WO2016049565A1

WO2016049565A1 - Compositions and methods for inhibition of ras

Info

Publication number: WO2016049565A1
Application number: PCT/US2015/052427
Authority: WO
Inventors: Liansheng Li; Jun Feng; Pingda Ren; Yi Liu
Original assignee: Araxes Pharma Llc
Priority date: 2014-09-25
Filing date: 2015-09-25
Publication date: 2016-03-31

Abstract

Inhibitors of Ras protein; methods to modulate the activity of Ras protein; and methods of treatment of disorders mediated by Ras protein are provided. A method for regulating activity of a K-Ras, HRas or N-Ras mutant protein with a compound is described. Disorders that can be treated include cancer, such as pancreatic cancer, colon cancer, MYH associated polyposis, colorectal cancer, lung cancer or NSCLC.

Description

COMPOSITIONS AND METHODS FOR INHIBITION OF RAS

CROSS REFERENCE TO RELATED APPLICATION

[1] This application claims the benefit of U.S. Provisional Application No. 62/055,544, filed on September 25, 2014, incorporated herein by reference in its entirety.

BACKGROUND

[2] Ras represents a group of closely related monomeric globular proteins of 189 amino acids (21 kDa molecular mass) which are associated with the plasma membrane and which bind either GDP or GTP. Ras acts as a molecular switch. When Ras contains bound GDP it is in the resting or off position and is "inactive". In response to exposure of the cell to certain growth promoting stimuli, Ras is induced to exchange its bound GDP for a GTP. With GTP bound, Ras is "switched on" and is able to interact with and activate other proteins (its "downstream targets"). The Ras protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thus turning itself into the off state. Switching Ras off requires extrinsic proteins termed GTPase-activating proteins (GAPs) that interact with Ras and greatly accelerate the conversion of GTP to GDP. Any mutation in Ras which affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive Ras signaling may ultimately lead to cancer.

[3] Structurally, Ras proteins contain a G domain which is responsible for the enzymatic activity of Ras - the guanine nucleotide binding and the hydrolysis (GTPase reaction). It also contains a C-terminal extension, known as the CAAX box, which may be post-translationally modified and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and it contains a phosphate binding loop (P-loop). The P- loop represents the pocket where the nucleotides are bound in the protein, and this is the rigid part of the domain with conserved amino acid residues which are essential for nucleotide binding and hydrolysis (Glycine 12, Threonine 26 and Lysine 16). The G domain also contains the so called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are the dynamic parts of the protein which are often represented as the "spring- loaded" mechanism because of their ability to switch between the resting and loaded state. The key interaction is the hydrogen bonds formed by Threonine-35 and glycine-60 with the γ-phosphate of GTP which maintain Switch 1 and Switch 2 regions respectively in their active conformation. After hydrolysis of GTP and release of phosphate, these two relax into the inactive GDP conformation.

[4] The most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer. However, there are many other members including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1;

NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP IB; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REMl; REM2; RERG; RERGL; RRAD; RRAS; and RRAS2.

[5] Mutations in any one of the three main iso forms of RAS (H-Ras, N-Ras, or K-Ras) genes are among the most common events in human tumorigenesis. About 30% of all human tumors are found to carry some mutation in Ras genes. Remarkably, K-Ras mutations are detected in 25-30% of tumors. By comparison, the rates of oncogenic mutation occurring in the N-Ras and H-Ras family members are much lower (8% and 3% respectively). The most common K-Ras mutations are found at residue G12 and G13 in the P-loop and at residue Q61.

[6] G12C is a frequent mutation of K-Ras gene (glycine- 12 to cysteine). This mutation had been found in about 13 > of cancer occurrences, about 43 %> of lung cancer occurrences, and in almost 100% of MYH-associates polyposis (familial colon cancer syndrome).

However targeting this gene with small molecules is a challenge. Accordingly, there is a need in the art for small molecules for targeting Ras (e.g., K-Ras, H-Ras and/or N-Ras) and use of the same for treatment of various diseases, such as cancer. The present invention provides these and other related advantages.

INCORPORATION BY REFERENCE

[7] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

SUMMARY OF THE INVENTION

[8] In one aspect, the disclosure provides a method for regulating activity of a K-Ras, H- Ras or N-Ras mutant protein. In one embodiment, the method comprises reacting the K-Ras, H-Ras or N-Ras mutant protein with a compound in accordance with an embodiment of the present invention.

[9] In one aspect, the disclosure provides a method of treating a disorder in a subject in need thereof. In one embodiments, the method comprises (a) determining if the subject has a K-Ras, H-Ras or N-Ras mutation; and (b) if the subject is determined to have the K-Ras, H- Ras or N-Ras mutation then administering to the subject a therapeutically effective dose of a pharmaceutical composition comprising at least one compound in accordance with an embodiment of the present invention or a salt thereof. In some embodiments, the disorder is cancer, such as pancreatic cancer, colon cancer, MYH associated polyposis, colorectal cancer, lung cancer or NSCLC.

[10] In one aspect, the disclosure provides a method of preparing a labeled K-Ras, H-Ras or N-Ras mutant protein. In one embodiment, the method comprises contacting the K-Ras, H-Ras or N-Ras mutant protein with a compound in accordance with an embodiment of the invention, to result in the labeled K-Ras, H-Ras or N-Ras protein. In some embodiments, the compound is selected from the group of compounds shown in Table 1.

[11] In one aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound in accordance with an embodiment of the present invention. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for injection.

[12] The present invention provides compounds which are capable of modulating a Ras protein, for example K-Ras, H-Ras and/or N-Ras proteins. In some instances, the compound is capable of forming a complex with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is capable of forming a complex with a metal ion that is complexed with the Ras protein. In some embodiments, T is capable of forming an interaction with a mutation residue in the Ras protein, for example, G12D.

[13] In one aspect, a method is provided. The method comprises a method of regulating activity of Ras protein wherein the method comprises contacting the Ras protein with any of the compounds described herein. In some embodiments, the method inhibits proliferation of a cell population by contacting the cell population with any of the compounds described herein. In some embodiments, the method of inhibiting proliferation of a cell is measured as a decrease in cell viability of the cell population.

[14] In one aspect, a compound of Formula I is provided:

(I)

wherein X is O or NH, S, or CR₂₃,R₂4; Y is CH₂, CHR₂₂, CO, SO, or S0₂; n is an integer of value 1-6; Ri is aryl or heteroaryl, each of which is unsubstituted or substituted by one or more independent R₂ substituents; R₂ is halogen, -OH, oxo, alkoxy, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R₃ substituents; R₃ is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R₄ substituents; R₄ is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl,

heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene; Ci is alkyl, cycloalkyl, heterocycloalkyl, arylene, heteroarylene, or heterocycloalkylene; each of which may be substituted with an R₅ substituent; C₂ is a bond, cycloalkyl, heterocycloalkyl, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene, wherein Ci and C₂ may form a fused or spiro bicyclic ring; D is a bond, -NH-CH₂-, -NH-, or -CH₂-; R₅ is OH, alkyl, or -CH₂OH; and T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K- Ras, H-Ras or N-Ras G12C mutant protein.

[15] In some embodiments, the compound of Formula I has an O at position X. In other embodiments, the X represents an NH group.

[16] In some embodiments, the compound of Formula I has a bond at position D. In other embodiments, D is an NH group. In other embodiments, the compound of Formula I has - NH-CH₂- at position D connected to -NH-CH₂- connected to the carbonyl carbon.

[17] In some embodiments, T is selected from the group consisting of: -NH₂, -OH, -

NHR 38a

and m, when present, is 0, 1 , 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1 or 2.

[18] In some embodiments, the compound of Formula I has a phenyl moiety at position Ri and the phenyl moiety at position Ri is unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the compound of Formula I has a benzothiadiazolyl moiety is at position Ri and is unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the compound of Formula I has a naphthalenyl moiety at position Ri and is unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the compound of Formula I has an imidazopyridinyl moiety is at position Ri and is unsubstituted or substituted by one or more independent R₂ substituents.

[19] In some embodiments, the compound of Formula I has a halogen at position R₂. In other embodiments, the compound of Formula I has an OH at position R₂. In other embodiments, the compound of Formula I has an OMe at position R₂. In other embodiments, the compound of Formula I has an aryl or heteroaryl moiety at position R₂ that is

unsubstituted or substituted by one or more independent R₃ substituents. In other

embodiments, the compound of Formula I has a phenyl, pyridinyl, or thiophenyl moiety at position R₂ that is unsubstituted or substituted by one or more independent R₃ substituents.

[20] In some embodiments, the compound of Formula I has a fused bicyclic ring structure at the -Ci-C₂- position. In some embodiments, the compound of Formula I has a ΓΝ CO at the -Ci-C2-position. In other embodiments, the compound of Formula I

has a

-Ci-C2-position. In other embodiments, the compound of

Formula I has

position.

[21] In some embodiments, the compound of Formula I has group at Ci that is selected from the group consisting of:

[22] In some embodiments, the compound of Formula I has group at C₂ that is selected from the group consisting of:

[23] In some embodiments, the compound of Formula I is selected from the compounds shown in Table 1.

24] In another aspect, provided herein is a compound of Formula II having the structure

CH₂-, -0-, or -NH-; R₆ is aryl or heteroaryl, each of which is unsubstituted or substituted by one or more independent R₇ substituents; R₇ is halogen, -OH, -ORio, -NR11R12, alkyl, oxo, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R₈ substituents; Rs is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R substituents; Rio, R11 and R12 are independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted by one or more independent R13 substituents; R and Ri3 are independently halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene; T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

[25] In some embodiments, T is selected from the group consisting of: -NH₂, -OH, -

; and m, when present, is 0, 1 , 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1 or 2. In some embodiments, the Ri of the Formula II compound represents an aryl, unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the Ri of the Formula II compound is a heteroaryl, unsubstituted or substituted by one or more independent R₂ substituents. In some embodiments, the Ri of the Formula II compound represents a phenyl moiety unsubstituted or substituted by one or more independent R₂ substituents. In some embodiments, the Ri of the Formula II compound represents a pyridinyl moiety unsubstituted or substituted by one or more independent R₂ substituents.

[26] In some embodiments, the A of the Formula II compound is O. In other

embodiments, the A of the Formula II compound is NH.

[27] In some embodiments, the Formula II compound is selected from the compounds shown in Table 1.

[28] In another aspect, provided herein is a compound of Formula III having the structure:

(III)

wherein A is a bond, O, NH, or -C(O)-; n is 0 or 2; R14 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted by one or more independent Ri₅ substituents; Ri₅ is halogen, ORis, NR19R20, oxo, alkyl, cycloalkyl, heteroalkyl,

heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent Ri₆ substituents; Ri₆ is halogen, OH, alkyl, alkoxy, cyano, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R₁₇ substituents; Ri8, Ri and R₂o are independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R₂i substituents; R17 and R₂i are independently halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene; Ci is cycloalkyl or heterocycloalkyl; C₂ is a bond, cycloalkyl, heterocycloalkyl, arylene, or heteroarylene; wherein Ci and C₂ may form a fused or spiro bicyclic ring; and T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

[29] In some embodiments, the A of the Formula III compound represents O. In other embodiments, the A of the Formula III compound represents -C(O)-. In other embodiments, the A of the Formula III compound represents a bond.

[30] In some embodiments, the n of the Formula III compound represents 0. In other embodiments, the n of the Formula III compound represents 1. In other embodiments, the n of the Formula III compound represents 2.

[31] In some embodiments, the C₂ of the Formula III compound represents a bond. In some embodiments, the C₂ of the Formula III compound represents a pyridinyl.

[32] In some embodiments, the Ci of the Formula III compound is selected from the group consisting of:

[33] In some embodiments, the Ri of the Formula III compound is an aryl or heteroaryl moiety unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the Ri of the Formula III compound is a phenyl moiety unsubstituted or substituted by one or more independent R₂ substituents. In other embodiments, the Ri of the

Formula . In other embodiments, Ri of the Formula III compou

represents . i_n other embodiments, Ri represents a pyridinyl moiety unsubstituted or substituted by one or more independent R₂ substituents. In other

embodiments, the Ri of the Formula III compound represents . In other embodiments, the Ri of the Formula III compound represents

[34] In some embodiments, the R₂ of the Formula III compound represents a halogen, other embodiments, the R₂ of the Formula III compound represents an alkyl. In other embodiments, the R₂ of the Formula III compound represents a -CH₃.

[35] In some embodiments, T is selected from the group consisting of: -NH₂, -OH, -

NHR 38a

; and m, when present, is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1 or 2.

[36] In some embodiments, the Formula III compound is selected from the compounds shown in Table 1.

[37] In other embodiments, a compound of structure (V) is provided:

(V)

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein R ,

.1 2 _T pi 2 _P3 >30a >30b >31a >31b _r)32a _r)32b r,33a r,33b 1 2 3 _A 4

L,L,T, G,G,G,G,R ,R ,R ,R ,R ,R ,R ,R ,η,η,η and n are as defined herein.

[38] Also provided in various different embodiments, is a compound of structure (VI):

(VI)

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, B, C, L^la, L², T, G³, G⁴, R^32a, R^32b, R^33a, R^33b, R^37a, R^37e, n³, n⁴ and m are as defined herein.

[39] In some embodiments, provided herein is a compound having the following structure (V):

(V) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: R¹ is aryl or heteroaryl; R^30a and R^30b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^30a and R^30b join to form oxo or a carbocyclic or heterocyclic ring; or R^30a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, C3-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^30b joins

3 lb 31 3 lb

with R to form a carbocyclic or heterocyclic ring; R ^a and R are, at each occurrence, independently H, halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^31a and R^31b join to form oxo or a carbocyclic or heterocyclic ring; or R^31a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci- Cealkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and

31b 30b 32 32b

R joins with R to form a carbocyclic or heterocyclic ring; R ^a and R are, at each occurrence, independently H, halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^32a and R^32b join to form oxo or a carbocyclic or heterocyclic ring; or R^32a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or

32b 33b 33 aminocarbonyl and R joins with R to form a carbocyclic or heterocyclic ring; R ^a and R^33b are, at each occurrence, independently H, halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or

33 33b 33

R"^a and R^e join to form oxo or a carbocyclic or heterocyclic ring; or R ^a is H,

halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring; L¹ is carbonyl, -NHC(=0)-, alkylene, alkenylene, heteroalkylene, heterocycloalkylene, heteroarylene, alkylenecarbonyl, alkenylenecarbonyl, heteroalkylenecarbonyl,

heterocycloalkylenecarbonyl or heteroarylenecarbonyl; L 2 is a bond or alkylene; G 1 , G2 , G 3 and G⁴ are each independently N or CR, where R is H, cyano, halo or Ci-Cealkyl; n¹, n², n³ and n⁴ are each independently 1, 2 or 3; and T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

[40] In some embodiments, provided herein is a compound having the following structure

(VI):

(VI)

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: A is CR^37b, N or NR^38a; B is CR^37c, N, NR^38b or S; C is CR^37d, N, NR^38c or S; G³ and G⁴ are each independently N or CR, wherein R is H, cyano, halo or C¹-C⁶alkyl; L^la is a bond, -NH-,

2 32 32b

alkylene or heteroalkylene; L is a bond or alkylene; R ^a and R are, at each occurrence, independently H, halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^32a and R^32b join to form oxo or a carbocyclic or heterocyclic ring; or R^32a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci- C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring; R^33a and R^33b are, at each occurrence, independently H, halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^33a and R^33b join to form oxo or a carbocyclic or heterocyclic ring; or R^33a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or

aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring; R 37^{" a}, R 37^"b ,

R 37^{" c}, R 37^"d and R 37^{" e} are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-C₆alkyl, Ci-Cealkylsulfonyl, Ci-C₆haloalkyl, C₃-C₈cycloalkyl, Ci-C₆alkoxy, Ci- C₆hydroxylalkyl, Ci-Cealkoxyalkyl, Ci-Ceaminoalkyl, heterocyclyl, amino, aminoaryl, aminoheteroaryl, aryl or heteroaryl; or R^37a and R^37e join to form a carbocyclic or heterocyclic ring; R^38a, R^38b and R^38c are each independently H, Ci-C₆alkyl or aryl; n³ and n⁴ are each independently 1, 2 or 3; m is 0 or 1; is a single or double bond such that all valences are satisfied; and T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

[41] In some embodiments, provided herein is a compound having the following structure (VII):

(VII)

2 32 32b

[42] In some embodiments of the compounds provided herein, R¹ is aryl or heteroaryl. In some embodiments, R¹ is substituted with one or more substituents, for example, fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano. In some embodiments, R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl. In some embodiments, said aryl is substituted with one or more halo substituents.

