-NRC
23
(O)R
24 , -SO 2 NR 2 5
R
26 , -C(O)R 24 , -C(O)OR20, -SR 1 9 , -S(O)R' 1 , -S0 2
R
1 ,
-OC(O)R
2 4, -C(O)NR 25
R
2 6 , -NRC 23
(N-CN)NR
25
R
26 and -NR 23
C(O)NR
25
R
2 6 . In one embodiment, in Formula (lli.b.), B is an unsubstituted 5-membered 10 heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0. In one embodiment, in Formula (Ill.b.), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, 15 each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NRR 22 , -C(O)R 24
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , and -C(O)NR 25
R
2 6 , In one embodiment, in Formula (Ill.b.), B is a 5-membered heteroaromatic ring 20 having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR 2
R
22 , -C(O)R 24 , -C(O)OR2o, -SR' 9 ,
-S(O)R'
9 , -S02R' 9 , -OC(O)R 24 , and -C(O)NR 2 5
R
2 . 25 In one embodiment, in Formula (Il.b.), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom. In one embodiment, in Formula (1ll.b.), B is selected from the group consisting of WO 2009/061596 PCT/US2008/080176 -142 ,and . In one embodiment, in Formula (Ill.b.), R' is unsubstituted aryl. 5 In one embodiment, in Formula (Ill b.), R 1 is unsubstituted phenyl. In one embodiment, in Formula (ll.b), R' is unsubstituted naphthyl. In one embodiment, in Formula (Ill.b.), R' is substituted aryl. In one embodiment, in Formula (Ill.b.), R is substituted phenyl. In one embodiment, in Formula (Ill.b.), R' is substituted naphthyl. 10 In one embodiment, in Formula (Ilb.), R 1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2, -NR'R 22 , -NR 23 S0 2
H
2 4
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR 2 0 , -SR 9 ,
-S(O)R'
9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and
-NR
2 3
C(O)NR
25 26 . 20 In one embodiment, in Formula (Illb.), R' is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 25 heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2
R
22 , -NR 23
SO
2
R
24
-NR
2 3
C(O)OR
2 0 , -N R 2 3 C(O)R 24 , -S0 2 NR2R2 6 , -C(0)R 24 , -C(O)OR20, -SR' 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5 R2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and
-NR
23
C(O)NR
25 26
.
WO 2009/061596 PCT/US2008/080176 -143 In one embodiment, in Formula (ll.b.), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 , 5 -NR 2 1
R
22 , and haloalkyl. In one embodiment, in Formula (Ill.b.), R' is selected from the group consisting of: halo' HO - NC - 0 2 N halo halo halo halo alkyi haloalkyl halo halo ,and .7' 10 In one embodiment, in Formula (lil.b.), R' is: perfluoroalkyl halo In one embodiment, in Formula (1ll.b.), R1 is phenyl substituted with one to three fluoro groups. In one embodiment, in Formula (Illb.), R 1 is phenyl substituted with two fluoro 15 groups. In one embodiment, in Formula (Ill.b.), R 1 is phenyl substituted with one fluoro group. In one embodiment, in Formula (llb.), R' is: F / F WO 2009/061596 PCT/US2008/080176 - 144 In one embodiment, in Formula (ll.b.), R27 and R"a are each independently selected from the group consisting of H and alkyl. 5 In one embodiment, in Formula (lll.b.), R2 is -C(Z)R 7 . In one embodiment, in Formula (111.b.), R2 is -C(Z)NR8R' . In one embodiment, in Formula (lil.b.), R 2 is -C(Z)R. In one embodiment, in Formula (11.b.), R 2 is -S0 2
NR
9
R'
0 . In one embodiment, in Formula (lil.b.), R 2 is alkyl. 10 In one embodiment, in Formula (|11.b.), R2 is heteroalkyl. In one embodiment, in Formula (Ill.b.), R 2 is awrl. In one embodiment, in Formula (ll.b.), R2 is heteroaryl. In one embodiment, in Formula (Ill.b.), R2 is cycloalkyl. In one embodiment, in Formula (Ill.b.), R 2 is cycloalkenyl. 15 In one embodiment, in Formula (Ill.b.), R 2 is heterocycloalkyl. In one embodiment, in Formula (lll.b.), R2 is heterocycloalkenyl. In one embodiment, in Formula (111.b.), Z is (=0). In one embodiment, in Formula (Ill.b.), Z is (=S). 20 In one embodiment, in Formula (Ill.b.), Z is (=N(R)). In one embodiment, in Formula (1ll.b.), Z is (=N(CN)). In one embodiment, in Formula (1ll.b.), Z is (=N(ORM)). In one embodiment, in Formula (111.b.), Z is (=N(R( 1 4)). In one embodiment, in Formula (ll.b.), Z is (=O(Rl)(R16)). 25 WO 2009/061596 PCT/US2008/080176 -145 In one embodiment, in Formula (lll.b.), R2 is -C(Z)R 7 , and Z is (=O). In one embodiment, in Formula (Ill.b.), R 2 is -C(O)H. In one embodiment, in Formula (11l.b.), R 2 is -C(O)alkyl. In one embodiment, in Formula (Ill.b.), R2 is -C(O)CH 3 . 5 In one embodiment, in Formula (Ill.b.), R 2 is -C(O)R 7 , wherein said R7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 10 heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2), -NR 2 ' R 22 , -NR 23
SO
2
R
24 ,
-NR
2 3
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2 NR2 5
R
2 6 , -C(O)R24, -C(O)OR2o, -SR'S,
-S(O)R'
9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3 C(N-CN)NR 2
R
2 6 and
-NR
2 3
C(O)NR
2 5
R
2 6 . 15 In one embodiment, in Formula (Il-b.), R2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR's, -NR 21 R22, and cycloalkyL 20 In one embodiment, in Formula (Ill.b.), R 2 is -C(O)R , wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In one embodiment, in Formula (Ill.b.), R 2 is -C(O)R, wherein said R is alkyl substituted with one to three substituents, which can be the same or different, 25 each substituent being independently selected from the group consisting of -OH,
-NH
2 , and cyclopropyl. In one embodiment, in Formula (lll.b.), R2 is -C(O)R, wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each WO 2009/061596 PCT/US2008/080176 - 146 substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. In one embodiment, in Formula (ll.b.), R 2 is -C(O)R, wherein said R is alkyl 5 substituted with -OH. In one embodiment, in Formula (Ill.b.), R 2 is -C(0) R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 10 In one embodiment, in Formula (Illi.b.), R 2 is -C(O)R 7 , wherein said R 7 is substituted heterocycloalkyl. In one embodiment, in Formula (Ill.b.), R 2 is -C(O)R7, wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the 15 same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR2'R 22 -N R 23 SO2R 24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -SO 2 NR2 5
R
26 , -C(O)R 24 , 20 -C(O)R 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25 2 6 ,
-NR
23
C(N-CN)NR
2 5
R
2 3 and -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (lil.b.), R 2 is -C(O)R, wherein said R is selected from the group consisting of substituted piperidine, substituted piperazine, 25 substituted morpholine, substituted pyrrolidine, and substituted azetidine. In one embodiment, in Formula (Ill.b.), R 2 is selected from: WO 2009/061596 PCT/US2008/080176 -147 N N H3C ,H3C , and H 3 C In one embodiment, in Formula (111.b.), R2 is -C(O)NR 9
R
0 . In one embodiment, in Formula (ll.b.), R2 is -C(O)NH 2 . 5 In one embodiment, in Formula (ill.b.), R2 is -C(O)NR9R' 0 , wherein R9 and R' 0 can be the same or different, each being independently selected from alkyl. In one embodiment, in Formula (lil.b.), R2 is -C(O)NR 9 R, wherein R9 is unsubstituted heterocycloalkyl and R 1 0 is selected from the group consisting of H and alkyl. 10 In one embodiment, in Formula (Illib.), R2 is -C(O)NR9R 0 , wherein R9 is substituted heterocycloalkyl and R 1 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (Ill.b.), R2 is -C(O)NR 9 R ', wherein R9 is 15 heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and Rio is selected from the group consisting of H and alkyl. In one embodiment, in Formula (ll.b.), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 -C(O)OR, and 20 -C(O)NKR"' In one embodiment, in Formula (ilt.b.), R2 is selected from the group consisting of 0 0 0 pPr C 3 CH F 2 r o ,\0 H if 0 HO 7? WO 2009/061596 PCT/US2008/080176 -148 0o- 00 O -J N \ 0 OH OH NH-N
NH
2
NH
2
NH
2 , NH 0 0 0 ONH2 HN HN NH
HN"'-
01-T HH 2 N H 2 N O H O N O 2 N 5 NH ~N H ,?H
H
2 NH o oP o 0O 5 2 2H 2
,H
2 NH 0 $11171NH N H, 2 il , an d \ 0 In one embodiment, in Formula (111.b.), R 2 iS CF3. 0 In one embodiment, in Formula (Ill.b.), R2 is WO 2009/061596 PCT/US2008/080176 - 149 0 In one embodiment, in Formula (Ill.b.), R 2 is 0 In one embodiment, in Formula (llI.b.), R2 is OH 0 In one embodiment, in Formula (1Lb.), R2 is 0 In one embodiment, in Formula (Ill.b.), R2 is \ NH 2 0 \A N 5 In one embodiment, in Formula (Ill.b.), R2 is 0 \ N- N In one embodiment, in Formula (Illb.), R2 is I In one embodiment, in Formula (ll.b.), p is 0 and R3 is not present. In one embodiment, in Formula (II1b.), p is 1. In one embodiment, in Formula (Illb.), p is 2. 10 In one embodiment, in Formula (ll.b.), p is 3. In one embodiment, in Formula (111.b.), p is 4. In one embodiment, in Formula (Illb.), p is > 2 and at least two groups R3 are attached to the same ring atom. In one embodiment, in Formula (Ill.b.), p is 1 and R3 is independently selected 15 from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR's, -OC(O)OR20, -NR 2 1
R
22
-NR
23 SO2R 24 , -NR 2 3
C(O)OR
2 0 , -NR 23C(O)R 24, -SO 2 NR 25R26, -C(O)R24, -C(O)OR 2, -SR 1 9 , -S(O)R' 9 , -S0 2
R
9 , -OC(O)R24, -C(O)NR 2 5R2 6 , 20 -NR 2 3 C(N-CN)NR2 5 R 26 and -NR 2 3
C(O)NR
2 5
R
2
.
WO 2009/061596 PCT/US2008/080176 - 150 In one embodiment, in Formula (1l.b.), p is 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR20 5 -NR 2
R
22 , -NR 23 S0 2
R
24 , -NRC 23
(O)OR
2 , -NRC 2 3
(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R24
-C(O)OR
20 , -SR'9, -S(O)R9', -S0 2 R'9, -OC(O)R 24 , -C(0) NR 2 5
R
2 6,
-NR
23
C(N-CN)NR
25
R
26 and -NR 23
C(O)N
2 5
R
26 . In one embodiment, in Formula (lll.b.), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein each R 3 , which may be the 10 same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN,
-NO
2 , , -OR' 9 , -OC(O)OR 20 , -NR 2
R
22 , -N RSO2R 24 , -NR 23
C(O)OR
20 ,
-NR
23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R', -SO 2
R'
9 , 15 -OC(O)R 2 4 , -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
25
R
2 6 . In one embodiment, in Formula (ll.b.), p is 2, 3, or 4 and at least two groups R* are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to 20 three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (Ill.b.), p is 1 or 2 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 25 -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR 2
'R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 ,
-NRC
23
(O)R
24 , -S0 2
N
25
R
26 , -C(O)R 24 , -C(S)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 , -NR 23
C(N-CN)NR
25
R
26 , -NRC 23
(O)NR
25
R
2 6 , and -NR 2
-C(NH)-NR
26
B
2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 30 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or WO 2009/061596 PCT/US2008/080176 - 151 different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 2 4, -NR R 22 5 -NR 23 S0 2
R
24 , -NR 23
C(O)OR
20 , -NR 2 3
C(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R24
-C(O)OR
2 4, -SR 9 , -S(O)R 9 , -S0 2
R
1 9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
23
C(N-CN)NR
2 5
R
26 and -NR 23
C(O)NR
2 5
R
26 . In one embodiment, in Formula (IIl.b.), p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, 10 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 15 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)OR 2 0 , -NRR 21 22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
2 , -NR 23 C(O)R 24 , -SO 2 N R 25
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR 1 9 , -S(O)R 9 , -SO2R' 9 , -OC(O)R 24 , -C(O)NH 2 5
R
2
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . 20 In one embodiment, in Formula (111.b.), p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In one embodiment, in Formula (Ill.b.), p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of 25 -NH-, -NR 6 -, 0, S, S(O), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR-, 0, S, S(O), and S(0)2. In one embodiment, in Formula (Illb.), R 3 is alkyl. In one embodiment, in Formula (ll.b.), R 3 is heteroalkyl. 30 In one embodiment, in Formula (1ll.b.), R 3 is alkenyl.
WO 2009/061596 PCT/US2008/080176 - 152 In one embodiment, in Formula (Ill.b.), R 3 is heteroalkenyl. In one embodiment, in Formula (Ill.b.), R 3 is alkynyl. In one embodiment, in Formula (llI.b.), R 3 is heteroalkynyl. In one embodiment, in Formula (lIl.b.), R 3 is aryl. 5 In one embodiment, in Formula (Il.b.), R 3 is heteroaryl. In one embodiment, in Formula (Ill.b.), R 3 is cycloalkyl. In one embodiment, in Formula (IIL.b.), R 3 is cycloalkenyl. In one embodiment, in Formula (Ill.b.), R 3 is heterocycloalkyl. In one embodiment, in Formula (lIl.b.), R 3 is heterocycloalkenyl. 10 In one embodiment, in Formula (Illb.), R 3 is halogen. In one embodiment, in Formula (Ill.b.), R 3 is -CN. In one embodiment, in Formula (1Il.b.), R 3 is -NO 2 . In one embodiment, in Formula (IIl.b.), R 3 is -OR' 9 . In one embodiment, in Formula (ll.b.), R 3 is -OC(O)OR 0 . 15 In one embodiment, in Formula (Ilitb.), R 3 is -NR 21
R
22 ,. In one embodiment, in Formula (Ill.b.), R 3 is -NR 23 S0 2
R
2 4 . In one embodiment, in Formula (Il.b.), B 3 is -NR 23 C(O)0B 2 0 In one embodiment, in Formula (ll.b.), R 3 is -NR 2 3
C(O)R
24 In one embodiment, in Formula (Illb.), R33 is -S 2
N
2
R
26 . 20 In one embodiment, in Formula (III.b.), R 3 is -C(O)R 24 . In one embodiment, in Formula (llI.b.), 3 is -C(O)OR 2 0 In one embodiment, in Formula (IllI.b.), R 3 is -SB'R5 In one embodiment, in Formula (IlI.b.), R 3 is -S(O)R 9 . In one embodiment, in Formula (i.b.), R 3 is -SO 2
R'
9 ,. 25 In one embodiment, in Formula (Ill.b.), R 3 is -OC(O)R 24
.
WO 2009/061596 PCT/US2008/080176 - 153 In one embodiment, in Formula (Illlb.), R 3 is -C(O)NR 25
R
2 In one embodiment, in Formula (Ill.b.), R 3 is -NR 2 3
C(N-CN)NR
2 5
R
26 . In one embodiment, in Formula (ll.b.), R 3 is -NR 2 3
C(O)NR
25 8 2 6 . In one embodiment, in Formula (Ill-b.), R 3 is selected from the group consisting 5 of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl, N N, NH 2
H
2 N H 2 N OH OH, OH, HO, , O o NH2 HHN NH2 ,HN0 HN N\, OH ,and
H
2N 10 In one embodiment, in Formula (Ill.b.), when E is -NR 6 -, R 3 is absent.
WO 2009/061596 PCT/US2008/080176 -154 In one embodiment, Formula (IlLb.) has the general structure (lll.b.1): R 1 R 27 R 28 N N I E (R3 ) 2R R (lll.b.1) wherein R', R 2 , R 3
R
27 , R 2 , p, E, and ring B are selected independently of each 5 other and wherein: E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -C(R4)(R5)-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, and -N(C(Y)N(R 9
)(R'
0
))
and p, R', R 2 , R 3 , Rt , 5
,R
6 , R R, R, R 9 , R1 0 , R 27 , R 28 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above 10 in Formula (lil.b.).
WO 2009/061596 PCT/US2008/080176 - 155 In one embodiment, Formula (ll.b) has the general structure shown in Formula (Il1.b.2): R1 R27 R28 )NN E R2 (R3 (ll.b.2) 5 In one embodiment, Formula (lil.b) has the general structure shown in Formula (Illb.2.1): R1 R 27 R 28 B N N E R 2 (R 3 ) (1ll.b.2.1). In one embodiment, Formula (llI.b) has the general structure shown in Figure 10 (1Il.b.2.2): 1 R 27 R28 R B N , N f E
R
2 (R3) WO 2009/061596 PCT/US2008/080176 - 156 (llI.b.2.2). In one embodiment, Formula (11.b) has the general structure shown in Formula (ll.b.2.3):
R
1
R
2 7 R28 B N I E
R
2 ( R 3 ) p 5 (ll.b.2.3). In one embodiment, Formula (Ill-b) has the general structure shown in Formula (llI..)ad(ll.b.2.4)pis1 1I R 27 R 28 N, N R2 ( R 3)p (Il11.b. 2.4), 10 In some embodiments, in each of Formulas (1ll.b.1), (ll.b.2), (ll1.b.2.1), (ill.b.2.2), (111.b.2.3), and (11l.b.2.4),p is 0. In some embodiments, in each of Formulas (111.b.1I), (Ill.b.2), (111.b.2.1), (111.b.2.2), (Illi.b.2.3), and (Illi.b.2.4), p is 1. 15 In some embodiments, in each of Formulas (111.b.1), (i.b.2), (Ill.b.2.1), (111.b.2.2), (Ill.b.2.3), and (Ill-b.2.4),p is 2.
WO 2009/061596 PCT/US2008/080176 - 157 In some embodiments, in each of Formulas (lILb.1), (1lltb.2), (I.b.2.1), (Ill.b.2.2), (1l.b.2.3), and (iILb.2.4), E is -C(R 4
)(R
5 )-. In some embodiments, in each of Formulas (1ll.b.1), (111.b.2), (111Ib.21), (ll1b.2.2), (IlLb.2.3), and (ill.b.2.4), E is selected from the group consisting of -0-, -S-, 5 -S(O)-, -S(0)2-, and -N(R 6 )-. In some embodiments, in each of Formulas (Ill.b.1), (IILb.2), (IlI.b.2.1), (illb.2.2), (lIb.2.3), and (II.b.2.4), E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, and -N(R)-, wherein R6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 24 . 10 In some embodiments, in each of Formulas (Il1.b.1), (IlI.b.2), (llI.b.2.1), (IlILb.2.2), (Il.b.2.3), and (llIb.2.4), E is selected from the group consisting of -0- and
-N(R
6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 and -C(S)R 24 In some embodiments, in each of Formulas (IIlb.1), (111.b.2), (Il.b.2.1), (ill.b.2.2), 15 (llI0b.2.3), and (Il.b.2.4),E is -0 In some embodiments, in each of Formulas (IlLb.1), (lII.b.2), (Ill.b.2.1), (ill.b.2.2), (liLb.2.3), and (Ill.b.2.4),E is -S-. In some embodiments, in each of Formulas (Ill.b.1), (111.b.2), (1I1 b.2.1), (Ill.b.2.2), (Ill.b.2.3), and (Ill.b.2.4),E is -S(O)-. 20 In some embodiments, in each of Formulas (Ill.b.1), (1ll.b.2), (lIlb.2.1), (Ill.b.2.2), (ll.b.2.3), and (Ill.b.2.4),E is -S(0)2-. In some embodiments, in each of Formulas (IlLb.1), (111.b.2), (Ill.b.2.1), (ill.b.2.2), (Il.b.2.3), and (Ill.b.2.4),E is -C(R4)(R 5 )-. In some embodiments, in each of Formulas (Ill.b.1), (III1b.2), (Ill.b.2.1), (Illb.2.2), 25 (Il.b.2.3), and (Ill.b.2.4),E is -N(R)-. In some embodiments, in each of Formulas (11l.b.1), (IlI.b.2), (Il.b.2.1), (Ill.b.2.2), (111.b.2.3), and (Ill.b.2.4),E is -N(C(Y)R 7
)-.
WO 2009/061596 PCT/US2008/080176 -158 In some embodiments, in each of Formulas (Ill.b.1), (111.b.2), (ll.b.2.1), (ill.b.2.2), (ll.b.2.3), and (ill.b.2.4),E is -N(C(Y)OR 8 )-. In some embodiments, in each of Formulas (lll.b.1), (Ill.b.2), (ll.b.2.1), (Ill.b.2.2), (Il.b.2.3), and (1lIlb.2.4),E is -N(C(Y)N(R 9 )(R"'))-, 5 In some embodiments, in each of Formulas (llb.1), (lll.b.2), (11.b.21), (Il.b.2.2), (III.b.2.3), and (Ill.b.2.4),Y is (=O). In some embodiments, in each of Formulas (1ll.b.1), (llI.b.2), (I.b.2.1), (Iltb.2.2), (1I1.b.2.3), and (IILb.2.4),Y is (=S). 10 In some embodiments, in each of Formulas (Ill b.1), (Illb.2), (lIl.b.2.1), (Ill.b.2.2), (Ill.b.2.3), and (Ill.b.2.4),Y is (=N(R 13 )). In some embodiments, in each of Formulas (ill.b.1), (Illlb.2), (ll.b.2.1), (lIi.b.2.2), (ll.b.2.3), and (lII.b.2.4),Y is (=N(CN)). In some embodiments, in each of Formulas (llI.b.1), (Ill.b.2), (llIlb.2.1), (llI.b.2.2), 15 (Ill.b.2.3), and (lll.b.2.4),Y is (=N(OR 14 )). In some embodiments, in each of Formulas (Ill.b.1), (Illlb.2), (Ill.b.2.1), (lIl.b.2.2), (Illb.2.3), and (Ill.b.2.4),Y is (=N(R 15
)(R'
6 )). In some embodiments, in each of Formulas (Ill.b.1), (lll.b.2), (Ill.b.2.1), (lIl.b.2.2), (Illb.2.3), and (Illb.2.4),Y is (=C(R 17 )(R'")). 20 In some embodiments, in each of Formulas (IIL.b.1), (Illb.2), (IlLb.2.1), (IL.b.2.2), (lIl.b.2.3), and (Ill.b.2.4), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 1 R 22 , and haloalkyl. 25 In some embodiments, in each of Formulas (1lllb.1), (I1.b.2), (Illlb.2.1), (IIl.b.2.2), (ll.b.2.3), and (11l.b.2.4), R' is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 - 159 halo --- O0 2 N halo halo halo halo alkyf --- haloalkyl halo halo and in one embodiment, in Formula (1), R' is: perfluoroalkyi halo 5 In some embodiments, in each of Formulas (1Il.b.1), (1ll.b.2), (Ill.b.2.1), (111.b.2.2), (IllI.b.2.3), and (Ill.b.2.4), R' is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas (Ill.b.1), (111.b.2), (Il.b.2.1), (1I1.b.2.2), (Ill.b.2.3), and (Il.b.2.4), R' is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (Ill.b.1), (Ill-b.2), (11.b.2.1), (Ill.b.22), 10 (IIl.b.2.3), and (1ll.b.2.4), R 1 is phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (ill.b.1), (Il.b.2), (111.b.2.1), (1lLb.2.2), (Il.b.2.3), and (Ill.b.2.4), R' is: F 15 In some embodiments, in each of Formulas (1ll.b.1), (111.b.2), (IllIb.2.1), (lli.b.2.2), (Ill.b.2.3), and (1ll.b.2.4), R2 7 and R 28 are each independently selected from the group consisting of H and alkyl.
WO 2009/061596 PCT/US2008/080176 -160 In some embodiments, in each of Formulas (Ill.b.1), (Ill.b.2), (ll.b.2.1), (ill.b.2.2), (IlLb.2.3), and (ll.b.2.4), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R'. -C(O)OR, and -C(O)NR 9
R'
0 . In some embodiments, in each of Formulas (Il.b.1), (llI.b.2), (Ill.b.2.1), (11l.b.2.2), 5 (111.b.2.3), and (11b.2.4), R2 is selected from the group consisting of: 0000 O CF 3 0
%CHF
2 F 0 0 0 0 O 0 OH o O HO -p 0 0 0 0 0 0 \" N OH OH 2, NH 2 , NH , NH 2 , NH OO oOA 0 N N N H 0 HNr0 HN NH 0
NH
2 HNHN 10 HN 2 N H 2 N N 0 0 0 1 P' HN ,H 2
,
2 N 00 0o J 0j 0 NH NH NH NH IH 2 N H 2
N
WO 2009/061596 PCT/US2008/080176 - 161 0A 1C 00 0$ 0 C N -0 H2 OH 2 N NH, c N N 0 o 0 0 I N-- N> 0N is NH H and N In some embodiments, in each of Formulas (ll.b.1), (Ill.b.2), (IlIl.b.2.1), (Ill.b.2.2), 5 (111.b.2.3), and (Ill.b.2.4),p is 1 or 2 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 ,
-OR
1 9 , -OC(O)OR 20 , -NR 21 R22, -NR 23 SO2R 24 , -NR 23
C(O)OR
20 , -NR 2 3
C(O)R
2 4 , -S0 2
NR
25
R
2 6 , -C(O)R24, -C(S)R24, -C(O)OR20, -SR 1 9 , -S(O)R 9 , -S0 2
R
1 ,
-OC(O)R
24 , -C(O)NR 25
R
2 , -NR 2 3
C(N-CN)NR
2 5
R
2 6, -NRC 2 3
(O)NR
25
R
2 , and 10 NR 23
-C(NH)-NR
26
R
2 6 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 15 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycfoalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 1
R
2
-NR
23
SO
2
R
24 , -NR 2 3
C(O)OR
2 0 , -NR 23 C(O)R 24, -SO 2 N R 25
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR 1 9 , -S(O)R' 9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 5
R
2 20 -NR 23 C(N-CN)NR 25
R
26 and -NR 23
C(O)NR
25
R
26 . In some embodiments, in each of Formulas (Ilil.b.1), (III.b.2), (llI.b.2.1), (I.b.2.2), (II b.2.3), and (Ill.b.2.4),p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 25 each said heteroalkenyl, is unsubstituted or optionally independently WO 2009/061596 PCT/US2008/080176 - 162 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 5 heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 , -OC(0)ORE, -NR 2
R
22
-NR
23 S0 2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -SO 2
NR
2
R
2 6 , -C(0)R 24 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2
R
2
-NR
23
C(N-CN)NRR
2 5
H
2 and -NR 23
C(O)NR
2 5
R
26 . In some embodiments, in each of Formulas (II.b.1), (IlLb.2), (11.b.21), (111.b.2.2), 10 (Ill.b.2.3), and (Ill-b.2.4),p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In some embodiments, in each of Formulas (llI.b.1), (IlL.b.2), (Ilb.2.1), (I.b.2.2), (Ill.b.2.3), and (IIl.b.2.4),p is 2 and any two R 3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 15 ring heteroatoms independently selected from the group consisting of -NH-,
-NR
6 -, 0, S, S(O), and S(O) 2 , or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-,
-NR
6 -, 0, S, S(O), and S(O) 2 . 20 In one embodiment, the compounds of the invention have a structure shown in Formula (IV) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: 1 R(27 R2 NN A E R2 R3 i R (lv) WO 2009/061596 PCT/US2008/080176 -163 wherein R 1 , R 2 , R 3 , R27, R 28 , p, E, ring A, and ring B and the optional groups attached to ring B are each selected independently of each other and wherein: E is selected from the group consisting of -C(R 4
)(R
5 )-, -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R3-; 5 ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 , said substituents on said aromatic ring or said heteroaromatic ring (when 10 present) being independently selected from the group consisting of halogen, -CN,
-NO
2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR19, -OC(O)OR 20 , -NR'R , -NR S0 2
R
24 ,
-NR
23
C(O)R
20 , -NRC 23
(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR20, -SR 1 , 15 -S(O)R' 9 , -S0 2
R
1 9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3C(N-CN)NR 2 5
R
2 6 and NR 2 C(O)NR 25 26 ; R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, 20 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR20, -NR 21R 22 , -NR 2 3
SO
2
R
24 , -NR 23 C(0)OR 20 , -NR 23C(O)R24$ -S0 2
NR
2 5
R
26 , -C(O)R24, -C(O)OR20, -SR'9, -S(O)R' 9 , -S0 2
R
9 , -OC(O)R24 -C(O)NR 25 R26, -NR 23
C(N-CN)NR
2 5
R
2 6 and -NRC 23
(O)NR
2 5
R
2 6; 25 R2 is selected from the group consisting of -C(O)R7, -C(O)NR 9
R'
0 , and -C(O)ORa; p is 0, 1, or 2; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -ORl§, -OC(O)OR20,
-NR
21
R
22 , -C(O)R24, -C(S)R 24 , -C(O)OR20, and -C(O)NR 2 5 1R 2 6, WO 2009/061596 PCT/US2008/080176 -164 wherein each said alkyl, each said heteroalky, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 5 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR 2 0 , -NR 2 R 22
-NR
23 S0 2
R
24 , -NR 23
C(O)OR
2 0 , -NRC 23
(O)R
24 , -SO 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , 10 -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 ; and all remaining variables are as defined in each of the embodiments described above in Formula (1). In one such embodiment, in Formula (IV): 15 E is selected from the group consisting of -0- and -N(R 6 )-; ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; 20 Ri is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO 2 , -NR 1
R
22 , and haloalkyl;
R
27 and R 2 are each independently selected from the group consisting of H and alkyl; 25 R2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R', and -C(O)OR p is 0 or 1; and each R3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, WO 2009/061596 PCT/US2008/080176 -165 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 5 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2
R
22
-NR
23
SO
2
R
24 , -NR 23 C(O)OR20, -NR 23 C(O)R 24 , -SO 2
NR
2 9R 2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR'9, -S(O)R' 9 , -SO2R' 9 , -OC(O)R 24 , -C(O)NR 2 5
R
26 , 10 -NR 23
C(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . In one such embodiment, in Formula (IV): R' is: F F ;and 15 R 6 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR 20 , and
-C(S)R
24 In one embodiment, the compounds of the invention have a structure shown in Formula (IV.a) and include pharmaceutically acceptable salts, solvates, 20 esters, prodrugs, or isomers of said compounds: WO 2009/061596 PCT/US2008/080176 - 166 R 1 R27 R28 B R3 N E R 2 (IV.a.) wherein R 1 , R 2 , R 3 , R 27 , R 2 8 , p, E, ring A, and ring B are selected independently of each other and wherein: 5 ring A (including E and the unsaturation shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R4)(R 5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R')-, -N(R')-C(O)-, -S(0) 2 -N(R")-, -N(R 1
)-S(Q)
2 -, -C(O)-O-, -0-C(0)-, -0-N(R 6 )-, 10 -N(R)-O-, -N(R 6
)-N(R
12 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, -C(0)-N=N-, -0-C(Y)-N(R)-, -N(R')-C(Y)-O-, -N(R 1
)-C(Y)-N(R
12 )-, -C(Y)-N(R)-O-, -C(Y)-N(R')-N(R1 2 )-, -0-N(R")-C(Y)-, and -N(R 12 )-N(R')-C(Y)-, ring B is a substituted or unsubstituted aromatic ring; and p, R', R2, R3, R4R ,t R, R1, R1, R9, R1', R1, R, R, R 2 , Y, and the 15 optional substituents on ring B are as defined in each of the embodiments described above in Formula (1). In one embodiment, Formula (IVa) has the general structure shown in Formula (IV.a.1): WO 2009/061596 PCT/US2008/080176 -167 R1 R27 R28 B R3 R 2 (IV.a. 1). In one embodiment, Formula (IV.a) has the general structure shown in Formula 5 (IV.a.2): B RR N A E-4R3) N - R 2 (IV.a.2). In one embodiment, Formula (IV.a) has the general structure shown in Formula 10 (IV.a.3): WO 2009/061596 PCT/US2008/080176 -168 1i R 27 R28 NA C4R 3 HN E R2
R
(IV.a.3), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (IV.a) has the general structure shown in Formula 5 (IV.a.4): R R28 RR R B I3 N, A R3 AE N R2 R3 (IV.a.4), wherein P is 0, 1, 2, or 3. 10 In one embodiment, Formula (IV.a) has the general structure shown in Formula (IV.a.5): WO 2009/061596 PCT/US2008/080176 - 169 R1 R27 R 28 RA R3 N E R 2 R3 (IV.a.5), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (lV.a) has the general structure shown in Formula 5 (IV.a.6): 27 R 28 B N A R3) N E R2 R R (IV.a.6), wherein P is 0, 1, 2, or 3. 10 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a cycloalkenyl ring and E is -C(R4)(R 5 )-.. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )-. 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IVa.3), (IV.a.4), (IV.a.5), and (IVa.6), ring A is a heterocycloalkenyl ring and E is WO 2009/061596 PCT/US2008/080176 - 170 selected from the group consisting of -0-, -S-, -S(O), -S(0)2-, and -N(R 6 )_, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and
-C(S)R
24 , In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 5 (IV.a.4), (IV.a.5), and (IV.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0- and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 24 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -0-. 10 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV-a.6), E is -S-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(O)-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 15 (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(0)2-. In some embodiments, in each of Formulas (IV.a), (Va.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(R 4
)(R
5 )-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R 6 )-. 20 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(C(Y)R 7 )-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a,5), and (IV.a.6), E is -N(C(Y)OR 8 )-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 25 (IV.a.4), (JV.a.5), and (IV.a.6), E is -N(C(Y)N(R 9
)(R
0
))-.
