US010111874B2 (12 ) United States Patent (10 ) Patent No. : US 10 ,111 , 874 B2 Janes et al. ( 45 ) Date of Patent: * Oct . 30 , 2018

(54 ) COMBINATION THERAPIES FOR 5 , 052 ,558 A 10 / 1991 Carter 5 , 212 , 162 A 5 / 1993 Missel et al. TREATMENT OF CANCER 5 , 288 ,514 A 2 / 1994 Ellman 5 ,323 , 907 A 6 / 1994 Kalvelage (71 ) Applicant: Araxes Pharma LLC , La Jolla , CA 5 ,403 ,841 A 4 / 1995 Lang et al . (US ) 5 ,538 ,848 A 7 / 1996 Livak et al. 5 , 539 , 083 A 7 / 1996 Cook et al . (72 ) Inventors : Matthew Robert Janes, Encinitas, CA 5 , 593 , 853 A 1 / 1997 Chen et al. 5 ,605 , 798 A 2 / 1997 Köster (US ) ; Matthew Peter Patricelli , San 5 ,731 ,352 A 3 / 1998 Lesieur et al. Diego , CA ( US) ; Liansheng Li, San 5 , 777 , 324 A 7 / 1998 Hillenkamp Diego , CA ( US) ; Pingda Ren , San 5 , 858 ,659 A 1/ 1999 Sapolsky et al. Diego , CA (US ) ; Yi Liu , San Diego , 5 , 861, 510 A 1 / 1999 Piscopio et al. 5 , 863 , 949 A 1 / 1999 Robinson et al . CA (US ) 5 , 919 ,626 A 7 / 1999 Shi et al. 5 , 925 ,525 A 7 / 1999 Fodor et al. ( 73 ) Assignee : Araxes Pharma LLC , San Diego , CA 5 , 952 , 174 A 9 / 1999 Nikiforov et al . (US ) 6 ,017 ,696 A 1 / 2000 Heller 6 ,043 , 031 A 3 / 2000 Köster et al. ( * ) Notice : Subject to any disclaimer, the term of this 6 ,045 ,996 A 4 /2000 Cronin et al . patent is extended or adjusted under 35 6 ,051 , 380 A 4 / 2000 Sosnowski et al. 6 ,068 ,818 A 5 / 2000 Ackley et al . U . S . C . 154 (b ) by 0 days. 6 , 214 ,872 B1 4 / 2001 Robinson 6 ,251 ,639 B1 6 / 2001 Kurn This patent is subject to a terminal dis 6 , 903 , 118 B1 6 / 2005 Biedermann et al . claimer . 7 ,595 , 397 B2 9 /2009 Zindell et al . 7 , 879 ,863 B2 2 / 2011 Tokumasu et al. (21 ) Appl. No. : 14 /858 , 766 8 , 399 , 454 B2 3 / 2013 Bian et al. 8 ,426 , 401 B2 4 / 2013 Bian et al . 8 ,604 ,017 B2 12 / 2013 Bian et al. (22 ) Filed : Sep . 18 , 2015 8 ,697 ,684 B2 4 /2014 Bian et al . 8 ,741 , 887 B2 6 / 2014 Bian et al. (65 ) Prior Publication Data 8 ,759 , 333 B2 6 /2014 Connolly et al. US 2016 /0166571 A1 Jun . 16 , 2016 (Continued ) Related U .S . Application Data FOREIGN PATENT DOCUMENTS (60 ) Provisional application No . 62 / 195 ,633 , filed on Jul. CN 1267291 A 9 /2000 CN 104 418 860 B 9 / 2016 22 , 2015 , provisional application No . 62 /052 ,332 , EP 0 094 498 A2 11 / 1983 filed on Sep . 18 , 2014 . EP 0 606 046 AL 7 / 1994 EP 0 780 386 A 6 / 1997 (51 ) Int. Cl. 0 818 442 A2 1 / 1998 A61K 31/ 517 ( 2006 .01 ) EP 0 931 788 A2 7 / 1999 A61K 31/ 00 ( 2006 .01 ) EP 1 004 578 A1 5 / 2000 EP 1 736 465 A112 / 2006 A61K 31 / 337 ( 2006 . 