[43] In some embodiments of the compounds provided herein, T is selected from the group consisting of:

-NH -OH, -NHR 38a

I ^{NH H}

and ; and m, when present, is 0, 1, 2, or 3.

[44] In some embodiments of the compounds provided herein, L is heteroalkylene. In some embodiments, L^la is -NH- or heteroalkylene. In some embodiments, L² is a bond. In

30 30b 31 31b some embodiments, R ^a and R join to form oxo. In some embodiments, R ^a and R join to form oxo. In some embodiments, R^32a and R^32b join to form oxo. In some embodiments, R^33a and R^33b join to form oxo.

[45] These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE FIGURES

[46] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[47] Fig. 1 Shows the enzymatic activity of Ras.

[48] Fig. 2 Shows a signal transduction pathway for Ras.

[49] Fig. 3 Shows some common oncogenes, their respective tumor type and cumulative mutation frequencies (all tumors).

DETAILED DESCRIPTION

[50] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

All patents and publications referred to herein are incorporated by reference.

[51] As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[52] "Amino" refers to the -NH₂ radical. [53] "Carboxy" or "carboxyl" refers to the -C0₂H radical.

[54] "Cyano" refers to the -CN radical.

[55] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[56] "Imino" refers to the =NH substituent.

[57] "Nitro" refers to the -N0₂ radical.

[58] "Oxo" refers to the =0 substituent.

[59] "Thioxo" refers to the =S substituent.

[60] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (Ci-Ci₂ alkyl), preferably one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-C₆ alkyl), and which is attached to the rest of the molecule by a single bond, e.g. , methyl, ethyl, n-propyl, 1 -methylethyl (z^'so-propyl), n-butyl, n-pentyl, 1,1 -dimethyl ethyl (t-butyl),

3-methylhexyl, 2-methylhexyl, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl,

penta-l,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkyl includes alkenyls (one or more carbon-carbon double bonds) and alkynyls (one or more carbon-carbon triple bonds). Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

[61] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted.

[62] "Alkenylene" is an alkylene, as defined above, which comprises one or more carbon- carbon double bonds. Unless stated otherwise specifically in the specification, an alkenylene is optionally substituted

[63] "Alkylenecarbonyl" refers to a radical of the formula -C(=0)R_a-, where R_a is an alkylene chain as defined above. Unless stated otherwise specifically in the specification, an alkylenecarbonyl is optionally substituted. [64] "Alkenylenecarbonyl" refers to an alkylenecarbonyl, as defined above, which comprises one or more carbon-carbon double bonds. Unless stated otherwise specifically in the specification, an alkenylenecarbonyl is optionally substituted.

[65] "Alkoxy" refers to a radical of the formula -OR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[66] "Alkylamino" refers to a radical of the formula -NHR_a or -NR_aR_a where each R_a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group is optionally substituted.

[67] "Aminoalkyl" refers to an alkyl group comprising at least one amino substituent. The amino substituent can be on a tertiary, secondary or primary carbon. Unless stated otherwise specifically in the specification, an aminoalkyl group is optionally substituted.

[68] "Alkylaminoalkyl" refers to an alkyl group comprising at least one alkylamino substituent. The alkylamino substituent can be on a tertiary, secondary or primary carbon. Unless stated otherwise specifically in the specification, an alkylaminoalkyl group is optionally substituted.

[69] "Aminocarbonyl" refers to a radical of the formula -C(=0)NR_aR_b, where R_a and R_b are each independently H or alkyl. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[70] "Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

[71] "Arylene" refers to a divalent aryl group which links the rest of the molecule (e.g., compound of structure I- VI) to a radical group and/or to the rest of the molecule. Unless stated specifically otherwise, an arylene is optionally substituted.

[72] "Aralkyl" refers to a radical of the formula -R_b-R_c where R_b is an alkylene chain as defined above and R_c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group is optionally substituted.

[73] "Carboxyalkyl" refers to a radical of the formula -R_b-R_c where R_b is an alkylene chain as defined above and R_c is a carboxy group as defined above. Unless stated otherwise specifically in the specification, carboxyalkyl group is optionally substituted.

[74] "Cyanoalkyl" refers to a radical of the formula -R_b-R_c where R_b is an alkylene chain as defined above and R_c is a cyano group as defined above. Unless stated otherwise specifically in the specification, a cyanoalkyl group is optionally substituted.

[75] "Cycloalkyl" or "carbocyclic ring" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl,

7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A "cycloalkenyl" is a cycloalkyl comprising one or more carbob-carbon double bonds within the ring. Unless otherwise stated specifically in the specification, a cycloalkyl (or cycloalkenyl) group is optionally substituted.

[76] The term "bicycloalkyl" refers to a structure consisting of two cycloalkyl moieties, unsubstituted or substituted, that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be "fused". Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. If the cycloalkyl moieties have more than two atoms in common they are said to be "bridged". Examples include, but are not limited to, bicyclo[3.2.1]heptyl ("norbornyl"), bicyclo[2.2.2]octyl, and the like.

[77] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[78] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, comprising of at least one carbon atoms and at least one heteroatom selected from the group comprising of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be

quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. The alkyl portion of the moiety is unsubstituted or substituted.

[79] "Heteroalkylene" refers to an alkylene group comprising at least one heteroatom (e.g.,

N, O or S). In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene comprises at least one carbon-heteroatom-carbon bond. In other

embodiments, the heteroatom is at a terminus of the alkylene and thus serves to join the alkylene to the remainder of the molecule (e.g., M1-H-A-M2, where Ml and M2 are portions of the a molecule, H is a heteroatom and A is an alkylene). Unless stated otherwise specifically in the specification, a heteroalkylene is optionally substituted.

[80] "Heteroalkylenecarbonyl" refers to a radical of the formula -C(=0)R_a-, where R_a is a heteroalkylene chain as defined above. Unless stated otherwise specifically in the

specification, a heteroalkylenecarbonyl is optionally substituted.

[81] The term "heterobicycloalkyl" refers to a bicycloalkyl structure, which is

unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.

[82] The term "spiroalkyl" refers to a structure, which is unsubstituted or substituted, which comprises at least two cycloalkyl units joined at single carbon. In various

embodiments, the spiroalkyl rings can be 1-18 carbons.

[83] The term "heterospiroalkyl" refers to a spiroalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.

[84] "Cycloalkylalkyl" refers to a radical of the formula -R_bR_d where R_b is an alkylene chain as defined above and Rd is a cycloalkyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group is optionally substituted.

[85] "Fused" refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring is replaced with a nitrogen atom.

[86] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[87] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted. [88] "Heterocyclyl" or "heterocyclic ring" refers to a stable 3- to 18-membered

non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical is optionally oxidized; the nitrogen atom is optionally quaternized; and the heterocyclyl radical is partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

[89] "Heterocycloalkylene" refers to a divalent saturated heterocyclyl group which links the rest of the molecule (e.g., compound of structure I- VI) to a radical group and/or to the rest of the molecule. Unless stated specifically otherwise, a heterocycloalkylene is optionally substituted.

[90] "Heterocycloalkylenecarbonyl" refers to a radical of the formula -R_aC(=0)-, wherein R_a is a heterocycloalkylene as defined above. Unless stated specifically otherwise, a heterocycloalkylenecarbonyl is optionally substituted.

[91] "N-heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group is optionally substituted.

[92] "Heterocyclylalkyl" or "heterocycloalkyl" refers to a radical of the formula -RbR_e where R_b is an alkylene chain as defined above and R_e is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[93] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[¾][l,4]dioxepinyl, 1 ,4-benzodioxanyl,

benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),

benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1 -oxidopyridinyl, 1 -oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.

[94] "Heteroarylene" refers to a divalent saturated heteroaryl group which links the rest of the molecule (e.g., compound of structure I-VI) to a radical group and/or to the rest of the molecule. Unless stated specifically otherwise, a heteroarylene is optionally substituted.

[95] "Heteroarylenecarbonyl" refers to a radical of the formula -R_aC(=0)-, wherein R_a is a heteroarylene as defined above. Unless stated specifically otherwise, a heteroarylenecarbonyl is optionally substituted.

[96] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group is optionally substituted.

[97] "Heteroarylalkyl" refers to a radical of the formula -R_bR_f where R_b is an alkylene chain as defined above and R_f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted. [98] "Hydroxylalkyl" refers to an alkyl group comprising at least one hydroxyl substituent. The -OH substituent may be on a primary, secondary or tertiary carbon. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.

[99] "Thioalkyl" refers to a radical of the formula -SR_a where R_a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group is optionally substituted.

[100] The term "substituted" used herein means any of the above groups (e.g.., alkyl, alkylene, alkenylene, alkenylenecarbonyl, alkoxy, alkylamino, aminoalkyl, alkylaminoalkyl, thioalkyl, aryl, arylene, aralkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroalkylene, heteroalkylenecarbonyl, heterobicycloalkyl, spiroalkyl, heterospiroalkyl, haloalkyl, heterocyclyl, heterocycloalkylene, heterocycloalkylenecarbonyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylene, heteroarylenecarbonyl, N- heteroaryl, hydroxylalkyl, thioalkyl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced

with -NR_gR_h, -NR_gC(=0)R_h, -NR_gC(=0)NR_gR_h, -NR_gC(=0)OR_h, -NR_gS0₂R_h, -OC(=0)NR_g R_h, -OR_g, -SR_g, -SOR_g, -S0₂R_g, -OS0₂R_g, -S0₂OR_g, =NS0₂R_g, and -S0₂NR_gR_h.

"Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=0)R_g, -C(=0)OR_g, -C(=0)NR_gR_h, -CH₂S0₂R_g, -CH₂S0₂NR_gR_h. In the foregoing, R_g and R are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.

"Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or

heteroarylalkyl group. In addition, each of the foregoing substituents is optionally substituted with one or more of the above substituents.

[101] "Electrophile" or "electrophilic moiety" is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and/or an excess of electrons, for example a -SH group). Electrohiles typically are electron poor or comprise atoms which are electron poor. In certain

embodiments, an electrohile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge or is a moiety in which derealization or polarization of electrons results in one or more atom which contains a positive charge or partial positive charge. In some embodiments, the electrophiles comprise conjugated double bonds, for example an α, β -unsaturated carbonyl or α,β- unsaturated thiocarbonyl compound.

[102] A "polar group" refers to a moiety with one or more dipoles as a result of opposing charges from one or more polar bonds arranged asymmetrically. A polar bond is any bond between non-identical atoms. A polar group can be a group that is more hydrophilic than an alkyl group. In some embodiments, a polar group is a metal chelator or a metal chelator moiety. In some embodiments, a polar gorup comprises at least one heteroatom selected from S, O, and N. For example, a polar group can be an alkyl group that is substituted with one or more functional groups comprising a heteroatom. For example, a polar group can be an alkyl group substituted with one or more alcohol, ether, amine, hydroxyamine, aldehyde, ketone, ester, carboxylic acid, thiol, thioether, thiocarbonyl, sulfonate, sulfunite, phosphonate ester, amide, heterocycle and/or oxime.

[103] The term "metal chelator" or "metal chelator moiety" is any moiety capable of forming two or more separate coordinate bonds between the metal chelator group and a single central metal atom or metal ion. Metal chelators typically have at least one pair of unbonded electrons which can bind to a metal atom or metal ion. In certain embodiments, a metal chelator moiety comprises at least two heteroatoms selected from S, O, and N. In some embodiments, the metal chelator moeity is a bidentate or tridenate functional group. In some embodiments, a metal chelator moeity comprises a bidentate functional group selected from the group consisting of hydroxyamine, hydroxyamide, sulfonamide, urea, amide and oxime. In some embodiments, a metal chelator moeity comprises two or more monodentate functional groups selected from the group consisting of hydroxy, amino, ether, aldehyde, ketone, amide, thiol, thioether, heterocycle (e.g. imidazole) or oxime.

[104] The term "forming a complex" refers to two or more moieties having interactions that can occur through a direct association, an indirect association, or a combination thereof. Direct association includes, for example, covalent bonds, noncovalent bonds, Lewis acid/base interactions, hydrogen bonding, or a ligand interaction with a metal atom or ion. Indirect association includes, for example, bridging, association through an amino acid of a protien, or association through one or more molecules of a solvent, for example water.

[105] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[106] As used herein, "treatment" or "treating" refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[107] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[108] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[109] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[110] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5- disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, /?-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[Ill] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol,

2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[112] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as K-Ras, H-Ras or N-Ras G12C. Accordingly, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g. bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.

[113] The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g. bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[114] As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like.

[115] "Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

[116] An "anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. "Chemotherapy" means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.

[117] The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

[118] The term "selective inhibition" or "selectively inhibit" refers to a biologically active agent refers to the agent's ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[119] "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[120] "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non- domestic animals such as wildlife and the like.

[121] "Radiation therapy" means exposing a subject, using routine methods and

compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium- 153-EDTMP, or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.

[122] An "anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. "Chemotherapy" means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.

[123] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of structure (I)). Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American

Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[124] The term "in vivo" refers to an event that takes place in a subject's body.

[125] The invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of structure (I) being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen,

2 3 11 carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as H, H, C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labeled compounds of structure (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. H, and carbon- 14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[126] Substitution with heavier isotopes such as deuterium, i.e. H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence are preferred in some circumstances.

[127] Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate

isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[128] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[129] "Stable compound" and "stable structure" are meant to indicate 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.

[130] Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. In some embodiments, the solvent wise water, in which embodiment the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some aspects, the compound of the invention is a true solvate, while in other embodiments, the compound of the invention merely retains adventitious water or is a mixture of water plus some adventitious solvent.

[131] "Optional" or "optionally" means that the subsequently described event of

circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[132] A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. , humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[133] "Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[134] The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers,

diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the

preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefmic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[135] The present invention includes all manner of rotamers and conformationally restricted states of a compound of the invention. [136] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[137] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.

[138] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program and/or ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

Compounds

[139] In an aspect, the invention provides compounds which are capable of selectively binding to and/or modulating a Ras protein. In some embodiments, the Ras protien includes but is not limited to a mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, the compounds modulate the Ras protein by binding to or interacting with one or more amino acids and/or one or more metal ion. Some subject compounds may also perturb the switch I conformation. The binding of these compounds may disrupt Ras (non-limiting examples include, K-Ras, H-Ras or N-Ras) downstream signaling.

[140] In some embodiments, the invention rovides a compound of Formula I

Formula I

[141] In various embodiments, Y is -CH₂-, -CHR₂₂-, CO, SO or S0₂. In some embodiments, Y is -CH₂-. In some embodiments, Y is -CHR₂₂-. In some embodiments, Y is CO. In some embodiments, Y is SO. In some embodiments, Y is S0₂.

[142] In various embodiments, n is an integer with value 1-6. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. [143] In some embodiments, Ri is aryl or heteroaryl each of which is unsubstituted or substituted by one or more independent R₂ substituents. In some embodiments, Ri is substituted aryl. In some embodiments, Ri is unsubstituted aryl. In some embodiments, Ri is substituted heteroaryl. In some embodiments, Ri is unsubstituted heteroaryl. In some embodiments, Ri an aryl group substituted with one or more R₃ groups. In some

embodiments, Ri a heteroaryl group substituted with one or more R₃ groups. In some embodiments, Ri is a substituted or unsubstituted phenyl group. In some embodiments, Ri is an unsubstituted benzyl group. In some embodiments, Ri is a phenyl group substituted with one or more independent R₂ substituents. In some embodiments, Ri is an unsubstituted benzothiadiazolyl group. In some embodiments, Ri is a benzothiadiazolyl group substituted with one or more independent R₂ substituents. In some embodiments, Ri is an unsubstituted benzothiadiazolyl group. In some embodiments, Ri is a benzothiadiazolyl group substituted with one or more independent R₂ substituents. In some embodiments, Ri is an unsubstituted naphthalenyl group. In some embodiments, Ri is a naphthalenyl group substituted with one or more independent R₂ substituents. In some embodiments, Ri is an imidazopyridinyl naphthalenyl group. In some embodiments, Ri is an imidazopyridinyl group substituted with one or more independent R₂ substituents.