WO 2009/061596 PCT/US2008/080176 - 171 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(O)-N(R"')-. In some embodiments, in each of Formulas (lV.a), (IV.a.1), (IV.a.2), (IV.a,3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R")-C(O)-. 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -S(O) 2 -N(R")-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R")-S(O) 2 -. In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(O)-O-. In some embodiments, in each of Formulas (IV.a), (lV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -O-C(O)-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -O-N(R 6 )-. 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R 6 )-O-. In some embodiments, in each of Formulas (IV.a), (lV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R 6
)-N(R
12 )_. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), 20 (IV.a.4), (IV.a.5), and (IV.a.6), E is -N=N-. In some embodiments, in each of Formulas (IV.a), (IV,a.1), (IV-a.2), (IV.a,3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(R 7 )=N-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV-a.6), E is -C(O)-C(R7)=N-.
WO 2009/061596 PCT/US2008/080176 - 172 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(O)-N=N-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -O-C(Y)-N(R")-. 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R')-C(Y)-O-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R' 1
)-C(Y)-N(R
12 )-. In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IVa.5), and (IVa.6), E is -C(Y)-N(R")-O-. In some embodiments, in each of Formulas (IV.a), (IV-a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -C(Y)-N(R")-N(R 2 )-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -O-N(R")-C(Y)-. 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), E is -N(R 12 )-N(R")-C(Y)-. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=0). 20 In some embodiments, in each of Formulas (IV.a), (lV.a.1), (IV.a.2), (IVa.3), (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=S). In some embodiments, in each of Formulas (IVa), (IV~a.1), (iV.a.2), (IV.a.3), (IV.a.4), (IVa.5), and (lV.a.6), Y is (=N(R1)). In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), 25 (IV.a.4), (IV.a.5), and (IV.a.6), Y is (=N(CN)).
WO 2009/061596 PCT/US2008/080176 - 173 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), ([Va.5), and (IV-a.6), Y is (=N(OR 1 )). In some embodiments, in each of Formulas (IV.a), (IVa.1), (IVa.2), (IV.a.3), (IV.a.4), (lVa.5), and (IV.a.6), Y is (=N(R' 5 )(R'6)) 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), Y is (=C(R 1 7 )(R')). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is an unsubstituted aromatic ring. 10 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), B is an unsubstituted benzo ring, and Formula (IVa.) has the general structure: R28 R1R27 R 2 R R3 N I R 2 15 In some embodiments, in each of Formulas (IV.a), (IVa.l), (IV.a.2), (IV.a.3), (IV.a.4), (IVa.5), and (IV.a.6), B is an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, 20 aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR 20 , -NR 2
R
22 , -NR 23 S0 2
R
24
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR 20 , -SR 1 9, WO 2009/061596 PCT/US2008/080176 -174 -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR2 3
C(N-CN)NR
2 5
R
2 6 and NR 23 C(O)N R 25
R
26 , In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 5 (IV.a.4), (IV.a.5), and (IV.a.6), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, 10 heterocycloalkenyl, azido, -OR 19 , -OC(O)OR20, -NR2 1 R2 2 , -NR2 3
SO
2 R24 -NR2 3 C(O)OR2 0 , -NR2 3 C(O)R2 4 , -SO 2 NR2 5 R2 6 , -C(O)R 4 , -C(O)OR0, -SR'9,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR25R2 6 , -NR2 3 C(N-CN)NR2 5 R2 6 and NR 23
C(O)NR
2 5
R
2 6 . 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 1 is unsubstituted aryl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R' is unsubstituted phenyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 20 (IV.a.4), (IV.a.5), and (IV.a.6), R 1 is unsubstituted naphthyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R is substituted aryl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R' is substituted phenyl. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 1 is substituted naphthyl. In some embodiments, in each of Formulas (IV.a), (lV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 1 is aryl substituted with one or more substituents, which can be the same or different, each substituent being WO 2009/061596 PCT/US2008/080176 - 175 independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 ', -OC(O)OR 20 , -NR 2 ' R 22 , -NR 23
SO
2
R
24 , 5 -NR 23
C(O)OR
2 ), -NR 23
C(O)R
24 , -SO 2
NR
25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR'
-S(O)R'
9 , -SO 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
25
R
2 6 and
-NR
23
C(O)NR
5
R
2 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R' is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkeny, azido, -OR' 9 , -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2
R
24
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2 NR2 5
R
26 , -C(O)R 24 , -C(O)R2, -SR1 9 ,
-S(O)R'
9 , -SO 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NRC 23
(N-CN)NR
25
R
2 6 and
-NR
2 3 C(0)NR 2 5
R
2 6 . 20 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 , -NR 2 R 22 , and haloalkyl, 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R' is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 -176 halo -HO NC"- 0 2 N halo halo halo halo alkyl haloalky halo halo ,and In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), RI is: perfluoroalkyl halo 5 In some embodiments, in each of Formulas (IV.a), (JV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 1 is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R' is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R' is phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (JV.a.4), (IV.a.5), and (IV.a.6), R' is: F F 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (lV.a.6), R 27 and RA 2 8 are each independently selected from the group consisting of H and alkyl.
WO 2009/061596 PCT/US2008/080176 -177 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(Z)R 7 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 5 (IV.a.4), (lV.a.5), and (IV.a.6), R 2 is -C(Z)NR 9 R'. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(Z)OR 8 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV-a.6), R 2 is -SO 2
NR
9 R'. 10 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is alkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lV-a.5), and (IV.a.6), R 2 is heteroalkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 15 (IV.a.4), (IV.a.5), and (IVa.6), R 2 is aryl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (lV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is heteroaryL In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is cycloalkyl. 20 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is cycloalkenyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heterocycloalkyl. In some embodiments, in each of Formulas (lV.a), (IV.a.1), (IV.a.2), (IV.a.3), 25 (IV.a.4), (IV.a.5), and (IV.a.6), R2 is heterocycloalkenyl. In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=0).
WO 2009/061596 PCT/US2008/080176 - 178 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=S). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(R 13 )). 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), Z is (=N(CN)). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (lV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV-a.6), Z is (=N(OR'4)). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV-a.6), Z is (=N(R'5)(R' 6 )). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), Z is (=C(R17)(Rl")). In some embodiments, in each of Formulas (lV.a), (IV.a.1), (IV.a.2), (IV.a.3), 15 (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(Z)R 7 , and Z is (=0). In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lVa.5), and (IV.a.6), R2 is -C(0)H. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -- C(O)akyl. 20 in some embodiments, in each of Formulas (V.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (lVa.6), R2 is -C(O)CH 3 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)R , wherein said R is alkyl substituted with one or more substituents, which can be the same or different, each 25 substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR1s, -OC(O)OR20, -NR 21 R22, -NR 23
SO
2
R
24 , -NR 23C(O)OR20, -NR 23 C(O)R 24 , -S0 2 NR25R26, -C(O)R24, -C(O)OR20, -SR, WO 2009/061596 PCT/US2008/080176 - 179 -S(O)R9, -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR2 5 R2 6 , -NR 23
C(N-CN)NR
25 R2 6 and
-NR
23
C(O)NR
2 5
R
26 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 5 (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)R, wherein said R is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR' 9 ,
-NR
2 ' R 22 , and cycloalkyl. 10 In some embodiments, in each of Formulas (IV.a), (lV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R is -C(O)R, wherein said R is alkyl, wherein said alkyl is substituted with alkyl and -OH. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 15 (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R 7 , wherein said R is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH 2 , and cyclopropyl. 20 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R, wherein said R is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R , wherein said R is alkyl substituted with -OH.
WO 2009/061596 PCT/US2008/080176 - 180 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R 7 , wherein said R 7 is substituted heterocycloalkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is -C(O)R, wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkenyl, azido, -OR 19 , -OC(O)OR20, -NR 2 1
R
22 , -NR 2 3
S
O
2R 24
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(O)R', -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR2 5 R2 6 , -NR23C(N-CN)NR2 5 R23 and
-NR
3 C(O)NR2 5 R2. 20 In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)R 7 , wherein said R7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is selected from: H3 N, 0
H
3 C ~ ,N 3 C and H 3 Cx WO 2009/061596 PCT/US2008/080176 - 181 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (lV.a.6), R2 is -C(O)NR 9 R'. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), 5 (ZV.a4), (IV.a.5), and (lVa.6), R2 is -C(O)NH 2 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)NR 9 R', wherein R9 and R10 can be the same or different, each being independently selected from alkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)NR 9 R', wherein R9 is unsubstituted heterocycloalkyl and R1 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)NR 9 R', wherein R9 is substituted 15 heterocycloakyl and R10 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is -C(O)NR 9
R
10 , wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or 20 different, each substituent being independently selected from alkyl, and RO is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7. -C(O)OR 8 , and -C(O)NR9R'. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lVa.5), and (IV.a.6), R2 is selected from the group consisting of WO 2009/06 1596 PCT/US2008/080176 - 182 j'JP 00 W ~ 0 K. s.,-i-- rCF3 0 k'H 2 ~ J\r 0 0 0 0 o 0 7. 01 OHH O 0N 0 010-0 \-k NH- 2 , NH 2
INH
2 , NH,, NH, 0H 02 2 0N 00 HN-N iN" 5 KN H 2 ,N H 2 N N 0 00R 00 K NH F NI- NH NHr 2
H
2
-
2 N NH 2 , N , N, NH ,0 0 0 0 ONC N N N 0, Y"ONHH and WO 2009/061596 PCT/US2008/080176 -183 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), A (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is \ CF 3 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 5 (IV.a.4), (IV-a.5), and (IV-a.6), R2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 OH (IV.a.4), (IV.a.5), and (IV.a.6), R2 is 10 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 (IV.a.4), (IV.a.5), and (IV.a.6), R 2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 (IV a.4), (IV.a.5), and (IV.a.6), R2 is \ NH 2 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IVa.3), O 15 (IV.a.4), (IV.a.5), and (IV.a.6), R2 is In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 0 \ N(VN (IV.a.4), (IV.a.5), and (IV-a.6), R 2 i WO 2009/061596 PCT/US2008/080176 -184 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV-a.6), p is 0 and R 3 is not present. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (lV.a.4), (lV.a.5), and (IV.a.6), p is 1. 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 3. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (lV.a.6), p is 4. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is > 2 and at least two groups R 3 are attached to the same ring atom. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 15 (IV.a.4), (IV.a.5), and (IVa.6), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR 2 1R
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , 20 -C(O)OR 0 , -SR' 9 , -S(O)R 9 , -S02R 9 , -OC(O)R2 4 , -C(O)NR2R2 6 ,
-NR
2 3
C(N-CN)NR
2 5R 2 6 and -NR23C(O)NR 5 R2 6 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and each R3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 25 alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR 1 9 , -OC(O)OR2 0 , -NR2'R 2 , -NR 3
SO
2 R2 4 , -NR 23
C(O)OR
2 0 , -NR 3 C(0)R2 4 , -S0 2
NR
2 5 23, -C(O)R24, -C(O)OR0, -SR 1 9 , -S(O)R' 9 , -S0 2
R
9 , -OC(O)R 4 , -C(O)NR 5 R
-NRC
23 (N-CN)NRR2 6 and -NR 3
C(O)N
5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 -185 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IVa.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, 5 alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, halogen, -CN, -NO 2 , , -OR9,
-OC(O)OR
2 0 , -NR 2 'R 22 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
20 , -NR 2 3 C(O)R 24 , -S0 2
NRR
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R4,
-C(O)NR
25
R
2 6 , -NRC 23
(N-CN)NR
2 5
R
26 and -NRC 23
(O)NR
25
R
26 . 10 In some embodiments, in each of Formulas (IV.a), (IVa.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three 15 heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (IV.a), p is 1, 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, 20 heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 2
R
22 , -NR 23
SO
2
R
24 ,
-NR
23 C(O)OR 2, -NR 2 3
C(O)R
24 , -S0 2
NR
25
R
26 , -C(O)R 24 , -C(S)R 24 , -C(O)R 20 ,
-SR'
9 , -S(O)R' 9 , -SO 2
R
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
25
R
2 6 ,
-NR
2 3
C(O)NR
25 e 26 , and -NR- 23
C(NH)-NRR
26 26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 25 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 30 heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR 2
R
22 -NR 23 SO2R 24 , -NR 23
C(O)OR
20 , -NR 2 3 C(O)R 24 , -SO2NR 25 R 2 6 , -C(O)R 24
,
WO 2009/061596 PCT/US2008/080176 -186 -C(O)OR 20 , -SR' 9 , -S(O)R 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
26 ,
-NR
2 3
C(N-CN)NR
2
R
2 ' and -NR 2 3
C(O)NR
2 5
R
26 . In one embodiment, in Formula (IV.a), p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, 5 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 10 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR R 22
-NR
23 S02R 24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
H
2 6 ,
-NR
2 3
C(N-CN)NR
2 5 R2e and -NR 23
C(O)NR
2 5
R
26 . 15 In one embodiment, in Formula (IV.a), p is 2, 3, or 4 and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In one embodiment, in Formula (IV.a), p is 2, 3, or 4 and any two R 3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group 20 consisting of -NH-, -NR-, 0, S, S(O), and S(Q)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, 0, S, S(0), and S(0)2. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is alkyl. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is heteroalkyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is alkenyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (V.a.2), (IV.a.3), 30 (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is heteroalkenyl.
WO 2009/061596 PCT/US2008/080176 -187 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R3 is alkynyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is heteroalkynyl. 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is aryl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is heteroaryl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is cycloalkyl. In some embodiments, in each of Formulas (IVa), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), R 3 is cycloalkenyl. In some embodiments, in each of Formulas (iV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is heterocycloalkyl. 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), R3 is heterocycloalkenyl. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is halogen. In some embodiments, in each of Formulas (IV.a), (Va.1), (IV.a.2), (lV.a.3), 20 (lV.a.4), (IV.a.5), and (IV.a.6), R 3 is -CN. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IVa.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -NO 2 In some embodiments, in each of Formulas (IV.a), (IVa.1), (lV-a.2), (lV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -OR 19 . 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), R 3 is -OC(O)OR2. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (lV.a.3), (IV.a.4), (lV.a.5), and (IV.a.6), R 3 is -NRR 22
,.
WO 2009/061596 PCT/US2008/080176 - 188 In some embodiments, in each of Formulas (IV-a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -NR 23
SO
2 R24 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV,a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -NR 23
C(O)OR
2 0 . 5 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -NR 2
C(O)R
24 . in some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -S0 2
NR
2 5
R
26 . In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), 10 (IV.a.4), (IV.a.5), and (IV.a.6), R3 is -C(O)R 2 4 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV-a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -C(O)OR 20 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IVa.3), (lV.a.4), (IV.a.5), and (IV.a.6), R 3 is -SR 9 . 15 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (V.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -S(O)R'. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -SO2R' 9 ,. In some embodiments, in each of Formulas (IV.a), (lV-a.1), (IV.a.2), (IV.a.3), 20 (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -OC(O)R 24 . In some embodiments, in each of Formulas (lV.a), (IV.a.1), (IV-a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -C(O)NR 25
R
2 6. In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R is -NR 23
C(N-CN)NR
2
R
2 R. 25 In some embodiments, in each of Formulas (IV.a), (IV.a.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is -NR 23
C(O)NR
2 5
R
26 In some embodiments, in each of Formulas (IV.a), (lVa.1), (IV.a.2), (IV.a.3), (IV.a.4), (IV.a.5), and (IV.a.6), R 3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or WO 2009/061596 PCT/US2008/080176 - 189 branched), phenyl, N, N NH 2 , H 2 N H 2 N , OH 2H H N H HO OH NH 2 HN HN\ 'OH HN HN\ rNH 2 N, OH 2N In some embodiments, in each of Formulas (IV.a), (IVa.1), (IVa.2), (IV.a.3), 5 (IV.a.4), (IV.a.5), and (IV.a.6), when E is -NR 6 -, R 3 is absent. In one embodiment, the compounds of the invention have a structure shown in Formula (IV.b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R27 R28 B RR N A R P N E 10 R (IV.b.) wherein R', R2, R 3 , R, R 2 3, p, E, ring A, and ring B are selected independently of each other and wherein: WO 2009/061596 PCT/US2008/080176 -190 ring A (including E and the unsaturation shown) is a 6-membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -,
-C(R
4 )(R5)-, -N(R 6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-, 5 -C(O)-N(R )-, -N(R1)-C(O)-, -S(0) 2 -N(R )-, -N(R")-S(O) 2 -, -C(0)-O-, -O-C(O)-, -O-N(R 6)-, -N(R3)-O-, -N(R 6)-N(R 1)-, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R")-C(Y)-O-, -N(R")-C(Y)-N(R 1)-, -C(Y)-N(R")-O-, -C(Y)-N(R')-N(R12)-, -O N(R")-C(Y)-, and -N(R 2 )-N(R')-C(Y)-; 10 ring B is a substituted or unsubstituted heteroaromatic ring; and p, RR', R 2 , R 3 , R R 5 , R6, R 7 , R 8 , R9, R1 0 , R", R' 2 , R 27 , R 28 , Y, and the optional substituents on ring B are as defined in any of the embodiments described above in Formula (I). In one embodiment, Formula (IV.b) has the general structure shown in Formula 15 (IV.b.1): R1 R27 R28 R3 NN AP R 2 (IV-b. 1). 20 In one embodiment, Formula (IV~b) has the general structure shown in Formula (IV.b.2): WO 2009/061596 PCT/US2008/080176 -191 R1 R27 R28 B N R2 (lVb.2). In one embodiment, Formula (IV.b) has the general structure shown in Formula 5 (IV.b.3): R1 R 2 R 28 B NA /P N R 2 (IVb.3), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (IV.b) has the general structure shown in Formula 10 (IV.b.4): WO 2009/061596 PCT/US2008/080176 -192 "27 R 28 B R3) N A )p N R2 R3 (IV.b.4), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (IV.b) has the general structure shown in Formula 5 (IV.b.5): R1 R7 R 28 B R3 N, A /p N R 2 R 3 (Vb.5), wherein P is 0, 1, 2, or 3. 10 In one embodiment, Formula (IV.b) has the general structure shown in Formula (IV.b.6): WO 2009/061596 PCT/US2008/080176 -193 1 R R2 FR R3 B N A N I :
R
2 3 R R (IV.b.6), wherein P is 0, 1, 2, or 3. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV-b.2), (IV.b.3), 5 (IV.b.4), (IV.b.5), and (IV.b.6), ring A is a cycloalkenyl ring and E is -C(R4)(R 5 )-.. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )_. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(Q) 2 -, and -N(R6)-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 2 4 In some embodiments, in each of Formulas (IVb), (IV.b.1), (IV.b.2), ([V.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is selected from the group consisting of -0- and 15 -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 and -C(S)R 24 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), ([V.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 20 (IV.b.4), (V.b.5), and (IV.b.6), E is -S-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -S(O)-.
WO 2009/061596 PCT/US2008/080176 -194 In some embodiments, in each of Formulas (IV.b), (IV~b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -S(O) 2 -. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(R4)(R 5 )-. 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R6)-. In some embodiments, in each of Formulas (IV.b), (IV-b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)R 7 )_, In some embodiments, in each of Formulas (IV.b), (IV.b1), (IV-b.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)OR)-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV-b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(C(Y)N(R 9 )(R1 0 ))-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(O)-N(R 1 )-. 15 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R")-C(O)-. In some embodiments, in each of Formulas (lV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lVb.5), and (IV.b.6), E is -S(O) 2 -N(R)-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 20 (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R' 1
)-S(O)
2 -. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV-b.5), and (lV.b.6), E is -C(O)-O. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-C(O)-.
WO 2009/061596 PCT/US2008/080176 - 195 In some embodiments, in each of Formulas (IV-b), (IV.b.1), (IV.b.2), (VSb.3), (IV.b.4), (IV.b.5), and (IVb.6), E is -O-N(R)-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), E is -N(R 6 )-O-. 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R 6 )-N(R1 2 )-. In some embodiments, in each of Formulas (V.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV-b.6), E is -N=N-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(R 7 )=N-. In some embodiments, in each of Formulas (IVb), (IV.b.1), (IV-b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(O)-C(R 7 )=N-. In some embodiments, in each of Formulas (V.b), (IV~b.1), (lV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(O)-N=N-. 15 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), E is -O-C(Y)-N(R)-. In some embodiments, in each of Formulas (lV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (lV.b.6), E is -N(R")-C(Y)-O-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IVJb.3), 20 (IV.b.4), (IV.b.5), and (IV.b.6), E is -N(R")-C(Y)-N(R' 2 )-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -C(Y)-N(R")-O-. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IVb.6), E is -C(Y)-N(R')-N(R 2
)-.
WO 2009/061596 PCT/US2008/080176 -196 In some embodiments, in each of Formulas (V.b), (IVb.1), (IV.b.2), (IV,b.3), (IV.b.4), (IV.b.5), and (IV.b.6), E is -0-N(R")-C(Y)-. In some embodiments, in each of Formulas (IV.b), (lV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IVb.5), and (FV.b.6), E is -N(R 1 2
)-N(R
1 )-C(Y)-. 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IVb.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=0). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=S). 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(R' 3 )). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (N.b.3), (IV.b.4), (IV-b.5), and (lV-b.6), Y is (=N(CN)). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 15 (IV.b.4), (IV.b.5), and (iV.b.6), Y is (=N(OR 1 )). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=N(R 15
)(R'
6 )). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Y is (=C(R 7
)(R
18 )). 20 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (V.b.5), and (IV.b.6), B is an unsubstituted heteroaromatic ring. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-6-membered 25 heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(0) 2
.
WO 2009/061596 PCT/US2008/080176 -197 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV,b.5), and (IV.b.6), B is a heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , 5 alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR2 0 , -NR 2R22, -NR 23SO2R24
-NR
23
C(O)OR
2 0 , -NR 23 C(O)R 24, -S0 2
NR
2 5 R2 6 , -C(O)R24, -C(O)OR20, -S R 19 , -S(O)R9, -SO2R'9, -OC(O)R 24 , -C(O)NR 2 sR 2 6 , -NR 2 3 C(N-CN)NR 25R26 and 10 NR 23 C(O)NR2 5
R
2 6 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring 15 atom being independently selected from the group consisting of N, S, 0, S(O), and S(0)2, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, 20 aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR20, -NR 2 'R 2 2 , -NR 23SO2R24
-NR
23
C(O)OR
20 , -NR 2 3 C(0)R 24 , -S0 2
NR
2 5
R
2 , -C(O)R24, -C(O)OR20, -SR.19 -S(O)R'9, -SO2R', -OC(O)R24,
-C(O)NR
2 5
R
26 , -NR23C(N-CN)NR25R26 and NR 23 C(O)NR25R26 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (lV.b.6), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 30 and 0.
WO 2009/061596 PCT/US2008/080176 - 198 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV-b.5), and (IV.b.6), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, 5 which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, azido, -OR' 9 , 10 -OC(O)OR 20 , -NR 2R 2 2 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24
-C(O)NR
2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 15 (IV.b.4), (IV.b.5), and (lV.b.6), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0. In some embodiments, in each of Formulas (lV.b), (IV.b.1), (IV.b.2), (IV.b.3), 20 (IV.b.4), (IV.b.5), and (lV.b.6), B is a 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, 25 haloalkyl, -OR' 9 , -NR 2 R R 22 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO2R'9,
-OC(O)R
24 , and -C(O)NR 25
R
2 6 In some embodiments, in each of Formulas (IV.b), (IV-b.1), (IV.b.2), (IV~b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic 30 ring having from 1-2 ring heteroatoms, which can be the same or different, each WO 2009/061596 PCT/US2008/080176 - 199 hetero ring atom being independently selected from the group consisting of N, S, and 0. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 5 (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the 10 group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 ,
-OC(O)OR
20 , -NRR 2 'R 2 2 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , -NR 2 3 C(O)R 24 , -S0 2 NRR, -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 15 -C(O)NR 2 5 R2 6 , -NR 23
C(N-CN)NR
25
R
2 6 and -NR 23 C(O)NR 2
R
2 6 . In some embodiments, in each of Formulas ([V.b), (IV.b.1), (IV.b.2), (IV.b.3), (Vb.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0. 20 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b5), and (lVb.6), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, 25 each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR'R, -C(O)R 24
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , and -C(O)NR 25 2 . In some embodiments, in each of Formulas (V.b), (IV.b.1), (IV.b.2), (lV.b.3), 30 (IV.b.4), (IV.b.5), and (IV.b.6), B is a 5-membered heteroaromatic ring having S WO 2009/061596 PCT/US2008/080176 - 200 as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR 2 1 R 22 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , 5 -SO 2
R'
9 , -OC(O)R24, and -C(O)NR 25 R. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom. 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), B is selected from the group consisting of R, and 15 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is unsubstituted aryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (EV,b.4), (IV.b.5), and (IVb.6), R' is unsubstituted phenyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 20 (IV.b.4), (IV.b.5), and (IV.b.6), R' is unsubstituted naphthyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is substituted aryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is substituted phenyl. 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is substituted naphthyl.
WO 2009/061596 PCT/US2008/080176 -201 In some embodiments, in each of Formulas (IV.b), (IV,b.1), (IV.b.2), (IV-b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, 5 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR20, -NR 2 'R 22 , -NR 23
SO
2
R
24 ,
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
26 , -C(O)R 24 , -C(0)OR02, -SR' 9 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26 , -NR 23
C(N-CN)NR
25
R
2 6 and 10 -NR 2 3
C(O)NR
25
R
2 6 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is phenyl substituted with one or more substituents, which can be the same or different, each substituent being 15 independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR0, -NR 2 ' 2 , -NR 23 SO2R 24
-NR
2 3
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
25 R2 6 , -C(O)R24, -C(O)OR24, -SR1 9 , 20 -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR2 5
R
2 6 , -NR23C(N-CN)NR 2 5 R2 and
-NR
23 C(O)NR2R2 6 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is phenyl substituted with one to four 25 substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 ,
-NR
21
R
22 , and haloalkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R' is selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 -202 halo'. HO NC 0 2 N habo halo halo halo alkyi , haloalkyl halo halo and In some embodiments, in each of Formulas (IV.b), (lV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R1 is: perfluoroalkyl halo 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IVb.3), (IV.b.4), (IV.b.5), and (IV-b.6), R' is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas ([Vb), (IV.b.1), (IV.b.2), (IV.b.3), 10 ([V.b.4), (IV.b.5), and (IV-b.6), R 1 is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (lV.b.3), (lV.b.4), (IV.b.5), and (IV.b.6), R' is phenyl substituted with one fluoro group. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IVb.5), and (IV.b.6), R' is: F F 15 In some embodiments, in each of Formulas (Vb), (IV.b.1), (IV.b.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), R 27 and R 2 are each independently selected from the group consisting of H and alkyl.
WO 2009/061596 PCT/US2008/080176 - 203 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV-b.3), (IV.b.4), (IVb.5), and (IV.b.6), R 2 is -C(Z)R 7 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 5 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(Z)NR 9 R1' 0 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(Z)OR. In some embodiments, in each of Formulas (IV.b), (IV-b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -S0 2
NR
9
R
0 . 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is alkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is heteroalkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (lV.b.3), 15 (IV.b.4), (IV.b.5), and (IV.b.6), R2 is aryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is heteroaryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is cycloalkyl. 20 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), R2 is cycloalkenyl. in some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is heterocycloalkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 25 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is heterocycloalkenyL In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=0).