01 ) EP 2 270 002 A11 /2011 A61K 31/ 4745 ( 2006 .01 ) EP 2 889 291 AL 7 / 2015 A61K 31496 ( 2006 .01 ) GB 939516 A 10 / 1963 A61K 45 / 06 ( 2006 .01 ) ( Continued ) ( 52 ) U .S . CI. CPC ...... A61K 31/ 517 ( 2013 . 01 ) ; A61K 31/ 00 OTHER PUBLICATIONS (2013 .01 ); A61K 31/ 337 ( 2013 .01 ) ; A61K 31/ 4745 (2013 . 01 ) ; A61K 31/ 496 (2013 .01 ) ; Arkin et al. , “ Binding of small molecules to an adaptive protein A61K 45 /06 (2013 . 01 ) protein interface, ” PNAS 100 ( 4 ) : 1603 - 1608, Feb . 2003 . (58 ) Field of Classification Search ( Continued ) CPC . .. A61K 31/ 517 ; A61K 31/ 00 ; A61K 31/ 337 ; A61K 31 /4745 ; A61K 31/ 496 ; A61K 45 /06 Primary Examiner — Sahar Javanmard See application file for complete search history . ( 74 ) Attorney , Agent, or Firm — Seed IP Law Group LLP ( 56 ) References Cited (57 ) ABSTRACT U . S . PATENT DOCUMENTS Combination therapies for treatment of cancers associated 3 , 702 ,849 A 11/ 1972 Cronin et al . with mutations in the KRAS gene are provided. Composi 3 , 752 ,660 A 8 / 1973 Little tions comprising therapeutic agents for treatment of cancers 4 ,439 ,606 A 3 / 1984 Du et al. 4 ,649 ,219 A 3 / 1987 Itoh et al. associated with mutations in the KRAS gene are also 4 , 861, 760 A 8 / 1989 Mazuel et al . provided . 4 ,911 , 920 A 3 / 1990 Jani et al . 5 , 010 , 175 A 4 / 1991 Rutter et al . 5 ,033 ,252 A 7 / 1991 Carter 20 Claims, 16 Drawing Sheets US 10 ,111 ,874 B2 Page 2

(56 ) References Cited WO 98 / 34918 AL 8 / 1998 WO 98 / 57948 A1 12 / 1998 U . S . PATENT DOCUMENTS WO 99 /29667 AL 6 / 1999 WO 99 /52889 Al 10 / 1999 9 ,227 ,978 B2 1 / 2016 Ren et al . WO 99 /52910 A 10 / 1999 9 , 376 ,559 B26 / 2016 Holtcamp et al. WO 99 /67641 A112 / 1999 9 ,745 , 319 B2 8 / 2017 Ren et al. Wo 00 / 39587 AL 7 /2000 9 ,810 ,690 B2 11/ 2017 Patricelli et al . wo 03 / 004480 A2 1 / 2003 9 , 840 ,516 B2 12 / 2017 Li et al. wo 2004 / 074283 A1 9 / 2004 9 , 862, 701 B2 1 /2018 Li et al . WO 2014 / 152588 Al 9 / 2004 9 ,926 ,267 B2 3 / 2018 Ren et al. WO 2005 / 070891 A2 8 / 2005 2002/ 0169300 A1 * 11/ 2002 Waterman ...... CO7K 14 /4705 WO 2005 /082892 A2 9 / 2005 536 / 23 . 1 WO 2006 / 066948 AL 6 / 2006 2003 /0022344 AL 1 / 2003 Williams et al. WO 2006 / 135993 AL 12 / 2006 2003/ 0166620 AL 9 / 2003 Lee et al. WO 2017 /015562 A1 1 / 2007 2005 / 0012070 A1 1/ 2005 Inoue et al. WO 2007 /095588 AL 8 / 2007 2005 / 0227997 A 10 / 2005 Noe et al. WO 2007 / 113226 A1 10 / 2007 2008 /0004285 AL 1 /2008 De Jonghe et al. WO 2007 / 144394 A2 12 / 2007 2008 /0004348 A1 1 / 2008 Yous et al . WO 2008 /009078 