[144] In some embodiments, Ri is an unsubstituted phenyl group. In some embodiments, Ri is a substituted phenyl group (Formula la). In some embodiments, Ri is a phenyl group with a halogen substituent at the 4-position of the phenyl ring. In some embodiments, Ri is a phenyl substituted with a substituted or unsubstituted aryl at the 5 -position. In some embodiments, Ri is a phenyl substituted with a substituted or unsubstituted heteroaryl at the 5 -position. In some embodiments, Ri is a phenyl substituted with a substituted or unsubstituted cycloalkyl at the 5 -position. In some embodiments, Ri is a phenyl substituted with a substituted or unsubstituted heterocycloaryl (heteroaryl) at the 5-position. In some embodiments, Ri is a phenyl with an alkoxy substituent at the 2 position of the phenyl ring. In some embodiments, Ri is a phenyl with methoxy substituent at the 2 position of the phenyl ring. In some embodiments, Ri is a phenyl group with a methoxy substituent at the 2 position, a halogen substituent at the 4 position and an aryl or heteroaryl substituent (both of which are substituted or unsubstituted) at the 5 position of the phenyl ring.

Formula la, Ri = Ph

[145] In some embodiments, Ri is capable of reversible interaction with a K-Ras, H-Ras or N-Ras G12C mutant protein. In some embodiments, Ri has high affinity towards K-Ras, H- Ras or N-Ras and is highly specific towards G12C K-Ras, H-Ras or N-Ras. In some embodiments, Ri is capable of hydrophobic interaction with K-Ras, H-Ras or N-Ras G12C. In some embodiments, Ri is able to form hydrogen bonds with various residues of G12C K- Ras, H-Ras or N-Ras protein. In some embodiments, Ri interacts with one or more of G10, R68, Y71, Y96 or Q99 residues in K-Ras G12C. In some embodiments, Ri interacts with the G10 residue of K-Ras G12C. In some embodiments, Ri interacts with the R68 residue of K- Ras G12C. In some embodiments, Ri interacts with the Y71 residue of K-Ras G12C. In some embodiments, Ri interacts with the Y96 residue of K-Ras G12C. In some embodiments, Ri interacts with the Q99 residue of K-Ras G12C.

[146] In some embodiments, R₂ is, at each occurrence, independently halogen, oxo, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylene, or substituted or unsubstituted arylene heteroaryl ene, each of which is unsubstituted or substituted by one or more independent R₃ substituents. In some embodiments, R₂ is halogen. In some embodiments, R₂ is hydroxy. In some embodiments, R₂ is an alkoxy group substituted with one or more R₃ substituents. In some embodiments, R₂ is an unsubstituted alkoxy group. In some embodiments, R₃ is an alkyl group substituted with one or more R₃ groups. In some embodiments, R₂ is an unsubstituted alkyl group. In some embodiments, R₂ is a heteroalkyl group substituted with one or more R₃ groups. In some embodiments, R₂ is an unsubstituted heteroalkyl group. In some embodiments, R₂ a cycloalkyl group substituted with one or more R₃ groups. In some embodiments, R₂ is an unsubstituted cycloalkyl group. In some embodiments, R₂ is a heterocycloalkyl substituted with one or more R₃ groups. In some embodiments, R₂ is an unsubstituted heterocycloalkyl group. In some embodiments, R₂ is an aryl substituted with one or more R₃ groups. In some embodiments, R₂ is an

unsubstituted aryl group. In some embodiments, R₂ is a heteroaryl group substituted with one or more R₃ groups. In some embodiments, R₂ unsubstituted a heteroaryl group. In some embodiments, R₂ is an arylene substituted with one or more R₃ groups. In some embodiments, R₂ is an unsubstituted arylene group. In some embodiments, R₂ is a heteroarylene group substituted with one or more R₃ groups. In some embodiments, R₂ unsubstituted a heteroarylene group. In some embodiments, R₂ is halogen. In some embodiments, R₂ is hydroxy. In some embodiments, R₂ is alkoxy. In some embodiments, R₂ is methoxy. In some embodiments, R₂ is oxo.

[147] R₃ is halogen, OH, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene. In some embodiments, R₃ is halogen. In some embodiments, R₃ is hydroxy. In some embodiments, R₃ is cyano. In some embodiments, R₃ is unsubstituted alkyl. In some embodiments, R₃ is an alkyl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted alkoxy. In some embodiments, R₃ is an alkoxy substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted cycloalkyl. In some embodiments, R₃ is a cycloalkyl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted hetero alkyl. In some embodiments, R₃ is a hetero alkyl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted heterocycloalkyl. In some embodiments, R₃ is a heterocycloalkyl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted aryl. In some embodiments, R₃ is an aryl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted heteroaryl. In some embodiments, R₃ is a heteroaryl substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted arylene. In some embodiments, R₃ is an arylene substituted with one or more R₄ groups. In some embodiments, R₃ is unsubstituted heteroarylene. In some embodiments, R₃ is a heteroarylene substituted with one or more R₄ groups. In some embodiments, R₃ is halogen. In some embodiments, R₃ is hydroxyl. In some embodiments, R₃ is cyano.

[148] In various embodiments, R₄ is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene moiety. In some embodiments, R₄ is halogen. In some embodiments, R₄ is hydroxyl. In some embodiments, R₄ is cyano. In some embodiments, R₄ is an alkyl. In some embodiments, R₄ is an alkoxy. In some embodiments, R₄ is a cycloalkyl. In some embodiments, R₄ is heteroalkyl. In some embodiments, R₄ is heterocycloalkyl. In some embodiments, R₄ is aryl. In some embodiments, R₄ is heteroaryl. In some embodiments, R₄ is arylene, in some embodiments, R₄ is heteroarylene.

[149] In various embodiments, Ci is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, Ci is a cycloalkylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted cycloalkylene. In some embodiments, Ci is a heterocycloalkylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted

heterocycloalkylene. In some embodiments, Ci is an arylene substituted with one or more R5 groups. In some embodiments, Ci is an unsubstituted arylene. In some embodiments, Ci is a heteroarylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted heteroarylene. In some embodiments, Ci is selected from:

-N N-l- , -i-

' N-S- . H-OiA _/ ''

[151] In some embodiments, R₅ is -OH. In some embodiments, R₅ is -CH₂OH. In some embodiments R₅ is alkyl. In some embodiments, R₅ is methyl.

[152] In various embodiments, C₂ is a bond, a cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. In some embodiments, C₂ is a bond. In some embodiments, C₂ is an unsubstituted cycloalkylene. In some embodiments, C₂ is an unsubstituted

heterocycloalkylene. In some embodiments, C₂ is an unsubstituted arylene. In some embodiments, C₂ is an unsubstituted heteroarylene. In some embodiments, C₂ is selected from:

[153] In some embodiments, Ci and C₂ form a fused or spiro bicyclic ring. In some embodiments, -C₁-C₂- form a fused bicylic ring. In some embodiments, -C₁-C₂- form a spiro -l-N I Ν-l·

bicyclic ring. In some embodiments, -Ci-C₂- is -^^- ⁵ . In some embodiments, -Cr

. In some embodiments, -Ci-C₂- is

[154] In various embodiments, X is O, NH, S or CR₂₃R₂₄. In some embodiments, X is O. In some embodiments, X is NH. In various embodiments, X is S. In various embodiments, X is CR₂₃R₂₄.

[155] In various embodiments, D is a bond, -NH-CH₂-, -NH-, or -CH₂-. In various embodiments, D is a bond. In various embodiments, D is -NH-CH₂-. In various embodiments, D is -NH-. In various embodiments, D is -CH₂-.

[156] R₂₂, R₂₃ and R₂₄ are each independently hydrogen, halogen, -OH, alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl.

[157] In some embodiments, T is not E. In some embodiments, E is an electrophile capable of bonding with a K-Ras, H-Ras or N-Ras protein comprising a G12C mutation. In some embodiments, the electrophile E is capable of forming an irreversible covalent bond with a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, the electrophile E binds with the cysteine residue at position 12 of a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, E is selected from:

R₂6 and R₂₇ can form cyclo alkene

N

[158] In some embodiments, E is H . In some embodiments, E is H . In

some embodiments E is

In some embodiments, E is some

embodiments, E is

[159] In some embodiments, T is a moiety that is not E. In some embodiments, E is an electrophile capable of bonding with a K-Ras, H-Ras or N-Ras protein comprising a G12C mutation. In some embodiments, the electrophile E is capable of forming an irreversible covalent bond with a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, the electrophile E may bind with the cysteine residue at the position 12 of a G12C mutant K- Ras protein. In some embodiments, E is an electrophile capable of forming a covalent bond with a residue near the Switch 2 in a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, E is an electrophilic capable of forming a covalent bond with a residue in the Switch 2 - Binding Pocket of a G12C mutant K-Ras, H-Ras or N-Ras protein.

[160] In some embodiments, T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with a Ras protein. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a polar group capable of directly or indirectly (e.g through water) forming one or more interactions with a beta-phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N- Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein.

[161] In some embodiments, T has a molecular weight less than 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 Daltons. For example, in some embodiments, T has a molecular weight less than 200 daltons. In some embodiments, T has a molecular weight of greater than 40, 50, 60, 70, 80, 90, 100, or 110 Daltons. For example, in some embodiments, T has a molecular weight of greater than 50 Daltons. In some embodiments, T has a molecular weight between about 50 and 300, 50 and 250, 50 and 200, 50 and 150, or 50 and 100 Daltons.

[162] In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 nitrogen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 oxygen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 sulfur atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S, wherein T has a molecular weight between 50 and 300 Daltons, and wherein T does not comprise an electrophilic group capable of forming a covalent bond with a cysteine. In some embodiments, T does not comprise a Michael acceptor. In some embodiments, T does not comprise an alpha-beta unsaturated carbonyl group.

163] In some embodiments, T is selected from the roup consisting of

and ; and m, when present, is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. 164] In some embodiments, T is

. In some embodiments, T is

and

[165] In some embodiments, the invention provides compounds of Formula I as shown in Table 1.

[166] In some embodiments, the invention provides compounds of Formula II

_T^^/A._Rf5

Formula II

[167] In various embodiments, A is CH₂, O- or NH. In some embodiments, A is CH₂. In some embodiments, A is O. In some embodiments, A is NH.

[168] In various embodiments, R₆ is aryl or heteroaryl moiety, each of which is either unsubstituted or substituted with one or more R₇ groups. In some embodiments, R₆ is an unsubstituted aryl. In some embodiments, R₆ is an aryl substituted with one or more R₇ groups. In some embodiments, R₆ is an unsubstituted heteroaryl. In some embodiments, R₆ is a heteroaryl substituted with one or more R₇ groups. In some embodiments, R₆ is a substituted or unsubstituted phenyl moiety. In some embodiments, R₆ is an unsubstituted phenyl moiety. In some embodiments, R₆ is a phenyl moiety substituted with one or more R₇ substituents. In some embodiments, R₆ is a substituted or unsubstituted pyridinyl moiety. In some embodiments, R₆ is an unsubstituted pyridinyl moiety. In some embodiments, R₆ is a pyridinyl moiety substituted with one or more R₇ substituents.

[169] R₇ is halogen, -OH, ORio, NRnR₁₂, oxo, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene. In some embodiments, R₇ is a halogen. In some embodiments, R₇ is OH. In some

embodiments, R₇ is ORio. In some embodiments, R₇ is NR₁₁R₁₂. In some embodiments, R₇ is unsubstituted alkyl. In some embodiments, R₇ is an alkyl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted cycloalkyl. In some embodiments, R₇ is a cycloalkyl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted heteroalkyl. In some embodiments, R₇ is a heteroalkyl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted heterocycloalkyl. In some embodiments, R₇ is a heterocycloalkyl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted aryl. In some embodiments, R₇ is an aryl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted heteroaryl. In some embodiments, R₇ is a heteroaryl substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted arylene. In some embodiments, R₇ is an arylene substituted with one or more Rs substituents. In some embodiments, R₇ is unsubstituted heteroarylene. In some embodiments, R₇ is a heteroarylene substituted with one or more Rs substituents.

[170] In various embodiments, Rs is halogen, OH, cyano, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene. In some embodiments, Rs is halogen. In some embodiments, Rs is OH. In some embodiments, Rs is cyano. In some embodiments, Rs is unsubstituted alkyl. In some embodiments, Rs is an alkyl substituted with one or more R9 groups. In some embodiments, Rs is unsubstituted alkoxy. In some embodiments, Rs is an alkoxy substituted with one or more R groups. In some embodiments, Rs is unsubstituted cycloalkyl. In some embodiments, Rs is a cycloalkyl substituted with one or more R groups. In some embodiments, Rs is unsubstituted heteroalkyl. In some embodiments, Rs is a heteroalkyl substituted with one or more R9 groups. In some embodiments, Rs is

unsubstituted heterocycloalkyl. In some embodiments, Rs is a heterocycloalkyl substituted with one or more R9 groups. In some embodiments, Rs is unsubstituted aryl. In some embodiments, Rs is an aryl substituted with one or more R groups. In some embodiments, Rs is unsubstituted heteroaryl. In some embodiments, Rs is a heteroaryl substituted with one or more R₉ groups. In some embodiments, Rs is unsubstituted arylene. In some embodiments, Rs is an arylene substituted with one or more R₉ groups. In some embodiments, Rs is unsubstituted heteroarylene. In some embodiments, Rs is a heteroarylene substituted with one or more R groups.

[171] In various embodiments, Rio is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, Rio is hydrogen. In some embodiments, Rio is unsubstituted alkyl. In some embodiments, Rio is alkyl substituted with one or more R13 groups. In some embodiments, Rio is unsubstituted cycloalkyl. In some embodiments, Rio is cycloalkyl substituted with one or more R13 groups. In some embodiments, Rio is

unsubstituted heteroalkyl. In some embodiments, Rio is heteroalkyl substituted with one or more R13 groups. In some embodiments, Rio is unsubstituted heterocycloalkyl. In some embodiments, Rio is heterocycloalkyl substituted with one or more R13 groups. In some embodiments, Rio is unsubstituted aryl. In some embodiments, Rio is aryl substituted with one or more R13 groups. In some embodiments, Rio is unsubstituted heteroaryl. In some embodiments, Rio is heteroaryl substituted with one or more R13 groups.

[172] In various embodiments, Rn is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, Rn is hydrogen. In some embodiments, Rn is unsubstituted alkyl. In some embodiments, Rn is alkyl substituted with one or more R13 groups. In some embodiments, Rn is unsubstituted cycloalkyl. In some embodiments, Rn is cycloalkyl substituted with one or more R13 groups. In some embodiments, R is

unsubstituted heteroalkyl. In some embodiments, Rn is heteroalkyl substituted with one or more R13 groups. In some embodiments, Rn is unsubstituted heterocycloalkyl. In some embodiments, Rn is heterocycloalkyl substituted with one or more R13 groups. In some embodiments, Rn is unsubstituted aryl. In some embodiments, Rn is aryl substituted with one or more R13 groups. In some embodiments, Rn is unsubstituted heteroaryl. In some embodiments, Rn is heteroaryl substituted with one or more R13 groups.

[173] In various embodiments, R12 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, R12 is hydrogen. In some embodiments, R12 is unsubstituted alkyl. In some embodiments, R12 is alkyl substituted with one or more R13 groups. In some embodiments, R12 is unsubstituted cycloalkyl. In some embodiments, R12 is cycloalkyl substituted with one or more R13 groups. In some embodiments, R12 is

unsubstituted heteroalkyl. In some embodiments, R12 is heteroalkyl substituted with one or more R13 groups. In some embodiments, R12 is unsubstituted heterocycloalkyl. In some embodiments, R12 is heterocycloalkyl substituted with one or more R13 groups. In some embodiments, R12 is unsubstituted aryl. In some embodiments, R12 is aryl substituted with one or more R13 groups. In some embodiments, R12 is unsubstituted heteroaryl. In some embodiments, R12 is heteroaryl substituted with one or more R13 groups.