WO 2009/061596 PCT/US2008/080176 - 204 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IV.b.4), (IV.b.5), and (lV.b.6), Z is (=S). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (lV.b.4), (IV.b.5), and (lV.b.6), Z is (=N(R 13 )). 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(CN)). In some embodiments, in each of Formulas ([Vb), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(OR 1 4)). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), Z is (=N(R' 5 )(R16)). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (JV.b.4), (IV.b.5), and (IV.b.6), Z is (=C(R' 7 )(R"')). In some embodiments, in each of Formulas ([V.b), (IV.b.1), (IV.b.2), (IV.b.3), 15 (Vb.4), (IV.b.5), and (IV.b.6), R 2 is -C(Z)R 7 , and Z is (=O). In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), R 2 is -C(0)H. In some embodiments, in each of Formulas (lVb), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)alkyl. 20 In some embodiments, in each of Formulas (IV.b), (lV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)CH 3 . In some embodiments, in each of Formulas (Vb), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IVb.6), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one or more substituents, which can be the same or different, each 25 substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(O)OR 20 , -NR R 22 , -NR 23 S0 2
R
24
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
H
26 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9
,
WO 2009/061596 PCT/US2008/080176 -205 -S(O)R , -SO 2 R'9, -OC(O)R 24 , -C(O) NR 25
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and
-NR
2 3
C(O)NR
25
R
2 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 5 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR' 9 , -NR 2R 22 , and cycloalkyl. 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R 7 , wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 15 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH 2 , and cyclopropyl. 20 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R, wherein said R is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R 7 , wherein said R7 is alkyl substituted with -OH.
WO 2009/061596 PCT/US2008/080176 - 206 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IVb.5), and (IV.b.6), R 2 is -C(O)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R 7 , wherein said R 7 is substituted heterocycloalkyL In some embodiments, in each of Formulas (IVb), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is -C(O)R, wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 15 heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR20, -NR 2
R
22 , -NR 2 3 S0 2
R
24
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR 19 ,
-S(O)R'
9 , -S02R 9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2
R
2 6 and
-NR
23
C(O)NR
25
H
26 . 20 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IVb.5), and (IV.b.6), R 2 is -C(O)R , wherein said R is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is selected from: 0 0 N ' N / N
H
3 C ~ H 3 Cr , and H 3
C
WO 2009/061596 PCT/US2008/080176 - 207 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV,b.6), R2 is -C(O)NRR 0 . In some embodiments, in each of Formulas (IVb), (IV.b.1), (IV.b.2), (IV.b.3), 5 (IV.b.4), (IV.b.5), and (lV.b.6), R2 is -C(O)NH 2 . In some embodiments, in each of Formulas (IV.b), (IV-b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is -C(O)NR9R', wherein R9 and R' 0 can be the same or different, each being independently selected from alkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV.b.4), (Vb.5), and (IV.b.6), R2 is -C(O)NR9R', wherein R9 is unsubstituted heterocycloalkyl and R1 0 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV-b.4), (IV.b.5), and (IV.b.6), R2 is -C(O)NR 9 R', wherein R 9 is substituted 15 heterocycloalkyl and R 1 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), R2 is -C(O)NR 9
R'
0 , wherein R 9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or 20 different, each substituent being independently selected from alkyl, and Rio is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R 7 . -C(O)OR, and -C(O)NR9R' 0 . 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R2 is selected from the group consisting of WO 2009/061596 PCT/US2008/080176 - 208 O CF CHF2 F O 0 0000 OO HO P~r 0 0 0 0 0 N 10 \0 'OH OH 0 QOr 0 0 N NH 2
NH
2 , NH, O NH 5
NH
2 , 0 H N Q 0 NHH 0 oHN H 2 N H 2 N H 0 0 o1 ' H NH NH H 2 N OHO Sf-I if 00 0 $hIIand 0 N N N H N
NH
2 , NH , N, NH , 00 00 0 ~.0 0N 0 K 0- NN WO 2009/061596 PCT/US2008/080176 - 209 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV-b.3), j (IV.b.4), (IV.b.5), and (lV.b.6), R 2 is \ CF 3 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 0 5 (IV.b.4), (IV.b.5), and (IV.b-6), R2 is In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 0 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), 0 OH (IV-b.4), (IV.b.5), and (IV.b.6), R 2 is N O 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 0 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 0 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is \ NH 2 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), O \ N 15 (IV.b.4), (IV.b.5), and (IV.b.6), R 2 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 0 N N (IV.b.4), (IV.b.5), and (IV.b.6), R 2 is I WO 2009/061596 PCT/US2008/080176 -210 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b4), (IV.b.5), and (IV.b.6), p is 0 and R 3 is not present. In some embodiments, in each of Formulas (Vb), (IV.b-1), (IV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (lV.b.6), p is 1. 5 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 3. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), p is 4. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), p is > 2 and at least two groups R 3 are attached to the same ring atom. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), 15 (IV.b.4), (IV.b.5), and (IV.b.6), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR 2
R
22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 20 -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(0)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 In some embodiments, in each of Formulas (IV.b), (IVb.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 25 alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 2 0 , -NR 2
R
22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
2 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R
9 , -OC(O)R 24 , -C(O)NR 2 5
H
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
25 26
.
WO 2009/061596 PCT/US2008/080176 -211 In some embodiments, in each of Formulas (IV.b), (lV~b.1), (IV.b.2), (IV.b.3), (lV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, 5 alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkeny, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 ,
-OC(O)OR
2 0 , -NR 2 R R 2 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , -NR 23 C(O)R 24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24
-C(O)NR
25
R
2 6 , -NRC 23
(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
25
R
26 . 10 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three 15 heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (IV.b), p is 1, 2, 3, or 4, and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, 20 heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 0 , -NR 2R 22 , -NR 3 SO2R24,
-NR
23 C()OR0, -NR 2 3
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(S) R2 4 , -C(O)R20,
-SR'
9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26 , -NRC(N-CN)NRR26,
-NRC
23
(O)NR
5 R2 6 , and -NR 3
-C(NH)-NR
2 6
R
2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 25 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 30 heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR20, -NR 2 'R 22 , -NR 23
SO
2
R
24 , -NRC 23 (O)OR20, -NRC 23 (O)R 24 , -S0 2 NR 25
R
2 6 , -C(O)R 24 WO 2009/061596 PCT/US2008/080176 -212
-C(O)OR
20 , -SR 19 , -S(O)R' 9 , -S02R' 9 , -OC(O)R 24 , -C(O)NR 2 Ras
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
26 . In one embodiment, in Formula (IV.b), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, 5 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, 10 alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9 , -OC(O)OR 20 , -NR 2
R
22
-NR
23
SO
2
R
24 , -NR 23 C()OR2 0 , -NR 23
C(O)R
2 4 , -SO 2 N R 25
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR 19 , -S(O)R' 9 , -SO2R19, -OC(O)R 24 , -C(O)NR 2 5
R
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
26 . 15 In one embodiment, in Formula (IV.b), p is 2, 3, or 4, and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In one embodiment, in Formula (IV.b), p is > 2 and any two R 3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group 20 consisting of -NH-, -NR 6 -, 0, S, S(O), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, 0, S, S(O), and S(0)2. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (V.b.6), R 3 is alkyl. 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is heteroalkyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is alkenyl. In some embodiments, in each of Formulas (IV.b), (IVb.1), (IV.b.2), (IV.b.3), 30 (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is heteroalkenyl.
WO 2009/061596 PCT/US2008/080176 -213 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (lVIb.4), (IV.b.5), and (IV.b.6), R 3 is alkynyl. In some embodiments, in each of Formulas (V.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is heteroalkynyl. 5 In some embodiments, in each of Formulas (IVb), (IV~b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lVb.5), and (IV.b.6), R 3 is aryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is heteroaryl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is cycloalkyl. In some embodiments, in each of Formulas (IV~b), (IV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (lV.b.6), R 3 is cycloalkenyl. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IVb.6), R 3 is heterocycloalkyl. 15 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IVb.6), R 3 is heterocycloalkenyl. In some embodiments, in each of Formulas (lV.b), (lV.b.1), (IV.b.2), (lV.b.3), (IV.b.4), (IV.b.5), and (IVb.6), R 3 is halogen. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 20 (IV.b.4), (IVb.5), and (IV.b.6), R 3 is -CN. In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is -NO 2 In some embodiments, in each of Formulas (IV.b), (IVb.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is -OR' 9 . 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is -OC(O)OR 20 In some embodiments, in each of Formulas (V.b), (IV.b.1), (IV-b.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), R 3 is -NR 21 22
.
WO 2009/061596 PCT/US2008/080176 -214 In some embodiments, in each of Formulas (V.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (lV.b.6), R3 is -NR 23 SO2R2 4 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (lV,b.4), (IV.b.5), and (IV.b.6), R3 is -NR 23
C(O)OR
20 . 5 In some embodiments, in each of Formulas (lV.b), (IV.b.1), (IV.b.2), (IV.b.3), (lVb.4), (IV.b.5), and (IV.b.6), R3 is -NR 23 C(O)R24 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (V.b.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), R is -SO 2
NR
2
-R
6 . In some embodiments, in each of Formulas (Vb), (IV.b.1), (IV.b.2), (IV.b.3), 10 (IV-b.4), (IV.b.5), and (IV.b.6), R3 is -C(O)R 2 4 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IVb.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), R3 is -C(O)OR 20 . In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV.b.2), (IV.b.3), (IV.b.4), (IV.b.5), and (IV.b.6), R 3 is -SR' 9 . 15 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (lV-b.2), (IV.b.3), (IV.b.4), ([V.b.5), and (IVb.6), R3 is -S(O)R' 9 . In some embodiments, in each of Formulas ([V.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (IV-b.5), and (IV.b.6), R3 is -SO 2 R',. In some embodiments, in each of Formulas (lV.b), (IV.b.1), (IVb.2), (IV.b.3), 20 (IV.b.4), (IV b.5), and (IV.b.6), R3 is -OC(O)R 24 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV-b.3), (lV-b.4), (IV.b.5), and (IV.b.6), R3 is -C(O)NR 25 R26. In some embodiments, in each of Formulas (IV.b), (IV.b.), (IV.b.2), (IVb.3), (IV.b.4), (IV.b.5), and (IV.b.6), R3 is -NR 2 3
C(N-CN)NR
2 5 R2 6 . 25 In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), (IVb.4), (IV.b.5), and (IV.b.6), R3 is -NR 2 3 C(O)NR25R2 6 In some embodiments, in each of Formulas ([V.b), (IV.b.1), (IV.b.2), (IV.b.3), (IV.b.4), (lV.b.5), and (IV.b.6), R3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or WO 2009/061596 PCT/US2008/080176 -215 branched), phenyl, NN
NH
2 , H 2 N H 2 N OH OH HO, Y OH NH 2 H HN H,, 0 o , o , Q x-- N HN NH OH a H N \ , H and 2 N In some embodiments, in each of Formulas (IV.b), (IV.b.1), (IV.b.2), (IV.b.3), 5 (IV.b.4), (IV~b.5), and (IV.b.6), when E is -NR 6 -, R 3 is absent. In one embodiment, the compounds of the invention have a structure shown in Formula (V.a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R 2 R'8 RR N A R P NE 10 R (V.a.) wherein R', R 2 , R 3 , R, R 28 , p, E, ring A, and ring B are selected independently of each other and wherein: WO 2009/061596 PCT/US2008/080176 -216 ring A (including E and the unsaturation shown) is a 7- to 8-membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R)-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R'l)-, 5 -N(R)-C(O)-,
-S(O)
2 -N(R")-, -N(R")-S(0) 2 -, -C(O)-0-, -0-C(O)-, -0-N(R 6 )-, -N(R6)-O-, -N(R6)-N(R 1)-, -N=N-, -C(R 7)=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R')-, -N(R")-C(Y)-O-,
-N(R
1 )-C(Y)-N(R1 2 )-, -C(Y)-N(R")-O-,
-C(Y)-N(R")-N(R
12 )-, -0-N(R")-C(Y)-, and -N(R' 2 )-N(FR")-C(Y)-; ring B is a substituted or unsubstituted aromatic ring; 10 and p, R', R 2 , R 3 , R 4 , R5, R6, R 7 , R 8 , R 9 , R 1 0 , R 1 , R 1 , R 27 , R 28 , Y, and the optional substituents on ring B are as defined in each of the embodiments described above in Formula (1). In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.1): 15 R1 R27 R 2 R3 N AP HN R 2 (V.a.1). In one embodiment, Formula (V.a) has the general structure shown in Formula 20 (V.a.2): WO 2009/061596 PCT/US2008/080176 -217 R1 R7 R 28 B R3 N R 2 (V a.2). In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.3): 5 R1 R 2 R 28 B N 2 R" R g (V.a.3), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (V.a) has the general structure shown in Formula 10 (V.a.4): WO 2009/061596 PCT/US2008/080176 -218 RiR27 R28 1RR Rs I R3 N, AP N I R2 R3 (V.a.4), wherein P is 0, 1, 2, or 3. In one embodiment, Formula (V.a) has the general structure shown in Formula 5 (V.a.5): R1 R 27 R28 B RR3 ) N R 2 R 3 (V.a.5), wherein P is 0, 1, 2, or 3. 10 In one embodiment, Formula (V.a) has the general structure shown in Formula (V.a.6): WO 2009/061596 PCT/US2008/080176 -219 R1 R27 R28 1iRN Ra B A 3 N, AP N
R
2 3 R R (V.a.6), wherein P is 0, 1, 2, or 3. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 5 (V.a.4), (V.a.5), and (V.a.6), ring A is a cycloalkenyl ring and E is -C(R 4 )(R 5 )_ In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (V~a.4), (V.a.5), and (V.a.6), ring A is a heterocycloalkenyl ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 2 4 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is selected from the group consisting of -0- and 15 -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 and -C(S)R 24 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), E is -S-.
WO 2009/061596 PCT/US2008/080176 - 220 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -S(O)-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), E is -S(O) 2 -, 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(R 4
)(R
5 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V-a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R 6 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)R). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)OR 8 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(C(Y)N(R 9
)(R
10 ))-. 15 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(O)-N(R")-. In some embodiments, in each of Formulas (V.a), (V-a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R 11 )-C(O)-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), E is -S(Q) 2 -N(R")-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (Va.4), (V.a.5), and (V.a.6), E is -N(R 1
)-S(O)
2 -. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V-a.4), (V.a.5), and (V.a.6), E is -C(O)-O-.
WO 2009/061596 PCT/US2008/080176 -221 In some embodiments, in each of Formulas (V.a), (Va.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), E is -0-C(O)-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-N(R)-. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R 6 )-0-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R 6 )-N(R1 2 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), E is -N=N-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(R 7 )=N-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(O)-C(R 7 )=N 15 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(O)-N=N-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -0-C(Y)-N(R 1 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), E is -N(R')-C(Y)-O-. In some embodiments, in each of Formulas (Va), (V.a.1), (V-a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R")-C(Y)-N(R' 2 )-. In some embodiments, in each of Formulas (V.a), (V.a.1), (Va.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -C(Y)-N(R)-O-.
WO 2009/061596 PCT/US2008/080176 - 222 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), E is -C(Y)-N(R 1
)-N(R
2 )-. in some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), E is -0-N(R)-C(Y)-. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), E is -N(R' 2 )-N(R'")-C(Y)-. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=0). 10 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=S). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(R1 3 )). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (V.a.6), Y is (=N(CN)). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(OR 14 )). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=N(R 5
)(R
1 6 )). 20 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Y is (=C(R 17
)(R
18 )). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an unsubstituted aromatic ring. 25 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an unsubstituted benzo ring, and Formula (IV.a.) has the general structure: WO 2009/061596 PCT/US2008/080176 - 223 R 1 R R 2 " RR NP R 2 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), B is an aromatic ring which is substituted with one or 5 more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 20 , -NR R 22 , -NR 23 S0 2
R
24 10 -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0, -SR' 9 ,
-S(O)R'
9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 2 5
R
26 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and NR 23 C(O) NR 25
R
2 6 . In some embodiments, in each of Formulas (V.a), (V.a, 1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (V~a.6), B is a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, 20 heterocycloalkenyl, azido, -OR 1 9 , -OC(O)OR2 0 , -NR2R 22 , -NR 23 S02R24 -NR2 3 C(O)OR20, -NR2 3 C(O)R 2 4 , -SO 2 NR2 5 R2 6 , -C(O)R 2 4 , -C(O)OR20, -SR 1 9,
-S(O)R'
9 , -S0 2
R'
9 , -OC(O)R2 4 , -C(O)NR2 5 R2 6 , -NR2 3 C(N-CN)NR2 5 R2 6 and NR 23
C(O)NR
2 5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 - 224 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is unsubstituted aryl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is unsubstituted phenyl. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is unsubstituted naphthyl In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is substituted aryl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), R' is substituted phenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (Va.4), (V.a.5), and (V.a.6), R 1 is substituted naphthyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is aryl substituted with one or more substituents, 15 which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroakyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , -OC(O)OR 2 0, -NR 2 R 22 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
20 , 20 -NR 2
C(O)R
24 , -S0 2
NR
2 5
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(0)R 24 , -C(O)NR 25
R
2 6 , -NRC 23
(N-CN)NRR
2 5 26 and -NR 23
C(O)NR
25 2 6 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), R' is phenyl substituted with one or more 25 substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-akyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , -OC(O)OR 20 , -NR 2
R
22 , -NR 23 S0 2
R
24 , 30 -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR 9
,
WO 2009/061596 PCT/US2008/080176 - 225 -S(O)R'9, -SO 2
R'
9 , -OC(O)R24, -C(O)NR 2 5
R
2 3, -NR 2 3
C(N-CN)NR
2 5
R
26 and
-NR
23
C(O)NR
2 5
R
2 6 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 5 (V.a.4), (V.a.5), and (V.a.6), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, -NO 2 , -NR 21
R
22 , and haloalkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), R 1 is selected from the group consisting of: HO NC 0 2 N halo halo halo halo alkyl haloalkyl halo halo and In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 1 is: perfluoroalkyl halo 15 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 1 is phenyl substituted with one to three fluoro groups. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), R' is phenyl substituted with two fluoro groups. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is phenyl substituted with one fluoro group, WO 2009/061596 PCT/US2008/080176 - 226 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R' is: F F 5 In some embodiments, in each of Formulas (V.a), (V-a.1), (V.a.2), (V.a.3), (V-a.4), (V.a.5), and (V.a.6), R 7 and R are each independently selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)R 7 _ In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)NR 9
R'
0 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(Z)OR. 15 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -S0 2
NR
9
R'
0 . In some embodiments, in each of Formulas (V.a), (Va.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is alkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), R2 is heteroalkyl. In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is aryl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is heteroaryl. 25 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is cycloalkyl.
WO 2009/061596 PCT/US2008/080176 - 227 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V-a.4), (V.a.5), and (V.a.6), R 2 is cycloalkenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), R 2 is heterocycloalkyl. 5 In some embodiments, in each of Formulas (V-a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is heterocycloalkenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=O). 10 In some embodiments, in each of Formulas (V.a), (V-a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=S). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=N(R 3 )). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (V.a.6), Z is (=N(CN)). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), Z is (=N(OR1 4 )). In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (Va.6), Z is (=N(R' 5 )(R'6). 20 In some embodiments, in each of Formulas (V-a), (V.a.1), (V.a.2), (V-a.3), (V.a.4), (V.a.5), and (V.a.6), Z is (=C(R 17 )(R')). In some embodiments, in each of Formulas (V-a), (V.a.1), (V.a.2), (Va.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(Z)R 7 , and Z is (=0). 25 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)H. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), R 2 is -C(0)alkyl.
WO 2009/061596 PCT/US2008/080176 -228 In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(O)CH 3 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(O)R, wherein said R 7 is alkyl substituted 5 with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 0 2, -NR 2
'R
2 2 , -NR2 3
SO
2
R
24 , 10 -NR2 3 C(O)OR2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR',
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)N R 2 5R 2 6 , -NR 23 C(N-CN)NR 2 5
R
2 6 and
-NR
23
C(O)NR
2 5
R
2 6 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V-a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OR19,
-NR
2
R
22 , and cycloalkyl. 20 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R, wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 25 (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH, -NH 2 , and cyclopropyl.
WO 2009/061596 PCT/US2008/080176 - 229 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R wherein said R is alkyl substituted with -OH. 10 In some embodiments, in each of Formulas (V-a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is -C(O)R , wherein said R is unsubstituted heterocycloalkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R wherein said R is substituted heterocycloalkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R is -C(O)R wherein said R is heterocycloalkyl 20 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR20, -NR 2
R
22 , -NR 23
SO
2 R24 25 -NR 23 C(O)OR20, -NR2 3 C(O)R 24 , -SO 2 N R 25
R
2 6 , -C(O)R 24 , -C(O)OR2 0 , -SR' 1 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25 R2 6 , -NR 2 3 C(N-CN)NR26R26 and -NR2 3 C(O)NR2 2 6
.
WO 2009/061596 PCT/US2008/080176 - 230 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)R, wherein said R 7 is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (Va.4), (V.a.5), and (V.a.6), R 2 is selected from: 00 0 N N /ND
H
3 C ,H 3 C , and H 3 C 10 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)NR 9
R
0 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)NH 2 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)NR 9 R'", wherein R 9 and R' 0 can be the same or different, each being independently selected from alkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)NR 9
R'
0 , wherein R 9 is unsubstituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. 20 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (Va.4), (V.a.5), and (V.a.6), R 2 is -C(O)NRR' 0 , wherein R 9 is substituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. 25 In some embodiments, in each of Formulas (V.a), (V.aA1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 2 is -C(O)NRR' 0 , wherein R 9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or WO 2009/061596 PCT/US2008/080176 - 231 different, each substituent being independently selected from alkyl, and R' 0 is selected from the group consisting of H and alkyl. In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (Va.4), (V.a.5), and (V.a.6), R2 is selected from the group consisting of: alkyl, 5 haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R . -C(O)OR, and -C(O)NR 9 R''. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R2 is selected from the group consisting of 0p 0 0 1'f0 OY, Q CF 3 0
"CHF
2 0 0, ,,\ 0HO 10 N 10 0" c(-o 0'OH OH 1NH 2
NH
2 NH,
NH
2 , NH 0 0 0 HNr0 HN~N 0 0N, O ~ yNH 2 0 O O O NH
H
2 N H 2 N H 2 N 0 0 0 P -0 H N NH HN NHN 2 N H 2 N 0 0 O0y O0> NH NH NH N H H 5N H 2 WO 2009/061596 PCT/US2008/080176 - 232 H2N H2 OH 2 , N , N, NH , O , 0 0 0 0 N N 0N N - NH H t and
N
In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), O (V.a.4), (V.a.5), and (V.a.6), R 2 is \ CF 3 . 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 0 (V.a.4), (V.a.5), and (V.a.6), R 2 is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 0 (V.a.4), (V.a.5), and (V.a.6), R 2 is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 0 OH 10 (V.a.4), (V.a.5), and (V.a.6), R 2 is N OH In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 0 (V~a.4), (V.a.5), and (V.a.6), R2 is O In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 0 (V.a.4), (V.a.5), and (V.a.6), R 2 is \ NH 2 WO 2009/061596 PCT/US2008/080176 - 233 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), O \ N (V.a.4), (V.a.5), and (V.a.6), R 2 is In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (Va.3), 0 \ N-- N (V.a.4), (V.a.5), and (V.a.6), R 2 is . 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 0 and R 3 is not present. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 1. 10 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 3. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 15 (V.a.4), (V.a.5), and (Va.6), p is 4. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is > 2 and at least two groups R 3 are attached to the same ring atom. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR 19 , -OC(O)OR 2 o, -NR 2 1R 22
-NR
23
SO
2
R
24 , -NR23C(O)OR 2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 25 -C(O)OR0, -SR 19 , -S(O)R' 9 , -S0 2
R
19 , -OC(O)R 24 , -C(O)NR 5
R
26 ,
-NR
23
C(N-CN)NR
2 5R26 and -NR23C(O)NR 25 R26.
WO 2009/061596 PCT/US2008/080176 - 234 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 5 heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR R,
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2
NR
25
R
26 , -C(O)R 24 ,
-C(O)OR
2 0 , -SR' 9 , -S(O)R' 9 , -S0 2 R1 9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 ,
-NR
23
C(N-CN)NR
25
R
26 and -NRC 23
(O)NR
25
R
2 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V-a.5), and (V.a.6), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein each R, which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , 15 -OC(O)OR2 0 , -NRR 2 ' 2 , -NR 3
SO
2 R2 4 , -NR 3
C(O)OR
2 0 , -NR 3 C(O)R 24,
-SO
2 NRR , -C(O)R 4 , -C(O)OR , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 4
-C(O)NR
5
R
2 6 , -NR 23 C(N-CN)NR2R2 6 and -NR 3 C(O)NR2 5 R In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), p is 2, 3, or 4 and at least two groups R3 are bound 20 to the same ring carbon atom, wherein two R groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from 25 the group consisting of N, 0, and S. In one embodiment, in Formula (V.a), p is 1, 2, 3, or 4, and each R is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR R 2 , -NR 3
SO
2
R
24 ,
-NR
3 C(O)OR0, -NR 3 C(O)R2 4 , -SO 2
NR
5
R
6 , -C(O)R 24 , -C(S)R24, -C(O)OR0, 30 -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR 5 R2, -NR 3
C(N-CN)NR
5
R
6 ,
-NR
3
C(O)NR
5 R2 6 , and -NR 3 -C(NH)-NR2R2 6
,
WO 2009/061596 PCT/US2008/080176 - 235 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 5 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2 0 , -N R 2 'R2 2 ,
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NRC 23
(O)R
24 , -SO 2
NR
2 5 R2 6 , -C(O)R 24 , -C(O)OR2 0 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 4 , -C(O)NR 5 R2 6 , 10 -NR 3 C(N-CN)NR2R2 6 and -NR 3
C(O)NR
25
R
26 . In one embodiment, in Formula (V.a), p is 1 and R3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 15 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 2 0 , -NR R 22 20
-NR
23 SO2R2 4 , -NR 3
C()OR
20 , -NR 23 C(O)R 24 , -SO 2
NR
5 R23, -C(O)R24, -C(O)OR0,
-SR'
9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R2 4 , -C(O)NR 5
R
6 ,
-NR
3
C(N-CN)NR
5 R2 6 and -NRC(O)NR 5 R2 6 In one embodiment, in Formula (V.a), p is 2, 3, or 4, and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. 25 In one embodiment, in Formula (V.a), p is 2, 3, or 4,_and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, 0, S, S(O), and S(0) 2 , or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group 30 consisting of -NH-, -NR 6 -, 0, S, S(0), and S(0) 2
.
WO 2009/061596 PCT/US2008/080176 - 236 In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is alkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heteroalkyl. 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is alkenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (Va.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heteroalkenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 10 (V.a.4), (V.a.5), and (V.a.6), R 3 is alkynyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heteroalkynyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is aryl. 15 In some embodiments, in each of Formulas (V.a), (V.a 1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heteroaryl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is cycloalkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), R 3 is cycloalkenyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heterocycloalkyl. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is heterocycloalkenyl. 25 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is halogen. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -CN.
WO 2009/061596 PCT/US2008/080176 -237 In some embodiments, in each of Formulas (V.a), (V-a.1), (V.a.2), (Va.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -NO 2 In some embodiments, in each of Formulas (V.a), (V-a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V-a.6), R 3 is -OR 9 . 5 In some embodiments, in each of Formulas (V.a), (Va.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R is -OC(O)OR0 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), R is -NRR 22 , In some embodiments, in each of Formulas (Va), (Va.1), (V.a.2), (V.a.3), 10 (Va.4), (V.a.5), and (V.a.6), R 3 is -NR 3
SO
2 R2 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -NR2 3 C(O)OR20. In some embodiments, in each of Formulas (V.a), (V~a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V-a.6), R 3 is -NR2 3 C(O)R24 15 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R is -SO 2 NRR. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), R 3 is -C(O)R 2 4 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), 20 (V.a.4), (V.a.5), and (V.a.6), R is -C(O)OR0 In some embodiments, in each of Formulas (Va), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R is -SR 9 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -S(O)R'. 25 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -SO 2 R',. In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (Va.5), and (V.a.6), R 3 is -OC(O)R24 WO 2009/061596 PCT/US2008/080176 - 238 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -C(O)NR 25
R
2 . In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -NR 2 3 C(N-CN)NR25 2 6 . 5 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is -NR 2 3
C(O)NR
2 5
R
2 6 In some embodiments, in each of Formulas (V.a), (V.a.1), (V.a.2), (V.a.3), (V.a.4), (V.a.5), and (V.a.6), R 3 is selected from the group consisting of: methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or 10 branched), phenyl, N, N, NH 2
H
2 N H 2 N OH OH NH2 \HN HOH O HN OH, HO, 0, o 0H 0N~ HI N HN NH2 N MOH H HN\ OVN OH , and H2N In some embodiments, in each of Formulas (V.a), (V.a.1), (Va.2), (V.a.3), (V.a.4), (V-a.5), and (V.a.6), when E is -NR-, R 3 is absent. 15 WO 2009/061596 PCT/US2008/080176 -239 In one embodiment, the compounds of the invention have a structure shown in Formula (Vb) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R1 R27 R 2 B RR3 N
R
2 5 (V.b.) wherein R', R 2 R, 827, R 2 3, p, E, ring A, and ring B are selected independently of each other and wherein: ring A (including E and the unsaturation shown) is a 7-8-membered cycloalkenyl or heterocycloalkenyl ring; 10 E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R)-, -N(C(Y)R7)-, -N(C(Y)OR8)-,
-N(C(Y)N(R
9 )(R I))-, -C(O)-N(R")-, -N(R")-C(O)-, -S(O)r-N(R'1)-, -N(Rll)-S(O)r-, -C(O)-O-, -O-C(O)-, -O-N(R6) -N(R)-O-, -N(R)-N(R 12 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R'l)-C(Y)-O-, -N(R")-C(Y)-N(R 1)_' -C(Y)-N(Rll)-O-, 15 -C(Y)-N(R' 1 )-N(R1 2 )-, -0-N(R")-C(Y)-, and -N(R )-N(Rl)-C(Y) ring B is a substituted or unsubstituted heteroaromatic ring; and p, R', R 2 R ,t R 4 , R5, R 6 , R, R 8 , R 9 , R 1 0 , R", R, 827, R2, Y, and the optional substituents on ring B are as defined above in Formula (I). 20 In one embodiment, in Formula (V.b.), ring A is a cycloalkenyl ring. In one embodiment, in Formula (V.b.), ring A is a heterocycloalkenyl ring. In one embodiment, in Formula (V.b.), E is -C(R4)(R5)-.
WO 2009/061596 PCT/US2008/080176 - 240 In one embodiment, in Formula (V.b.), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R 6 )-, -N(C(Y)R 7 ), -N(C(Y)OR 8 )-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R")-, -N(R")-C(O)-, -S(O)2-N(R")-, -N(R")-S(O)r-, -C(O)-O-, -O-C(O)-, -0-N(R6)-, -N(R)-0-,
-N(R
6 )-N(R1 2 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, 5 -C(O)-N=N-, -0-C(Y)-N(R) , -N(R")-C(Y)-O-, -N(R")-C(Y)-N(R1 2 )-, -C(Y)-N(R')-O-,
-C(Y)-N(R")-N(R
12 )-, -0-N(R")-C(Y)-, and -N(R )-N(R")-C(Y), In one embodiment, in Formula (Vb.), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, and -N(R -. In one embodiment, in Formula (V.b.), E is selected from the group consisting of 10 -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , and -C(S)R 2 4 In one embodiment, in Formula (V.b.), E is selected from the group consisting of -0- and -N(R6)-, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R24, and -C(S) R 2 4 . 15 In one embodiment, in Formula (Vb.), E is -0-. In one embodiment, in Formula (V.b.), E is -S-. In one embodiment, in Formula (V.b.), E is -S(O)-. In one embodiment, in Formula (V.b.), E is -S(0)2-. In one embodiment, in Formula (V.b.), E is -C(R4)(R 5 )-. 20 In one embodiment, in Formula (V.b.), E is -N(R 6 )-. In one embodiment, in Formula (Vb.), E is -N(C(Y)R 7 )_. In one embodiment, in Formula (V.b.), E is -N(C(Y)OR)-. In one embodiment, in Formula (V.b.), E is -N(C(Y)N(R 9
)(R
10 ))-. In one embodiment, in Formula (V.b.), E is -C(O)-N(R')-.