[174] In various embodiments, R9 is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene. In various embodiments, R is halogen. In various embodiments, R9 is OH. In various embodiments, R9 is cyano. In various embodiments, R9 is alkyl. In various embodiments, R9 is cycloalkyl. In various embodiments, R9 is heteroalkyl. In various embodiments, R9 is heterocycloalkyl. In various embodiments, R9 is aryl. In various embodiments, R9 is heteroaryl. In various embodiments, R9 is arylene. In various embodiments, R9 is heteroarylene.

[175] In various embodiments, R13 is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene. In various embodiments, R13 is halogen. In various embodiments, R13 is OH. In various embodiments, Ri3 is cyano. In various embodiments, R13 is alkyl. In various embodiments, R13 is cycloalkyl. In various embodiments, R13 is heteroalkyl. In various embodiments, R13 is heterocycloalkyl. In various embodiments, R13 is aryl. In various embodiments, R13 is heteroaryl. In various embodiments, R13 is arylene. In various embodiments, R13 is heteroarylene.

[176] In some embodiments, T is not E. In some embodiments, E is an electrophile capable of bonding with a K-Ras, H-Ras or N-Ras protein comprising G12C mutation. In some embodiments, the electrophile E is capable of forming an irreversible covalent bond with a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, the electrophile E binds with the cysteine residue at position 12 of a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, E has the general structure

wherein: R₂₅ is alkyl; R₂₆ is cyano or alkyl or R₂₆ joins with R₂₇ to form a cycloalkene; and R₂₇ is alkyl or R₂₇ joins with R₂₆ to form a cycloalkene. In some

embodiments, not E, and E is selected from:

H . In some embodiments, E is

some embodiments, E is

[177] In some embodiments, T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with a Ras protein. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a polar group capable of directly or indirectly (e.g through water) forming one or more interactions with a beta-phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N- Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein.

[178] In some embodiments, T is a polar group capable of forming a complex with a metal ion, wherein the metal ion is complexed to a Ras protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with the metal ion. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a polar group capable of directly or indirectly (e.g through water) forming one or more interactions with a beta- phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein, and wherein T is not an eletrophile capable of forming a bond with a cysteine.

[179] In some embodiments, T has a molecular weight less than 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 Daltons. For example, in some embodiments, T has a molecular weight less than 200 daltons. In some embodiments, T has a molecular weight of greater than 40, 50, 60, 70, 80, 90, 100, or 110 Daltons. For example, in some embodiment, T has a molecular weight of greater than 50 Daltons. In some embodiments, T has a molecular weight between about 50 and 300, 50 and 250, 50 and 200, 50 and 150, or 50 and 100 Daltons.

[180] In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 nitrogen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 oxygen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 sulfur atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S, wherein T has a molecular weight between 50 and 300 Daltons, and wherein T does not comprise an electrophilic group capable of forming a covalent bond with a cysteine. In some embodiments, T does not comprise a Michael acceptor. In some embodiments, T does not comprise an alpha-beta unsaturated carbonyl group.

181] In some embodiments, T is selected from the group consisting of

and ; and m, when present, is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. 182] In some embodiments, T is

. In some embodiments, T is

0 0 and

[183] In some embodiments, R₆ is capable of reversible interaction with K-Ras, H-Ras or N-Ras G12C mutant protein. In some embodiments, the R₆ moiety has high affinity towards K-Ras, H-Ras or N-Ras and is highly specific towards G12C K-Ras, H-Ras or N-Ras. In some embodiments, R₆ is capable of hydrophobic interaction with K-Ras, H-Ras or N-Ras G12C. In some embodiments, R₆ is able to form hydrogen bonds with various residues of G12C K-Ras, H-Ras or N-Ras protein. In some embodiments, R₆ interacts with one or more of G10, R68, Y71, Y96 or Q99 residues in K-Ras G12C. In some embodiments, R₆ moiety interacts with the G10 residue of K-Ras G12C. In some embodiments, R₆ interacts with the R68 residue of K-Ras G12C. In some embodiments, R₆ interacts with the Y71 residue of K- Ras G12C. In some embodiments, R₆ interacts with the Y96 residue of K-Ras G12C. In some embodiments, R₆ interacts with the Q99 residue of K-Ras G12C.

[184] In some embodiments, the ^^^fi^ unit in Formula II provides proper length and geometry to the compound such that the electrophile E interacts with the cysteine residue at ion in G12C K-Ras, H-Ras or N-Ras protein. In some embodiments, the

also interacts with other protein backbone residues.

[185] In some embodiments, the invention provides compounds of Formula II as shown in Table 1.

[186] In some embodiments, the invention provides com ounds of Formula III

Formula III

[187] In various embodiments, A is a bond, O, NH or -(CO)-. In some embodiments, A is a bond. In some embodiments, A is O. In some embodiments, A is NH. In some embodiments, A is -C(O)-.

[188] In various embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[189] In various embodiments, R14 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety. In some embodiments, Ri₄ is an unsubstituted cycloalkyl. In some embodiments, Ri₄ is cycloalkyl substituted with one or more R15 groups. In some embodiments, Ri₄ is an unsubstituted heterocycloalkyl. In some embodiments, Ri₄ is heterocycloalkyl substituted with one or more R15 groups. In some embodiments, Ri₄ is an unsubstituted aryl. In some embodiments, Ri₄ is aryl substituted with one or more R15 groups. In some embodiments, Ri₄ is an unsubstituted heteroaryl. In some embodiments, Ri₄ is heteroaryl substituted with one or more R15 groups. In some embodiments, Ri₄ is an unsubstituted phenyl. In some

embodiments, Ri₄ is phenyl substituted with one or more R15 groups.

[190] In various embodiments, R15 is halogen, ORis, NR19R20, oxo, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent R3 substituents. In some embodiments, R15 is halogen. In some embodiments, R15 is cyano. In some embodiments, R15 is NR19R20. In some embodiments, R15 is oxo. In some embodiments, R15 is ORis. In some embodiments, R 5 is unsubstituted alkyl. In some embodiments, R 5 is an alkyl substituted with one or more Ri₆ groups. In some embodiments, R15 is unsubstituted alkoxy. In some embodiments, Ri₆ is an alkoxy substituted with one or more R½ groups. In some

embodiments, R15 is unsubstituted cycloalkyl. In some embodiments, R15 is a cycloalkyl substituted with one or more Ri₆ groups. In some embodiments, R15 is unsubstituted heteroalkyl. In some embodiments, R15 is a heteroalkyl substituted with one or more Ri₆ groups. In some embodiments, R15 is unsubstituted heterocycloalkyl. In some embodiments, Ri5 is a heterocycloalkyl substituted with one or more R½ groups. In some embodiments, R15 is unsubstituted aryl. In some embodiments, R15 is an aryl substituted with one or more Ri₆ groups. In some embodiments, R15 is unsubstituted heteroaryl. In some embodiments, R15 is a heteroaryl substituted with one or more Ri₆ groups. In some embodiments, R15 is

unsubstituted arylene. In some embodiments, R15 is an arylene substituted with one or more Ri6 groups. In some embodiments, R15 is unsubstituted heteroarylene. In some embodiments, Ri5 is a heteroarylene substituted with one or more Ri₆ groups

[191] In various embodiments, Ri₆ is halogen, OH, oxo, cyano alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene, each of which is unsubstituted or substituted by one or more independent Rn substituents. In some embodiments, Ri₆ is halogen. In some embodiments, Ri₆ is OH. In some embodiments, Ri₆ is cyano. In some embodiments, R½ is unsubstituted alkyl. In some embodiments, R½ is an alkyl substituted with one or more Rn groups. In some embodiments, R½ is unsubstituted alkoxy. In some embodiments, Ri₆ is an alkoxy substituted with one or more Rn groups. In some embodiments, Ri₆ is unsubstituted cycloalkyl. In some embodiments, Ri₆ is a cycloalkyl substituted with one or more Rn groups. In some embodiments, Ri₆ is

unsubstituted heteroalkyl. In some embodiments, Ri₆ is a heteroalkyl substituted with one or more Rn groups. In some embodiments, Ri₆ is unsubstituted heterocycloalkyl. In some embodiments, Ri₆ is a heterocycloalkyl substituted with one or more Rn groups. In some embodiments, Ri₆ is unsubstituted aryl. In some embodiments, Ri₆ is an aryl substituted with one or more Rn groups. In some embodiments, R½ is unsubstituted heteroaryl. In some embodiments, Ri₆ is a heteroaryl substituted with one or more Rn groups. In some embodiments, Ri₆ is unsubstituted arylene. In some embodiments, Ri₆ is an arylene substituted with one or more Rn groups. In some embodiments, R½ is unsubstituted heteroarylene. In some embodiments, R½ is a heteroarylene substituted with one or more Rn groups. [192] In various embodiments, Ris is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, Ris is hydrogen. In some embodiments, Ris is unsubstituted alkyl. In some embodiments, Ris is alkyl substituted with one or more R₂i groups. In some embodiments, Ris is unsubstituted cycloalkyl. In some embodiments, Ris is cycloalkyl substituted with one or more R₂i groups. In some embodiments, Ris is

unsubstituted heteroalkyl. In one embodiments, Ris is heteroalkyl substituted with one or more R₂i groups. In some embodiments, Ris is unsubstituted heterocycloalkyl. In some embodiments, Ris is heterocycloalkyl substituted with one or more R₂i groups. In some embodiments, Ris is unsubstituted aryl. In some embodiments, Ris is aryl substituted with one or more R₂i groups. In some embodiments, Ris is unsubstituted heteroaryl. In some embodiments, Ris is heteroaryl substituted with one or more R₂i groups.

[193] In various embodiments, R1 is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, R1 is hydrogen. In some embodiments, R1 is unsubstituted alkyl. In some embodiments, R1 is alkyl substituted with one or more R₂i groups. In some embodiments, R19 is unsubstituted cycloalkyl. In some embodiments, R19 is cycloalkyl substituted with one or more R₂i groups. In some embodiments, R19 is

unsubstituted heteroalkyl. In some embodiments, R19 is heteroalkyl substituted with one or more R₂i groups. In some embodiments, R19 is unsubstituted heterocycloalkyl. In some embodiments, R19 is heterocycloalkyl substituted with one or more R₂i groups. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is aryl substituted with one or more R₂i groups. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is heteroaryl substituted with one or more R₂i groups.

[194] In various embodiments, R₂₀ is hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl. In some embodiments, R₂₀ is hydrogen. In some embodiments, R₂₀ is unsubstituted alkyl. In some embodiments, R₂₀ is alkyl substituted with one or more R₂i groups. In some embodiments, R₂₀ is unsubstituted cycloalkyl. In some embodiments, R₂₀ is cycloalkyl substituted with one or more R13 groups. In some embodiments, R₂₀ is

unsubstituted heteroalkyl. In some embodiments, R₂₀ is heteroalkyl substituted with one or more R₂i groups. In some embodiments, R₂₀ is unsubstituted heterocycloalkyl. In some embodiments, R₂₀ is heterocycloalkyl substituted with one or more R₂i groups. In some embodiments, R₂₀ is unsubstituted aryl. In some embodiments, R₂₀ is aryl substituted with one or more R₂i groups. In some embodiments, R₂₀ is unsubstituted heteroaryl. In some embodiments, R₂₀ is heteroaryl substituted with one or more R₂i groups.

[195] In various embodiments, Rn is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene. In various embodiments, Rn is halogen. In various embodiments, Rn is OH. In various embodiments, Rn is cyano. In various embodiments, Rn is alkyl. In various embodiments, Rn is cycloalkyl. In various embodiments, Rn is heteroalkyl. In various embodiments, Rn is heterocycloalkyl. In various embodiments, Rn is aryl. In various embodiments, Rn is heteroaryl. In various embodiments, Rn is arylene. In various embodiments, Rn is heteroarylene.

[196] In various embodiments, R₂i is halogen, OH, cyano, alkyl, alkoxy, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, arylene, or heteroarylene. In various embodiments, R₂i is halogen. In various embodiments, R₂i is OH. In various embodiments, R₂i is cyano. In various embodiments, R₂i is alkyl. In various embodiments, R₂i is cycloalkyl. In various embodiments, R₂i is heteroalkyl. In various embodiments, R₂i is heterocycloalkyl. In various embodiments, R₂i is aryl. In various embodiments, R₂i is heteroaryl. In various embodiments, R₂i is arylene. In various embodiments, R₂i is heteroarylene.

[197] In various embodiments, Ci is a substituted or unsubstituted alkyl, embodiments, Ci is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, Ci is a cycloalkylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted cycloalkylene. In some embodiments, Ci is a

heterocycloalkylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted heterocycloalkylene. In some embodiments, Ci is an arylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted arylene. In some embodiments, Ci is a heteroarylene substituted with one or more R₅ groups. In some embodiments, Ci is an unsubstituted heteroarylene. In some embodiments, Ci is selected from the group consisting of

[

In some embodiments, Ci is ,

[199] In some embodiments, R₅ is -OH. In some embodiments, R₅ is -CH₂OH, in some embodiments, R5 is alkyl.

[200] In various embodiments, C₂ is a bond, a cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. In some embodiments, C₂ is a bond. In some embodiments, C₂ is an unsubstituted cycloalkylene. In some embodiments, C₂ is an unsubstituted

heterocycloalkylene. In some embodiments, C₂ is an unsubstituted arylene. In some embodiments, C₂ is an unsubstituted heteroarylene. In some embodiments, C₂ is selected form the group consisting of

[201] In some embodiments, Ci and C₂ form a fused or spiro bicyclic ring. In some embodiments, -Ci-C₂- form a fused bicylic ring. In some embodiments, -Ci-C₂- form a spiro

bicyclic ring. In some embodiments, -Ci-C₂- is . In some embodiments, -Ci-

C₂-

j_{n some} embodiments, -Ci-C₂- is

[202] In some embodiments, T is not E. In some embodiments, E is an electrophile capable of bonding with a K-Ras, H-Ras or N-Ras protein comprising G12C mutation. In some embodiments, the electrophile E is capable of forming an irreversible covalent bond with a G12C mutant K-Ras, H-Ras or N-Ras protein. In some embodiments, E has the general structure

O

^N ^_R27

R R

^{25 26} , wherein R₂₅ is alkyl, R₂₆ is cyano or alkyl, R₂₇ is alkyl, or R₂₆ and R₂₇ together with the carbons to which they are attached form cycloalkene. In some of the foregoing embodiments of compounds of Formula III, T is not E, and E is selected from:

e

mbodiments, E is . In some

embodiments, E is

. In some embodiments, E is

[203] In some embodiments, T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with a Ras protein. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a polar group capable of directly or indirectly (e.g through water) forming one or more interactions with a beta-phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N- Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein.

[204] In some embodiments, T has a molecular weight less than 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 Daltons. For example, in some embodiments, T has a molecular weight less than 200 Daltons. In some embodiments, T has a molecular weight of greater than 40, 50, 60, 70, 80, 90, 100, or 110 Daltons. For example, in some embodiments, T has a molecular weight of greater than 50 Daltons. In some embodiments, T has a molecular weight between about 50 and 300, 50 and 250, 50 and 200, 50 and 150, or 50 and 100 Daltons.

[205] In some embodiments, T is an optionally substituted alkyl group comprising at least 1 , 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 nitrogen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 oxygen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 sulfur atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S, wherein T has a molecular weight between 50 and 300 Daltons, and wherein T does not comprise an electrophilic group capable of forming a covalent bond with a cysteine. In some embodiments, T does not comprise a Michael acceptor. In some embodiments, T does not comprise an alpha-beta unsaturated carbonyl group.

206] In some embodiments, T is selected from the group consisting of

and ; and m, when present, is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. 207] In some embodiments, T is

. In some embodiments, T is

and

[208] In some embodiments, R 4 is capable of reversible interaction with a K-Ras, H-Ras or N-Ras G12C mutant protein. In some embodiments, the R14 moiety has high affinity towards K-Ras, H-Ras or N-Ras and is highly specific towards G12C K-Ras, H-Ras or N-Ras. In some embodiments, R14 IS capable of hydrophobic interaction with K-Ras, H-Ras or N-Ras G12C. In some embodiments, R14 is able to form hydrogen bonds with various residues of G12C K-Ras, H-Ras or N-Ras protein. In some embodiments, R14 interacts with one or more of G10, R68, Y71, Y96 or Q99 residues in K-Ras G12C. In some embodiments, R14 moiety interacts with the G10 residue of K-Ras G12C. In some embodiments, R14 interacts with the R68 residue of K-Ras G12C. In some embodiments, R14 interacts with the Y71 residue of K- Ras G12C. In some embodiments, R14 interacts with the Y96 residue of K-Ras G12C. In some embodiments, R14 interacts with the Q99 residue of K-Ras G12C.

[209] In some embodiments, th

in Formula III provides proper length and geometry to the compound such that the T group is able to interact with a metal ion bound to a Ras protein such as K-Ras, H-Ras or N-Ras protein. In some embodiments, the

also interacts with other protein backbone residues.

[210] In some embodiments, the invention provides compounds of Formula III as shown in Table 1.

[211] In still other embodiments, the invention provides a compound having the following structure (Formula V):

(Formula V)

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:

R¹ is aryl or heteroaryl;

R^30a and R^30b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 30 ^a and R 30b join to form a carbocyclic or heterocyclic ring; or R 30 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^30b joins with R^31b to form a carbocyclic or heterocyclic ring;

R^31a and R^31b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 31 ^a and R31b join to form a carbocyclic or heterocyclic ring; or R 31 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^31b joins with R^30b to form a carbocyclic or heterocyclic ring;

R ^a and R are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32 ^a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring; R ^a and R are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33 ^a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;

L¹ is carbonyl, -NHC(=0)-, alkylene, alkenylene, heteroalkylene,

heterocycloalkylene, heteroarylene, alkylenecarbonyl, alkenylenecarbonyl,

heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl;

L is a bond or alkylene;

G¹, G², G³ and G⁴ are each independently N or CR, where R is H, cyano, halo or Ci-

Cealkyl;

n¹, n², n³ and n⁴ are each independently 1, 2 or 3; and

T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K- Ras, H-Ras or N-Ras G12C mutant protein. In some embodiments, T is a polar group capable of forming a direct complex with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a polar group capable of forming an indirect complex with a metal ion, for example T is capable of forming a complex through one or more water molecules, wherein the metal ion is complexed to a Ras protein.

[212] In some embodiments of the compounds of structure V, L¹ is carbonyl, -NHC(=0)-, alkylene, heteroalkylene, alkylenecarbonyl or heteroalkylenecarbonyl.

[213] In some other embodiments, the compound has the following structure (Formula Va):

(Formula Va)

wherein: L^la is a bond, -NH-, alkylene, alkeneylene, heteroalkylene, heterocycloalkylene or heteroarylene.

[214] In other embodiments of compound (Formula Va), L^la is a bond, -NH-, alkylene or heteroalkylene

[215] In various other embodiments, R¹ is aryl. For example, in some embodiments, the aryl is bicyclic, such as a fused bicyclic aryl. In some more specific embodiments, the aryl is naphthyl.

[216] In various other embodiments, the aryl is monocyclic. For example, in some embodiments, the aryl is phenyl.

[217] In some of the foregoing embodiments, the aryl is unsubstituted. In other of the foregoing embodiments, the aryl is substituted with one or more substituents. For example, in some embodiments, the substituents are selected from halo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-C₆alkyl, Ci-Cealkylsulfonyl, Ci-C₆haloalkyl, Cs-Cscycloalkyl, Ci-C₆alkoxy, Ci- C₆hydroxylalkyl, Ci-Cealkoxyalkyl, Ci-Ceaminoalkyl, aliphatic heterocyclyl, heteroaryl and aryl.

[218] In other embodiments, the aryl substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclopropyl and phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano.

[219] In some different embodiments, the substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, cyclopropyl and phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from halo, hydroxyl and cyano.

[220] In other exemplary embodiments, the aryl substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, methyl, ethyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-C6alkyl, halo, hydroxyl and cyano

[221] In some more embodiments, the substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, methyl, ethyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from halo, hydroxyl and cyano.

[222] In still more embodiments, the substituents are selected from fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano. [223] In some more specific embodiments, the substituents are selected from fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from halo, hydroxyl and cyano. For example, in some embodiments, the cyclopropyl comprises a geminal difluoro substitution.

224] In still other embodiments, R¹ has one of the following structures:

[225] In still other embodiments, R¹ has one of the following structures:

[226] In still other embodiments, R is heteroaryl. For example, in some embodiments, the heteroaryl is bicyclic, such as a fused bicyclic heteroaryl.

[227] In some more embodiments, the heteroaryl is monocyclic. [228] In some of the foregoing embodiments, the heteroaryl comprises nitrogen, sulfur or a combination thereof. For example, in some embodiments, the heteroaryl is

dihydroquinoxalinyl, indolyl, benzimidazolyl, pyridinyl or thiazolyl.

[229] In some embodiments, the heteroaryl is unsubstituted. In some other embodiments, the heteroaryl is substituted with one or more substituents. In some embodiments, the substituents are selected from Ci-C₆alkyl, halo and oxo. For example, in some embodiments, the substituents are selected from halo and oxo. In other embodiments, the substituents are selected from ethyl and chloro. In some more specific embodiments, the substituents are chloro.

[230] In some embodiments of the forgoing compounds of structure (V), R¹ has one of the following structures:

wherein R ^a is, at each occurrence, independently H, Ci-C₆alkyl or halo.

[231] In various other embodiments, R¹ has one of the following structures:

wherein R ^a is, at each occurrence, independently H or halo.

[232] In still other embodiments of structure (V), R¹ has one of the following structures:

[233] In some embodiments, Q is -C(=0)-. In some other embodiments, Q is -S(=0)₂-. In still other embodiments, Q is -NR³⁴C(=0)-. In still more other embodiments, Q is - NR³⁴S(=0)₂-.

[234] In some embodiments, T is not E. In some embodiments, T is not E, and E has one of the following structures:

is

[235] In some embodiments, T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with a Ras protein. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a polar group capable of directly or indirectly (e.g through water) forming one or more interactions with a beta-phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N- Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein. [236] In some embodiments, T has a molecular weight less than 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 Daltons. For example, in some embodiments, T has a molecular weight less than 200 Daltons. In some

embodiments, T has a molecular weight of greater than 40, 50, 60, 70, 80, 90, 100, or 110 Daltons. For example, in some embodiments, T has a molecular weight of greater than 50 Daltons. In some embodiments, T has a molecular weight between about 50 and 300, 50 and 250, 50 and 200, 50 and 150, or 50 and 100 Daltons.

[237] In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 nitrogen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 oxygen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 sulfur atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S, wherein T has a molecular weight between 50 and 300 Daltons, and wherein T does not comprise an electrophilic group capable of forming a covalent bond with a cysteine. In some embodiments, T does not comprise a Michael acceptor. In some embodiments, T does not comprise an alpha-beta unsaturated carbonyl group.

238] In some embodiments, T is selected from the group consisting of

is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1 , 2, or 3. In some embodiments, m is 1 or 2. 239] In some embodiments, T is

. In some embodiments, T is

s O O and

[240] In some more of the foregoing embodiments, L¹ is heteroalkylene. In some more embodiments, the heteroalkylene is unsubstituted. In some different embodiments, the heteroalkylene is substituted.

[241] In various other embodiments, L¹ is aminoalkylene. For example, in some embodiments, L¹ is -CH₂CH₂NH-.

[242] In other embodiments of the foregoing, L¹ is heterocycloalkylene or heteroarylene. In some embodiments, the heterocycloalkylene or heteroarylene is unsubstituted. In other embodiments, the heterocycloalkylene or heteroarylene is substitu In some further

embodiments, L¹ has one of the following structures:

[243] In some different embodiments, L^la is a bond.

[244] In some embodiments, L^la is alkylene, alkenylene, heteroalkylene or

heterocycloalkylene. In some other embodiments, L^la is alkylene or heteroalkylene. In some of these embodiments, L^la is substituted alkylene. In various other embodiments, L^la is

unsubstituted alkylene. For example, in some embodiments, L l ^a is or

[245] In some different embodiments, L^la is substituted heteroalkylene. In some other embodiments, L^la is unsubstituted heteroalkylene. In some of the foregoing embodiments, L^la is aminoalkylene or thioalkylene, for example aminoalkylene. For example, in some embodiments, L^la has one of the following structures:

[246] In other embodiments, L ^a is

[247] In other embodiments, L^la is substituted alkenylene. In different embodiments, L^la is unsubstituted alkenylene. In some more specific embodiments, L^la has the following structure:

[248] In yet other embodiments, L^la is substituted heterocycloalkylene. In some other embodiments, L^la is unsubstituted heterocycloalkylene. For Example, in some embodiments, l^a has the following structure:

2

[249] In some of the foregoing embodiments, L is a bond.

[250] In various other embodiments, L is substituted alkylene. In still other embodiments, L is unsubstituted alkylene.

[251] In various embodiments of any of the foregoing compounds of structure (V): R^30a and R^30b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl;

R^31a and R^31b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl;

R^32a and R^32b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; and

R^33a and R^33b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl.

[252] In other embodiments, R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a and R^33b are selected from H, Ci-Cealkyl, hydroxylalkyl, cyano, cyanoalkyl and aminocarbonyl, for example H, Ci- Cealkyl, hydroxylalkyl, cyano, and aminocarbonyl or in other embodiments, H, Ci-Cealkyl and hydroxylalkyl.

[253] In some of the foregoing embodiments, at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, _R33a _{or R}33b _{is H For example? in some} embodiments, each of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is H.

[254] In some other of the foregoing embodiments, at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is hydroxylalkyl.

[255] In still other of the foregoing embodiments, at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is cyano.

[256] In still more of the foregoing embodiments of compound (V), at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is aminocarbonyl.

[257] In other embodiments, at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is Ci-Cealkyl.

[258] In some embodiments, R^30a and R^30b join to form a carbocyclic or heterocyclic ring. In different embodiments, R^31a and R^31b join to form a carbocyclic or heterocyclic ring. In more embodiments, R^32a and R^32b join to form a carbocyclic or heterocyclic ring. In yet other embodiments, R^33a and R^33b join to form a carbocyclic or heterocyclic ring.

[259] In even other embodiments, R^30a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^30b joins with R^31b to form a carbocyclic or heterocyclic ring. [260] In more embodiments, R^31a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^31b joins with R^30b to form a carbocyclic or heterocyclic ring.

[261] In other embodiments, R^32a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring.

[262] In still more embodiments, R^33a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^33b joins with R^32b to form a carbocyclic or heterocyclic ring.

[263] In some other embodiments, the compound is selected from a compound in Table 1.

[264] Compounds of structure V are prepared according to procedures well-known or derivable by one of ordinary skill in the art, for example by procedures analogous to those exemplified in general schemes or examples provided below. Each of the compounds in Table 1 was prepared in such a manner and analyzed by mass spectrometry. The mass spectrum ([M+H⁺] or [M+Na⁺]) was found to be consistent with at least one of the structures in Table 1.

[265] General Reaction Scheme I illustrates an exemplary procedure for preparing compounds of structure (V).

[266] General Reaction Scheme I

(V') (V") (Va)

[267] Referring to General Reaction Scheme I, (V) and (V") are available from commercial sources and/or are easily prepared according to procedures known in the art. All variables on

(V) and (V"), with the exception of M¹, are as defined above. In some procedures, M¹ is

NH. Briefly, an appropriately substituted acid (V) is activated and reacted with an appropriately substituted heterocycle (V") under appropriate coupling conditions. The L -T moiety may be present in (V") as illustrated or may be installed after coupling For example L -T may be installed before or after coupling via acylation (or thioacylation) using a reagent such as an acid chloride or thionyl chloride.

[268] It should be noted that variations of the above procdure are possible, some of which are exemplified in the examples. For example, in some procedures (V") is moncyclic and the second cyclic moiety is added after the coupling step. In other procedures, the acid moiety is present on the cyclic moiety (V") and R¹ is appropriately substituted with a nucleophilic moiety to enable coupling to form (Va).

[269] Various other options are available to one of ordinary skill in the art to add various substituents and or modify or reorder the above described steps to arrive at different embodiments of compounds of structure V. It should also be noted that various substitutions on (V) and/or (V") can be present during the coupling step (in protected or unprotected form) or the substituents can be added after (V) and (V") are coupled. Methods for inclusion of these substituents are known in the art.

[270] It is understood that although an exemplary procedure to prepare (Va) is provided above, other compounds of structure (V) can be prepared by analogous methods. For example, the carbonyl of (Va) may be reduced to form compounds of structure (V) wherein L¹ does not comprise a carbonyl. Embodiments, wherein L¹ is heterocycloalkylene or heteroarylene can be prepared from analogous methods, for example by use of Buchwald chemistry to include the heterocycloalkylene or heteroarylene portion. Other methods for preparation of different compounds of structure (V) are known in the art.

[271] Briefly, an appropriately substituted acid is reacted with an appropriately substituted heterocycle under amide coupling conditions. Acylation (or thioacylation) using a reagent such as an acid chloride or thionyl chloride results in compounds of structure V. Various options are available to one of ordinary skill in the art to add various substituents and/or modify or reorder the above described steps to arrive at different embodiments of compounds of structure V. The appropriate acid is purchased commercially or made according to well- known procedures.

[272] In still other embodiments, the invention provides a compound having the structure of Formula VI or II:

(FormulaVI) (Formula VII)

A is CR^37b, N or NR^38a;

B is CR^37c, N, NR^38b or S;

C is CR^37d, N, NR^38c or S;

G³ and G⁴ are each independently N or CR, wherein R is H, cyano, halo or C - C⁶alkyl;

L^la is a bond, -NH-, alkylene or heteroalkylene;

L is a bond or alkylene;

R^32a and R^32b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32 ^a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring;

R^33a and R^33b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33 ^a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;

37^" 37^"b 37^" 37^"d 37^"

R ^a, R , R ^c, R and R ^e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-C₆alkyl, Ci-C₆alkylsulfonyl, Ci-Cehaloalkyl, Cs-Cscycloalkyl, Ci- Cealkoxy, Ci-Cehydroxylalkyl, Ci-C₆alkoxyalkyl, Ci-C₆aminoalkyl, heterocyclyl, amino, aminoaryl, aminoheteroaryl, aryl or heteroaryl; or R^37a and R^37e join to form a carbocyclic or heterocyclic ring;

R^38a, R^38b and R^38c are each independently H, Ci-C₆alkyl or aryl;

n³ and n⁴ are each independently 1, 2 or 3;

m is 0 or 1 ;

is a single or double bond such that all valences are satisfied; and

T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K- Ras, H-Ras or N-Ras G12C mutant protein. [273] In various other embodiments, the compound has one of the following structures (Via), (VIb), Vic), (VId), (Vie), (Vlf) or (VIg):

(Vie (Vlf)

(vig).

[274] In various other embodiments, the compound has one of the following structures (Vila), (Vllb) (VIIc), (Vlld), (Vile), (Vllf) or (Vllg):

(Vila) (Vllb)

IIc) (Vlld)

(vug).

[275] In some specific embodiments of the foregoing compounds of structure (VI) and (VII), and substructures thereof, R^37a is halo, aryl or heteroaryl. In further such embodiments, R³⁵ and R³⁶ are each H.

[276] In various other embodiments, G³ is N and G⁴ is CR, for example CH.

[277] In some different embodiments, G³ is CR, for example, CH, and G⁴ is N.

[278] In still other embodiments, G³ is N and G⁴ is N.

[279] 3 4 3

In various other embodiments, n is 2 and n is 2. In still other embodiments, n is 1 and n⁴ is 1. In some more embodiments, n³ is 2 and n⁴ is 1.

[280] In other of the foregoing embodiments, R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, -OH, halo, oxo, Ci-C₆alkyl, Ci-C₆alkoxy, heterocyclyl or aryl.

[281] In still other embodiments, R^37a, R^37b, R^37c, R^37d and R^37e are each independently

H, -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.

[282] In some embodiments, R^37a or R^37e is aryl. In some more specific embodiments, R^37a is aryl, such as phenyl.

[283] In some different embodiments, the aryl is unsubstituted. In some other

embodiments, the aryl is substituted. For example, in some embodiments, the aryl is substituted with one or more halo substituents. In some of these embodiments, the halo substituents are selected from fluoro and chloro.

[284] In still other embodiments, R^37a is heteroaryl. In some of these embodiments, the heteroaryl is unsubstituted. In various other embodiments, the heteroaryl is substituted. In some more embodiments, the heteroaryl comprises nitrogen, sulfur or a combination thereof.