WO 2009/061596 PCT/US2008/080176 -241 In one embodiment, in Formula (V.b.), E is -N(R")-C(O)-, In one embodiment, in Formula (Vb.), E is -S(O) 2 -N(R")-. In one embodiment, in Formula (V.b.), E is -N(R 1
)-S(O)
2 -. In one embodiment, in Formula (V.b.), E is -C(O)-O-. 5 In one embodiment, in Formula (V.b.), E is -0-C(0)-. In one embodiment, in Formula (V.b.), E is -0-N(R 6 )-. In one embodiment, in Formula (V.b.), E is -N(R 6 )-O-. In one embodiment, in Formula (V.b.), E is -N(R 6
)-N(R
12 )_. In one embodiment, in Formula (V.b.), E is -N=N-. 10 In one embodiment, in Formula (V.b.), E is -C(R 7 )=N-. In one embodiment, in Formula (V.b.), E is -C(O)-C(R 7 )=N-. In one embodiment, in Formula (V.b.), E is -C(O)-N=N-. In one embodiment, in Formula (Vb.), E is -0-C(Y)-N(R)-, In one embodiment, in Formula (V.b.), E is -N(R 1 )-C(Y)-O-. 15 In one embodiment, in Formula (V.bj), E is -N(R")-C(Y)-N(R1 2 )_ In one embodiment, in Formula (V.b.), E is -C(Y)-N(R')-O-. In one embodiment, in Formula (V.b.), E is -C(Y)-N(R 1 )-N(R1 2 )-. In one embodiment, in Formula (V.b.), E is -0-N(R 1 )-C(Y)-, In one embodiment, in Formula (V-b.), E is -N(R 12 )-N(R")-C(Y)-. 20 in one embodiment, in Formula (V.b.), Y is (=O).
WO 2009/061596 PCT/US2008/080176 - 242 In one embodiment, in Formula (Vb.), Y is (=S). In one embodiment, in Formula (V.b.), Y is (=N(R1 3 )), in one embodiment, in Formula (V.b.), Y is (=N(CN)). In one embodiment, in Formula (V.b.), Y is (=N(OR' 4 )). 5 In one embodiment, in Formula (V.b.), Y is (=N(R' 5
)(R'
6 )). In one embodiment, in Formula (Vb.), Y is (=C(R1 7
)(R'
8 )). In one embodiment, in Formula (Vb.), B is an unsubstituted heteroaromatic ring. In one embodiment, in Formula (V.b.), B is an unsubstituted 5-6-membered 10 heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 . In one embodiment, in Formula (V.b.), B is a heteroaromatic ring which is 15 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2
R
22 20 -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23 C(O) R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NR
2 3
C(N-CN)NR
2 5 R23 and -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (V.b.), B is a 5-6-membered heteroaromatic ring 25 having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 , which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 243 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 2 0 , -NR 2
'R
22 , -NR 23
SO
2
R
24 ,
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
2 4 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , 5 -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6, -NR 2 3
C(N-CN)NR
2 5
R
2 6 and NR 23 C(O)NR25 2 6 . In one embodiment, in Formula (V.b.), B is an unsubstituted 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or 10 different, each hetero ring atom being independently selected from the group consisting of N, S, and 0. In one embodiment, in Formula (V.b.), B is a 6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each 15 hetero ring atom being independently selected from the group consisting of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, 20 heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 2 0 , -NR 21
R
22 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
2 0 ,
-NR
23 C(0)R 24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 2 4 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , -S0 2
R
19 ,
-OC(O)R
24 , -C(O)NR 25
R
26 , -NR 23
C(N-CN)NR
25
R
26 and -NR 23 0(O)NR 25
R
2 . 25 In one embodiment, in Formula (V.b.), B is an unsubstituted 6-membered heteroaromatic ring having 2 ring heteroatoms, each ring heteroatom being independently selected from of N, S, and 0. In one embodiment, in Formula (V.b.), B is a 6-membered heteroaromatic ring 30 having 2 ring heteroatoms, each ring heteroatom being independently selected WO 2009/061596 PCT/US2008/080176 - 244 from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR 2
'R
22 , -C(O)R24, -C(O)OR 2 , -SR' 9 , -S(O)R' 9 , 5 -S0 2
R
9 , -OC(O)R 24 , and -C(O)NRR 2 . In one embodiment, in Formula (V.b.), B is an unsubstituted 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group 10 consisting of N, S, and 0. In one embodiment, in Formula (V.b.), B is a 5-membered heteroaromatic ring having from 1-2 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 15 and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, 20 azido, -OR' , -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 ,
-NR
23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 , -C(O)OR20, -SR 9 , -S(0)R' 9 , -S0 2
R
19 ,
-OC(O)R
24 , -C(O)NR 25
R
26 , -NR 23 C(N-CN)NR25R26 and -NR 2 3
C(O)N
5
R
2 . In one embodiment, in Formula (V.b.), B is an unsubstituted 5-membered 25 heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0. In one embodiment, in Formula (V,b.), B is a 5-membered heteroaromatic ring having 1 ring heteroatom selected from of N, S, and 0, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, 30 each substituent being independently selected from the group consisting of WO 2009/061596 PCT/US2008/080176 - 245 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR R 22 , -C(O)R 24
-C(O)OR
2 , -SR 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , and -C(O)NR 2 5R 2 . In one embodiment, in Formula (V.b.), B is a 5-membered heteroaromatic ring 5 having S as the ring heteroatom, which heteroaromatic ring is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, -OR' 9 , -NR 21
R
22 , -C(O)R 24 , -C(O)OR 20 , -SR 9 ,
-S(O)R'
9 , -S0 2
R'
9 , -OC(O)R 24 , and -C(O)NR 25
R
2 6 10 In one embodiment, in Formula (V.b.), B is an unsubstituted 5-membered heteroaromatic ring having S as the ring heteroatom. In one embodiment, in Formula (Vb.), B is selected from the group consisting of 15 ,and In one embodiment, in Formula (V,b.), R is unsubstituted aryl. In one embodiment, in Formula (V.b.), R is unsubstituted phenyl. In one embodiment, in Formula (V.b.), R1 is unsubstituted naphthyl. 20 In one embodiment, in Formula (V.b.), R is substituted aryl. In one embodiment, in Formula (Vb.), R' is substituted phenyl. In one embodiment, in Formula (V.b.), R' is substituted naphthyl. In one embodiment, in Formula (V.b.), R' is aryl substituted with one or more substituents, which can be the same or different, each substituent being 25 independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, WO 2009/061596 PCT/US2008/080176 - 246 aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR R 22 , -NR 23
SO
2
R
2 4
-NR
23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
2
R
2 3, -C(O)R 2 4 , -C(O)OR 20 , -SR 19 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)N R 25
R
26 , -NR 2 3
C(N-CN)NR
25
R
2 6 and 5 -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (V.b.), R' is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, 10 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)R 2 0 , -NR 21
R
22 , -NR 2 3
SO
2
R
24 ,
-NR
23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR2, -SR 9 ,
-S(O)R'
9 , -S0 2
R
19 , -OC(O)R24 -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and 15 -NR 2 3
C(O)NR
2 5
R
2 6 , In one embodiment, in Formula (V-b.), R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN, and 20 haloalkyl. In one embodiment, in Formula (V.b.), R' is selected from the group consisting of: halo HO - NC 02N halo halo halo halo alky haloalkyl halo halo and In one embodiment, in Formula (V,b.), R' is: WO 2009/061596 PCT/US2008/080176 - 247 perfluoroalkyl halo In one embodiment, in Formula (Vb.), R' is phenyl substituted with one to three fluoro groups. In one embodiment, in Formula (V.b.), R' is phenyl substituted with two fluoro 5 groups. In one embodiment, in Formula (V.b.), R' is phenyl substituted with one fluoro group. In one embodiment, in Formula (V.b.), R' is: F F 10 In one embodiment, in Formula (V.b.), R 27 and R 28 are each independently selected from the group consisting of H and alkyl. In one embodiment, in Formula (V-b.), R 2 is -C(Z)R7. 15 In one embodiment, in Formula (V.b.), R 2 is -C(Z)NR"R 1 4. In one embodiment, in Formula (V.b.), R 2 is -C(Z)OR 8 . In one embodiment, in Formula (Vb.), R 2 is -S0 2
NR
9 R'. In one embodiment, in Formula (V-b.), R 2 is alkyl. In one embodiment, in Formula (Vb.), R 2 is heteroalkyl. 20 In one embodiment, in Formula (V.b.), R 2 is aryl. In one embodiment, in Formula (V.b.), R 2 is heteroaryl, in one embodiment, in Formula (V.b.), R 2 is cycloalkyl.
WO 2009/061596 PCT/US2008/080176 - 248 In one embodiment, in Formula (V.b.), R 2 is cycloalkenyL In one embodiment, in Formula (Vb.), R 2 is heterocycloalkyl. In one embodiment, in Formula (V.b.), R 2 is heterocycloalkenyl. 5 In one embodiment, in Formula (V.b.), Z is (=0). In one embodiment, in Formula (V.b.), Z is (=S). In one embodiment, in Formula (Vb.), Z is (=N(R' 3 )). In one embodiment, in Formula (V.b.), Z is (=N(CN)). In one embodiment, in Formula (Vb.), Z is (=N(OR 14 )). 10 In one embodiment, in Formula (V.b.), Z is (=N(R' 5 )(R'6). In one embodiment, in Formula (V.b.), Z is (=C(R1 7 )(R'")). In one embodiment, in Formula (V.b.), R 2 is -C(Z)R7, and Z is (=0). In one embodiment, in Formula (V.b.), R 2 is -C(O)H. 15 In one embodiment, in Formula (V.b.), R 2 is -C(O)alkyl. In one embodiment, in Formula (V.b.), R 2 is -C(0)CH 3 . In one embodiment, in Formula (V.b.), R 2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, 20 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(0)OR 20 , -NR2'R 2 , -NR 23 S0 2
R
24
-NR
23
C(O)OR
20 , -NR 23 C(O)R 24 , -SO 2
NR
2 5
R
26 , -C(O)R 24 , -C(O)OR 2 0 , -SR'9,
-S(O)R'
9 , -SO2R'9, -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3 C(N-CN)N R 25
R
2 6 and 25 -NR 2 3
C(O)NR
2 5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 - 249 In one embodiment, in Formula (Vb.), R 2 is -C(O)R 7 , wherein said R 7 is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of
-OR'
9 , -NR 2
R
22 , and cycloalkyl. 5 In one embodiment, in Formula (V.b.), R 2 is -C(O)R, wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. In one embodiment, in Formula (V.b.), R 2 is -C(O)R
T
, wherein said R is alkyl 10 substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH,
-NH
2 , and cyclopropyl. In one embodiment, in Formula (V-b.), R 2 is -C(O)R, wherein said R is alkyl 15 substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl. In one embodiment, in Formula (V-b.), R 2 is -C(O)R, wherein said R 7 is alkyl 20 substituted with -OH. In one embodiment, in Formula (V.b.), R 2 is -C(0)R 7 , wherein said R 7 is unsubstituted heterocycloalkyl. 25 In one embodiment, in Formula (V.b.), R 2 is -C(O)R 7 , wherein said R 7 is substituted heterocycloalkyl.
WO 2009/061596 PCT/US2008/080176 - 250 In one embodiment, in Formula (Vb.)., R2 is -C(O)R , wherein said R 7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, 5 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR2o, -NR 21R22 -NR2 3 S0 2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R 24, -S0 2 NR25R26, -C(O)R24, -C(O)OR20, -SR 9 , -S(O)R' 9 , -SO2R 9 , -OC(O)R24,
-C(O)NR
2 5
R
2 3,
-NR
23
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6 . 10 In one embodiment, in Formula (V.b.), R2 is -C(Q)R, wherein said R is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. 15 In one embodiment, in Formula (V.b.), R2 is selected from: N N N
H
3 C ,H 3 C> , and H 3 C In one embodiment, in Formula (V.b.), R2 is -C(O)NR 9
R'
0 . In one embodiment, in Formula (V.b.), R2 is -C(O)NH 2 . 20 In one embodiment, in Formula (V.b.), R2 is -C(O)NR 9
R'
0 , wherein R9 and RIOC can be the same or different, each being independently selected from alkyl. In one embodiment, in Formula (V.b.), R2 is -C(O)NR 9 R, wherein R is unsubstituted heterocycloalkyl and R10 is selected from the group consisting of H and alkyl. 25 WO 2009/061596 PCT/US2008/080176 -251 In one embodiment, in Formula (V.b.), R 2 is -C(O)NR 9
R'
0 , wherein R 9 is substituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. 5 In one embodiment, in Formula (V.b.), R 2 is -C(O)NR 9 R'4, wherein R 9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and
R'
0 is selected from the group consisting of H and alkyl. 0 In one embodiment, in Formula (V.b.), R 2 is \ CF 3 . 0 10 In one embodiment, in Formula (V.b.), R 2 is 0 In one embodiment, in Formula (V.b.), R 2 is 0 OH In one embodiment, in Formula (Vb.), R 2 is N 0 In one embodiment, in Formula (V.b.), R 2 i 0 In one embodiment, in Formula (V.b.), R 2 is NH 0 In ne mbdimnt inFomul (~b., 2 is N NH 2 15 In one embodiment, in Formula (V.b.), R 2 is . O 2 s\" N -
N
In one embodiment, in Formula (V~b.), R2I WO 2009/061596 PCT/US2008/080176 - 252 In one embodiment, in Formula (V.b.), p is 0 and R 3 is not present. In one embodiment, in Formula (V.b.), p is 1. In one embodiment, in Formula (V.b.), p is 2. In one embodiment, in Formula (V.b.), p is 3. 5 In one embodiment, in Formula (V.b.), p is 4. In one embodiment, in Formula (Vb.), p is > 2 and at least two groups R 3 are attached to the same ring atom. In one embodiment, in Formula (V.b.), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, 10 heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 2 0, -NR R 22
-NR
23 SO2R 24 , -NRC 2 3
(O)OR
2 0 , -NRC 2 3
(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R 24 , -C(O)NR 5
R
2
-NR
23
C(N-CN)NR
25
R
2 6 and -NR 23
C(O)NR
25
R
2 6 , 15 In one embodiment, in Formula (V.b.), p is 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR'9, -OC(O)OR 2 0 ,
-NR
2 R 22 , -NR 23
SO
2
R
24 , -NR 23 C(0)OR 20 , -NR 23
C(O)R
24 , -SO 2
NR
2 5
R
2 6 , -C(O)R 24 , 20 -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2
R
9 , -OC(O)R 2 4 , -C(O)NR 2 5
R
2 6 ,
-NRC
23
(N-CN)NR
2 5
R
2 6 and -NRC 23
(O)NR
25
R
2 6 . In one embodiment, in Formula (Vb.), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl. 25 heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN,
-NO
2 , , -OR' 9 , -OC(O)OR 20 , -NR 21
R
22 , -NR 23
SO
2
R
24 , -NRC 23
(O)OR
2 0 ,
-NR
23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 2 4 , -C(O)OR2G, -SR' 9 , -S(O)R' 9 , -S02R' 9 ,
-OC(O)R
24 , -C(O)NR 2 5
R
2 6 , -NRC 2 3
(N-CN)NR
25
R
2 6 and -NRC 23
(O)NR
25
R
2 6
.
WO 2009/061596 PCT/US2008/080176 - 253 In one embodiment, in Formula (V.b.), p is 2, 3, or 4 and at least two groups R3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to 5 three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. In one embodiment, in Formula (V.b), p is > 0 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 10 -CN, -NO 2 , -OR 19 , -OC(O)OR 2 0 , -NR 21
R
22 , -NR 23 S0 2
R
24 , -NR 23 C(O)OR24,
-NRC
23
(O)R
24 , -S0 2
NR
25
R
2 6, -C(O)R 24 , -C(S)R 2 4 , -C(O)OR 20 , -SR 1 9 , -S(O)R' 9 ,
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
25
R
26 , -NRC 23
(O)NR
25
R
2 6 , and -NR- 23
C(NH)-NR
2 6
R
26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and 15 each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 20 heterocycloalkyl, heterocycloalkenyl, azido, -ORN' 9 , -OC(O)OR 2 0 , -NR 21
R
22 ,
-NR
2 3
SO
2
R
24 , -NR 2 3
C()OR
20 , -NRC 23
(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)OR
2 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
2 6 ,
-NRC
23
(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (Vb), p is 1 and R 3 is selected from the group 25 consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 30 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, WO 2009/061596 PCT/US2008/080176 - 254 heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR0 , -N R 2 ' K 2 , -NR 2 3
SO
2 R24, -NR 23C(O)OR2 0 , -NR 23 C(O)R 2 4 , -SO 2 N R 25
R
2 6 , -C()R24, -C(O)OR2 0 , -SR' 9 , -S(O)R' 9 , -S0 2
R'
9 , -OC(O)R24, -C(O)NR2 5 R2 6 , -NR2 3 C(N-CN)NR2 5 R2 6 and -NR2 3
C(O)NR
25 R2 6 . 5 In one embodiment, in Formula (V.b), p is > 2 and any two R3 groups bound to the same ring A atom are taken together to form a -C(O)- group. In one embodiment, in Formula (V.b), p is > 2 and any two R3 groups bound to the same ring A atom are taken together to form a spiroheterocycloalkyl group having from 1 to 3 ring heteroatoms independently selected from the group 10 consisting of -NH-, -NR-, 0, S, S(O), and S(0)2, or spiroheterocycloalkenyl group having from 1 to 3 ring heteroatoms independently selected from the group consisting of -NH-, -NR-, 0, S, S(O), and S(0) 2 . In one embodiment, in Formula (V.b.), R3 is alkyl. 15 In one embodiment, in Formula (V.b.), R3 is heteroalkyl. In one embodiment, in Formula (V.b.), R3 is alkenyl. In one embodiment, in Formula (V.b.), R3 is heteroalkenyl. In one embodiment, in Formula (V.b.), R3 is alkynyl. In one embodiment, in Formula (V.b.), R3 is heteroalkynyl. 20 In one embodiment, in Formula (V.b.), R3 is aryl. In one embodiment, in Formula (V.b.), R3 is heteroaryl. In one embodiment, in Formula (V.b.), R3 is cycloalkyl. In one embodiment, in Formula (V.b.), R3 is cycloalkenyl. in one embodiment, in Formula (V.b.), R3 is heterocycloalkyl. 25 In one embodiment, in Formula (V.b.), R3 is heterocycloalkenyl. In one embodiment, in Formula (Vb.), R3 is halogen. In one embodiment, in Formula (V.b.), R3 is -CN.
WO 2009/061596 PCT/US2008/080176 - 255 In one embodiment, in Formula (V.b), R 3 is -NO 2 In one embodiment, in Formula (V.b.), R 3 is -OR' 9 . In one embodiment, in Formula (Vb.), R 3 is -OC(O)0R 2 0 In one embodiment, in Formula (V.b.), R 3 is -NR 21
R
22 5 In one embodiment, in Formula (Vb.), R 3 is -NR 23 S0 2
R
24 In one embodiment, in Formula (V.b.), R 3 is -NR 23 C(O)0R 20 In one embodiment, in Formula (Vb.), R 3 is -NR 23
C(O)R
24 . In one embodiment, in Formula (V.b.), R 3 is -S0 2
NRR
2 . In one embodiment, in Formula (Vtb.), R 3 is -C(O)R 2 4 10 In one embodiment, in Formula (V.b.), R 3 is -C(O)R 20 In one embodiment, in Formula (Vb.), R 3 is -SR 19 . In one embodiment, in Formula (V.b.), R 3 is -S(O)R' 9 . In one embodiment, in Formula (V.b.), R 3 is -SO 2
R
1 9 , In one embodiment, in Formula (V.b), R 3 is -OC(O)R 2 4 15 In one embodiment, in Formula (V.b.), R 3 is -C(O)NR 25
R
2 . In one embodiment, in Formula (V.b.), R 3 is -NR 23
C(N-CN)NR
2 5
R
2 . In one embodiment, in Formula (V.b.), R 3 is -NH 23 0(O)NR 2 5
R
26 In one embodiment, Formula (V.b) has the general structure: 20 WO 2009/061596 PCT/US2008/080176 - 256 B R3 HN
R
2 In one embodiment, Formula (V.b) has the general structure: B R3 N 5
R
2 In one embodiment, Formula (V.b) has the general structure: R1 R27R R28 B N, A R3) N R R 3 , wherein P is 0, 1, 2, or 3. 10 In one embodiment, Formula (V.b) has the general structure: WO 2009/061596 PCT/US2008/080176 - 257 R1
R
27
R
28 B R R) A P N I 2 R ,wherein P is 0, 1, 2, or 3. In one embodiment, Formula (V.b) has the general structure: 5 R1 R 27 R 28 H- B NJ A / N R ,wherein P is 0, 1, 2, or 3. In one embodiment, Formula (V.b) has the general structure: WO 2009/061596 PCT/US2008/080176 - 258 R1R27 R28 1RR Ra R R3) N A P N liz: 2 R3 R , wherein P is 0, 1, 2, or 3. In one embodiment, the compounds of the invention have a structure 5 shown in Formula (VI) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, or isomers of said compounds: R 1 R27 R28 B R3 N R 2 (VI) wherein R 1 , R 2 , R3 R 2 , R 2 8 , p, E, ring A, and ring B are selected independently 10 of each other and wherein: ring A (including E and the unsaturation shown) is a 4-8-membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R4)(R 5 )-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R9)(R 1 "))-, -C(O)-N(R 1 )-, 15 -N(R')-C(O)-, -S()-N(R)-, -N(R")-S(0) 2 -, -C(00)--, -O-C(O)-, -O-N(R 6 )-,
-N(R
6 )-O-, -N(R 6
)-N(R
12 )-, -N=N-, -C(R7)=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, WO 2009/061596 PCT/US2008/080176 -259 -O-C(Y)-N(R)-, -N(R')-C(Y)-O-, -N(R 1
)-C(Y)-N(R
12 )-, -C(Y)-N(R')-O-,
-C(Y)-N(R")-N(R
1 )-, -0-N(R' 1 )-C(Y)-, and -N(R 2 )-N(R")-C(Y)-; ring B is an unsubstituted or optionally independently substituted partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring, 5 and p, R', R 2 , R 3 , Rt ,, R 6 , RB, R 8 , R9, R' 0 , R", R 2 , R 27 , R 26 , Y, and the optional substituents on ring B are as defined above in Formula (1). In one embodiment, in Formula (VI), ring A is a cycloalkenyl ring. In one embodiment, in Formula (VI), ring A is a heterocycloalkenyl ring. 10 In one embodiment, in Formula (VI), ring A is a 4-membered ring. In one embodiment, in Formula (VI), ring A is a 5-membered ring. In one embodiment, in Formula (VI), ring A is a 6-membered ring. In one embodiment, in Formula (VI), ring A is a 7-membered ring. 15 In one embodiment, in Formula (VI), ring A is an 8-membered ring. In one embodiment, in Formula (VI), E is -C(R 4 )(R)-, In one embodiment, in Formula (VI), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R 9
)(R'
0 ))-, 20 -C(O)-N(R")-, -N(R")-C(O)-, -S(0) 2 -N(R')-, -N(R")-S(O) 2 -, -C(O)-Q-, -O-C(O)-, -0-N(R 6 )-, -N(R 6 )-O-, -N(R6)-N(R1)-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, -Q-C(Y)-N(R')-, -N(R")-C(Y)-O-, -N(R)-C(Y)-N(R1 2 )-, -C(Y)-N(R')-O-, -C(Y)-N(R)-N(R' 2 )-, -0-N(R")-C(Y)-, and -N(R' 2 )-N(R')-C(Y)-. In one embodiment, in Formula (VI), E is selected from the group consisting of 25 -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6
)_.
WO 2009/061596 PCT/US2008/080176 - 260 In one embodiment, in Formula (VI), E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-, wherein RA is selected from the group consisting of H, alkyl, -C(O)R 2 , and -C(S)R 2 4 In one embodiment, in Formula (VI), E is selected from the group consisting of 5 -0- and -N(R 6 )-, wherein R 6 is selected from the group consisting of H, alkyl,
-C(O)R
24 , and -C(S)R 24 . In one embodiment, in Formula (VI), E is -0-. In one embodiment, in Formula (VI), E is -S-. In one embodiment, in Formula (VI), E is -S(O)-. 10 In one embodiment, in Formula (VI), E is -S(O)-. In one embodiment, in Formula (VI), E is -C(R4)(R) In one embodiment, in Formula (VI), E is -N(R 6 )-. In one embodiment, in Formula (VI), E is -N(C(Y)R) In one embodiment, in Formula (VI), E is -N(C(Y)OR)-. 15 In one embodiment, in Formula (VI), E is -N(C(Y)N(R 9 )(R'))-. In one embodiment, in Formula (VI), E is -C(O)-N(R')-. In one embodiment, in Formula (VI), E is -N(R 11 )-C(O)-, In one embodiment, in Formula (VI), E is -S(0) 2
-N(R
1 ')-. In one embodiment, in Formula (VI), E is -N(R")-S(0) 2 -. 20 In one embodiment, in Formula (VI), E is -C(O)-C-. In one embodiment, in Formula (VI), E is -0-C(O)-. In one embodiment, in Formula (VI), E is -O-N(R 6
)_.
WO 2009/061596 PCT/US2008/080176 -261 In one embodiment, in Formula (VI), E is -N(R 6 )_O_. In one embodiment, in Formula (VI), E is -N(R 6 )-N(R1 2 )_. In one embodiment, in Formula (VI), E is -N=N-. In one embodiment, in Formula (VI), E is -C(R 7 )=N-. 5 In one embodiment, in Formula (VI), E is -C(O)-C(R 7 )=N-. In one embodiment, in Formula (VI), E is -C(O)-N=N-. In one embodiment, in Formula (VI), E is -O-C(Y)-N(R")-. In one embodiment, in Formula (VI), E is -N(R")-C(Y)-O-. In one embodiment, in Formula (VI), E is -N(R')-C(Y)-N(R')-. 10 In one embodiment, in Formula (VI), E is -C(Y)-N(R)-O-. In one embodiment, in Formula (VI), E is -C(Y)-N(R 1
')-N(R
2 )-. In one embodiment, in Formula (VI), E is -O-N(R' 1 )-C(Y)-. In one embodiment, in Formula (VI), E is -N(R')-N(R')-C(Y)-. 15 In one embodiment, in Formula (VI), Y is (=0). In one embodiment, in Formula (VI), Y is (=S). In one embodiment, in Formula (VI), Y is (=N(R')). In one embodiment, in Formula (VI), Y is (=N(CN)). In one embodiment, in Formula (VI), Y is (=N(OR 4 )). 20 In one embodiment, in Formula (VI), Y is (=N(R' 5 )(R'6). In one embodiment, in Formula (VI), Y is (=C(R 17
)(R"')).
WO 2009/061596 PCT/US2008/080176 -262 In one embodiment, in Formula (VI), ring A is a 4-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4 )(R)-,
-N(R
6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-. 5 In one embodiment, in Formula (VI), A is a 4-membered ring and E is selected from the group consisting of -CH 2 -, -CH(R-4), -C(R4)(R 5 )-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R 6 )-, 10 -N(C(Y)R 7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R
0 ))-, -C(0)-N(R)-, -N(R')-C(O)-,
-S(O)
2 -N(R)-, -N(R 1 )-S(0) 2 -, -C(O)-O, -0-C(0)-, -O-N(R 6 )-, -N(R 6 )-O-, -N(R )-N(R 12 )-, -N=N-, and -C(R 7 )=N-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -0-. 15 In one embodiment, in Formula (VI), A is a 5-membered ring and E is -S-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -S(O)-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -S(0) 2 -. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -C(R 4 )(R)-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(R 6 )-. 20 In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(C(Y)R7)-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is
-N(C(Y)OR
8 )-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is 25 -N(C(Y)N(R9)(R' ))-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is
-C(O)-N(R)-.
WO 2009/061596 PCT/US2008/080176 - 263 In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(R')-C(O)-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is
-S(O)
2 -N(R1)-. 5 In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(R")-S(0) 2 -. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -C(0)-0-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -0-C(O) In one embodiment, in Formula (VI), A is a 5-membered ring and E is -O-N(R -. 10 In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(R 6 )-0-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N(R6)-N(R 1)-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -N=N-. In one embodiment, in Formula (VI), A is a 5-membered ring and E is -C(R 7 )=N-. 15 In one embodiment, in Formula (VI), A is a 6-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R4)(R 5 )-, -N(R 6 )-,
-N(C(Y)R
7 )_, -N(C(Y)OR 8 )-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R")-, -N(R")-C(O)-, -S(0) 2 -N(R')-, -N(R")-S(0) 2 -, -C(O)-O-, -0-C(0)-, -0-N(R 6 )-, -N(R 6 )-0-, 20 -N(R 6
)-N(R
12 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R 7 )=N-, -C(O)-N=N-, -Q-C(Y)-N(R1)-, -N(R")-C(Y)-O-, -N(R')-C(Y)-N(R1 2 )-, -C(Y)-N(R")-O-, -C(Y)-N(R')-N(R 12 )-, -0 N(R")-C(Y)-, and -N(R' 2 )-N(R")-C(Y)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -0-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -S-. 25 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -S(O)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -S(0)2-.