[285] In some more specific embodiments, the heteroaryl is thiophenyl.

[286] In other of the foregoing embodiments, R^37a is halo. For example, in some embodiments, halo is chloro, bromo or iodo.

[287] In some embodiments, R^37a or R^37e has one of the following structures:

[289] In various different embodiments, R ^a, R and R ^c are each independently H or aryl. In still other embodiments, R 3 § ^a, R 3 Sfo and R 3 § ^c are each independently H.

[290] In some other different embodiments, R^38c is aryl. For example, in some

embodiments, the aryl is substituted with one or more halo substituents. In some of these embodiments, halo is chloro.

[291] In some other embodiments of the compounds of structure (VI) and (VII), Q is - C(=0)-. In some other embodiments, Q is -S(=0)₂-. In still other embodiments, Q is - NR³⁴C(=0)-. In still more other embodiments, Q is - NR³⁴S(=0)₂-.

[292] In some more specific embodiments, R³⁴ is H. For example, in some embodiments, R³⁴ is hydroxylalkyl, such as 2-hydroxylalkyl.

[293] In other of the foregoing embodiments, at least one of R³⁵ or R³⁶ is H. For example, in some embodiments, each of R³⁵ and R³⁶ are H. [294] In various other embodiments, R³⁶ is alkylaminoalkyl. For example, in some embodiments, R³⁶ has the following structure:

[295] In some different embodiments, R³⁶ is hydroxylalkyl, for example 2-hydroxylalkyl.

[296] In various other embodiments, R³⁵ and R³⁶ join to form a ring. In some of these embodiments, the ring is a cyclopentene, cyclohexene or phenyl ring.

[297] In some embodiments, T is not E. In some embodiments, T is not E, and E has one of the following structures:

is

[298] In some embodiments, T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein. The T group can form a direct or indirect (i.e. through one or more water molecules) complex with a Ras protein. In some embodiments, T is a polar group capable of forming a bond with a metal ion, wherein the metal ion is complexed to a Ras protein. In some embodiments, T is a metal chelating moiety. In some embodiments, T is a polar group capable of directly or indirectly (e.g.

through water) forming one or more interactions with a beta-phosphate of nucleotide (GDP) or G12D residue of a Ras protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras wild-type protein. In other embodiments, the Ras protein is a K-Ras, H-Ras or N- Ras mutant protein. In some embodiments, the Ras protein is a K-Ras, H-Ras or N-Ras G12C mutant protein.

[299] In some embodiments, T has a molecular weight less than 400, 350, 300, 250, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 Daltons. For example, in some embodiments, T has a molecular weight less than 200 Daltons. In some embodiments, T has a molecular weight of greater than 40, 50, 60, 70, 80, 90, 100, or 110 Daltons. For example, in some embodiments, T has a molecular weight of greater than 50 Daltons. In some embodiments, T has a molecular weight between about 50 and 300, 50 and 250, 50 and 200, 50 and 150, or 50 and 100 Daltons.

[300] In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 nitrogen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 oxygen atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, or 5 sulfur atoms. In some embodiments, T is an optionally substituted alkyl group comprising at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 heteroatoms selected from N, O, and S, wherein T has a molecular weight between 50 and 300 Daltons, and wherein T does not comprise an electrophilic group capable of forming a covalent bond with a cysteine. In some embodiments, T does not comprise a Michael acceptor. In some embodiments, T does not comprise an alpha-beta unsaturated carbonyl group.

301] In some embodiments, T is selected from the group consisting of

and ; and m, when present, is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 1,2, or 3. In some embodiments, m is 1 or 2. 302] In some embodiments, T is

In some embodiments, T is

[303] In some more of the foregoing embodiments, L¹ is heteroalkylene. In some more embodiments, the heteroalkylene is unsubstituted. In some different embodiments, the heteroalkylene is substituted.

[304] In various other embodiments, L¹ is aminoalkylene. For example, in some embodiments, L¹ is -CH₂CH₂NH-.

[305] In some different embodiments, L^la is a bond.

[306] In some embodiments, L^la is alkylene, alkenylene, heteroalkylene or

unsubstituted alkylene. For example, in some embodiments, L ^a is or

[307] In some different embodiments, L^la is substituted heteroalkylene. In some other embodiments, L^la is unsubstituted heteroalkylene. In some of the foregoing embodiments, L^la is aminoalkylene or thioalkylene, for example aminoalkylene. For example, in some embodiments, L^la has one of the following structures:

In other embodiments, L^la is

[309] In other embodiments, L^la is substituted alkenylene. In different embodiments, L^la is unsubstituted alkenylene. In some more specific embodiments, L^la has the following structure:

[310] In yet other embodiments, L^la is substituted heterocycloalkylene. In some other embodiments, L^la is unsubstituted heterocycloalkylene. For Example, in some embodiments, l^a has the following structure:

2

[311] In some of the foregoing embodiments, L is a bond.

[312] In various other embodiments, L is substituted alkylene. In still other embodiments, L is unsubstituted alkylene.

[313] In some embodiments of any of the foregoing compounds of structure (VI) or (VII):

R^32a and R^32b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; and

R^33a and R^33b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl.

[314] In other embodiments, R^32a, R^32b, R^33a or R^33b are selected from H, Ci-C₅alkyl, hydroxylalkyl, cyano, cyanoalkyl and aminocarbonyl, for example H, hydroxyl alkyl and cyano.

[315] In other of the foregoing embodiments, at least one of R^32a, R^32b, R^33a or R^33b is H.

32 32b 33 33b

For example, in some embodiments, each of R , R' , R"^a or R is H.

[316] In other of the foregoing embodiments, at least one of R^32a, R^32b, R^33a or R^33b is hydroxylalkyl.

[317] In still other embodiments, at least one of R^32a, R^32b, R^33a or R^33b is cyano. [318] In some other different embodiments, at least one of R^32a, R^32b, R^33a or R^33b is aminocarbonyl.

[319] In some embodiments, R^32a and R^32b join to form a carbocyclic or heterocyclic ring. In other embodiments, R^33a and R^33b join to form a carbocyclic or heterocyclic ring.

[320] In different embodiments, R^32a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring.

[321] In still other embodiments, R^33a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃- Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^33b joins with R^32b to form a carbocyclic or heterocyclic ring.

[322] In some more specific embodiments, the compound is selected from a compound in Table 1.

[323] Compounds of structure VI and VII are prepared according to procedures well-known or derivable by one of ordinary skill in the art, for example by procedures analogous to those exemplified in general reaction scheme II or other examples provided below. Each of the compounds in Table 1 was prepared in such a manner and analyzed by mass spectrometry. The mass spectrum ([M+H⁺] or [M+Na⁺]) was found to be consistent with the structures in Table 1.

[324] General Reaction Scheme II illustrates an exemplary procedure for preparing compounds of structure (VI) and (VII).

[325] General Reaction Scheme II

[326] Referring to General Reaction Scheme II, (VI'), (VII'), (VI") and (VII") are available from commercial sources and/or are easily prepared according to procedures known in the art. All variables on (VF), (VII'), (VI") and (VII"), with the exception of M¹ and M², are as 1 2 1 defined above. In some procedures, M is NH and M is absent. In other procedures M is N or CH and M² is a precursor to L^la which reacts with an activated acid. For example, in various procedures M is NH₂, aminoalkyl or other heterosubstituted alkyl. Embodiments where M 2 comprises a carbanion (or M 1 is a carbanion) are also contemplated such that L 1 is alkylene. Briefly, an appropriately substituted acid (VI') or (VII") is activated and reacted with an appropriately substituted ring (VI") or (VII') under appropriate coupling conditions. The L -T moiety may be present in (VI") or (VII") as illustrated or may be installed after coupling For example L -T may be installed before or after coupling via acylation (or thioacylation) using a reagent such as an acid chloride or thionyl chloride.

[327] It should be noted that variations of the above procedure are possible, some of which are exemplified in the examples. For example, in some procedures, the acid moiety is present on the cyclic moiety (VI") and (VI') is appropriately substituted with a nucleophilic moiety to enable coupling to form (VI). Other methods of bond formation which do not require reaction of an activated acid are also available for preparation of the compounds. It should also be noted that various substitutions on (VI'), (VII'), (VI") and/or (VII") can be present during the coupling step (in protected or unprotected form) or the substituents can be added after (VI') and (VI") or (VII') and (VII") are coupled. Methods for inclusion of these substituents are known in the art.

[328] Various options are available to one of ordinary skill in the art to add various substituents and or modify or reorder the above described steps to arrive at different embodiments of compounds of structure VI and VII. The appropriate acid is purchased commercially or made according to well-known procedures.

[329] It will also be appreciated by those skilled in the art that in the processes described herein (e.g., General Reaction Scheme I and II and the below examples) the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl,

benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), /?-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

[330] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of this invention are included within the scope of the invention.

[331] It is also understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is further understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of of the invention not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention.

Table 1

Synthesis of Compounds

[332] Compounds of Formula I- VII can be synthesized according to the general schemes described herein. For example, compound 2 (l-((4,5-dichloro-2-hydroxyphenyl)glycyl)-N- hydroxypiperidine-4-carboxamide) is synthesized according to the following scheme:

[333] The aniline was coupled to ethyl glyoxylate via reductive animation to form the corresponding amino ester. The ester was hydrolyzed with lithium hydroxide and

subsequently acidified to form the corresponding acid. The acid was coupled to an amino ester to form the corresponding amide. The ester was functionalized to form a variety of analogs, for example, the ester was coupled to hydroxylamine to form the corresponding hydroxyamide (compound 2).

[334] Analogously, further derivatives can be synthesized via a similar synthetic approach. For example, compound 10 (l-(4-(azetidin-3-yl)piperazin-l-yl)-2-((4,5-dichloro-2- hydroxyphenyl)amino)ethan-l-one) is synthesized according to the scheme:

[335] Additionally, the amino acid intermediate can be formed via demethylation of ethyl 2- (4,5-dichloro-2-methoxyphenylamino)acetate with BBr₃ in dichloromethane followed by hydrolysis of the ester with lithium hydroxide. The corresponding acid is alkylated with an amine, for example, tert-butyl 3-(piperazin-l-yl)azetidine-l-carboxylate to from the amide. The amine is deprotected via HCl/MeOH, and compound 10 is isolated via known techniques.

[336] Using a modified approach, compound 12 (3-(4-((4,5-dichloro-2- hydroxyphenyl)glycyl)piperazin-l-yl)azetidine-l-carbaldehyde) is synthesized according to the following scheme:

[337] Hydrolysis of ethyl 2-(4,5-dichloro-2-methoxyphenylamino)acetate with aqueous lithium hydroxide and subsequent acidification furnishes the corresponding acid. Coupling to tert-butyl 3-(piperazin-l-yl)azetidine-l-carboxylate to form the amide was achieved via BOP and diisopropyl ethyl amine in DMF. The Boc group was removed via HCl/methanol, and the resulting amine was coupled to formic acid via addition of BOP and DIPEA in DMF to furnish the corresponding formamide. The methyl group was removed to via BBr₃ in dichloromethane to give the corresponding phenol product, compound 12.

[338] The following synthetic scheme was used to synthesize compound 23 (l-(4-(2',6- dichloro-4-hydroxy-[ 1 , 1 '-biphenyl]-3-carbonyl)piperazin- 1 -yl)propan- 1 -one) :

[339] An amide coupling between 2',6-dichloro-4-methoxybiphenyl-3-carboxylic acid and tert-butyl piperazine-l-carboxylate was achieved via BOP and DIPEA in DMF. The resulting coupled product was deprotected with HCl/methanol to give the corresponding HC1 ammonium salt. The amine was formed via addition of TEA, and acylated with propionyl chloride to furnish the corresponding amide. The methyl group was removed with BBr₃ to furnish compound 23.

[340] The following synthetic scheme was used to synthesize compound 28 (N-hydroxy-1- (1 -(2',5',6-trichloro-4-hydroxy-[ 1 , 1 '-biphenyl]-3-carbonyl)piperidin-3-yl)azetidine-3- carboxamide):

Methyl azetidine-3-carboxylate and tert-butyl 3-oxopiperidine-l-carboxylate are coupled together via reductive amination in the presence of triacetoxyborohydride and TEA. The Boc group is removed from the resulting coupled product with HCl/methanol to form the corresponding deprotected amine. The amine is coupled to an acid, for example, 2',5',6- trichloro-4-methoxybiphenyl-3-carboxylic acid, with BOP and DIPEA in DMF to form the corresponding amide. The ester is hydrolyzed with 1 N sodium hydroxide and dioxane and subsequently coupled to hydroxylammonium chloride with BOP and DIPEA in DMF. The methyl group is removed with BBr₃ to furnish compound 28.

Pharmaceutical Compositions

[341] Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the foregoing compounds and a

pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.

[342] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[343] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[344] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that are used in some embodiments. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[345] In some embodiments, a compound of the invention is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes are used as appropriate. In some embodiments, a single dose of a compound of the invention is used for treatment of an acute condition.

[346] In some embodiments, a compound of the invention is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some embodiments, continuous dosing is achieved and maintained as long as necessary.

[347] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[348] In some embodiments, the compounds of the invention are administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[349] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds.,

Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &

Wilkinsl999).

[350] Provided herein are pharmaceutical compositions comprising a compound of structure (I-VII) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which compounds of structure (I-VII) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of structure (I-VII).

[351] A pharmaceutical composition, as used herein, refers to a mixture of a compound of structure (I-VII) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds of structure (I-VII) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[352] In one embodiment, one or more compounds of structure (I-VII) is formulated in an aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compound of structure (I-VII) is/are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments, wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.

[353] In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[354] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,

hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as:

polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[355] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.

[356] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[357] In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.

Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of the active compounds (e.g., compounds of structure (I-VII)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection

suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[358] In still other embodiments, the compounds of structure (I-VII) are administered topically. The compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[359] In yet other embodiments, the compounds of structure (I-VII) are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of structure (I-VII) is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of structure (I-VII). In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[360] In other embodiments, the compounds of structure (I-VII) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of any of compound of structure (I-VII) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator, are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[361] In still other embodiments, the compounds of structure (I-VII) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[362] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into

preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a compound of structure (I-VII) are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[363] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of structure (I-VII), described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.

[364] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[365] In some embodiments, pharmaceutical composition comprising at least one compound of structure (I- VII) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[366] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross- linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[367] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of structure (I- VII). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[368] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[369] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[370] Other useful pharmaceutical compositions optionally include one or more

preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[371] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. [372] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[373] In certain embodiments, aqueous suspension compositions are packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[374] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

[375] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1 % to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001%) to about 0.05%> w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[376] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%>, 70%>, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

[377] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 1 1%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

[378] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.

[379] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

[380] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[381] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

[382] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits/ Articles of Manufacture

[383] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[384] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[385] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the

pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods

[386] The present invention provides a method of inhibiting Ras-mediated cell signaling comprising contacting a cell with an effective amount of one or more compounds disclosed herein. Inhibition of Ras-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include a showing of (a) a decrease in GTPase activity of Ras; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream in the Ras pathway, such as a decrease in pMEK level; and/or (e) a decrease in binding of Ras complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above. [387] The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions implicated by K-Ras, H-Ras or N-Ras mutation, H-Ras mutation and/or N-Ras mutation (e.g., cancer).

[388] The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions implicated by G12C G12D, G12S, G12V, and/or G13D mutations in K-Ras, H- Ras and/or N-Ras, (e.g., cancer).

[389] In some embodiments, a method for treatment of cancer is provided, the method comprising administering an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of structure (I) to a subject in need thereof. In some embodiments, the cancer is mediated by a K-Ras, H-Ras or N-Ras G12C mutation. In other embodiments, the cancer is pancreatic cancer, colon cancer, MYH associated polyposis, colorectal cancer or lung cancer.

[390] In some embodiments, the invention provides method of treating a disorder in a subject in need thereof, wherein the said method comprises determining if the subject has a K-Ras, H-Ras or N-Ras G12C mutation and if the subject is determined to have the K-Ras, H-Ras or N-Ras G12C mutation, then administering to the subject a therapeutically effective dose of at least one compound of structure (I) or a pharmaceutically acceptable salt, ester, prodrug, tautomer, solvate, hydrate or derivative thereof.

[391] The disclosed compounds strongly inhibit anchorage-independent cell growth and therefore have the potential to inhibit tumor metastasis. Accordingly, in another embodiment the disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount a pharmaceutical composition of comprising any of the compounds disclosed herein and a pharmaceutically acceptable carrier to a subject in need thereof.

[392] Ras mutations including but not limited to K-Ras, H-Ras or N-Ras mutations have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow and/or lymph nodes). Accordingly, certain embodiments, are directed to

administration of a disclosed compounds (e.g., in the form of a pharmaceutical composition) to a patient in need of treatment of a hematological malignancy. Such malignancies include, but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronic myelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/ or other leukemias. In other embodiments, the compounds are useful for treatment of lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma.

[393] Determining whether a tumor or cancer comprises a Ras mutation including but not limited to a K-Ras, H-Ras or N-Ras mutation can be undertaken by assessing the nucleotide sequence encoding the Ras protein, by assessing the amino acid sequence of Ras protein, or by assessing the characteristics of a putative Ras mutant protein. The sequence of wild-type human Ras proteins including but not limited to K-Ras, H-Ras or N-Ras is known in the art, (e.g. Accession No. NP203524).

[394] Methods for detecting a mutation in a Ras nucleotide sequence including but not limited to K-Ras, H-Ras or N-Ras nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for Ras mutations including but not limited to K-Ras, H-Ras or N-Ras mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the Ras mutation including but not limited to K-Ras, H-Ras or N-Ras mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the Ras mutation including but not limited to a K-Ras, H-Ras or N- Ras mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the Ras gene or corresponding K-Ras, H-Ras or N-Ras gene, for example. This technique will identify all possible mutations in the region sequenced.

[395] Methods for detecting a mutation in a Ras protein including but not limited to a K- Ras, H-Ras or N-Ras protein are known by those of skill in the art. These methods include, but are not limited to, detection of a K-Ras, H-Ras or N-Ras mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[396] Methods for determining whether a tumor or cancer comprises a Ras mutation including but not limited to a K-Ras, H-Ras or N-Ras mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is taken from a subject having a cancer or tumor. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[397] The invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, said method relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and

osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,

neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer,

retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some embodiments, said method relates to the treatment of a non-cancerous

hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).

[398] In certain particular embodiments, the invention relates to methods for treatment of lung cancers, the methods comprise administering an effective amount of any of the above described compound (or a pharmaceutical composition comprising the same) to a subject in need thereof. In certain embodiments, the lung cancer is a non-small cell lung carcinoma (NSCLC), for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In other embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

[399] Subjects that can be treated with compounds of the invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative of said compounds, according to the methods of this invention include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers (e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer,

esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer,

nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Viral-Induced cancer. In some embodiments, subjects that are treated with the compounds of the invention include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).

[400] The invention further provides methods of modulating a mutant Ras including but not limited to a mutant K-Ras, H-Ras or N-Ras protein activity by contacting the protein with an effective amount of a compound of the invention. Modulation can be inhibiting or activating protein activity. In some embodiments, the invention provides methods of inhibiting protein activity by contacting the mutant Ras protein (for example, a Mutant K-Ras, H-Ras or N-Ras protein) with an effective amount of a compound of the invention in solution. In some embodiments, the invention provides methods of inhibiting the mutant Ras protein activity by contacting a cell, tissue, organ that express the protein of interest. In some embodiments, the invention provides methods of inhibiting protein activity in subject including but not limited to rodents and mammal (e.g., human) by administering into the subject an effective amount of a compound of the invention. In some embodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[401] In some embodiments, the invention provides methods of inhibiting Ras activity including but not limited to K-Ras, H-Ras or N-Ras mutant activity in a cell by contacting said cell with an amount of a compound of the invention sufficient to inhibit the activity of Ras or a K-Ras, H-Ras or N-Ras mutant in said cell. In some embodiments, the invention provides methods of inhibiting Ras or mutant K-Ras, H-Ras or N-Ras activity in a tissue by contacting said tissue with an amount of a compound of the invention sufficient to inhibit the activity of mutant Ras or including but not limited to mutant K-Ras, H-Ras or N-Ras in said tissue. In some embodiments, the invention provides methods of inhibiting Ras including but not limited to mutant K-Ras, H-Ras or N-Ras activity in an organism by contacting said organism with an amount of a compound of the invention sufficient to inhibit the activity of Ras including but not limited to mutant K-Ras, H-Ras or N-Ras in said organism. In some embodiments, the invention provides methods of inhibiting Ras including but not limited to mutant K-Ras, H-Ras or N-Ras activity in an animal by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of Ras including but not limited to mutant K-Ras, H-Ras or N-Ras in said animal. In some embodiments, the invention provides methods of inhibiting Ras including but not limited to mutant K-Ras, H- Ras or N-Ras activity in a mammal by contacting said mammal with an amount of a compound of the invention sufficient to inhibit the activity of Ras including but not limited to mutant K-Ras, H-Ras or N-Ras in said mammal. In some embodiments, the invention provides methods of inhibiting Ras including but not limited to mutant K-Ras, H-Ras or N- Ras activity in a human by contacting said human with an amount of a compound of the invention sufficient to inhibit the activity of Ras including but not limited to mutant K-Ras, H-Ras or N-Ras in said human. The present invention provides methods of treating a disease mediated by Ras including but not limited to mutant K-Ras, H-Ras or N-Ras activity in a subject in need of such treatment.

[402] The present invention also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the invention with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.

[403] Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention. In some embodiments, the

chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[404] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non- peptide small molecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin as well as a host of

chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine,

cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,

CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate;

hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine;

PSK.RTM.; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol;

mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid;

esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (NolvadexTM), raloxifene, aromatase inhibiting 4(5)- imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;

methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;

navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;

camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17- demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV

(chemotherapy), Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC- 1 , Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN- 38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfm, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,

Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

[405] This invention further relates to a method for using the compounds or pharmaceutical compositions provided herein, in combination with radiation therapy for inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.

[406] Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term

"brachytherapy," as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended without limitation to include exposure to radioactive isotopes (e.g. At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non- limiting example, the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.

[407] Without being limited by any theory, the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.

[408] The compounds or pharmaceutical compositions of the invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[409] Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX- 11 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the invention and pharmaceutical

compositions described herein. Anti-angiogenesis agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab.

Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24,1996), WO 96/27583 (published March 7,1996), European Patent Application No. 97304971.1 (filed July 8,1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26,1998), WO 98/03516 (published January 29,1998), WO 98/34918 (published August 13,1998), WO 98/34915 (published August 13,1998), WO 98/33768 (published August 6,1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13,1994), European Patent Publication 931, 788 (published July 28,1999), WO 90/05719 (published May 31,1990), WO 99/52910 (published October 21,1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17,1999), PCT International Application No. PCT/IB98/01113 (filed July 21,1998), European Patent Application No. 99302232.1 (filed March 25,1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12,1999), United States Patent 5,863, 949 (issued January 26,1999), United States Patent 5,861, 510 (issued January 19,1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or AMP-9 relative to the other matrix- metalloproteinases (i. e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, andMMP-13). Some specific examples of MMP inhibitors useful in the invention are AG-3340, RO 32-3555, and RS 13-0830.

Ill [410] Autophagy inhibitors include, but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin Al, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used.

[411] The invention also relates to a method of and to a pharmaceutical composition for treating a cardiovascular disease in a mammal which comprises an amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate or derivative thereof, or an isotopically-labeled derivative thereof, and an amount of one or more therapeutic agents use for the treatment of cardiovascular diseases.

[412] Exemplary agents for use in cardiovascular disease applications are anti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolytic agents, e.g., streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) and clopidrogel, vasodilating agents, e.g., nitrates, calcium channel blocking drugs, anti-proliferative agents, e.g., colchicine and alkylating agents, intercalating agents, growth modulating factors such as interleukins, transformation growth factor-beta and congeners of platelet derived growth factor, monoclonal antibodies directed against growth factors, anti-inflammatory agents, both steroidal and non-steroidal, and other agents that can modulate vessel tone, function, arteriosclerosis, and the healing response to vessel or organ injury post intervention.

Antibiotics can also be included in combinations or coatings comprised by the invention. Moreover, a coating can be used to effect therapeutic delivery focally within the vessel wall. By incorporation of the active agent in a swellable polymer, the active agent will be released upon swelling of the polymer.

[413] In some embodiments, the compounds described herein are formulated or

administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.

[414] In some embodiments, medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5- dichloro-a-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the

medicaments are used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimize the activity and/or stability of the medicament.

[415] Other exemplary therapeutic agents useful for a combination therapy include but are not limited to agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[416] Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5- hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids,

prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.

[417] Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, agents for the treatment of

hypercholesterolemia, and agents for the treatment of dyslipidemia.

[418] Other therapeutic agents contemplated include drugs used for control of gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease. Therapeutic agents used to treat protozoan infections, drugs used to treat Malaria, Amebiasis, Giardiasis,

Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the

chemotherapy of helminthiasis. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, β-lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretro viral agents and antiretro viral agents.

[419] Examples of therapeutic antibodies that can be combined with a compound of the invention include but are not limited to anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

[420] Moreover, therapeutic agents used for immunomodulation, such as

immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein. In addition, therapeutic agents acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.

[421] For treating renal carcinoma, one may combine a compound of the present invention with sorafenib and/or avastin. For treating an endometrial disorder, one may combine a compound of the present invention with doxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). For treating ovarian cancer, one may combine a compound of the present invention with cisplatin (carboplatin), taxotere, doxorubincin, topotecan, and/or tamoxifen. For treating breast cancer, one may combine a compound of the present invention with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib,

PD0325901, avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer, one may combine a compound of the present invention with taxotere (taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/or avastin.

[422] Further therapeutic agents that can be combined with a compound of the invention are found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[423] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments, the one or more compounds of the invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously.

Alternatively, a compound of the invention and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present invention can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the invention and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[424] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

EXAMPLES

EXAMPLE 1

BIOCHEMICAL AND CELLULAR ASSAYS OF THE COMPOUNDS

Inhibition of Cell Growth:

[425] The ability of the subject compounds to inhibit Ras-mediated cell growth is assessed and demonstrated as follows. Cells expressing a wildtype or a mutant Ras are plated in white, clear bottom 96 well plates at a density of 5,000 cells per well. Cells are allowed to attach for about 2 hours after plating before a compound disclosed herein is added. After certain hours (e.g., 24 hours, 48 hours, or 72 hours of cell growth), cell proliferation is determined by measuring total ATP content using the Cell Titer Glo reagent (Promega) according to manufacturer's instructions. Proliferation EC50s are determined by analyzing 8 point compound dose responses at half-log intervals decreasing from 100 μΜ.

Inhibition of Ras-mediated signaling transduction:

[426] The ability of the compounds disclosed herein in inhibiting Ras-mediated signaling is assessed and demonstrated as follows. Cells expressing wild type or a mutant Ras (such as G12C, G12D, G12V, or G12A) are treated with or without (control cells) a subject compound. Inhibition of Ras signaling by one or more subject compounds is demonstrated by a decrease in the steady-state level of phosphorylated MEK, and/or Raf binding in cells treated with the one or more of the subject compounds as compared to the control cells.

Inhibition of Ras-mediated signaling transduction:

[427] The ability of the compounds disclosed herein in inhibiting Ras-mediated signaling is assessed and demonstrated as follows. Cells expressing wild type or a mutant Ras (such as G12C, G12D, G12V, or G12A) are treated with or without (control cells) a subject compound. Inhibition of Ras signaling by one or more subject compounds is demonstrated by a decrease in binding of Ras complex to downstream signaling molecules (for example Raf) in cells treated with the one or more of the subject compounds as compared to the control cells. [428] A compound of Table 1 is tested according to the above procedures. The compound of Table 1 is expected to inhibit Ras-mediated signaling transduction by one or more of the procedures described herein.

EXAMPLE 2

ASSESSING INHIBITION OF CELL PROLIFERATION BY A COMPOUND DISCLOSED HEREIN

[429] Two cancer cell lines, NCI H441 (human lung adenenocarcinoma cells comprising a G12V mutation) and MIA paca-2 (human pancreatic carcinoma comprising a G12C mutation) are used in this experiment. Both the cell lines are treated with a compound of Table 1 disclosed herein at a concentration of 100 μΜ, 30 μΜ, 10 μΜ and 3 μΜ and cell potency is measured as described in Example 1.

EXAMPLE 3

COMPARISON OF CELL PROLIFERATION INHIBITION BY A COMPOUND DISCLOSED HEREIN

[430] Three cell lines, NCI H441 (human lung adenenocarcinoma cells), NCI 1568 (lung adenenocarcinoma cells) and MIA paca-2 (human pancreatic carcinoma) are used in this experiment. All of the cell lines are treated with a compound of Table 1 disclosed herein at a concentration of 100 μΜ, 30 μΜ, 10 μΜ and 3 μΜ and cell potency is measured.

[431] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or attached Application Data Sheet are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.

[432] From the foregoing it will be appreciated that, although specific embodiments, of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

CLAIMS What is claimed is:

1. A compound having the following structure (V):

(V)

R¹ is aryl or heteroaryl;

R^30a and R^30b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 30 ^a and R 30b join to form a carbocyclic or heterocyclic ring; or R 30 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^30b joins with R^31b to form a carbocyclic or heterocyclic ring;

R^31a and R^31b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 31 ^a and R31b join to form a carbocyclic or heterocyclic ring; or R 31 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^31b joins with R^30b to form a carbocyclic or heterocyclic ring;

R'^za and R^iZb are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32 ^a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring; R^jja and R^JJ are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33 ^a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;

L¹ is carbonyl, -NHC(=0)-, alkylene, alkenylene, heteroalkylene, heterocycloalkylene, heteroarylene, alkylenecarbonyl, alkenylenecarbonyl,

heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl;

L is a bond or alkylene;

G¹, G², G³ and G⁴ are each independently N or CR, where R is H, cyano, halo or Ci-C₆alkyl;

n¹, n², n³ and n⁴ are each independently 1, 2 or 3; and

T is a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

2. The compound of claim 1, wherein the compound has the following structure (Va):

(Va)

wherein:

L^la is a bond, -NH-, alkylene, alkeneylene, heteroalkylene,

heterocycloalkylene or heteroarylene.

3. The compound claim 1 or 2, wherein R¹ is aryl.

4. The compound of claim 3, wherein the aryl is bicyclic.

5. The compound of claim 4, wherein the aryl is a fused bicyclic aryl.

6. The compound of claim 5, wherein the aryl is naphthyl.

7. The compound of claim 3, wherein the aryl is monocyclic.

8. The compound of claim 7, wherein the aryl is phenyl.

9. The compound of any one of claims 3-8, wherein the aryl is

unsubstituted.

10. The compound of any one of claims 3-8, wherein the aryl is substituted with one or more substituents.

11. The compound of claim 10, wherein the substituents are selected from halo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-C₆alkyl, Ci-C₆alkylsulfonyl, Ci- C₆haloalkyl, Cs-Cscycloalkyl, Ci-Cealkoxy, Ci-C₆hydroxylalkyl, Ci-Cealkoxyalkyl, Ci- Ceaminoalkyl, aliphatic heterocyclyl, heteroaryl and aryl.

The compound of claim 11 , wherein the substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methylsulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclobutyl, cyclopropyl and phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano.

13. The compound of claim 12, wherein the substituents are selected from fluoro, chloro, bromo, iodo, hydroxyl, methyl, ethyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-Cealkyl, halo, hydroxyl and cyano.

14. The compound of claim 13, wherein the substituents are selected from fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano.

15. The compound of any one of claims 1-14, wherein R¹ has one of the following structures:

16. The compound of claims 1 or 2, wherein R is heteroaryl.

17. The compound of claim 16, wherein the heteroaryl is bicyclic.

18. The compound of claim 17, wherein the heteroaryl is a fused bicyclic heteroaryl.

19. The compound of claim 16, wherein the heteroaryl is monocyclic.

20. The compound of any one of claims 16-19, wherein the heteroaryl comprises nitrogen, sulfur or a combination thereof.

21. The compound of any one of claims 16-20, wherein the heteroaryl is dihydroquinoxalinyl, indoleyl, benzoimidazolyl, pyridinyl or thiazolyl.