WO 2009/061596 PCT/US2008/080176 -264 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(R 6 )-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(C(Y)R')-. 5 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(C(Y)OR)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-N(C(Y)N(RG)(R
1 '))-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is 10 -C(O)-N(R"), In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(R")-C(O)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-S(O)
2 -N(R1). 15 In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-N(R")-S(O)
2 -. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -C(O)-O-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -0-C(0)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -0-N(Rb)-. 20 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(R 6 )-O-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(R 6)-N(R e )-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N=N-. Ir) one embodiment, in Formula (VI), A is a 6-membered ring and E is -C(R 7)=N-, WO 2009/061596 PCT/US2008/080176 - 265 In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-C(O)-C(R
7 )=N-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -C(O)-N=N-. 5 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -O-C(Y)-N(R")-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is -N(R')-C(Y)-O-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is 10 -N(R")-C(Y)-N(R1)_ In one embodiment, in Formula (VI), A is a 6-membered ring and E is -C(Y)-N(R")-O-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-C(Y)-N(R")-N(R
1 )-. 15 In one embodiment, in Formula (VI), A is a 6-membered ring and E is -0
N(R
1 )-C(Y)-. In one embodiment, in Formula (VI), A is a 6-membered ring and E is
-N(R
1 )-N(R)-C(Y)-. 20 In one embodiment, in Formula (VI), A is a 7-membered ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0) 2 -, -C(R 4
)(R
5 )-, -N(R 6 )-,
-N(C(Y)R
7 )-, -N(C(Y)OR)-, -N(C(Y)N(R 9
)(R'
0 ))-, -C(O)-N(R')-, -N(R")-C(O)-, -S(0) 2 -N(R')-, -N(R')-S(0) 2 -, -C(O)-O-, -0-C(O)-, -0-N(R 6 )-, -N(R 6 )-O-, -N(R6)-N(R 1)-, -N=N-, -C(R 7)=N-, -C(0)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R'l)-, 25 -N(R")-C(Y)-O-, -N(R')-C(Y)-N(R1 2 )-, -C(Y)-N(R')-O-, -C(Y)-N(R")-N(R 12 )-, -O N(R)-C(Y)-, and -N(R 2
)-N(R")-C(Y)-.
WO 2009/061596 PCT/US2008/080176 - 266 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -0-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -S-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -S(O)-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -S(0) 2 -. 5 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(R 6 )_ In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(C(Y) R 7 )_. In one embodiment, in Formula (VI), A is a 7-membered ring and E is 10 -N(C(Y)OR 8 )-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(C(Y)N(R9)(Rlo))-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is
-C(O)-N(R
1 )-. 15 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(R'l)-C(O)-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -S(0) 2
-N(R
1 )-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is 20 -N(R")-S(O)r. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -C(0)-0-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -0-C(O)-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -O-N(R6-.
WO 2009/061596 PCT/US2008/080176 - 267 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(R 8 )-O-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is
-N(R
6 )-N(R 12). In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N=N-. 5 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -C(R 7 )=N-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is
-C(O)-C(R
7 )=N-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -C(O)-N=N-. 10 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -O-C(Y)-N(R'")-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(R)-C(Y)-O-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is 15 -N(R")-C(Y)-N(R2)-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -C(Y)-N(R)-0-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is
-C(Y)-N(R')-N(R'
2 )-. 20 In one embodiment, in Formula (VI), A is a 7-membered ring and E is -0
N(R
1 )-C(Y)-. In one embodiment, in Formula (VI), A is a 7-membered ring and E is -N(R'2)-N(R")-C(Y)-.
WO 2009/061596 PCT/US2008/080176 - 268 In one embodiment, in Formula (VI), A is a 8-membered ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -C(R 4
)(R
5 )-, -N(R)-,
-N(C(Y)R
7 )-, -N(C(Y)OR%)-, -N(C(Y)N(R 9 )(R'))-, -C(O)-N(R1)-, -N(R)-C(O)-, -S(0) 2 -N(R')-, -N(R")-S(Q) 2 -, -C(O)-O-, -0-C(O)-, -0-N(R)-, -N(R 6 )-O-, 5 -N(R6)-N(R1 2 )-, -N=N-, -C(R 7 )=N-, -C(O)-C(R7)=N-, -C(O)-N=N-, -0-C(Y)-N(R")-, -N(R)-C(Y)-O-, -N(R")-C(Y)-N(R)-, -C(Y)-N(R")-O-, -C(Y)-N(R )-N(R)-, -O
N(R
1 )-C(Y)-, and -N(R 12 )-N(R')-C(Y)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -0-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -S-. 10 In one embodiment, in Formula (VI), A is a 8-membered ring and E is -S(O)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -S(O)r-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(R 4
)(R
5 )-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(R 6 )-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is 15 -N(C(Y)R 7 )-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(C(Y)ORa)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(C(Y)N(Rm e n u )i m 20 In one embodiment, in Formula (VI), A is a 8-membered ring and E is
-C(O
)-
N(R0)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(R")-C(O)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is 25 -S(O)r-N(R")-.
WO 2009/061596 PCT/US2008/080176 - 269 In one embodiment, in Formula (VI), A is a 8-membered ring and E is
-N(R")-S(O)
2 -. in one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(O)-O-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -0-C(0)-. 5 In one embodiment, in Formula (VI), A is a 8-membered ring and E is -O-N(R)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(R 6 )-O. in one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(R )-N(R 1 2) In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N=N-. 10 In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(R7)=N-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(O)-C(R7)=N-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(O)-N=N-. 15 In one embodiment, in Formula (VI), A is a 8-membered ring and E is -0-C(Y)-N(R")-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is
-N(R'
1 )-C(Y)-O-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is 20 -N(R")-C(Y)-N(R1)_ In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(Y)-N(R")-O-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -C(Y)-N(R)-N(R1 2
)-.
WO 2009/061596 PCT/US2008/080176 - 270 In one embodiment, in Formula (VI), A is a 8-membered ring and E is -0 N(R")-C(Y)-. In one embodiment, in Formula (VI), A is a 8-membered ring and E is -N(R 12)-N(R")-C(Y) 5 In one embodiment, in Formula (VI), B is a partially unsaturated alicyclic ring, which ring is unsubstituted. In one embodiment, in Formula (VI), B is a partially unsaturated alicyclic ring which is substituted with one or more substituents, which can be the same or 10 different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 ,
-OC(O)OR
2 0 , -NR21 R 22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R24 15 -S0 2
NR
5
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24
-C(O)NR
25 R2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 3. in one embodiment, in Formula (VI), B is a partially unsaturated heterocyclic ring, which ring is unsubstituted. 20 In one embodiment, in Formula (VI), B is a partially unsaturated heterocyclic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, 25 cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2
'R
22 , -NR 23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
2 5 3R 2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R24
-C(O)NR
2 5
R
2 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 2 3
C(O)NR
2 5
R
2 6
.
WO 2009/061596 PCT/US2008/080176 -271 In one embodiment, in Formula (VI), R 1 is unsubstituted aryl. In one embodiment, in Formula (VI), R' is unsubstituted phenyl. In one embodiment, in Formula (VI), R' is unsubstituted naphthyl. In one embodiment, in Formula (VI), R 1 is substituted aryl. 5 In one embodiment, in Formula (VI), R 1 is substituted phenyl. In one embodiment, in Formula (VI), R 1 is substituted naphthyl. In one embodiment, in Formula (VI), R' is aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, 10 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 2 0 , -NR 2
R
22 , -NR 23 SO2R 2 4 ,
-NR
23 C(O)OR20, -NR 23
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 ,
-S(O)R'
9 , -SO2R' 9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 15 -NR 2 3
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (VI), R is phenyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting halogen, -CN, -NO 2 , alkyl, 20 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 , -OC(0)OR 20 , -NR 2 'R 22 , -NR 23
SO
2
R
2 4 ,
-NR
23
C(O)OR
2 0 , -NR 2 3C(O)R 24, -SO 2 N R 25
R
26 , -C(O)R 24 , -C(O)OR 20 , -SR 1 ,
-S(O)R'
9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
2 5
R
2 6 and 25 -NR 2 3
C(O)NR
2 5
R
2 6 . In one embodiment, in Formula (VI), R 1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being WO 2009/061596 PCT/US2008/080176 - 272 independently selected from the group consisting of halo, -OH, -CN, -NO 2 , and
-NR
1 2R2 2 , and haloalkyl. In one embodiment, in Formula (VI), R' is selected from the group consisting of: habo HO ~~- NC ---- 0 2 N halo halo halo halo aikyl haloalkyl halo halo and In one embodiment, in Formula (VI), R" is: pertluoroalkyl halo In one embodiment, in Formula (VI), R is phenyl substituted with one to three 10 fluoro groups. In one embodiment, in Formula (VI), R 1 is phenyl substituted with two fluoro groups. In one embodiment, in Formula (VI), R 1 is phenyl substituted with one fluoro group. 15 In one embodiment, in Formula (VI), R is: F F In one embodiment, in Formula (VI), R 27 and R 28 are each independently selected from the group consisting of H and alkyl.
WO 2009/061596 PCT/US2008/080176 -273 In one embodiment, in Formula (VI), R 2 is -C(Z)R 7 . In one embodiment, in Formula (VI), R 2 is -C(Z)NR 9 R'. In one embodiment, in Formula (VI), R 2 is -C(Z)OR 8 . 5 in one embodiment, in Formula (VI), R 2 is -SO 2
NR
9 R'4. In one embodiment, in Formula (VI), R 2 is alkyl. In one embodiment, in Formula (VI), R 2 is heteroalkyl. In one embodiment, in Formula (VI), R 2 is aryl. In one embodiment, in Formula (VI), R 2 is heteroaryl. 10 In one embodiment, in Formula (VI), R 2 is cycloalkyl. In one embodiment, in Formula (VI), R 2 is cycloalkenyl. In one embodiment, in Formula (VI), R 2 is heterocycloalkyl. In one embodiment, in Formula (VI), R 2 is heterocycloalkenyl. 15 In one embodiment, in Formula (VI), Z is (=0). In one embodiment, in Formula (VI), Z is (=S). In one embodiment, in Formula (VI), Z is (=N(R 13 )). In one embodiment, in Formula (VI), Z is (=N(CN)). In one embodiment, in Formula (VI), Z is (=N(OR1). 20 In one embodiment, in Formula (VI), Z is (=N(R' 5
)(R'
6 )). In one embodiment, in Formula (VI), Z is (=C(R 17
)(R
18 )). In one embodiment, in Formula (VI), R 2 is -C(Z)R 7 , and Z is (=0). In one embodiment, in Formula (VI), R 2 is -C(O)H. 25 In one embodiment, in Formula (VI), R 2 is -C(O)alkyi.
WO 2009/061596 PCT/US2008/080176 - 274 In one embodiment, in Formula (VI), R 2 is -C(O)CH 3 . In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R 7 is alkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, 5 halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)ORaO, -NR 2 ' R 2 2 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
2 ), -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R24, -C(O)OR20, -SR' 9 ,
-S(O)R'
9 , -S0 2
R
9 , -OC(O)R24, -C(O)NR 2 5
R
2 6 , -NR 2 3
C(N-CN)NR
2 5
R
2 6 and 10 -NR 2 3
C(O)NR
25 26 . In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said Rt is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of 15 -OR 9 , -NR 21 R22, and cycloalkyl. In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R 7 is alkyl, wherein said alkyl is substituted with alkyl and -OH. 20 In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R is alkyl substituted with one to three substituents, which can be the same or different, each substituent being independently selected from the group consisting of -OH,
-NH
2 , and cyclopropyl. 25 In one embodiment, in Formula (VI), R 2 is -C(O)R , wherein said R 7 is alkyl substituted with one to two substituents, which can be the same or different, each substituent being independently selected from the group consisting of -NH 2 , and cyclopropyl.
WO 2009/061596 PCT/US2008/080176 - 275 In one embodiment, in Formula (VI), R 2 is -C(O)R7, wherein said R is alkyl substituted with -OH. In one embodiment, in Formula (VI), R 2 is -C(O)R7, wherein said R is 5 unsubstituted heterocycloalkyl. In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R is substituted heterocycloalkyl 10 In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R7 is heterocycloalkyl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 15 heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 20 , -NR R 22
-NR
23
SO
2
R
24 , -NR 23 C(O)O R 20 , -NR 2 3 C(O)R 24 , -S0 2
NR
2 5
R
26 , -C(O)R 24 ,
-C(O)OR
20 , -SR 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25 2
-NR
2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
2 6 . 20 In one embodiment, in Formula (VI), R 2 is -C(O)R, wherein said R is selected from the group consisting of substituted piperidine, substituted piperazine, substituted morpholine, substituted pyrrolidine, and substituted azetidine. In one embodiment, in Formula (VI), R 2 is selected from: N N 25 H 3 C ,H 3 C , and H 3
C
WO 2009/061596 PCT/US2008/080176 -276 In one embodiment, in Formula (VI), R 2 is -C(O)NR 9
R'
0 . In one embodiment, in Formula (VI), R 2 is -C(O)NH 2 . In one embodiment, in Formula (VI), R 2 is -C(O)NR9R' 0 , wherein R and R'4 can be the same or different, each being independently selected from alkyl. 5 In one embodiment, in Formula (VI), R 2 is -C(O)NR9R't, wherein R9 is unsubstituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (VI), R 2 is -C(O)NR9R'4, wherein R9 is 10 substituted heterocycloalkyl and R' 0 is selected from the group consisting of H and alkyl. In one embodiment, in Formula (VI), R 2 is selected from the group consisting of: alkyl, haloalkyl, heteroalkyl, heterohaloalkyl, -C(O)R . -C(0)OR, and
-C(O)NR
9 R'4. 15 In one embodiment, in Formula (VI), R 2 is selected from the group consisting of: 0 00 A CF3 O CHF 2 O 0" 3, 000 0 0 OH o O HO Sx 00 0 A0 Yo 0 N OH OH 0 2[Y NH , N 4 NH 2 N H 2 N NH 2 , NH,,
,NH
WO 2009/061596 PCT/US2008/080176 -277 Q o 000 0 N HN NH -0H 00
NH
2 H HN HN
H
2 N H 2 N H 2 N -00 0 3l ' HN H 2 N H 2 N NH NH NH NH H 2 N H 2 H N O2 H2N 0I i0t.~z 0 N \ / N
I
2 IHN NH, N , N, NH ,0 0 O 00 0, 0 H and N In one embodiment, in Formula (VI), R2 is -C(O)NR 9
R'
0 , wherein R9 is heterocycloalkyl substituted with from one to three substituents, which can be the same or different, each substituent being independently selected from alkyl, and R'H is selected from the group consisting of H and alkyl. 10 0 In one embodiment, in Formula (VI), R 2 is \ CF 3 0 In one embodiment, in Formula (VI), R2 is WO 2009/061596 PCT/US2008/080176 -278 0 In one embodiment, in Formula (VI), R 2 is 0 OH In one embodiment, in Formula (VI), R 2 is 0 In one embodiment, in Formula (VI), R 2 is 0 In one embodiment, in Formula (VI), R 2 is N NH 2 0 5 In one embodiment, in Formula (VI), R 2,S|. \AN -N In one embodiment, in Formula (VI), R2 i In one embodiment, in Formula (VI), p is 0 and R3 is not present. In one embodiment, in Formula (VI), p is 1. 10 In one embodiment, in Formula (VI), p is 2. In one embodiment, in Formula (VI), p is 3. In one embodiment, in Formula (VI), p is 4. In one embodiment, in Formula (VI), p is > 2 and at least two groups R3 are attached to the same ring atom. 15 In one embodiment, in Formula (VI), p is 1 and R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR 2 1
R
22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23 C(O)R 24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24
,
WO 2009/061596 PCT/US2008/080176 -279
-C(O)OR
20 , -SRI9, -S(O)R' 9 , -SO 2 R', -OC(O)R 24 , -C(O)NRR
-NRC
23
(N-CN)NR
25
R
26 and -NRC 23
(O)NR
2 5
R
2 6 , In one embodiment, in Formula (VI), p is 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, 5 alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR R 22
-NR
23
SO
2
R
24 , -NR 23
C(O)OR
2 0 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 25
R
26 ,
-NR
2 3
C(N-CN)NR
2 5
R
26 and -NR 23 C(O)NR 25
R
26 10 In one embodiment, in Formula (VI), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein each R 3 , which may be the same or different, is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, halogen, -CN, 15 -NO 2 , , -OR' 9 , -OC(O)OR 20 , -NR 2 1 R 22 , -NR 23 S0 2
R
24 , -NR 23
C(O)OR
20 ,
-NR
2 3
C(O)R
24 , -S0 2
NR
2 5
R
2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R1 9 ,
-OC(O)R
24 , -C(O)NR 25
R
26 , -NRC 23
(N-CN)N
25
R
26 and -NR 23
C(O)NR
2 5H 2 6 , In one embodiment, in Formula (VI), p is 2, 3, or 4 and at least two groups R 3 are bound to the same ring carbon atom, wherein two R 3 groups, which may be the 20 same or different, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S. 25 In one embodiment, in Formula (VI), p is > 0 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 2R 22 , -NR 23 S02R 24 , -NR 23
C(O)OR
2 0 -NR 23 C(O)R 24 , -S0 2
NR
2 5
H
26 , -C(O)R 24 , -C(S)R 24 , -C(O)OR20, -SR' 9 , -S(O)R',
-SO
2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 , -NR 23
C(N-CN)NR
25
R
26 , -NR 23
C(O)NR
2 5
R
26 , 30 and -NR- 2 3
C(NH)-NR
2
R
2 6
,
WO 2009/061596 PCT/US2008/080176 - 280 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of 5 oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 2 0, -NRR 22
-NR
23
SO
2
R
24 , -NRC 23
(O)R
20 , -NR 23 C(O)R24, -S0 2
NR
2 5
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO0 2 R, -OC(O)R 24 , -C(O)NR 25
R
26 10 -NR 2 3
C(N-CN)NR
2 5
R
2 6 and -NR 23
C(O)NR
2 5
R
26 . In one embodiment, in Formula (VI), p is 1 and R 3 is selected from the group consisting of alkyl, heteroalkyl, alkenyl, and heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently 15 substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 2 0 , -NR 21
R
22 , 20 -NR 23
SO
2
R
24 , -NR 23
C(O)OR
20 , -NR 23
C(O)R
24 , -S0 2
NR
25
R
2 6 , -C(O)R 24 ,
-C(O)OR
20 , -SR' 9 , -S(O)R' 9 , -SO 2
R'
9 , -OC(O)R 24 , -C(O)NR 2 5
R
2 6 ,
-NRC
2 3
(N-CN)NR
5
R
2 6 and -NRC 23
(O)NR
25
R
2 6 In one embodiment, in Formula (VI), p is 2, 3, or 4, and any two R 3 groups bound to the same ring A atom are taken together to form a -C(O)- group. 25 In one embodiment, in Formula (IV), p is 2, 3, or 4, and any two R 3 groups bound to the same ring A atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, 30 -S(O) 2 -, and -0-, or a spiroheterocycloalkenyl ring containing from one to three WO 2009/061596 PCT/US2008/080176 -281 ring heteroatoms independently selected from the group consisting of -NH-,
-NR
6 -, -S-, -S(O)-, -S(0) 2 -, and -0-. In one embodiment, in Formula (IV), p is >0 and R 2 and R 3 are taken together 5 with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, 10 -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-. In one embodiment, in Formula (VI), R 3 is alkyl. In one embodiment, in Formula (VI), R 3 is heteroalkyl. In one embodiment, in Formula (VI), R 3 is alkenyl. 15 In one embodiment, in Formula (VI), R 3 is heteroalkenyl. In one embodiment, in Formula (VI), R 3 is alkynyl. In one embodiment, in Formula (VI), R 3 is heteroalkynyl. In one embodiment, in Formula (VI), R is aryl. In one embodiment, in Formula (VI), R 3 is heteroaryl. 20 In one embodiment, in Formula (VI), R 3 is cycloalkyl. In one embodiment, in Formula (VI), R 3 is cycloalkenyl. In one embodiment, in Formula (VI), R 3 is heterocycloalkyl. In one embodiment, in Formula (VI), R 3 is heterocycloalkenyl. In one embodiment, in Formula (VI), R 3 is halogen. 25 In one embodiment, in Formula (VI), R 3 is -CN. In one embodiment, in Formula (VI), R 3 is -NO 2 In one embodiment, in Formula (VI), R 3 is -OR' 9
.
WO 2009/061596 PCT/US2008/080176 - 282 In one embodiment, in Formula (VI), R 3 is -OC(O)OR 2 Q In one embodiment, in Formula (VI), R 3 is -NR 2R 2 2. In one embodiment, in Formula (VI), R 3 is -NR 23
SO
2
R
2 4 . In one embodiment, in Formula (VI), R 3 is -NR 23
C(O)OR
2 0 . 5 In one embodiment, in Formula (VI), R 3 is -NR 23
C(O)R
24 . In one embodiment, in Formula (VI), R 3 is -SO 2
NR
25 R3. In one embodiment, in Formula (VI), R 3 is -C(O)R 2 4 . In one embodiment, in Formula (VI), R 3 is -O(S)R 2 4 In one embodiment, in Formula (VI), R 3 is -C(O)0R 20 10 In one embodiment, in Formula (VI), R 3 is -SR24 In one embodiment, in Formula (VI), R 3 is -S(O)R' 9 . In one embodiment, in Formula (VI), R 3 is -SO 2
R
9 ,. In one embodiment, in Formula (VI), R 3 is -OC(O)R 24 In one embodiment, in Formula (VI), R 3 is -C(O)NR 2
R
2 e. 15 In one embodiment, in Formula (VI), R 3 is -NR 23 0(N-CN)NR 2 5
R
2 6 In one embodiment, in Formula (VI), R 3 is -NR 23
C(O)NR
2 5
R
26 In one embodiment, in Formula (VI), R 3 is selected from the group consisting of methyl, ethyl, propyl (straight or branched), butyl (straight or branched), pentyl (straight or branched), phenyl, N, N, NH 2 , H 2 N H 2 N / OH 20 OH, OH, HO , o o WO 2009/061596 PCT/US2008/080176 -283 HNtHNH
ONH
2 O , HN HN N HN NH2 N 0 o 0 N OH ,and
H
2 N In one embodiment, in Formula (IV), when E is -NR 6 -, R 3 is absent. 5 In one embodiment, Formula (VI) has the general structure: R1 R27 R28 RR3 N R 2 In one embodiment, Formula (VI) has the general structure: 10 WO 2009/061596 PCT/US2008/080176 - 284 B R- A R2 In one embodiment, Formula (VI) has the general structure: R1 R27 R28 B N, A / P N 2 R , wherein P is 0, 1, 2, or 3. 5 In one embodiment, Formula (VI) has the general structure: 1
R
27
R
28 B S3 R3) Ny AP N 2 RN 3 R , wherein P is 0, 1, 2, or 3. 10 In one embodiment, Formula (VI) has the general structure: WO 2009/061596 PCT/US2008/080176 -285 R27 R28 B NA P N R R , wherein P is 0, 1, 2, or 3. In one embodiment, Formula (VI) has the general structure: 5 1i R 27 R 28 F 3 N, A R P N R 2 -3 R ,wherein P is 0, 1, 2, or 3. In one embodiment, the compounds of the invention have a structure shown in the Table below, and include pharmaceutically acceptable salts, 10 solvates, esters, prodrugs, or isomers of said compounds. F F0 00 0 WO 2009/06 1596 PCT/US2008/080176 - 286 F FF N-N-N N-N O 0 0 F FN NHNNF F NN MN HN 0 F N-
N
F F FNN F N-N F N F N-N -N H, N N F
FF
0 IF N-N o 0 o F N-N \-F N-N H-N HN N F F N F 0 "N-.,N F N-N0 >-O>0 I-N HN / 0F N-N MN0 N 0N OH FF F F N 4F F N-NF NNN NH
NH
2
,
WO 2009/061596 PCT/US2008/080176 - 287 FF F N N F F F F N-N F N-NNN N 0 0 N-N F F\/ F F F FN-&N FO NN 'NN F~~ NNN
-N
0H2N in, 0h iO F FF F F -N NH FH IN F NN F Nt O N NH and ' In other embodiments, the present invention provides processes for producing the compounds described in each of the various embodiments above, pharmaceutical formulations or compositions comprising one or more of such 5 compounds, and methods of treating or preventing one or more conditions or diseases associated with KSP kinesin activity such as those discussed in detail below. As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: 10 "Subject" includes both mammals and non-mammalian animals. "Mammal" includes humans and other mammalian animals. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided WO 2009/061596 PCT/US2008/080176 -288 that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable 5 structure" is meant 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 "optionally substituted" means optional substitution with the specified groups, radicals or moieties, It should be noted that any atom with 10 unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the hydrogen atom(s) to satisfy the valences. The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of 15 "hydroxyalkyl", "haloalkyl", "alkoxy", etc. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about I to about 6 carbon atoms in the chain. 20 Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents as described herein. Non-limiting examples of suitable alkyl groups include 25 methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkyl" includes "Alkylene" which refers to a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene (-CH 2 -) , ethylene (-CH 2
CH
2 -) and propylene (-C 3
H
6 -); which may be linear or branched. 30 "Heteroalkyl" means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of WO 2009/061596 PCT/US2008/080176 - 289 attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical. Suitable such heteroatoms include 0, S, (and S(O), S(0)2, etc.) and N. Non-limiting examples include ethers, thioethers, amines, 2 aminoethyl, 2-dimethylaminoethyl, and the like. 5 "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more 10 lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents as described herein. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3 15 methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to 20 about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted 25 or optionally substituted by one or more substituents as described herein. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. 30 Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring WO 2009/061596 PCT/US2008/080176 - 290 atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the 5 same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, 10 pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, 15 pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and 20 alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryi are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non 25 limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. 30 The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, WO 2009/061596 PCT/US2008/080176 - 291 cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. "Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an 5 alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantyimethyl and the like. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred 10 cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic 15 cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like. 20 "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Ring system substituent" means a substituent attached to a ring system (such as an aromatic, heteroaromatic, saturated or partially unsaturated alicyclic or heterocyclic ring systems) which, for example, replaces an available hydrogen 25 on a carbon atom or a heteroatom of the ring system. "Ring system substituents" may be referred to as such, or may be referred to as a variable or specific functional group or groups that are attached to a ring system. For example, when
R
2 in Formula (1) is -C(O)R' 7 and R 17 is a substituted heterocycloalkyl, the substituent attached to the heterocycloalkyl is a ring system substituent. If two or 30 more ring system substituents are present on a given ring, such multiple substituents may be attached to the same or different available ring carbon or heteroatom. Ring system substituents may be the same or different, and are as WO 2009/061596 PCT/US2008/080176 - 292 described herein. Other non-limiting examples of ring system substituents include alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, 5 aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH 2 , -C(=NH)-NH 2 , -C(=NH)-NH(alkyl), Y 1
Y
2 N-, Y 1
Y
2
N
alkyl-, Y1Y 2 NC(O)-, Y 1
Y
2 NS0 2 - and -SO 2
NY
1
Y
2 , wherein Y 1 and Y can be the same or different and are independently selected from the group consisting of 10 hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3
)
2 - and the like which form moieties such as, for example: po 150\ 00 15 0 and "Heteroarylalkyl" (or "heteroary-alkyl-") means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like. 20 "Heterocyclyl" (or "heterocycloalkyl") means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms 25 present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also 30 considered part of this invention. The heterocyclyl can be optionally substituted WO 2009/061596 PCT/US2008/080176 - 293 by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, 5 pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahyd rothiophenyl, azetidinyl, lactam, lactone, and the like, "Heterocyclyl" also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). An example of such moiety is pyrrolidone: H N 10 0. "Heterocyclylalkyl" (or "heterocycloalkylalkyl" or "heterocycloalkyl-alkyl-") means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls 15 include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" (or "heterocycloalkenyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or 20 sulfur atom, alone or in combination, and which contains at least one carbon carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom 25 respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
WO 2009/061596 PCT/US2008/080176 - 294 Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4 tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6 tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2 imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, 5 dihydrothiazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7 oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone: H N 10 0 "Heterocyclenylalkyl" (or "heterocycloalkenylalkyl" or "heterococloalkenyl-alkyl-") means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. 15 It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: 4 2 2 5 i CN H 20 there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: N0 NO H and N OH are considered equivalent in certain embodiments of this invention.
WO 2009/061596 PCT/US2008/080176 - 295 "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl, Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. 5 "Heteroaralkyl" means a heteroary-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. 10 "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is 15 through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl. 20 "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously 25 described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkyloxy" means an aralkyl-Q- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is 30 through the ether oxygen.
WO 2009/061596 PCT/US2008/080176 -296 "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously 5 described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. 10 "Alkylsilyl" means an alkyl-Si- group in which alkyl is as previously defined and the point of attachment to the parent moiety is on Si. Preferred alkylsilyls contain lower alkyl. An example of an alkylsilyl group is trimethylsilyl (-Si(CH 3
)
3 ). "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. 15 The bond to the parent moiety is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example 20 of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl. "Alkylsulfonyl" means an alkyl-S(0 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl The bond to the parent moiety is through the sulfonyl. 25 "Arylsulfonyl" means an aryl-S(0 2 )- group. The bond to the parent moiety is through the sulfonyl, The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is 30 not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable WO 2009/061596 PCT/US2008/080176 -297 structure", it is meant 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 "optionally substituted" means optional substitution with the 5 specified or implied groups, radicals or moieties. The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound 10 refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. It should also be noted that any carbon as well as heteroatom with 15 unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the 20 protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R , etc.) occurs more than one 25 time in any constituent or in any one of The invention, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified 30 ingredients in the specified amounts. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than WO 2009/061596 PCT/US2008/080176 - 298 one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain 5 fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also 10 intended to encompass the administration of the afore-said bulk composition and individual dosage units. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium 15 Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various 20 mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 25 1987. For example, if a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Cl 30 C 8 )alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- WO 2009/061596 PCT/US2008/080176 - 299 (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1 (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4 5 crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Cr-C 2 )alkylamino(C 2
-C
3 )alky (such as P-dimethylaminoethyl), carbamoyl-(C-C 2 )alkyl, N,N-di (C C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2 C 3 )alkyl, and the like. Similarly, if a compound of Formula (1) contains an alcohol functional 10 group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C-C6)alkanoyloxymethyl, 1 ((CI -Ce)alkanoyloxy)ethyl, 1-methyl-1-((C -C6)alkanoyloxy)ethyl, (Cl Ce)alkoxycarbonyloxymethyl, N-(Cr-C6)alkoxycarbonylaminomethyl, succinoyl, (C-Ce)alkanoyl, a-amino(C-C4)alkany, arylacyl and a-aminoacyl, or a 15 aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C)alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like. If a compound of Formula (1) incorporates an amine functional group, a 20 prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR' carbonyl where R and R' are each independently (C-Clo)alkyl,
(C
3
-C
7 ) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, C(OH)C(O)OY' wherein Y' is H, (C -C 6 )alkyl or benzyl, -C(OY2)Y 3 wherein Y 2 is 25 (C-C 4 ) alkyl and Y3 is (CI-C 6 )alkyl, carboxy (C-C 6 )alkyl, amino(C-C4)akyl or mono-N-or di-N,N-(C-Cs)alkylaminoalkyl, -C(Y4)Y 5 wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N,N-(C-C 6 )alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. One or more compounds of the invention may exist in unsolvated as well 30 as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of WO 2009/061596 PCT/US2008/080176 - 300 this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the 5 crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H20. One or more compounds of the invention may optionally be converted to a 10 solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., _5_(1, article 12 (2004); and A. L. 15 Bingham et a, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for 20 example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). The compounds of the invention can form salts which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The 25 term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of any one of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") 30 may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the The WO 2009/061596 PCT/US2008/080176 -301 invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. 5 Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, 10 thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; 15 S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. 20 Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be 25 quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. 30 All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are WO 2009/061596 PCT/US2008/080176 - 302 considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the compounds of the invention include the following groups: (1) carboxylic acid esters obtained by esterification 5 of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for 10 example, halogen, C1.
4 alkyl, or C1- 4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Cl 20 alcohol or reactive derivative thereof, or by a 2,3-di (Ce- 2 4)acyl 15 glycerol. Compounds of The invention, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. 20 The compounds of Formula (1) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (1) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. 25 For example, if a compound of Formula (1) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well 30 known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an WO 2009/061596 PCT/US2008/080176 - 303 appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (1) may be atropisomers 5 (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the 10 compounds are included in the invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on 15 various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the 20 cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other 25 selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the JUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive 30 compounds. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact WO 2009/061596 PCT/US2008/080176 - 304 that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and 5 chlorine, such as 2 H, 3 H, 13C, 14C, ' 5 N, 180, 170, 3 P, 32 p, aS, 8 F, and 36C1, respectively. Certain isotopically-labelled compounds of Formula (1) (e.g., those labeled with 3 H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14C) isotopes are particularly 10 preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula (1) can generally be 15 prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent. Polymorphic forms of the compounds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to 20 be included in the present invention. PREPARATIVE EXAMPLES Generally, the compounds of the invention can be prepared by a variety of methods well known to those skilled in the art, for example, by the methods as outlined in the general scheme below and in the examples that follow. The 25 examples should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. Available EC 5 0 values for the exemplified compounds appearing in the Table below are indicated according to the following ranges: 30 A-<500nM B - > 500 nM C - > 500 nM to < 1000 nM WO 2009/061596 PCT/US2008/080176 - 305 D - > 1000 nM The following abbreviations are used in the procedures and schemes: ACN Acetonitrile AcOH Acetic acid 5 Aq Aqueous BOC tert-Butoxycarbonyl BOC-ON [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile]
BOC
2 0 BOC Anhydride C degrees Celsius 10 Cpd Compound CBZCI Benzyl chloroformate DCM Dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropylazodicarboxylate 15 DIEA Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-N,N-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide 20 DMSO Dimethyl sulfoxide EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride El Electron ionization Eq Equivalents EtOAc Ethyl acetate 25 EtOH Ethanol 9 grams h. hours 'H proton HATU N,N,N',N'-Tetramethyl-O-(7-Azabenzotriazol-1-yl)Uronium 30 hexafluorophosphate Hex hexanes HOBT 1 -Hydroxybenzotriazole WO 2009/061596 PCT/US2008/080176 - 306 HPLC High pressure liquid chromatography KSP Kinesin spindle protein LAH Lithium aluminum hydride LDA Lithium diisopropylamide 5 LHMDS Lithium hexamethyldisilylamide M Molar mmol milimolar mCPBA meta-Chloroperoxybenzoic acid Me Methyl 10 MeCN Acetonitrile MeOH Methanol min Minutes mg Milligrams MHZ Megahertz 15 mL Milliliter MPLC Medium Pressure Liquid Chromatography NMR Nuclear Magnetic Resonance MS Mass Spectroscopy NBS N-Bromosuccinimide 20 NIS N-lodosuccinimide NMM N-Methylmorpholine NMP 1 -methyl-2-pyrrolidone ON Overnight PCC Pyridinium Chlorochromate 25 PTLC Preparative thin layer chromatography Pyr Pyridine RT Room temperature sgc Silica gel 60 chromatography tBOC tert-Butoxycarbonyl 30 TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran WO 2009/061596 PCT/US2008/080176 - 307 TLC Thin layer chromatography tR Retention time 5 EXAMPLES General Scheme 1: 'N
R
1 0 0 0 0 E Part A Part B Part C E AI E 3AjB AII B EA B Part D R 1 Part E R 1 O- I A - ~i A N-N N-N P ~R2 (9 10 General Scheme 2: 0 R7 R28 7 28 0 H i B Part A N + R Part B A E AI E EA IB + -lk Ak--- N-N (W),2 (W),) 15 Example 101: WO 2009/061596 PCT/US2008/080176 - 308 F 1 0 N Part A Part B Pan C IOlA 101B 101C 1OID Part D ) F Part E F 1 N-NH N-N to 101E 101 Part A: To a suspension of sodium hydride (800 mg, 20 mmol) in THF (30 mL) was 5 added a solution of triethyl phosphonoacetate (4 mL, 20 mmol) in THF (10 mL) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1 tetralone 101A (2.92 g, 20 mmol) in THF (10 mL) was added and the reaction mixture refluxed for 16 hours. The volatiles were removed in vacuo, the residue re-dissolved in DCM and washed with water. Drying over magnesium sulfate, 10 concentration and purification by flash silica chromatography, gradient elution (0 to 100 %) hexane /ethyl acetate afforded Z- and E-isomers of compound 101B (1.7 g, 7.83 mmol, 39 %). HPLC-MS tR = 1.97 - 2.12 min (UV 254 m); mass calculated for formula C 14
H
1 6 0 2 216.1, observed LCMS m/z 217.1 (M+H). 15 Part B: Isopropytmagnesium chloride (2M, 6.94 mL, 13.9 mmol) was added dropwise over 15 minutes to a stirred solution of NQ-dimethylhydroxylamine hydrochloride (677 mg, 6.94 mmol) and compound 101B (1.0 g, 4.63 mmol) in THF (20 mL) at 20 'C. The reaction mixture was aged to -10 0C, stirred for an additional 20 20 minutes and quenched with the addition of saturated ammonium chloride solution. Extraction with ethyl acetate, drying over magnesium sulfate, concentration and purification by flash silica chromatography, gradient elution (0 to 100 %) hexane /ethyl acetate afforded Z- and E-isomers of compound 101C WO 2009/061596 PCT/US2008/080176 - 309 (685 mg, 2.96 mmol, 64 %). HPLC-MS tR = 1.55 - 1.80 min (UV 254 am); mass calculated for formula C 14
H
17
NO
2 231.1, observed LCMS m/z 232.1 (M+H). Part C: 5 Isopropylmagnesium chloride (2M, 4.5 mL, 9.0 mmol) was added dropwise to a stirred solution of 2,5-difluoroiodomethane (1.1 mL, 9.0 mmol) in THF (20 mL) at 78 0C, The reaction mixture was aged to -40 0C and a solution of compound 101C (685 mg, 2.97 mmol) in THF (10 mL) added. Warming to room temperature and stirring for 16 hours resulted in the formation of compound 4 10 which was confirmed by LCMS analysis. The reaction mixture was quenched with the addition of saturated ammonium chloride solution, extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by flash silica chromatography, gradient elution (0 to 100 %) hexane /ethyl acetate to afford Z and E-isomers of compound 101D (481 mg, 1.69 mmol, 57 %). HPLC-MS tR = 15 2.4 - 2.6 min (UV 254 am); mass calculated for formula C, 81
-
4
F
2 0 284.1, observed LCMS m/z 285.1 (M+H). Part D: To a solution of compound 101D (100 mg, 0.35 mmol) in THF (2 mL) was added 20 hydrazine monohydrate (12 pL, 0.39 mmol) and the reaction mixture heated in a microwave at 150 0C for 20 minutes. The reaction mixture was concentrated and purified by flash silica chromatography, gradient elution (0 to 100 %) hexane /ethyl acetate to afford compound 101E (45 mg, 0.15 mmol, 43 %). HPLC-MS tR = 2.45 (UV 254 nm); mass calculated for formula C 18
H
1 2
F
2
N
2 298.1, observed LCMS 25 m/z 299.1 (M+H). Part E: A mixture of compound 101E (20 mg, 0.07 mmol), acetyl chloride (14 gL, 0.2 mmol) and potassium carbonate (14 mg, 0.1 mmol) in THF (2 mL) was stirred at 30 room temperature for 3 hours. Product formation was confirmed by LCMS analysis. The reaction mixture was quenched by the addition of 1 N HCI, WO 2009/061596 PCT/US2008/080176 -310 extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by prep.HPLC to afford compound 101 as an off white solid. The following compounds were synthesized using this procedure: 5 Cpd ID Structure Exact MS m/z tR EC50 mass (M*+H) (min) (nW) 101 N 304.2 305.1 4.24 D 0 F 102 340.1 341.1 4.33 D F NN 0 F 103 342.1 343.1 3.93 B F N 0 F 104 326.1 327.1 4.78 B F 0 105 312.1 313.1 4.53 D 106 276.1 277.1 4.26 D 0 WO 2009/061596 PCT/US2008/080176 -311 107 NH 341.1 342.1 3.04 A F Example 201: F N PartA O F o - 3 F o N-NH N-N N 101E 201B 0 R -N 201 5 NO 2 Part A: A mixture of compound 101E (120 mg, 0.4 mmol), 4-nitrophenyichloroformate (242 mg, 1.2 mmol) and potassium carbonate (83 mg, 0.6 mmol) in THF (10 mL) 10 was stirred at room temperature for 3 hours. Product formation was confirmed by LCMS analysis. The reaction mixture was quenched by the addition of saturated NaHCO 3 , extracted with ethyl acetate, dried over magnesium sulfate and concentrated to afford crude compound 201 B as an off white solid. HPLC-MS tR = 2.18 (UV 254 nm); mass calculated for formula C 24
H
17
F
2
N
3 0 5 465.1, observed 15 LCMS m/z 466.1 (M+H). Part B: To a solution of compound 201B (18 mg, 0.04 mmol) in DMF (1.5 mL) was added amine (0.49 mmol) and the reaction mixture heated in a microwave at 150 0 C for 20 5 minutes. The reaction mixture was concentrated and purified by prep.HPLC to afford compound 201 as an off white solid. The following compounds were synthesized using this procedure: WO 2009/061596 PCT/US2008/080176 -312 Cpd ID Structure Exact MS m/z tR EC50 Smass (M*+H) (min) (nM) nD 201 412.2 413.2 3.53 HN
N
/ 0 202 414.2 415.2 3.11 /-0 H D N 203 b 343.1 344.1 3,48 F NNN
H
2 N F D 204 F0- 440.2 441.2 3.24 FiN N D F N 205 >0 454.2 455.2 3.27 WO 2009/061596 PCT/US2008/080176 -313 F D 206 37.1 372.1 4.02 H N F D n\ 207 357.1 358.1 3.76 F N HN F D 0 F N-N 208 $0 456.2 457.2 3.12 N F D 0 209 F -N470.2 471.2 3.25 HN 0 F 1 210 F N- 428.2 429.2 3.24 HN
N/
WO 2009/061596 PCT/US2008/080176 -314 D 211 0 373.1 374.1 4.18 F N HN OH Example 3: ,F -F F a A F I A F Part A N-N N-N
(R
3 ),R'Z JL (n 3 ), 5 11 Part A: A mixture of compound 10 (0.1 mmol), acid chloride (0.12 mmol) and DIEA (0.2 mmol) in THF (2 mL) is stirred at room temperature for 16 hours. Product 10 formation is confirmed by LCMS analysis. The reaction mixture is concentrated and purified by prep.HPLC to afford compound 11 as a white solid. The following compounds were synthesized using this procedure: Cpd io Structure Exact MS m/z tR EC50 _ mass M*+H) (min) (nM) | 301 381.1 302 385.2 WO 2009/061596 PCT/US2008/080176 -315 303 384.2 304 365.1 F 305 369.2 F 306 351.1 N 307 355.1 Example 401: FF Part APart a F at 101A 401 B 401C 41 NN r F Part AF P P F Part F 0 Oa O N N1 P N40 N 4010 [01 40 C0 H WO 2009/061596 PCT/US2008/080176 -316 Part A: The reaction mixture of 1-tetralone (101A, 1.33 mL, 10 mmol), allyl alcohol (3.4 mL, 50 mmol), 2,2-dimethoxypropane (1.84 mL, 15 mmol)., p-toluenesulfonic acid 5 (345 mg, 2 mmol) and 3 A molecular sieves (3 g) in toluene (15 mL) sealed in a schlenk tube was put into a 200 2C oil bath. The reaction mixture was stirred for 15 hours at 200 2C, and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was concentrated. The residue was purified by column chromatography using an eluant of 20% DCM in hexane to 10 give compound 401B as pale yellow oil (774 mg, 42% yield). 'H NMR (400 MHz, CDCis) 6 8.04 (dd, J = 1.2, 7.6 Hz, 1 H), 7.46 (dt, J = 1.6, 7.6 Hz, 1 H), 7.30 (tt, J = 0.8, 7.6 Hz, IH), 7.23 (d, J= 8.0, 1H), 5.92-5.78 (m, 1H), 5.14-5.04 (m, 2H), 2.99 (dd, J= 4.8, 7.6 Hz, 2H), 2.80-2.72 (m, 1H), 2.60-2.50 (m, 1H), 2.32-2.20 (m, 2H), 1.92-1.80 (m, 1H). 15 Part B: A reaction mixture of compound 401 B (46 mg, 0.25 mmol), 2-ethynyl-1,4 difluorobenzene (34 mg, 0.25 mmol) and sodium t-butoxide (38 mg, 0.4 mmol) was stirred in t-butanol (1 mL). Column chromatography using an eluant of 10% 20 EtOAc in hexane gave compound 401C (13 mg, 16% yield). HPLC-MS RT= 2.54 min, mass calculated for formula C 21
H
18
F
2 0 324.1, observed LCMS m/z 325.1 (M+H). Part C: 25 To the solution of compound 401C (13 mg) in dioxane (0.2 mL) and water (50 uL) was added sulfuric acid (50 uL) while stirring. The reaction mixture was stirred in microwave at 150 2C for 15 minutes. The reaction mixture was concentrated. Column chromatography using an eluant of 20% EtOAc in hexane gave compound 401 D. HPLC-MS RT= 2.51 min, mass calculated for formula 30 C 21
H,
8
F
2 0 324.1, observed LCMS m/z 325.1 (M+H). Part D: WO 2009/061596 PCT/US2008/080176 -317 A reaction mixture of compound 401 D obtained from Part C and hydrazine monohydrate (0.1 mL) in acetic acid (0.5 mL) was stirred in microwave at 160 2 C for 15 min. Purification using reverse phase HPLC gave compound 401 as a HCI salt after lyophilization. HPLC-MS RT= 6,54 min, mass calculated for formula 5 C 23
H
22
F
2
N
2 0 380.17, observed LCMS m/z 381.28 (M+H). Part E: To the solution of compound 401 in THF (0.2 mL) obtained from Part D was added the solution of 9-BBN in THF (0.2 mL, 0.5 M). The reaction mixture was 10 stirred at room temperature for 2 hours. Then, aqueous NaOH solution (1 mL, 1 M) and aqueous hydrogen peroxide solution (1 mL, 30%) were added. The reaction mixture was stirred at room temperature for 1 hour. Purification using reverse phase HPLC gave compound 402 as an HCl salt after lyophilization. HPLC-MS RT= 5.66 min, mass calculated for formula C 23
H
24
F
2
N
2 0 2 398.18, 15 observed LCMS m/z 399.29 (M+H). Part F: To the solution of compound 402 obtained from Part E and 2,6-lutidine (8.1 1 iL, 0.07 mmol) in DCM (0.5 mL) was added triflic anhydride (8.4 pL, 0.05 mmol). The 20 reaction mixture was stirred at room temperature for 2 hours. Then, ammonia in dioxane (0.5 M, 3 mL) was added. The reaction mixture was sealed in a schlenk tube and stirred at 58 *C for overnight. Purification using reverse phase HPLC gave compound 403 as an HCI salt after lyophilization. HPLC-MS RT= 3.89 min, mass calculated for formula C 23
H
25
F
2
N
3 0 397.20, observed LCMS m/z 398.23 25 (M+H). The following compounds were synthesized using this procedure: WO 2009/061596 PCT/US2008/080176 - 318 Cpd I [Structure Exact MS m/z tR (min) EC50 Mass TM+Hm (nM) FD 401 380.17 381.28 6.54 FN F E 402 F 398 18 399.29 5.66 0 OH F I \ F D 403 4 N-N 397.20 398.23 3.89 01
NH
2 F ' 0 404 F" N-N 400.16 401.27 4.46D OH F F IN F N 0 Example 501: WO 2009/061596 PCT/US2008/080176 -:319 F FF P Pa A rt E a F N Fart N N
~
N "N H N 0Hz 0HZH 501A 01B 501C 501 FN - F FF jN Part : NH NF N-NH -F N-N N H/ Sl 501IF 501 Part A: To the solution of 2,3-dihydro-1H-quinolin-4-one (501A, 1 g, 6.8 mmol) and DIEA 5 (4.7 mL, 27 mmol) in DCM (30 mL) was added benzyl chloroformate (2.8 mL, 20 mmol).The reaction mixture was stirred at room temperature for overnight, and then concentrated. The residue was purified by column chromatography. Elution using 20% EtOAc in hexane gave compound 501B (1.585 g, 83% yield) as a yellow solid. 'H NMR (400 MHz, CDCl 3 ) 6 8.00 (dd, J= 1.2, 8.0 Hz, 1 H), 7.81 (d, 10 J= 8.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.44-7.32 (m, 5H), 7.21-7.16 (m, 1 H), 5.29 (s, 2H), 4.23 (t, J= 6.4, 2H), 2.81-2.76 (m, 2H). Part B: The reaction mixture of compound 501 B (1.4 g, 5 mmol), allyl alcohol (1.7 mL, 25 15 mmol), 2,2-dimethoxypropane (0.922 mL, 7.5 mmol), p-toluenesulfonic acid (172 mg, 1 mmol) and 3 A molecular sieves (1.5 g) in xylenes (5 mL) was loaded into a schlenk tube. The schlenk tube was sealed and put into a 200 *C oil bath. The reaction mixture was stirred for 15 hours at 200 *C, and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was 20 concentrated. The residue was purified by column chromatography. Elution using 12% EtOAc in hexane gave compound 501C as pale yellow oil (1.0 g, 62% yield). 'H NMR (400 MHz, CDC1 3 ) S 8.04-7.98 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.53 7.47 (m, 1H), 7.44-7.32 (m, 5H), 7.21-7.15 (m, 1H), 5.86-5.72 (m, 1H), 5.31 (d, J = 12 Hz, 1H), 5.26 (d, J= 12.4 Hz, 1H), 5.08 (d, J= 16.4 Hz, 1H), 5.07 (d, J= WO 2009/061596 PCT/US2008/080176 - 320 10.8 Hz, 1 H), 4.37 (dd, J= 4.0, 13.6 Hz, 1 H), 3.85 (dd, J = 9.2, 13.6 Hz, 1 H), 2.76-2.60 (m, 2H), 2.30-2,20 (m, 1H). 5 Part C: To the solution of compound 501C (64.2 mg, 0.2 mmol) and ((2,5 difluorophenyl)ethynyl)trimethylsilane (84 mg, 0.4 mmol) in THF (0.4 mL) was added a solution of TBAF in THF (0.5 mL, 1.0 M). The reaction mixture was stirred in microwave at 130 9 C for 30 minutes. The reaction mixture was 10 quenched using aqueous NaHCO 3 solution. The organics were extracted with EtOAc. The EtOAc solution was concentrated to give compound 501 D. HPLC-MS RT= 2.10 min, mass calculated for formula C2 0
H
17
F
2 NO 325.1, observed LCMS m/z 326.1 (M+H). 15 Part D: To the solution of compound 501D in dioxane (0.5 mL) and water (100 uL) was added sulfuric acid (100 uL) while stirring. The reaction mixture was stirred in microwave at 150 2 C for 30 minutes. The reaction mixture was quenched using aqueous NaHCO 3 solution. The 20 organics were extracted with EtOAc. The EtOAc solution was concentrated. The residue was purified by flash chromatography using eluant of 25% EtOAc in hexane to give compound 501E. HPLC-MS RT= 2.02 - 2.34 min, mass calculated for formula C 20
H
17
F
2 NO 325.1, observed LCMS m/z 326.1 (M+H). 25 Part E: A reaction mixture of compound 501E obtained from Part D, DIEA (30 uL) and hydrazine monohydrochloride (10 mg) in EtOH (0.2 mL) was stirred in microwave at 140 *C for 40 min. The reaction mixture was quenched using aqueous 30 NaHCO 3 solution. The organics were extracted with EtOAc. The EtOAc solution was concentrated to give compound 501 F. HPLC-MS RT= 1.22 - 1.33 min, mass calculated for formula C 2 0
H
1 9
F
2
N
3 339.1, observed LCMS m/z 340.1 (M+H).
WO 2009/061596 PCT/US2008/080176 -321 Part F: To the solution of compound 501 F in dioxane was added acetyl chloride (10 mg). The reaction mixture was stirred, and then concentrated. Purification using reverse phase HPLC gave compound 501 as an HCI salt after lyophilization. 5 H PLC-MS RT= 3.62 min, mass calculated for formula C 22
H
21
F
2
N
3 0 381.17, observed LCMS m/z 382.29 (M+H). Example 601: N N H A Part B N> NA Cbz Cbz Cbz 501B 6016 601C O pn n N N. N Pr C jN PartS Bn Cbz Cbz 6010 601E H H Sn F 8n H Part E H ParF FF F 601lF 601 601H F NH F /F I 1F N'N,- N-Cbz F HN N SN BH B Part F Car Bn F 1 F 10 ~601H G601H1 10 601E FS60 H 6011 Bn--NBn 601 Hg N Part A: The reaction mixture of compound 501B (1.4 g, 5 mmol), allyl alcohol (1.7 mL, 25 15 mmol), 2,2-dimethoxypropane (0.922 mL, 7.5 mmol), p-toluenesulfonic acid (172 mg, 1 mmol) and 3 A molecular sieves (1.5 g) in xylenes (5 mL) was loaded into a schlenk tube. The schlenk tube was sealed and put into a 200 9C oil bath. The reaction mixture was stirred for 15 hours at 200 9C, and then cooled to room temperature. The reaction mixture was filtered through celite. The filtrate was 20 concentrated. The residue was purified by column chromatography. Elution using WO 2009/061596 PCT/US2008/080176 - 322 12% EtOAc in hexane gave compound 601 B as pale yellow oil (1.0 g, 62% yield). 'H NMR (400 MHz, CDC1 3 ) 6 8.04-7.98 (m, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.53 7.47 (m, 1H), 7.44-7.32 (m, 5H), 7.21-7.15 (m, 1H), 5.86-5.72 (m, 1H), 5.31 (d, J = 12 Hz, 1H), 5.26 (d, J= 12.4 Hz, 1H), 5.12-5.04 (m, 2H), 4.37 (dd, J= 4.0, 13.6 5 Hz, 1H), 3.85 (dd, J= 9.2, 13.6 Hz, 1H), 2.76-2.60 (m, 2H), 2.30-2.20 (m, 1H). Part B: Ozone was bubbled into the solution of compound 601 B (94.5 mg, 0.3 mmol) in 10 DCM (5 mL) at -78 9C for 15 minutes. Triphenylphosphine (262 mg, 1 mmol) was then added to solution. The reaction mixture was allowed to warm to room temperature while stirring for 3 hours. The reaction mixture was concentrated. The residue was purified by flash chromatography using an eluant of 20% EtOAc in hexane to give compound 601C (74 mg, 76% yield). 'H NMFR (400 MHz, 15 CDCl 3 ) " 9.80 (s, 1H), 7.99 (dd, J= 1.6, 7.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.55-7.49 (m, 1H), 7.44-7.32 (m, 5H), 7.19 (dt, J= 1.2, 7.6 Hz, 1H), 5.29 (s, 2H), 4.58 (dd, J = 4.8, 13.6 Hz, 1 H), 3.74 (dd, J = 11.2, 13.2 Hz, 1 H), 3.34-3.26 (m, 1H), 2.99 (ddd, J= 0.8, 5.2, 18.4 Hz, 1H), 2.66 (dd, J= 7.2, 18.4 Hz, 1H). 20 Part C: To the mixture of compound 601C (780 mg, 2.4 mmol) and powdered 4 A molecular sieves (2.77 g) in chloroform (11 mL) was added dibenzylamine (553 L, 2.88 mmol) at 0 2C. The reaction mixture was stirred at 0 9 C for 2 hours, and 25 then filtered to remove molecular sieves. To the filtrate solution in chloroform was added sodium triacetoxyborohydride (610 mg, 2.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with aqueous HCI solution (1 M). The mixture was then basified with aqueous NaOH solution. The organics were extracted with DCM. The organic 30 layers were combined and concentrated. The residue was purified by flash chromatography using an eluant of 10% EtOAc in hexane to give compound 601D (800 mg, 66% yield) in a yellowish gel. 'H NMR (400 MHz, CDCI 3 ) 7.97 WO 2009/061596 PCT/US2008/080176 - 323 (dd, J= 1.6, 8.0 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.40-7.12 (m, 16H), 5.24 (d, J= 12 Hz, 1H), 5.18 (d, J= 12.4 Hz, 1H), 4.03 (dd, J= 4.0, 14 Hz, 1H), 3.65 (d, J = 13.2 Hz, 2H), 3.63 (dd, J= 8.4, 13.6 Hz, 1H), 3.42 (d, J= 13.2 Hz, 5 2H), 2.84-2.72 (m, 1H), 2.61-2.45 (m, 2H), 2.08-1.98 (m, 1H), 1.64-1.52 (m, 1H). Part D: To a flask containing compound 601D (75.6 mg, 0.15 mmol) was added Petasis reagent in toluene (5% wt, 3 mL, 0.75 mmol) under an atmosphere of argon. The 10 reaction mixture was stirred in toluene in dark at 70 *C for 4 hours. Reaction mixture was quenched with a mixture of EtOAc and acetone (1:1), and then concentrated. The residue was purified by flash chromatography using an eluant of 10% EtOAc in hexane to give compound 601 E (66.2 mg, 88% yield) in a white solid. 'H NMR (400 MHz, CDCI 3 ) 7.66 (d, J = 8.0 Hz, 1 H), 7.50 (dd, J 1.6, 8.4 15 Hz, 1H), 7.31-7.10 (m, 16H), 6.99-6.93 (m, 1H), 5.38 (s, 1H), 5.12 (d, Jr 12.4 Hz, 1H), 5.06 (d, J= 12.8 Hz, 1H), 4.60 (s, 1H), 3.82 (dd, J= 4.0, 13.2 Hz, 1H), 3.48 (d, J= 13.6 Hz, 2H), 3.36 (d, J= 13.6 Hz, 2H), 3.28 (dd, J= 3.2, 13.2 Hz, 1H), 2.72-2.64 (m, 1H), 2.45-2.32 (m, 2H), 1.54-1.46 (m, 2H). 20 Part E: A mixture of benzylhydrazine monohydrochloride (0.8 g, 5 mmol) and sodium hydroxide (0.6 g, 15 mmol) in THF (5 mL) was stirred at room temperature for overnight. The reaction mixture was filtered. To the filtrate was added 2,5 difluorobenzaldehyde (601 F, 0.71 g, 5 mmol). The reaction mixture was stirred at 25 room temperature for overnight, and then concentrated to give compound 601G. HPLC-MS RT= 2.23 min, mass calculated for formula C1 4
H,
2
F
2
N
2 246.1, observed LCMS m/z 247.2 (M+H). 30 Part F: To the solution of compound 601G (615 mg, 2.5 mmol) in EtOAc (5 mL) was added N-chlorosuccinimide (334 mg, 2.5 mmol). The reaction mixture was stirred WO 2009/061596 PCT/US2008/080176 - 324 at 60 2C for 3 hours, and then concentrated. The residue was purified by flash chromatography using an eluant of 10% EtOAc in hexane to give compound 601H (460 mg, 66% yield) in a yellow solid. 'H NMR (400 MHz, CDCh3) K 7.40 7.28 (m, 6H), 7.10-6.95 (m, 2H), 6.31 (br s, 1H), 4.57 (s, 2H). 5 Part G: To the solution of compound 601 E (20 mg, 0.04 mmol) and 601 H (11.2 mg, 0.04 mmol) in chloroform (1 mL) was added triethylamine (27.8 EL, 0.2 mmol). The reaction mixture was stirred at 60 2C for overnight, and then concentrated. The 10 residue was purified by flash chromatography using an eluant of 10% EtOAc in hexane to give compound 6011 (15 mg, 50% yield). HPLC-MS RT = 2.37 min, mass calculated for formula C4 8
H
44
F
2
N
4 0 2 746.3, observed LCMS m/z 747.2 (M+H). 15 Part H: The solution of compound 6011 (15 mg, 0.02 mmol) in MeOH/EtOAc (4 mL, 1/1) was passed through a cartridge of 10% palladium on carbon in the H-cube at the temperature of 40 2 C and H 2 pressure of 40 bar with the flow rate of 0.4 mL/min. Purification using reverse phase HPLC gave compound 601 as a HCI salt after 20 lyophilization. HPLC-MS RT= 4.60 min, mass calculated for formula C 26
H
2 6
F
2
N
4 432.21, observed LCMS m/z 433.22 (M+H). The following compounds were synthesized using this procedure: Cpd ID Structure Exact MS m/z tR (min) C50 ctr _mass (Mt+H) (nM) F NH D 601 F N\-N 432.21 433.22 4.60 H 25 Example 701: WO 2009/061596 PCT/US2008/080176 - 325 0F \/ F Part A Part B -N C1 N Bn C NBn N En 701A 701B . NBn 701 Part A: 5 Wittig Salt (methyltriphenylphosphonium bromide, 2.0 equiv, 0.420 mmol, 150 mg) was weighed into a round bottom flask fitted with a stir bar. The flask was evacuated, purged with N 2 (g) and sealed with a septum. Dry THF (2 mL) was added and the solution was cooled to -78 'C, then LiHMDS (2.0 equiv, 0.420 mmol, 420 IL) was added. The ice bath was removed and the reaction was 10 allowed to warm for 15 min (to approx. -25 C). The reaction vessel was again cooled to -78 *C and a solution of commercially available 2-benzyl-2,3 dihydroisoquinolin-4(1 H)-one (701A, 1.0 equiv, 0.210 mmol, 50 mg in 2 mL of THF) was added. The reaction was allowed to proceed with warming for 15 h. After which time the reaction was quenched with MeOH, concentrated under 15 reduced pressure and purified by gradient eluent of hexanes/EtOAc on silica gel to afford compound 701 B (18 mg, 36% yield). HPLC-MS RT = 1.034 min (5 min method), mass calculated for formula C 1 7
H
17 N 235.14, observed LCMS m/z 236.20 (M+H). 'H NMR (400 MHz, DMSO) 6 7.63 (1H, m), 7.42-7.20 (6H, m), 6.96 (1 H, m), 6.76 (1 H, d), 5.56 (1H, s), 4.90 (1 H, s), 3.68 (2H, s), 3.62 (2H, s), 20 3.64 (2H, s). Part B: 2-Benzyl-4-methylene-1,2,3,4-tetrahydroisoquinoline (Compound 701B, 1.0 equiv, 0.076 mmol, 18 mg) and (Z)-A-benzyl-2,5-difluorobenzohydrazonoyl 25 chloride (601H, 43 mg, 0.153 mmol, 2.0 equiv) were weighed into a 20 mL vial and dissolved in dry CHCis (1 mL). Triethylamine (5.0 equiv, 0.380 mmol, 50tL) was added, the vial was purged with N 2 (g), sealed with a cap and heated to 70 "C for 18 h. After which time all volatiles were removed under reduced pressure WO 2009/061596 PCT/US2008/080176 - 326 and the residue was dissolved in DMSO/acetonitrile (3:1). The residue was purified using reverse phase HPLC to provide product 701. HPLC-MS RT = 5.801 min (10 min method), mass calculated for formula C1 H 2 7
F
2
N
3 479.2175, observed LCMS m/z 480.2749 (M+H). 5 The pharmacological properties of the compounds of this invention, including their efficacy as inhibitors of KSP activity, may be confirmed by a number of pharmacological assays. The inhibitory activity of the compounds of the invention towards KSP may be assayed by methods known in the art, for 10 example, by using the methods as described below and in the examples above. KSP Biochemical assay KSP biochemical enzyme assays were performed in 384-well plates. All reagents were thawed on ice. Compounds were diluted in 100% DMSO to desirable 15 concentrations. 10 mg microtubules (Cytoskeleton) were reconstituted in 10 mL tubulin buffer (80 mM PIPES pH 6.8, 1 mM EGTA, 1 mM MgC 2 , 0.005% sodium azide) plus 100 ul 2mM paclitaxel (Cytoskeleton). Each reaction consisted of 10 nM KSP motor domain (amino acid 15-368), 20 uM 20 paclitaxel (Cytoskeleton), 0.18 uM microtubules, 100 uM ATP (Roche) and kinesin buffer (20 mM ACES pH 7.0, 1 mM EGTA, 1 mM MgC 2 , 25 mM KCI, 1 mM DTT). For each reaction, 19 uL of mixture containing KSP motor domain, paclitaxel, microtubules and kinesin buffer were combined with 1 uL diluted compound. The reaction was started by the addition of 5 uL ATP. The reaction 25 was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 50 ul Biomol Green (Biomol International). After an additional 30 minutes, absorbance at OD620 nm was measured using an Envision. IC50 Determinations: Dose-response curves were plotted from inhibition 30 data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against enzyme activity (OD reading). To generate IC50 values, the dose-response curves were then WO 2009/061596 PCT/US2008/080176 - 327 fitted to a standard sigmoidal curve and IC50 values were derived by nonlinear regression analysis. KSP Cellular assay: 5 HCT1 16 colon cancer cells were grown in DMEM:F12 media with 10% heat inactivated FBS at 37 degrees with 5% C02. Cells were plated at 7,500 cells per well in PDL coated 384-well tissue culture plates. 6 hours later media was removed and new media containing drug was added. Cells were incubated with drug for 16 hours. All further steps were performed at room temperature in 10 the dark. Cells were fixed with 25 ul/well Prefer fixation solution plus 250 nM Hoechst dye and incubated for 30 minutes. The fixation solution was removed and cells were washed with PBS. Cells were then permeabilized with 25 ul/well 0.2% Triton-X in PBS and incubated for 10 minutes. Cells were washed with PBS and then incubated with 25 ul/well PBS containing 3% FBS for 30 minutes. 15 Cells were then stained overnight at 4 degrees with 25 ul/well antibody solution in PBS plus 3% FBS. Antibodies used were Phos-Histone H3 (serlo)-Alexa Flur 488 Conjugate and Phos-MPM2 Texas Red Conjugate. Cells were washed with PBS and then immunofluorescence images captured with HT Pathway microscope. The percent of cells staining positive was calculated and EC 5 o 20 values for the compounds of the invention that were tested were determined using Excel XLfit. EC50 Determinations: Dose-response curves were plotted from inhibition data generated each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against enzyme 25 activity (OD reading). To generate EC50 values, the dose-response curves were then fitted to a standard sigmoidal curve and EC50 values were derived by nonlinear regression analysis. Exemplary compounds of the invention that were tested in the above cellular assays exhibited ECO values reported as ranges in the Tables above.