22. The compound of any one of claims 16-21, wherein the heteroaryl is unsubstituted.

23. The compound of any one of claims 16-21, wherein the heteroaryl is substituted with one or more substituents.

24. The compound of claim 23, wherein the substituents are selected from Ci-C₆alkyl, halo and oxo.

25. The compound of claim 24, wherein the substituents are selected from ethyl and chloro.

26. The compound of any one of claims 16, wherein R¹ has one of the following structures:

wherein R^la is, at each occurrence, independently H, Ci-C₆alkyl or halo.

27. The compound of claim 26, wherein R¹ has one of the following

28. A compound having the following structure (VI):

(VI)

A is CR^37b, N or NR^38a;

B is CR^37c, N, NR^38b or S;

C is CR^37d, N, NR^38c or S;

G³ and G⁴ are each independently N or CR, wherein R is H, cyano, halo or C -

C⁶alkyl;

L^la is a bond, -NH-, alkylene or heteroalkylene;

L is a bond or alkylene;

R^32a and R^32b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, C₃-C₈cycioalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 32 ^a and R 32b join to form a carbocyclic or heterocyclic ring; or R 32 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycioalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 32b joins with R 33b to form a carbocyclic or heterocyclic ring;

R^33a and R^33b are, at each occurrence, independently H, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycioalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R 33 ^a and R 33b join to form a carbocyclic or heterocyclic ring; or R 33 ^a is H, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, C₃-C₈cycioalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R 33b joins with R 32b to form a carbocyclic or heterocyclic ring;

R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-Cealkyl, Ci-Cealkylsulfonyl, Ci-C₆haloalkyl, C₃- Cscycloalkyl, Ci-Cealkoxy, Ci-C₆hydroxylalkyl, Ci-Cealkoxyalkyl, Ci-Ceaminoalkyl, heterocyclyl, amino, aminoaryl, aminoheteroaryl, aryl or heteroaryl; or R^37a and R^37e join to form a carbocyclic or heterocyclic ring;

R^38a, R^38b and R^38c are each independently H, Ci-C₆alkyl or aryl; n³ and n⁴ are each independently 1, 2 or 3; m is 0 or 1 ;

is a single or double bond such that all valences are satisfied; and

29. The compound of claim 28, wherein the compound has one of the following structures (Via), (VIb), (Vic), (VId), (Vie), (Vlf) or (VIg):

(VIg)

30. The compound of any one of claims 27-29, wherein G³ is N and G⁴ is

CR.

31. The compound of any one of claims 27-29, wherein G³ is CR and G⁴ is

N.

32. The compound of any one of claims 27-29, wherein G³ is N and G⁴ is

N.

33. The compound of any one of claims 27-32, wherein n³ is 2 and n⁴ is 2.

34. The compound of any one of claims 27-32, wherein n³ is 1 and n⁴ is 1.

35. The compound of any one of claims 27-32, wherein n³ is 2 and n⁴ is 1.

37^" 37^"fo 37^"

36. The compound of any one of claims 28-35, wherein R ^a, R , R ^c, R^37d and R^37e are each independently H, -OH, halo, oxo, Ci-C₆alkyl, Ci-C6alkoxy, heterocyclyl or aryl.

37. The compound of claim 36, wherein R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.

38. The compound of any one of claims 28-37, wherein R^37a or R^37e is aryl.

39. The compound of claim 38, wherein aryl is phenyl.

40. The compound of any one of claims 38 or 39, wherein the aryl is unsubstituted.

41. The compound of any one of claims 38 or 39, wherein the aryl is substituted.

42. The compound of claim 41, where the aryl is substituted with one or more halo substituents.

43. The compound of claim 42, wherein the halo substituents are selected from fluoro and chloro.

44. The compound of any one of claims 28-37, wherein R^37a is heteroaryl.

45. The compound of claim 44, wherein the heteroaryl is unsubstituted.

46. The compound of claim 44, wherein the heteroaryl is substituted.

47. The compound of any one of claims 44-46, wherein the heteroaryl comprises nitrogen, sulfur or a combination thereof.

48. The compound of any one of claims 44-47, wherein the heteroaryl is thiophenyl.

49. The compound of any one of claims 28-37, wherein R^37a or R^37e, or both, is halo.

50. The compound of claim 49, wherein halo is chloro, bromo or iodo.

51. The compound of any one of claims 28-50, wherein R ^a or R ^e has one of the following structures:

The compound of any one of claims 28-51 , wherein R ^a, R and R are each independently H or aryl.

The compound of claim 52, wherein R ^a, R and R ^c are each independently H.

54. The compound of any one of claims 28-52, wherein R^JSC is aryl.

55. The compound of claim 54, wherein the aryl is substituted with one or more halo substituents.

56. The compound of claim 55, wherein halo is chloro.

57. The compound of any one of claims 1-56, wherein T is selected from the group consisting of:

.

58. The compound of claim 1, wherein L¹ is heteroalkylene.

59. The compound of claim 58, wherein the heteroalkylene is

unsubstituted.

60. The compound of claim 58, wherein the heteroalkylene is substituted.

61. The compound of any one of claims 58-60, wherein L¹ is aminoalkylene.

The compound of claim 61, wherein L¹ is -CH₂CH₂NH

63. The compound of claim 1, wherein L is heterocycloalkyl ene or heteroarylene.

64. The compound of claim 63, wherein the heterocycloalkyl ene or heteroarylene is unsubstituted.

65. The compound of claim 63, wherein the heterocycloalkyl ene or heteroarylene is substituted.

66. The compound of claim 63, wherein L¹ has one of the following structures:

67. The compound of any one of claims 2-57, wherein L^la is a bond.

68. The compound of any one of claims 2-62, wherein L ^a is alkylene, alkenylene, heteroalkylene or heterocycloalkylene.

69. The compound of claim 68, wherein L is substituted alkylene.

70. The compound of claim 68, wherein L¹ is unsubstituted alkylene.

71. The compound of claim 70, wherein L¹ is

or

72. The compound of claim 68, wherein L^la is substituted heteroalkylene.

73. The compound of claim 68, wherein L^la is unsubstituted heteroalkylene.

74. The compound of any one of claims 72 or 73, wherein L^la is aminoalkylene or thioalkylene.

75. The compound of claim 74, wherein L^la has one of the following structures:

76. The compound of claim 68, wherein L^la is substituted alkenylene.

77. The compound of claim 68, wherein L^la is unsubstituted alkenylene.

78. The compound of claim 77, wherein L^la has the following structure:

79. The compound of claim 68, wherein L^la is substituted heterocycloalkylene.

80. The compound of claim 68, wherein L^la is unsubstituted heterocycloalkylene.

81. The compound of claim 80, wherein L^la has the following structure:

2

82. The compound of any one of claims 1-81, wherein L is a bond.

83. The compound of any one of claims 1-81, wherein L is substituted alkylene.

2

84. The compound of any one of claims 1-81, wherein L is unsubstituted alkylene.

85. The compound of any one of claims 1-27 or 57-84, wherein at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is H.

86. The compound of any one of claims 1-27 or 57-84, wherein each of R^30a, R^30b, R^31a, R ^1b, R ^2a, R^32b, R^33a or R ^b is H.

87. The compound of any one of claims 1-27 or 57-85, wherein at least one of R^30a, R^30b, R^31a, R ^1b, R^32a, R^32b, R^33a or R^33b is hydroxylalkyl.

88. The compound of any one of claims 1-27 or 57-85, wherein at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is cyano.

89. The compound of any one of claims 1-27 or 57-85, wherein at least one of R^30a, R^30b, R^31a, R ^1b, R^32a, R^32b, R^33a or R ^b is aminocarbonyl.

90. The compound of any one of claims 1-27 or 57-85, wherein at least one of R^30a, R^30b, R^31a, R^31b, R^32a, R^32b, R^33a or R^33b is d-C₆alkyl.

91. The compound of any one of claims 28-84, wherein at least one of R^32a, R^32b, R^33a or R ^b is H.

92. The compound of any one of claims 28-84, wherein each of R^32a, R^~,2b,

_R33a _{or R}33b _{is H}

93. The compound of any one of claims 28-84, wherein at least one of R^32a, R^32b, R^33a or R^33b is hydroxylalkyl.

94. The compound of any one of claims 28-84, wherein at least one of R ^2a, R ^2b, R^33a or R^33b is cyano.

95. The compound of any one of claims 28-84, wherein at least one of R^32a, R^32b, R^33a or R^33b is aminocarbonyl.

96. A compound having one of the following structures:

130

132

, or

97. A pharmaceutical composition comprising a compound of any one of claims 1-96 and a pharmaceutically acceptable carrier.

98. The pharmaceutical composition of claim 97, wherein the

pharmaceutical composition is formulated for oral administration.

99. The pharmaceutical composition of claim 97, wherein the

pharmaceutical composition is formulated for injection.

100. The pharmaceutical composition of any one of claims 97-99, wherein the pharmaceutical composition comprises an additional anticancer agent.

101. A method for treatment of cancer, the method comprising

administering an effective amount of the pharmaceutical composition of any one of claims 97-100 to a subject in need thereof.

102. The method of claim 101 , wherein the cancer is mediated by a K-Ras, H-Ras or N-Ras mutant protein.

103. The method of claim 101 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

104. A method for regulating activity of a K-Ras, H-Ras or N-Ras mutant protein, the method comprising contacting the K-Ras, H-Ras or N-Ras mutant protein with the compound of any one of claims 1-96.

105. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of any one of claims 1-96 or the pharmaceutical composition of any one of claims 97-100.

106. The method of claim 105, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

107. A method for treating a disorder mediated by a K-Ras, H-Ras or N-Ras mutant protein in a subject in need thereof, the method comprising:

determining if the subject has a K-Ras, H-Ras or N-Ras mutation; and if the subject is determined to have the K-Ras, H-Ras or N-Ras mutation, then administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of claims 97-100.

108. The method of claim 107, wherein the disorder is a cancer.

109. The method of claim 108, wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.

110. A method for preparing a labeled K-Ras, H-Ras or N-Ras mutant protein, the method comprising contacting the K-Ras, H-Ras or N-Ras mutant with a compound of any one of claims 1-96, to result in the labeled K-Ras, H-Ras or N-Ras mutant protein.

111. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of any one of claims 97-100 to a subject in need thereof.

112. The method of claim 111, further comprising administering another anti-cancer agent.

113. The compound of any one of claims 1-96, wherein T is capable of forming a complex with a metal ion that is complexed with the Ras protein.

114. The compound of any one of claims 1-96, wherein T is capable of forming an interaction with a mutation residue in the Ras protein.

115. The compound of claim 114, wherein the mutation residue is G12D.

116. A compound having the following structure (V):

(V)

R¹ is aryl or heteroaryl;

R^30a and R^30b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^30a and R^30b join to form oxo or a carbocyclic or heterocyclic ring; or R^30a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^30b joins with R^31b to form a carbocyclic or heterocyclic ring;

R^31a and R^31b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^31a and R^31b join to form oxo or a carbocyclic or heterocyclic ring; or R^31a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^31b joins with R^30b to form a carbocyclic or heterocyclic ring;

R^32a and R^32b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^32a and R^32b join to form oxo or a carbocyclic or heterocyclic ring; or R^32a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring;

R^33a and R^33b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^33a and R^33b join to form oxo or a carbocyclic or heterocyclic ring; or R^33a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R joins with R^32b to form a carbocyclic or heterocyclic ring;

heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl;

L is a bond or alkylene;

G¹, G², G³ and G⁴ are each independently N or CR, where R is H, cyano, halo or Ci-Cealkyl;

n¹, n², n³ and n⁴ are each independently 1, 2 or 3; and

T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position

12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

117. A compound having the following structure (VI):

A is CR^37b, N or NR^38a;

B is CR^37c, N, NR^38b or S;

C is CR^37d, N, NR^38c or S;

G³ and G⁴ are each independently N or CR, wherein R is H, cyano, halo or C -

C⁶alkyl;

L^la is a bond, -NH-, alkylene or heteroalkylene;

L is a bond or alkylene;

R^32a and R^32b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-Cealkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^32a and R^32b join to form oxo or a carbocyclic or heterocyclic ring; or R^32a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring; R ^a and R are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^33a and R^33b join to form oxo or a carbocyclic or heterocyclic ring; or R^33a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-Cealkyl, C3-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^33b joins with R^32b to form a carbocyclic or heterocyclic ring;

R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-Cealkyl, Ci-Cealkylsulfonyl, Ci-C₆haloalkyl, C₃- Cscycloalkyl, Ci-C₆alkoxy, Ci-Cehydroxylalkyl, Ci-C₆alkoxyalkyl, Ci-C₆aminoalkyl, heterocyclyl, amino, aminoaryl, aminoheteroaryl, aryl or heteroaryl; or R^37a and R^37e join to form a carbocyclic or heterocyclic ring;

R^38a, R^38b and R^38c are each independently H, Ci-C₆alkyl or aryl; n³ and n⁴ are each independently 1, 2 or 3;

m is 0 or 1 ;

is a single or double bond such that all valences are satisfied; and

12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

118. A compound having the following structure (VII):

(VII)

A is CR^37b, N or NR^38a;

B is CR^37c, N, NR^38b or S;

C is CR^37d, N, NR^38c or S;

G³ and G⁴ are each independently N or CR, wherein R is H, cyano, halo or C -

C⁶alkyl;

L^la is a bond, -NH-, alkylene or heteroalkylene;

L is a bond or alkylene; R ^a and R are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, Cs-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^32a and R^32b join to form oxo or a carbocyclic or heterocyclic ring; or R^32a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C₆alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^32b joins with R^33b to form a carbocyclic or heterocyclic ring;

R^33a and R^33b are, at each occurrence, independently H,

halo, -OH, -NH₂, -C0₂H, cyano, cyanoalkyl, Ci-C₆alkyl, C₃-Cscycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R^33a and R^33b join to form oxo or a carbocyclic or heterocyclic ring; or R^33a is H, halo, -OH, -NH₂, -C0₂H, cyano, Ci-C6alkyl, C₃-C₈cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R^33b joins with R^32b to form a carbocyclic or heterocyclic ring;

R^37a, R^37b, R^37c, R^37d and R^37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, Ci-C₆alkyl, Ci-Cealkylsulfonyl, Ci-Cehaloalkyl, C3- Cscycloalkyl, Ci-C₆alkoxy, Ci-C₆hydroxylalkyl, Ci-Cealkoxyalkyl, Ci-Ceaminoalkyl, heterocyclyl, amino, aminoaryl, aminoheteroaryl, aryl or heteroaryl; or R^37a and R^37e join to form a carbocyclic or heterocyclic ring;

m is 0 or 1 ;

is a single or double bond such that all valences are satisfied; and

T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.

119. The compound of claim 116, wherein R¹ is aryl or heteroaryl.

120. The compound of claim 116 or 119, wherein R¹ is substituted with one or more substituents.

121. The compound of claim 120, wherein the substituents are selected from fluoro, chloro, bromo, hydroxyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from Ci-C₆alkyl, halo, hydroxyl and cyano.

122. The compound of claim 117 or 118, wherein R , R , R , R^{j /d} and R^37e are each independently H, -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl.

123. The compound of claim 122, wherein said aryl is substituted with one or more halo substituents.

124. The compound of any one of claims 116 to 123, wherein T is selected from the group consisting of:

o o

II d-NH II -NH I NH OH . N X N .

1, 2, or 3.

125. The compound

126. The compound :laim 117 or 118, wherein L^la is -NH- or

2

127. The compound my one of claims 116 to 126, wherein L is a bond.

128. The compound my one of claims 116 to 127, wherein G is N.

129. The compound my one of claims 116 to 128, wherein G⁴ is N.

130. The compound :laim 116, wherein R^30a and R^30b join to form oxo.

131. The compound :laim 116, wherein R^31a and R^31b join to form oxo.

13 i2.. T i ihiee c cuomiuppuouuniiud υι any one of claims 116 to 131 , wherein R^32a and R^32b join to form oxo.

133. The compound of any one of claims 116 to 132, wherein R^33a and R^33b join to form oxo.

134. A pharmaceutical composition comprising a compound of any one of claims 116 to 133 and a pharmaceutically acceptable carrier.

135. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 134 to a subject in need thereof.