WO 2009/061596 PCT/US2008/080176 - 328 Methods of Use As inhibitors of KSP activity, the compounds of the invention are contemplated as being useful in treating a wide variety of diseases, conditions, or disorders ("diseases"). 5 In one embodiment, the present invention provides a method of inhibiting KSP kinesin activity in a subject (e.g., cells, animals, or humans) in need thereof, comprising administering to said subject at least one compound or composition of the invention or a pharmaceutically acceptable salt, ester, isomer, tautomer, or prodrug thereof. 10 In one embodiment, the present invention provides a method of selectively inhibiting KSP kinesin activity in a subject (e.g., cells, animals, or humans) in need thereof, comprising administering to said subject at least one compound or composition of the invention or a pharmaceutically acceptable salt, ester, isomer, tautomer, or prodrug thereof. 15 In some embodiments, diseases which are amenable to treatment include those susceptible to alteration of mitosis by KSP activity inhibition. As will be appreciated by those skilled in the art, mitosis may be altered in a variety of ways, such as by increasing or decreasing the activity of a component in the mitotic pathway or by disturbing equilibrium (e.g., by inhibiting or activating 20 certain components). In one embodiment, the invention provides a method of treating or preventing a disease associated with KSP activity in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable salt or ester thereof 25 to said subject. In one embodiment, the compounds of the invention can be used to inhibit mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis. "Inhibit" in this context means decreasing or interfering with mitotic spindle formation or causing mitotic spindle dysfunction. "Mitotic spindle formation" 30 means the organization of microtubules into bipolar structures by mitotic kinesins. "Mitotic spindle dysfunction" means mitotic arrest and monopolar spindle formation.
WO 2009/061596 PCT/US2008/080176 -329 In one embodiment, the compounds of the invention can be useful for binding to, and/or inhibiting the activity of, KSP. In one embodiment, the KSP is human KSP. In one embodiment, such KSP activity is inhibited in vitro, in vivo (e.g., in a patient in need thereof), or ex vivo. 5 In other embodiments, the compounds of the invention may be used to bind to or inhibit the activity of KSP kinesins from non-human organisms. In this context, "inhibit" means increasing or decreasing spindle pole separation, causing malformation, i.e., splaying, of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle. 10 Also included within the definition of KSP for purposes of the present invention are variants and/or fragments of KSP (see, e.g., U.S. patent 6,437,115). The compounds of the invention can be used to treat diseases associated with or caused by aberrant cellular proliferation. Such disease states include, but are not limited to, cancer (further discussed below), hyperplasia, cardiac 15 hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, cellular proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like. Treatment includes inhibiting cellular proliferation. It is appreciated that in some cases the cells may not be in an 20 abnormally proliferative state and yet require treatment. For example, during wound healing, the cells may be proliferating "normally", but inhibition of cellular proliferation may be desired. Thus, in one embodiment, the invention herein includes application to cells or subjects afflicted with or subject to impending affliction with any one of these conditions, disorders or states. 25 The terms "treating cancer" and "treatment of cancer" refer to administration to a mammal afflicted with a cancerous condition and to an effect that alleviates the cancerous condition by killing at least some of the cancerous cells, and also to an effect that results in the inhibition of growth and/or metastasis of the cancer. 30 Due to their KSP inhibitory action, the compounds, compositions and methods provided herein are useful for the treatment of a wide variety of cancers. Non-limiting examples of such cancers include solid tumors and hematological WO 2009/061596 PCT/US2008/080176 - 330 cancers, such as those of the skin, breast, brain, colon, gall bladder, thyroid, cervical carcinomas, testicles, and blood. Additional non-limiting examples of cancers suitable for treatment include: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, 5 liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; 10 Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, 15 fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate 20 (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; 25 Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; 30 Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma WO 2009/061596 PCT/US2008/080176 - 331 (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, 5 pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, 10 squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), 15 Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, 20 dermatofibroma, keloids, psoriasis; Adrenal lands: neuroblastoma; and Other tumors: including xenoderoma pigmentosum, keratoctanthoma and thyroid follicular cancer. As used herein, treatment of cancer includes treatment of cancerous cells, 25 including cells afflicted by any one of the conditions, states, or disorders described above. The compounds of the present invention may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event 30 or by blocking the progression of pre-malignant cells that have already suffered an insult. The compounds of the present invention may also be useful in inhibiting cancer relapse.
WO 2009/061596 PCT/US2008/080176 - 332 The compounds of the present invention may also be useful in inhibiting tumor angiogenesis and metastasis. The compounds of the present invention may also be useful as antifungal agents, by modulating the activity of the fungal members of the bimC kinesin 5 subgroup, as is described in U.S. Patent 6,284,480. For each of the foregoing embodiments, the amount of the at least one compound of the invention administered is preferably an effective amount for the intended purpose. The phrase "effective amount" means that amount of a 10 compound of the invention, and other pharmacological or therapeutic agents described herein, that will elicit a biological or medical response of a tissue, a cell, a population of cells (e.g., a population of aberrantly proliferating cells such as cancer cells or psioratic cells), a system, or a subject (e.g., animal or human) that is being sought by the administrator (such as a researcher, doctor or 15 veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more cellular proliferation diseases. "Therapeutically effective amount" means effective amount where the purpose includes a therapeutic purpose, such as in a human or non-human patient in need of treatment. The formulations or 20 compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the targeted population of aberrantly proliferating cells or the body of the subject being treated. Suitable dosage ranges for the various embodiments of the invention are 25 readily determined by those skilled in the art and depend upon intended use. Suitable dose ranges include from about 0.001 to about 500 mg/kg of body weight/day of a compound of the invention or a pharmaceutically acceptable salt, ester, or prodrug (etc.) thereof. Another suitable dosage ranges from about 0.01 to about 25 mg/kg of body weight/day. For administration of pharmaceutically 30 acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.
WO 2009/061596 PCT/US2008/080176 - 333 It may be preferable to administer KSP kinesin inhibitors which can specifically inhibit KSP kinesin activity at low concentrations, for example, those that cause a level of inhibition of 50% or greater at a concentration of 50pM or less, 100 nM or less, or 50 nM or less. The administration of such compounds of 5 the invention represents various embodiments of the present invention. Compositions In some embodiments, the at least one compound of the invention is administered as the neat chemical. In other embodiments, the compounds of the invention are administered as a pharmaceutical composition, Thus, 10 pharmaceutical compositions comprising at least one compound of the invention are within the scope of the present invention. Such pharmaceutical compositions of the present invention comprise at least one compound of the invention (e.g., doses of one, two, three, or more different compounds of the invention), together with one or more acceptable carriers, and optionally other therapeutic agents. 15 Each carrier (including, e.g., adjuvants or vehicles) must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the intended purpose or, in the case of therapy, the subject being treated. Accordingly, in another embodiment, this invention also provides pharmaceutical compositions comprising at least one compound of the invention, 20 or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof and at least one pharmaceutically acceptable carrier. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, 25 dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. 30 Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's WO 2009/061596 PCT/US2008/080176 - 334 Pharmaceutical Sciences, 18 ' Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. The term pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one 5 (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". 10 The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a subject by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and 15 individual dosage units. Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing 20 layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for 25 parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically 30 acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or WO 2009/061596 PCT/US2008/080176 - 335 parenteral (e.g., subcutaneous, intramuscular, introrbital, intracapsular, intraspinal, intrasternal, intravenous, etc.) administration, Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. 5 The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. In one embodiment, the at least one compound or composition of the invention is formulated for subcutaneous administration. 10 In one embodiment, the at least one compound or composition of the invention is formulated for oral administration. In one embodiment, the at least one compound or composition of the invention is formulated for parenteral administration. In one embodiment, the at least one compound or composition of the 15 invention is formulated for intravenous administration. In one embodiment, the pharmaceutical preparation is provided in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. 20 As stated elsewhere herein, the quantity of active compound in a unit dose of preparation may be varied or adjusted to suit intended purpose. Additional non-limiting examples of such doses range from about 1 mg to about 100 mg, alternatively from about 1 mg to about 50 mg, or alternatively from about 1 mg to about 25 mg, according to the particular application. 25 The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. 30 The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts or esters thereof will be regulated according to the judgment of the attending clinician considering such WO 2009/061596 PCT/US2008/080176 - 336 factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses. 5 In another embodiment, the present invention provides a kit comprising a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle, and, optionally, inserts and/or labels which include instructions for use. 10 In another embodiment, the present invention provides a kit comprising an amount of at least one compound of the invention or a pharmaceutically acceptable salt or ester thereof and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect. 15 In another embodiment, the present invention provides for: the use of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to manufacture a medicament for inhibiting KSP kinesin activity in a subject in need thereof. In another embodiment, the present invention provides for: the use of at 20 least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, to manufacture a medicament for treating one or more diseases by inhibiting KSP kinesin activity in a patient in need thereof. In another embodiment, the present invention provides for: the use of at least one compound of the invention, or a pharmaceutically acceptable salt, 25 solvate, ester or prodrug thereof, to manufacture a medicament for treating any one of the conditions, disease, or disorders described herein. In another embodiment, the present invention provides for: the use of a combination comprising (i) at least one compound of the invention, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and (ii) at 30 least one second active ingredient described herein.
WO 2009/061596 PCT/US2008/080176 - 337 Combination Therapies The compounds of the invention (and the compositions comprising at least one compound of the invention) are also useful in combination with one or more therapeutic agents other than a compound of the invention. Such therapeutic 5 agents are selected according to intended purpose. Non-limiting examples of such agents include those which are effective for treating the underlying disease or condition, and/or for minimizing one or more side effects of a therapeutic agent, and/or for enhancing or altering the bioavailability of an administered therapeutic agent, etc. 10 Combinations of the compounds of the invention with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Non-limiting examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the 15 art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer (or other indication) involved. The following description provides additional non-limiting examples of such combination agents. Those of ordinary skill in the art will readily be able to determine additional suitable agents. 20 Thus, anti-cancer agents suitable for use in combination with at least one compound of the invention (or composition comprising at least one compound of the invention) include, but are not limited to the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase 25 inhibitors, antisense RNA and DNA oligonucleotides, antimetabolites, antibodies coupled to cyctotoxic agents or radioisotypes, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, and MDR inhibitors. Additional anticancer agents also include hypoxia 30 activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, and interferons (e.g., alpha interferon). Such anti-cancer agents can be small molecules or biologics (e.g., WO 2009/061596 PCT/US2008/080176 -338 RNA antisense and antibodies). The compounds of the invention are also useful when co-administered with radiation therapy. "Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. 5 Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LYl 17081, toremifene, fulvestrant, 4 [7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1 -piperidinyl)ethoxylphenyl]-2H-1 benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone 2,4-dinitrophenyl-ydrazone, aid SH646. Additional examples include anastrozole 10 and letrazole. "Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5a reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and 15 abiraterone acetate. "Retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13 cis-retinoic acid, 9-cis-retinoic acid, a difluoromethylornithine, ILX23-7553, trans 20 N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide. Examples of cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide
(TEMODAR
TM from Schering-Plough Corporation, Kenilworth, New 25 Jersey), cyclophosphamide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, doxorubicin, irofulven, dexifosfamide, cis-aminedichloro(2 methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine 30 platinum(lI)]bis[diamine(chloro)platinum(I)] tetrachloride, diarizidinylspermine, arsenic trioxide, 1 -(11 -dodecylamino-1 0-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, WO 2009/061596 PCT/US2008/080176 - 339 pinafide, valrubicin, amrubicin, antineoplaston, 3'-deansino-3'-morpholino-13 deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunombicin (see WO 00/50032), methoxtrexate, gemcitabine, and mixture thereof . 5 Examples of microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3
',
4 '-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxel, vincristine, vinblastin, vinorelobine, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2 ,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene 10 sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valy-L-valyl-N-methyl-L-valyl-L prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Patents 6,284,781 and 6,288,237) and BMS188797. Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3', 4 '-O-exo-benzylidene-chartreusin, 9 15 methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kqjacridine-2-(6H) propanamine, 1 amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H, 12 benzo[dejpyrano[3',4':b,7]-indolizino[1,2b]quinoline-1 0,13(9H,1 5H)dione, lurtotecan, 7-[2-(N-isopropylamino) ethyl]-(20S)camptothecin, BNP1350, BNPI 1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 20 2 '-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9 hydroxy-5,6-dimethyl-6H-pyrido[4,3-bcarbazole- 1 -carboxamide, asulacrine, (5a, SaB, 8 aa, 9 b)- 9 -[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy 3,5-di methoxyphenyl-5,5a,6,8,8a,9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1,3 dioxol-6-one, 2,3-(methylenedioxy)-5- methyl-7-hydroxy-8-methoxybenzo[c] 25 phenanthridinium, 6,9-bis[(2-aminoethyl)amino] benzo[gjisoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,1 0-di hydroxy-2- (2-hydroxyethylam inomethyl)-6 H pyrazolo[4,5,1-de]acridin-6-one, N-[1- [ 2 -(diethylamino)ethylamino]-7-methoxy-9 oxo-9H-thioxanthen-4-ymethyl]formamide, N-(2-(di methylam ino)ethyl) acrid i ne-4 carboxamide, 6
-[[
2 -(dimethylamino)ethylJamino]-3-hydroxy-7H-indeno[2,1 30 c]quinolin-7-one, dimesna, and camptostar. Examples of Antisense RNA and DNA oligonucleotides include: G3139, ODN698, RVASKRAS, GEM231, and INX3001.
WO 2009/061596 PCT/US2008/080176 -340 Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery 5 of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13), and gene therapy to interferon gamma (J Immunol 2000;164:217-222). For an overview of genetic strategies to treating cancer, see Hall et al (Am J Hum Genet 61:785-789,1997) and Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC 10 Decker, Hamilton 2000). Examples of antimetabolites include: 5-fluorouracil, enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 15 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-{5-(2,3 dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2 [2(E) ,4(E)-tetradecadienoyljglycylaminoj-L-glycero-B-L-manno heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo 4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L 20 glutamic acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8 (carbamoyloxymethyl)-4-formyl-6-methoxy-1 4-oxa-1,11 diazatetracyclo(7.4.1 .0.0)-tetradeca-2,4,6-trien-9-y acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4 palmitoyl-1 -B-D-arabino furanosyl cytosine and 3-aminopyridine-2 25 carboxaldehyde thiosemicarbazone. Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar. 30 "HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3 methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR*; see U.S.
WO 2009/061596 PCT/US2008/080176 -341 Patents 4,231,938, 4,294,926 and 4,319,039), simvastatin(ZOCOR*; see U.S. Patents 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL*; see U.S. Patents 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL*; see U.S. Patents 5,354,772, 4,911,165, 4,929,437, 5 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR*; see U.S. Patents 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US 10 Patents 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open acid and lactone forms 15 is included in the scope of this invention. "Prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-1), and geranylgeranyli-protein transferase type-Il (GGPTase-lI, also 20 called Rab GGPTase). Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patents 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, 25 European Patent Pub[. 0 618 221, European Patent Publ. 0 675 112, European Patent Pub. 0 604181, European Patent Pub[. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 30 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO WO 2009/061596 PCT/US2008/080176 - 342 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO, 97/30053, WO 97/44350, WO 98/02436, and U.S. Patent 5,532,359. For an example of the role 5 of a prenyl-protein transferase inhibitor on angiogenesis see European of Cancer, VoL 35, No. 9, pp.1394-1401(1999). Examples of farnesyl protein transferase inhibitors include SARASAR
TM
(4 [2-[4-[(11 R)-3,1 0-dibromo-8-chloro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2 b]pyridin-1 1 -yl-]-1 -piperidinyl]-2-oxoehtyl]-1 -piperidinecarboxamide from 10 Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra* or R 115777 from Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey). 15 "Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived 20 growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. OpthalmoL, Vol. 108, 25 p.573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters, VoL 372, p. 83 (1995); Clin. Orthop. Vol. 313, p. 76 (1995); J Mot EndocrinoL, Vol. 16, p.107 (1996); Jpn. J. PharrnacoL, Vol. 75, p.105 (1997); Cancer Res., Vol. 57, p.1625 (1997); Cell, Vol. 93, p. 705 (1998); IntL J. Mol Med, VoL 2, p. 715 (1998); J. BioL Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as 30 corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, WO 2009/061596 PCT/US2008/080176 - 343 troponin-1, angiotensin 11 antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol, 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186). 5 Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2 butenyl)oxiranyll-1 -oxaspiro[2,5]oct-6-yI(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1 -[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1
H
1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RP14610, 10 NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl 4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino}-bis-(1,3 naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylenej-2-indolinone (SU5416). Other therapeutic agents that modulate or inhibit angiogenesis and may 15 also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular 20 weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFla]) (see Thrombosis Res. 101:329-354 (2001)). Examples of TAFla inhibitors have been described in PCT Publication WO 03/013,526. Examples of kinase inhibitors include: agents that inhibit cell surface 25 receptors and signal transduction cascades downstream of those surface receptors. Such agents inhibit cell proliferation and survival. These include inhibitors of EGFR (for example gefitinib and erlotinib), antibodies to EGFR (for example C225), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors of P13K (for 30 example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43- WO 2009/061596 PCT/US2008/080176 - 344 9006), inhibitors of MEK (for example C1-1040 and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), and inhibitors of C-abl kinase (for example
GLEEVEC
T M , Novartis Pharmaceuticals). Additional kinase inhibitors include those that inhibit proteins involved in the cell cycle. These include Aurora kinase 5 inhibitors, CDK inhibitors (e.g., flavopiridol, CYC202, BMS387032 and polo-like kinase inhibitors.) These also include agents that interfere with cell cycle checkpoints and thereby sensitize cancer cells to DNA damaging agents. Such agents include, e.g., inhibitors of ART, ATM, Chk1 and Chk2. The invention also encompasses combinations with NSAID's which are 10 selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Inhibitors of COX-2 that are particularly useful in the instant method of treatment 15 are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4 methylsulfonyl)phenyl-2-(2-methyl-5 pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof. Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, 20 parecoxib, CELIEBREXO and BEXTRA* or a pharmaceutically acceptable salt thereof. "Integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the Us3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a 25 physiological ligand to the a0 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the aup03 integrin and the U0 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the axs, au0 8 , a1B 3 , a 2 0 1 , a01, aNo and aQD 4 30 integrins. The term also refers to antagonists of any combination of avB, avps, C46, a(3, c, 31, a 2 fb, a51, asP1 and C40 integrins.
WO 2009/061596 PCT/US2008/080176 - 345 Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods. For example, combinations of the compounds of the invention with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-6 (i.e., PPAR-delta) agonists (collectively "PPAR agonists") are useful in 5 the treatment of certain malingnancies. PPAR-y and PPAR-8 are the nuclear peroxisome proliferator-activated receptors y and 8, respectively. The expression of PPAR-y on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmaco/ 1998; 31:909-913; J. Bio. Chem. 1999;274:9116-9121; Invest. Ophthalmo Vis. Sci. 2000; 41:2309 10 2317). More recently, PPAR-y agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. OphthamoL 2001; 119:709-717). Examples of PPAR-y agonists and PPAR-y/a agonists include, but are not limited to, thiazolidinediones (such as DRF2725, 15 CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, G1262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6 yl)oxy]-2-methylpropionic acid, and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) 20 phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid. The compounds of the invention can also be administered in combination with one or more inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, 25 XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar). Additional anticancer agents also include hypoxia activatable agents (e.g., tirapazamine), proteasome inhibitors (e.g., lactacystin and bortezomib), ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, and interferon alpha. 30 The compounds of the invention can also be employed in conjunction with one or more anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a WO 2009/061596 PCT/US2008/080176 - 346 compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with one or more other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor, antagonists, such as 5 ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or those as described in U.S. Patents 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example 10 prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In one embodiment, an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the compounds of the invention. 15 Examples of neurokinin-1 receptor antagonists that can be used in conjunction with the compounds of the invention are described in U.S. Patents 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, and 5,719,147, content of which are incorporated herein by reference. In an embodiment, the neurokinin-1 receptor antagonist for use in 20 conjunction with the compounds of the present invention is selected from: 2-(R) (1 -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo 1 H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent 5,719,147. A compound of the present invention may also be administered with one 25 or more immunologic-enhancing drug, such as for example, levamisole, isoprinosine and Zadaxin. As described above, the present invention includes combinations comprising an amount of at least one compound (or a composition comprising a compound) of the invention or a pharmaceutically acceptable salt or ester 30 thereof, and an amount of one or more additional therapeutic agents listed above (administered together or sequentially) wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
WO 2009/061596 PCT/US2008/080176 - 347 When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, 5 together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for illustration purposes, a compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet 10 and the like). A commercial example of such single dosage unit containing fixed amounts of two different active compounds is VYTORIN* (available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey). If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the 15 other pharmaceutically active agent or treatment within its dosage range. Compounds of the invention may also be administered sequentially with known therapeutic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of the invention may be administered either prior to or after administration of the known 20 therapeutic agent. Such techniques are within the skills of persons skilled in the art as well as attending physicians. It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not 25 limited to the particular embodiments disclosed, but it is intended to cover modifications that are within the spirit and scope of the invention, as defined by the appended claims.

Claims (56)

1. A compound having the general structure shown in Formula (1), or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof: R 2'R R 2 B R ) P N E (I) wherein R 1 , R 2 , R 3 , p, R 2 , R 28 , E, ring A, and ring B are selected independently of each other and wherein: p is 0, 1, 2, 3, or 4; ring A (including E and the unsaturation shown) is a 4-8 membered cycloalkenyl or heterocycloalkenyl ring; E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O) 2 -, -C(R 4 )(R 5 )-, -N(R)-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, -N(C(Y)N(R 9 )(R"'))-, -C(O)-N(R')-, -N(R 1 )-C(O)-, -S(O) 2 -N(R')-, -N(R")-S(O) 2 -, -C(O)-O-, -0-C(O)-, -O-N(R 6, -N(R6)-O-, -N(R6)-N(R 1)-, -N=N-, -C(R")=N-, -C(O)-C(R 7)=N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R")-C(Y)-O-, -N(R'l)-C(Y)-N(R 1)-, -C(Y)-N(R'1)-Os' -C(Y)-N(R)-N(R 12 )-, -O-N(R 1 ')-C(Y)-, and -N(R' 2 )-N(R 1 ')-C(Y)-, wherein each Y is independently selected from the group consisting of (=0), (=S), (=N(R 1 )), (=N(CN)), (=N(OR 14 )), (=N(R 15 )(R')), and (=C(R17)(R'*)) WO 2009/061596 PCT/US2008/080176 - 349 ring B is an aromatic or heteroaromatic ring, or a partially unsaturated alicyclic ring, or a partially unsaturated heterocyclic ring, wherein said ring is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 0 , -NR 2 1 R2, -NR 23 SO 2 R 24 , -NRC 23 (O)OR 2 0 , -NR 2 3 C(O)R 24 , -SO 2 NR 5 R2, -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R 9 , -S0 2 R 9 , -OC(O)R 24 -C(O)NR 2 R 2 6 , -NR 23 C(N-CN)NR 25 R 26 and -NR 2 3 C(O)NR 25 R 2 6 . R 1 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, azido, -OR'9, -OC(O)OR 2 , -NR 2 1 R 2 2 , -NR 23 S0 2 R 24 , -NRC 23 (O)OR 20 , -NR 23 C(O)R 2 4 , -S0 2 NR 25 R 2 6 , -C(O)R 24 , -C(O)OR0, -SR' 9 , -S(O)R' 9 , -SO2R' 9 , -OC(O)R 24 -G(O)NR 2 R 2 6 , -NR 23 C(N-CN)NR 2 5 R 2 6 and -NRC 23 0(O)NRR 2 R2 is selected from the group consisting of -C(Z)R 7 , -C(Z)NR 9 R 0 , -C(Z)OR , -SO 2 NR9R'4, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, wherein each Z is independently selected from the group consisting of (=0), (=S), (=N(R1 3 )), (=N(CN)), (=N(OR'4)), (=N(R' 5 )(R'")), and (=C(R1 7 )(R' 8 )), and WO 2009/061596 PCT/US2008/080176 - 350 wherein each said alkyl, each said heteroalkyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo (with the proviso that said aryl and said heteroaryl are not substituted with oxo), halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR0, -NR R 22 -NR 23 S0 2 R 24 , -NR 2 C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R24 -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R2 4 , -C(O)NR 5 R2 6 , -NRC 23 (N-CN)NR2-R2 6 and -NRC 23 (O)NR 5 R 2 6 ; R 27 (when not joined with R 28 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR 2 1 2 2 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR2 0 , -NR 3 C(O)R 24 , -S0 2 NR 25 R 2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 3, -NR 3 C(N-CN)NR 25 R 2 6 and -NRC 23 (O)N 5 R 2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2R 22 , -NR 3 SO2R 24 , -NR 23 C(O)OR0, -NR 3 C(O)R 24 , -S0 2 NR 25 R 2 , -C(O)R 24 , -C(0)OR2 0 , -SR' 9 , -S(O)R 9 , WO 2009/061596 PCT/US2008/080176 - 351 -SO 2 R' 9 , -OC(O)R 2 4, -C(O)NR 25 R 26 , -NR 23 C(N-CN)NR 25 R 26 and -NR2C(O)N 25 R 2 ; R 28 (when not joined with R 2 7 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 21 R 22 , -NR 23 S0 2 R 24 , -NRC 23 (O)OR 2 0 , -NR 23 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R24, -C(O)OR 2 0 , -SR'9, -S(O)R', -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 25 R 2 3, -NR 23 C(N-CN)NR 25 R 2 6 and -NR 23 C(O)NR 2 5 R 2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , -OC(O)OR 2 0 , -NR 21 R 22 , -NR 23 SO 2 R 24 , -NRC 23 (O)OR 20 , -NRC 23 (O)R 24 , -S0 2 NR 25 R 2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R 9 , -SO 2 R 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)N 25 R 2 and -NRC 2 3 (O)NR 25 R 26 ; or, alternatively, R 27 and R, together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, WO 2009/061596 PCT/US2008/080176 - 352 -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2 'R 22 , -NR 2 3 SO 2 R24, -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR 2 5 R 2 3 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R', -SO 2 R'9, -OC(O)R 24 -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)NR 25 R 2 6 and -NR 23 C(O)NR 2 5 R 2 6 ; each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 21 R 22 , -NR 23 SO2R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR2 5 R 26 , -C(O) R 24 , -C(S)R 24 , -C(O)OR 20, -SR' , -S(O)R'9, -SO 2 R', -OC(O)R 24 , -C(O)NR 2 5 26 , -NR 2 3 C(N-CN)NR 2 5 R 2 6 , -NR 2 3 C(O)NR 2 5 R 2 6 , and -NR 2 3 -C(NH)-N(R 2 6) 2 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2, -NR 2 'R, -NR 23 S02R 24 , -NR 2 3 C(O)OR 20 -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO2R 9 , -OC(O)R 2 4 , -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)NR 2 5 R 2 6 and -NR 2 3 C(O)NR 2 5 R 26 , or, alternatively, when p is 2, 3, or 4, any two R 3 groups bound to the same ring carbon atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, or a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, WO 2009/061596 PCT/US2008/080176 - 353 -S(O)-, -S(0)2-, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-, or, alternatively, R 2 and R 3 , together with the atom to which they are attached, are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(O)r, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-; each R 4 (when not joined with R 5 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , -OR' 9 , -OC(O)OR 2, -NR 2R 22 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 3, -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR23C(O)NR 2 5 R 2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 t, -NR2R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 2 4 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR20, -SR 9 , -S(O)R' 9 , -S0 2 R 9 , -OC(O)R 24 , -C(O)NR 2 5 R 26 , -NR 2 3 C(N-CN)NR 2 5R2 6 and -NR23C(O) N25 2 6 WO 2009/061596 PCT/US2008/080176 - 354 each R 5 (when not joined with R 4 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halogen, -CN, -NO 2 , , -OR' 9 , -OC(O)OR 2 0 , -NR 2 'R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)R 2 , -SR't, -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 2 4, -C(O)NR 2 5 HR2, -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR 23 C(O)NR 25 R 26 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 21 R 2 2 , -NR 23 SO 2 R24 -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 26 , -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR 23 C(O)NR 25 R 2 R or, alternatively, R 4 and R 5 , together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-aikyl-, heteroaryl-alkyl-, cycloalkyl, WO 2009/061596 PCT/US2008/080176 - 355 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 20 , -NR 2 1 R 22 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 -S0 2 NR 25 R 2 6 , -C(O)R24, -C(O)OR 20 , -SR', -S(O)R' 9 , -SO 2 R', -OC(O)R 24 , -C(O)NR 25 R 2 6 , -NR 23 C(N-CN)NR 25 R 2 6 and -NR 23 C(O)NR 2 5 R 2 6 ; each R 6 is independently selected from the group consisting of H, alkyl, -C(O)R 2 , -C(O)OR 2 0 , -C(S)R 24 , heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 21 R 22 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 20 , -NR 2 3 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(S)R24, -C(O)OR 20 , -SR' 9 , -S(O)R'9, -SO 2 R' 9 , -OC(O)R24, -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR 2 3 C(O)N R 2 H 2 6 each R 7 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 - 356 heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2 1 R 2 2 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(0)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R24, -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)NR 2 5 R 2 6 and -NR 23 C(O)NR 2 5 R 2 6 ; each R 8 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalky, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)R 2 0 , -NR 2 'R 22 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 20 , -NR 2 3 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)R 2 0 , -SR' 9 , -S(O)R' 9 , -S0 2 R'9, -OC(O)R24, -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)NR 2 -R 2 6 and -NR 2 C(O)NRR 2 5 R, each R 9 (when not joined with R' 0 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 357 heteroalky, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloal kyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 20 , -NR 2 R 22 , -NR 23 SO 2 R 24 , -NRC 2 3 (O)OR 20 , -NR 2 3 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R24, -C(O)OR2, -SR 19 , -S(O)R , -S0 2 R 9 , -OC(O)R 24 , -C(O)NR 2 5R 26 , -NR 23 C(N-CN)NR 2 5 R 2 6 and -NRC(O)NR 25 R 2 I each R 1 0 (when not joined with R 9 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR's, -OC(0)OR 0 , -NR 21 R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -SO 2 N R 25 R 26 , -C(O)R 2 4, -C(O)OR 20 , -SR 19 , -S(O)R 9 , -SO 2 R'9, -OC(O)R 24 , -C(O)NR 25 R 2 , -NR 23 C(N-CN)NR 25 R 2 6 and -NR 23 C(O)NR 25 R 2 I or, alternatively, R 9 and R'), together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, WO 2009/061596 PCT/US2008/080176 - 358 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 9, -NR 2 R 22 , -NR 23 S0 2 R 2 4 , -NRC 23 (O)OR 20 , -NR2C(O)R 24 , -S0 2 N 2 5 R 2 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' , -S0 2 R' 9 , -OC(O)R 24 -C(0)NR 25 R2, -NRC(N-CN)NR 2 R 26 and -NRC(O)NR 2 5 R; each R" is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NRR 2 ' 22 , -NR 23 SO2R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -S0 2 NR 25 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 -R 2 6 , -NRC 23 (N-CN)NR2 5 R 26 and -NRC(O)NR 25 R 26 ; each R 2 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, WO 2009/061596 PCT/US2008/080176 - 359 heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9 , -OC(O)OR 20 , -NR 21 R 22 , -NR 23 SO 2 R24, -NRC 23 (O)OR 2 0 , -NRC 23 (O)R 24 , -S0 2 NR 2 5 R 26 , -C(O)R24, -C(O)OR 20 , -SR' 9 , -S(O)R 9 , -SO 2 R 9 , -OC(O)R 24 , -C(O)NR 25 R 2 6 , -NRC 23 (N-CN)NR 25 R 2 6 and -NRC 2 3 (O)NR 25 R 2 6 ; each R 1 3 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2 1 R 22 , -NR 23 SO2R 24 , -NR 23 C(0)OR 20 , -NR 23 C(O)R 2 4 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R', -OC(O)R 24, -C(O)NR 25 R 26 , -NR 23 C(N-CN)NR 25 R 26 and -NR 2 C(O)NR-R 6 ; each R' 4 is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, WO 2009/061596 PCT/US2008/080176 - 360 heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeny, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2 R 2 2 , -NR 2 3 SO 2 R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R24, -SO 2 NR 25 Ra6, -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 2 4, -C(O)NR 2 5 R 2 , -NR 2 3 C(N-CN)NR 2 5 R2 6 and -NR 23 C(O)N R 25 R 26 ; each R 5 (when not joined with R' 6 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR2R 2 6 and -NR 2 3 C(0)NR 2 5 R 2 6 each R' (when not joined with R 5 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being WO 2009/061596 PCT/US2008/080176 -361 independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, hete rocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2 0 , -NR 2 'R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 20 -NR 23 C(O)R24 -S0 2 NR 2 5 R 26 , -C(O)R 24 , -C(O)OR2 0 , -SR' 9 , -S(O)R' 9 , -S0 2 R' 9 , -OC(O)R 24 , -C(O)NRR 25 2 6 , -NRC 23 (N-CN)NR 2 -R 2 6 and -NR 23 C(O)NR 25 R 26 ; or, alternatively, R 5 and R' 6 , together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2 'R 22 , -NR 23 SO 2 R 24 , -NRC 23 (O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR 25 R 2 , -C(O)R 2 , -C(0)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 -C(O)NR 5 R 2 , -NRC(N-CN)NRR 2 5 R 6 and -NR 2 3 C(O)NRa 5 R 2 6 each R 7 (when not joined with R'8) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(0)OR 2 0 , -OR9, -N R 2 R 2 2 , -NR 23 S02R 24 , -NR 23 C(O)OR 20 , -NR 2 3 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(0)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 25 R 26 , -NR 23 C(N-CN)NR 2 5 R 2 6 and -NR 2 3 C(O)NRR 25 2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more WO 2009/061596 PCT/US2008/080176 - 362 substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2 R R 2 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 20 , -NRC 23 (O)R 24 , -SO 2 NRR 2 5 R 26 , -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 6 , -NR 23 C(N-CN)NR 25 R 2 6 and -NR 2 C(O)NR 2 R 2 ; each R' 8 (when not joined with R 1 7 ) is independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -CN, -OC(O)OR2 0 , -OR' 9 , -NR1R 2 , -NR 23 SO 2 R 24 , -NR 3 C(O)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR2 5 R2, -C(O)R 24 , -C(O)OR 20 , -SR' 9 , -S(O)R' 9 , -S0 2 R' 9 , -OC(O)R 24 , -C(O)N 5 R 26 , -NRC 23 (N-CN)NR 2 5 R 2 6 and -NR 3 C(O)NR 5 R2 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, each said heteroalkenyl, each said alkynyl, each said heteroalkynyl, each said aryl, each said heteroaryl, each said cycloalkyl, each said cycloalkenyl, each said heterocycloalkyl, and each said heterocycloalkenyl is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR1R 2 , -NR 23 SO2R2 4 , -NR 3 C(O)R20, -NR 3 C(O)R 24 , -SO 2 NR 5 R2 6 , -C(O)R 24 , -C(O)OR2 0 , -SR' 9 , -S(O)R' 9 , -S0 2 R' 9 , -OC(O)R2 4 , -C(O)NR 5 R2 6 , -NRC 23 (N-CN)NRR 2 5 K and -NRC(O)NR 25 Rt or, alternatively, R 1 7 and R' 8 , together with the carbon atom to which they are attached, form a cycloalkyl, a cycloalkenyl, a heterocycloalkyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, WO 2009/061596 PCT/US2008/080176 - 363 or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S, wherein said heterocycloalkyl ring and said heterocycloalkenyl ring are each unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2 ' R 2 2 , -NR 23 SO 2 R 24 , -NR 2 3 C(0)OR 20 , -NR 23 C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 25 R 26 , -NRC 23 (N-CN)NR 2 5 R 26 and -NR 23 C(O)NR 25 R 2 6 ; each R' 9 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 20 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 2 1 (when not joined with R 22 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 22 (when not joined with R 21 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or, alternatively, R' and R 2 , together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S; each R 23 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; WO 2009/061596 PCT/US2008/080176 -364 each R 24 is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; each R 25 (when not joined with R 2 6 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalky; and each R 26 (when not joined with R 25 ) is independently selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, cycloalkyl, halocycloalkyl; or, alternatively, R 25 and R 26 , together with the N atom to which they are attached, form a heterocycloalkyl or a heterocycloalkenyl ring containing from one to three heteroatoms selected from the group consisting of N, 0, and S.
2. A compound of claim 1, wherein ring A is a 4-7-membered cycloalkylene ring and E is -C(R4)(R5)-.
3. A compound of claim 1, wherein ring A is a 5-7-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(0)-, -S(O)-, -N(R 6 )_, -N(C(Y)R)-, -N(C(Y)OR)-, -N(C(Y)N(R 9 )(R' 0 ))-, -C(O)-N(R )-, -N(R")-C(O)-, -S(0) 2 -N(R")-, -N(Rl1)-S(O)2-, -C(O)-0-, -O-C(0)-, -O-N(R6)_, -N(R6)-O-, -N(R6)-N(R 1)-, -N=N-, -C(R7)=N-, -C(O)-C(R7) =N-, -C(O)-N=N-, -O-C(Y)-N(R")-, -N(R")-C(Y)-O-, -N(R")-C(Y)-N(R 1)- , -C(Y)-N(R 1 )-O-, -C(Y)-N(R')-N(R 2 )-, -0-N(R)-C(Y)-, and -N(R' 2 )-N(R')-C(Y)-.
4. A compound of claim 1, wherein ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0)2-, -N(R)-, -C(O)-N(R")-, and -N(R")-C(O)-. WO 2009/061596 PCT/US2008/080176 -365
5. A compound of claim 1, wherein ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-.
6. A compound of claim 5, wherein R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 20 , and -C(S)R 24
7. A compound of claim 1, wherein ring A is a 5-6-membered heterocycloalkylene ring and E is selected from the group consisting of -0- and -N(R 6 )-.
8. A compound of claim 7, wherein R 6 is selected from the group consisting of H, alkyl, -C(0)R 24 , -C(O)OR 20 , and -C(S)R 24
9. A compound of claim 8, wherein ring A is a 5-membered heterocycloalkylene ring.
10. A compound of claim 8, wherein ring A is a 6-membered heterocycloalkylene ring.
11. A compound of claim 1, wherein ring B is an unsubstituted aromatic ring or an aromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 19 , WO 2009/061596 PCT/US2008/080176 - 366 -OC(O)OR 20 , -NR 2 R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -SO2NR 25 R-6, -C(O)R 24 , -C(O)OR0, -SR 1 , -S(O)R' 9 , -SO 2 R'9, -OC(O)R 24 -C(O)NR 25 R 2 , -NR 23 C(N-CN)NR 25 R 26 and -NR 2 3 C(O)NR 25 R 2 6 .
12. A compound of claim 1, wherein ring B is an unsubstituted benzo ring or a benzo ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR20, -NR 2 H 22 , -NR2 3 SO2R 2 4 , -NR2 3 C(O)OR2w, -NR23C(O)R24 -SO 2 NR 2 5 R, -C(O)R 4 , -C(O)OR2, -SR' 9 , -S(O)R' 9 , -S0 2 R 19 , -OC(O)R 4 -C(O)NR 25 R 2 6 , -NR 23 C(N-CN)NRR25R2 and -NR 3 C(O)NR 2 5 26 .
13. A compound of claim 1, wherein ring B is an unsubstituted or substituted heteroaromatic ring or a substituted heteroaromatic ring which is substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2 0 , -NR 2 H 22 , -NR 23 SO2R24 -NR 3 C(O)OR20, -NR 23 C(O)R 24 , -S0 2 NR 25 R 26 , -C(O)R2 4 , -C(O)OR 2 , -SR' 9 , -S(O)R 9 , -SO 2 R 9 , -OC(O)R2 4 , -C(O)NR 5 R2 6 , -NR 23 C(N-CN)NR25R23 and NRC 23 (O)NR2GR.
14. A compound of claim 13, wherein ring B is a 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which can be the same or different, each hetero ring atom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 . WO 2009/061596 PCT/US2008/080176 - 367
15. A compound of claim 1, wherein ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
16. A compound of claim 1, wherein R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR2o, -NR 2 'R 22 , -NR 23 SO 2 R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O) R 24 , -SO 2 N R 25 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR 2 R 5 26 and -NR 23 C(O)NR 25 H 2 6 .
17. A compound of claim 1, wherein R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 1 R 22 , and haloalkyl.
18. A compound of claim 1, wherein R is selected from the group consisting of: halo HO NC 02N halo halo halo halo alkyl haloalky halo halo ,and
19. A compound of claim 1, wherein R' is a moiety selected from the group consisting of: WO 2009/061596 PCT/US2008/080176 - 368 perfluoroalky ~ halo halo and
20. A compound of claim 1, wherein: F F R 1 is: , and R 7 and R 2 are each independently selected from the group consisting of H and alkyl.
21. A compound of claim 1, wherein R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R1', and -C(0)OR 8 .
22. A compound of claim 1, wherein p is 0 and R3 is not present.
23. A compound of claim 1, wherein p is 1, 2, 3, or 4 and each R 3 is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR R 22 , -C(O)R 24 , -C(S)R
24 -C(O)OR , and -C(O)NR 25 R 2 wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 1 9, -OC(0)OR , -NR 2 R 22 -NR 23 SO 2 R 24 , -NR 2 3 C(O)OR 2 0 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 , -C(O)R 2 4 -C(O)OR2 0 , -SR' 9 , -S(O)R' 9 , -S0 2 R' 9 , -OC(O)R24, -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR 2 3 C(O)NR 2 5 R 2 6 . WO 2009/061596 PCT/US2008/080176 - 369 24. A compound of claim 1, wherein p is 2, 3, or 4, and any two R3 groups bound to the same ring A atom are taken together with the carbon atom to which they are attached to form a spirocycloalkyl, a spirocycloalkenyl, a spiroheterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0) 2 -, and -0-, or a spiroheterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-.
25. A compound of claim 1, wherein R 2 and R 3 are taken together with the carbon atom to which they are attached to form a cycloalkyl, a cycloalkeny, a heterocycloalkyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-, or a heterocycloalkenyl ring containing from one to three ring heteroatoms independently selected from the group consisting of -NH-, -NR 6 -, -S-, -S(O)-, -S(0)2-, and -0-.
26. A compound of Claim 1, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof, having the general structure shown in Formula (11): R1 R27 R 2 N E I R2 (II) WO 2009/061596 PCT/US2008/080176 -370 wherein R1, R 2 , R 27 , R 2 8, E, and ring B are selected independently of each other and wherein E is selected from the group consisting of -0-, -S-, -S(O)-, -S(O)-, -C(R4)(R 5 )-, -N(R 6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR")-, -N(C(Y)N(R 9 )(R' 0 ))-.
27. A compound of claim 26, wherein: E is selected from the group consisting of -0-, -S-, -S(O)-, -S(0) 2 -, -C(R 4 )(R 5 )-, and -N(R) ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; R 1 is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO 2 , -NR 2 1 R 22 , and haloalkyl; and R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R' 0 , and -C(O)OR.
28. A compound of claim 27, wherein R is: F F , and R 27 and R 28 are each independently selected from the group consisting of H and alkyl.
29. A compound of Claim 1, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof, having the general structure shown in Formula (111.1): WO 2009/061596 PCT/US2008/080176 -371 IE wherein R, R2, R, R 27 , R 2 R, p, E, and ring B are selected independently of each other and wherein: E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2-, -C(R4)(R 5 )-, -N(H 6 )-, -N(C(Y)R 7 )-, -N(C(Y)ORa)-, and -N(C(Y)N(R 9 )(R' 0 ))-; and p isO0, 1, or2.
30. A compound of Claim 29, wherein: E is selected from the group consisting of -C(R 4 )(R 5 )-, -0-, -S-, -S(0)-, -S(0)2-, and -N(R -; ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(0), and S(O)2, said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -cN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(0)oR0, -NR- R 22 , -NR 23 S0 2 R 2 4 ( -NR 23 0(O)0R 20 , -NR 23 0(O)R 24 , -S0 2 N 25 R 2 8 , -C(0)R24, -C(O)O 2 a, -SR's, -S(O)R' 9 , -SO2R', -OC(0)R24, -C(O)NR2dR 26 , -NR 23 C(N-CN)N 2 R 26 and NR 23 C(O)NR125R26; WO 2009/061596 PCT/US2008/080176 - 372 R 1 is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 , -NR2'R 22 , -NR 3 S0 2 R 24 , -NRC 23 (O)OR 2 0 , -NRC 23 (O)R 24 , -SO 2 NR 25 R 26 , -C(O)R 4 , -C(O)OR2 0 , -SR 19 , -S(O)R 19 , -S0 2 R 19 , -OC(O)R2 4 -C(O)NR 5 R 2 6 , -NR 3 C(N-CN)NR2 5 R2 6 and -NR 3 C(O)NR R 25 2 6 ; R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R' 0 , and -C(O)OR8; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR 9 , -OC(O)OR20 -NR 'R 22 , -C(O)R 4 , -C(S)R 4 , -C(O)OR0, and -C(O)NR 5 R 6 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 20 , -NR 2 'R 2 -NR 23 SO 2 R 24 , -NR 3 C(O)OR20, -NR 23 C(O)R 24 , -S0 2 NR 5 R 2 6 , -C(O)R 24 , -C(O)OR20, -SR 1 9 , -S(O)R' 9 , -S0 2 R 19 , -OC(O)R 24 , -C(O)NR25R 2 6 , -NR 2 C(N-CN)NR2sR26 and -NR 23 C(O)N 5 R 2 .
31. A compound of Claim 30, wherein: ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furany, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; WO 2009/061596 PCT/US2008/080176 - 373 R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NRR 21 R 22 , and haloalkyl; R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R' 0 , and -C(O)OR ; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyi, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR', -OC(O)OR 20 , -NRR 22 -NR 2 3 S0 2 R 24 , -NR 23 C()OR 2 0 , -NR 23C(O)R 24 , -SO 2 NR 2 5 R 2 6 , -C(O)R24 -C(O)OR 20 , -SR' 9 , -S(O)R'9, -S0 2 R' 9 , -OC(O)R24, -C(O)NR 25 R 2 6 -NR 23 C(N-CN)NR 25 R 2 6 and -NR 2 3 C(O)NRR 2 5 N 2
32. A compound of claim 31, wherein R' is: F F R 27 and R 2 are each independently selected from the group consisting of H and alkyl; and Rf3 is selected from the group consisting of H, alkyl, -C(O)R24, -C(O)OR20, and -C(S)R 24 WO 2009/061596 PCT/US2008/080176 - 374
33. A compound of Claim 1, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof, having the general structure shown in Formula (111.2): R1 R27 R 28 B N ,,V E R2( wherein R', R 2 , R 3 , R, R 28 , p, E, and ring B are selected independently of each other and wherein: E is selected from the group consisting of -0-, -S-, -S(0)-, -S(0) 2 -, -C(R 4 )(R 5 )-, -N(R 6 )-, -N(C(Y)R 7 )-, -N(C(Y)OR 8 )-, and -N(C(Y)N(R 9 )(R' 0 ))-; and p is 0, 1, or 2.
34. A compound of Claim 33, wherein: E is selected from the group consisting of -C(R 4 )(R 5 )-, -0-, -S-, -S(O)-, -S(0)2-, and -N(R 6 )-; ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(O), and S(0)2, said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0 , -NR 2R 2 2 , -NR 23 SO2R 24 , WO 2009/061596 PCT/US2008/080176 - 375 -NRC 23 (O)OR 2 0 , -NRC 23 (O)R 24 , -SO 2 NR 25 R 26 , -C(O)R 24 , -C(O)OR 20 , -SR 1 9, -S(O)R', -S0 2 R' 9 , -OC(O)R 24 , -C(O)NR 25 R 2 6 , -NRC 23 (N-CN)NR 25 R 2 6 and NR 2 3 C(O)NR 25 R 2 6 ; R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloal kyl, heterocycloalkenyl, azido, -OR'9, -OC(O)OR 2 0 , -NR 2 R 22 , -NR 23 S0 2 R 24 , -NR 23 C(O)OR 20 , -NRC 23 (O)R 24 , -S0 2 NR 2 -R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO2R'9, -OC(O)R 24 , -C(O)N R 25 R 2 6 , -NR 23 C(N-CN)NR 2 5R26 and -NR 2 C(O)NR 25 R 26 ; R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R' 0 , and -C(O)OR; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 20 , -NR 1 R, -C(O)R, -C(S)R, -C(O)OR , and -C(O)NR 5 R, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 20 , -NR 2 'R, -NR 23 S0 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 2 3 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 25 R 2 6 , -NR 2 C(N-CN)NR 2 5R26 and -NR 23 C(O)NR 2 5 R 26 ,
35. A compound of Claim 34, wherein: ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, WO 2009/061596 PCT/US2008/080176 - 376 pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-NO 2 , -NR 21 R 22 , and haloalkyl; R 2 is selected from the group consisting of -C(O)R7, -C(O)NR 9 R' 0 , and -C(O)ORS; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' , -OC(O)OR 2 o, -NR21R22 -NR 23 SO2R 24 , -NR 23 C(O)OR 20 , -NRC 23 (O)R 24 , -S0 2 NR 25 R 26 , -C(O)R24, -C(O)OR20, -SR' 9 , -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R24, -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR 25 R 2 6 and -NRC 23 (O)NR 25 R 2 6 .
36. A compound of claim 35, wherein R' is: F F R2 and R28, are each independently selected from the group consisting of H and alkyl; and R3 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR20, and -C(S)R 24 WO 2009/061596 PCT/US2008/080176 - 377
37. A compound of Claim 1, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof, having the general structure shown in Formula (IV): R1 R 2 R 28 B NsNA E R2 R3) R g3P (IV) E is selected from the group consisting of -C(R4)(R 5 )-, -0-, -S-, -S(O)-, -S(0) 2 -, and -N(R 6 )-; ring B is an unsubstituted or substituted aromatic ring or an unsubstituted or substituted 5-6-membered heteroaromatic ring having from 1-3 ring heteroatoms, which ring heteroatoms can be the same or different, each ring heteroatom being independently selected from the group consisting of N, S, 0, S(O), and S(O) 2 , said substituents on said aromatic ring or said heteroaromatic ring (when present) being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroary-alkyl-, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR , -OC(O)OR2 0 , -NR 2 1 R2 2 , -NR2 3 SO 2 R24 -NR2 3 C(O)OR2 0 , -NR2 3 C(O)R 24 , -SO 2 NR2 5 R2 6 , -C(O)R2 4 , -C(O)OR2 0 , -SR, 19 -S(O)R' 9 , -SO 2 R' 9 , -OC(O)R2 4 , -C(O)NR2 5 R2 6 , -NR2 3 C(N-CN)NR2 5 R2 6 and NR 23 C(O)NR25R 2 6 ; R' is unsubstituted aryl or aryl substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group consisting of halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, WO 2009/061596 PCT/US2008/080176 - 378 haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR' 9 , -OC(O)OR 2 0, -NR 2 ' R 22 , -NR 23 SO2R 24 , -NR 23 C(O)OR 20 , -NR 23 C(O)R 24 , -S0 2 NR 25 R 2 6 , -C(O)R24, -C(O)OR 2 0 , -SR' 9 , -S(O)R'9t -SO 2 R'9 -OC(O)R 2 4 -C(O)NR 2 5 R 2 6 , -NR 2 3C(N-CN)NR 2 5 R26 and -NR 23 C(O)NR 2 5 R 26 ; R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR9R' 0 , and -C(O)OR; p is 0, 1, or 2; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, -CN, -NO 2 , -OR' 9 , -OC(O)OR 2 0 , -NR 2 ' 22 , -C(O)R 24 , -C(S)R 24 , -C(O)OR2, and -C(O)NR 25 R 2 , wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR , -OC(O)OR0, -NR R 2 -NR 23 SO 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 2 3 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(0)R24, -C(0)OR 0 , -SR' 9 , -S(0)R' 9 , -SO 2 R' 9 , -OC(O)R 24 , -C(O)NR 2 5 B 2 R -NR23C(N-CN)NR 2 5R26 and -NR23C(O)NR 2 51 2 6.
38. A compound of Claim 37, wherein: E is selected from the group consisting of -0- and -N(RB-; ring B is an unsubstituted or substituted moiety selected from the group consisting of benzo, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; WO 2009/061596 PCT/US2008/080176 - 379 R' is phenyl substituted with one to four substituents, which can be the same or different, each substituent being independently selected from the group consisting of halo, -OH, -CN,-N0 2 , -NR 2 R R 22 , and haloalkyl; R 2 is selected from the group consisting of -C(O)R 7 , -C(O)NR 9 R'%, and -C(O)OR; p is 0 or 1; and each R 3 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, heteroalkenyl, wherein each said alkyl, each said heteroalkyl, each said alkenyl, and each said heteroalkenyl, is unsubstituted or optionally independently substituted with one or more substituents, which can be the same or different, each substituent being independently selected from the group of oxo, halogen, -CN, -NO 2 , alkyl, heteroalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, azido, -OR 9 , -OC(O)OR 20 , -NR R 22 -NR 23 SO 2 R 24 , -NR 23 C(O)OR 2 0 , -NR 23 C(O)R 24 , -S0 2 NR 2 5 R 2 6 , -C(O)R 24 , -C(O)OR 2 0 , -SR' 9 , -S(O)R' 9 , -SO2R'9, -OC(O)R 24 , -C(O)NR 2 5 R 2 6 , -NR 2 3 C(N-CN)NR 2 5 R 2 6 and -NR 2 3 C(O)NR 25 R 2 6 .
39. A compound of claim 38, wherein R' is: F F ; 27 and R 28 are each independently selected from the group consisting of H and alkyl; and R 6 is selected from the group consisting of H, alkyl, -C(O)R 24 , -C(O)OR 2 0 , and -C(S)R 2 4
40. A compound, or a pharmaceutically acceptable salt, solvate ester, prodrug, or isomer thereof, selected from the group consisting of: WO 2009/06 1596 PCT/US2008/080176 - 380 F F Nt F -NN F FF 0 0 (N N F UNF N-NN FF F N N IHF N-N F N-N F N-N MN 0MN o 00 0F N- N F >-F F F N N 00 NN N F F F N N \ Ot /- MN ON WO 2009/061596 PCT/US2008/080176 381 F F F 00 F N-N F N-N NN F N-N NH 2 F N F F LN FNN N-F N F NN 0 N~ NH 2 FF F H N
41. A o po n acodn toayo eoAis1 0i isltdorp rfe FNH 2 N-N N-N OH, F F F F F N-N F N-N o : F N-N N H 2 , OH, 0 F F" F
42- hamcuiclcmpsto cmrn aFhrpuial fetv - NH FNH N-N F N-NN o /I 'NF N ~-H 2 N and \ 41. A compound according to any one of claims 1- 40 in isolated or purified form. 42. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof, and at least one pharmaceutically acceptable carrier. WO 2009/061596 PCT/US2008/080176 - 382
43. A pharmaceutical composition of claim 42, further comprising at least one additional therapeutically active agent.
44. A pharmaceutical composition of claim 43, wherein said at least one additional therapeutically active agent is selected from: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolites, antibodies coupled to cyctotoxic agents, radioisotypes, HMG CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB R inhibitors, CENP-E inhibitors, interferon, and radiation.
45. A method of inhibiting KSP kinesin activity in a subject in need thereof comprising administering to said subject an effective amount of at least one compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester, prodrug, or isomer thereof.
46. A method of treating a disease associated with or caused by aberrant cellular proliferation in a subject in need thereof comprising administering to said subject an effective amount of at least one compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, prodrug, ester, or isomer thereof.
47. A method of claim 46, wherein the said disease is selected from the group consisting of cancer, hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, tumor angiogenesis, and cellular proliferation induced by a medical procedure. WO 2009/061596 PCT/US2008/080176 - 383
48. A method of claim 46, wherein the cellular proliferative disease is selected from solid tumor cancer and hematological cancer.
49. A method of claim 46, wherein said disease is a cancer selected from skin cancer, breast cancer, brain cancer, colon cancer, gall bladder cancer, thyroid cancer, cervics cancer, testicular cancer, and blood cancer.
50. A method of claim 46, wherein said disease is a cancer selected from: cardiac cancer, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, hematologic cancer, skin cancer, cancer of the adrenal gland, xenoderoma pigmentosum, keratoctanthoma, and thyroid follicular cancer.
51. The method of claim 46, wherein said cellular proliferative disease is selected from: adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate cancer, testicular cancer, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, meningioma, glioma, sarcoma; endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia., serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified WO 2009/061596 PCT/US2008/080176 - 384 carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma; myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia; malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, and neuroblastoma.
52. The method of claim 51, further comprising radiation therapy.
53. The method of claim 46, further comprising administering to the subject at least one additional therapeutically active agent selected from: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolites, antibodies coupled to cyctotoxic agents, radioisotypes, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, interferon, and radiation.
54. The use of at least one compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, for the WO 2009/061596 PCT/US2008/080176 - 385 manufacture a medicament for inhibiting KSP kinesin activity in a subject in need thereof.
55. The use of at least one compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, for the manufacture of a medicament for treating one or more diseases by inhibiting KSP kinesin activity in a patient in need thereof.
56. The use of a combination comprising (i) a compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and (ii) at least one second compound, the second compound being selected from: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors/stabilizing agents, topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolites, antibodies coupled to cyctotoxic agents, radioisotypes, HMG-CoA reductase inhibitors, prenyltransferase inhibitors, farnesyl protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors, hypoxia activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, interferon, and radiation to manufacture a medicament for treating one or more diseases by inhibiting KSP kinesin activity in a subject in need thereof.
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