A2 1 / 2008 2008 /0039450 A1 2 / 2008 Jensen et al. wo 2008 / 112440 A1 9 / 2008 2009 / 0036430 A1 2 / 2009 De Jonghe et al. WO 2010 / 027746 A2 3 / 2010 2009 / 0054402 A1 2 / 2009 Wang et al . WO 2010 /087399 A1 8 / 2010 2009/ 0124636 A1 5 / 2009 Barber et al. wo 2010 / 121918 A 10 / 2010 2009 /0298075 A1 12 / 2009 Travers et al . WO 2011 / 148922 A 10 / 2010 2010 / 0331300 AL 12 / 2010 Bian et al. WO 2011 /031896 A2 3 / 2011 2011/ 0046370 A1 2 / 2011 Sim et al . WO 2011 / 093524 AL 8 / 2011 2011/ 0230476 A1 9 / 2011 Niu et al. WO 2011 / 153553 A2 12 / 2011 2011/ 0269244 A1 11 / 2011 Petter et al . WO 2012 /016082 A1 2 / 2012 2011 / 0311447 Al 12 / 2011 Tu et al. WO 2012 /041872 A1 4 / 2012 2011/ 0319290 AI 12 / 2011 Raymond et al. WO 2012 /054716 A1 4 / 2012 2013 / 0012489 AL 1 / 2013 Mederski et al. WO 2012 / 174489 A2 12 / 2012 WO 2013 / 064068 A1 5 / 2013 2013 / 0029964 AL 1 / 2013 Aoki et al . WO 2013 / 140148 Al 9 / 2013 2013 / 0274252 A1 10 / 2013 Pandey et al . WO 2013 / 155223 Al 10 / 2013 2013 / 0302407 All 11/ 2013 Rao et al . WO 2013 / 184757 Al 12 / 2013 2014 / 0315886 AL 10 / 2014 Suzuki et al . WO 2014 /011900 A2 1 / 2014 2015 /0087628 A1 3 / 2015 Ostrem et al. WO 2014 / 143659 AL 9 / 2014 2015 / 0239900 A18 / 2015 Li et al. WO 2014 / 152588 Al 9 /2014 2016 /0031898 Al 2 / 2016 Ren et al . WO 2014 / 159837 Al 10 / 2014 2016 / 0297774 Al 10 / 2016 Li et al. WO 2014 / 201435 Al 12 / 2014 2016 /0368930 Al 12 / 2016 Ostrem et al. WO 2015 /003166 Al 1 / 2015 2017 / 0022184 A1 1 / 2017 Li et al . WO 2015 / 017501 al 2 /2015 2017 / 0131278 AL 5 / 2017 Patricelli et al. WO 2015 /054572 AL 4 / 2015 2017 /0190672 Al 7 / 2017 Mani et al. WO 2015 / 108992 A1 7 / 2015 2017 /0197945 Al 7 / 2017 Li et al . WO 2015 / 132799 A2 9 / 2015 2017 /0247376 A1 8 / 2017 Li et al . WO 2015 / 143148 Al 9 /2015 2018 /0015087 Al 1 / 2018 Liu et al. WO 2015 / 144001 Al 10 /2015 2018 / 0086753 Al 3/ 2018 Li et al. wo 2015 / 184349 A2 12 / 2015 2018 / 0127396 A1 5 / 2018 Li et al . WO 2016 / 044772 Al 3 /2016 2018 / 0141927 Al 5 / 2018 Li et al. WO 2016 /049524 A1 3 / 2016 2018 /0155348 A1 6 / 2018 Li et al. wo 2016 / 049565 Al 3 / 2016 WO 2016 /049568 A1 3 / 2016 WO 2016 / 118951 A2 7 / 2016 FOREIGN PATENT DOCUMENTS WO 2016 / 164675 Al 10 / 2016 WO 2016 / 168540 A 10 / 2016 58 - 203966 A 11 / 1983 WO 2017 / 058902 A1 4 / 2017 59 - 163372 A 9 / 1984 WO 2017 /058915 A 4 / 2017 2005 - 502623 A 1 / 2005 WO 2017 /070256 A2 4 / 2017 2005 - 179557 A 7 / 2005 WO 2017 /087528 Al 5 / 2017 2007 - 016011 A 1 / 2007 WO 2017 / 100546 Al 6 / 2017 2008 -524154 A 7 / 2008 WO 4775259 B2 9 / 2011 2017 / 172979 Al 10 / 2017 2013 - 504325 A 2 / 2013 WO 86 / 01207 Al 2 / 1986 OTHER PUBLICATIONS WO 90 /05719 Al 5 / 1990 WO 91/ 19735 Al 12 / 1991 Choong et al. , “ Identification of Potent and Selective Small WO 92 / 00091 Al 1 / 1992 Molecule Inhibitors of Caspase - 3 through the Use of Extended WO 93 / 20242 A1 10 / 1993 Tethering and Structure -Based Drug Design ,” J. Med . Chem . 45 :5005 WO 96 / 05309 A2 2 / 1996 WO 96 / 13262 A1 5 / 1996 5022 , 2002 . WO 96 / 27583 A1 9 / 1996 Erlanson et al. , “ Site -directed ligand discovery, ” Proc. Natl Acad . WO 96 / 33172 A1 10 / 1996 Sci. U . S . A . 97 ( 17 ) : 9367 - 9372 , Aug. 2000 . WO 97 / 00271 A1 1 / 1997 Forbes et al. , " COSMIC 2005 ,” British Journal of Cancer 94 :318 WO 98 / 57948 A1 1 / 1997 322 , 2006 . WO 98 /03516 A1 1 / 1998 Gorfe et al ., “ Mapping the Nucleotide and Isoform -Dependent WO 98 / 07697 A1 2 / 1998 Structural and Dynamical Features of Ras Proteins, ” Structure WO 98 / 30566 A1 7 / 1998 16 : 885 - 896 , Jun . 2008 . WO 98 / 33496 A1 8 / 1998 Hall et al ., “ The Effect of Mg2 + on Guanine Nucleotide Exchange WO 98 /33768 A1 8 / 1998 Rate of p21N -ras . " The Journal of Biological Chemistry 261 (24 ): 10963 wo 98 / 34915 A1 8 / 1998 10965 , 1986 . US 10 ,111 ,874 B2 Page 3

( 56 ) References Cited Singh et al. , “ A Gene Expression Signature Associated with “ K - Ras Addiction ” Reveals Regulators of EMT and Tumor Cell Survival, " OTHER PUBLICATIONS Cancer Cell 15 :489 -500 , Jun . 2009 . Sunaga et al ., “ Knockdown of Oncogenic KRAS in Non -Small Cell Hall et al. , “ The structural basis for the transition from Ras- GTP to Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Ras- GDP , ” PNAS 99( 19 ) : 12138 - 12142 , Sep . 2002 . Cells to Targeted Therapy, ” Molecular Cancer Therapeutics 10 ( 2 ) :336 Hardy et al. , “ Discovery of an allosteric in the caspases ,” PNAS 346 , Feb . 2011 . 101 (34 ) : 12461 - 12466 , Aug . 2004 . Young et al. , “ Oncogenic and Wild - type Ras Play Divergent Roles Hattori et al. , “ Neutralizing monoclonal antibody against ras onco in the Regulation of Mitogen - Activated Protein Kinase Signaling , " gene product p21 which impairs guanine nucleotide exchange , ” Cancer Discovery 3 ( 1 ) : 112 - 123 , Jan . 2013 . Mol. Cell. Biol. 7 ( 5 ) : 1999 - 2002, May 1987 . Appel et al. , “ Supramolecular Cross- Linked Networks via Host Ito et al. , “ Regional Polysterism in the GTP -Bound Form of the Guest Complexation with Cucurbit [ 8 ]uril ," J . Am . Chem . Soc . Human c -Ha - Ras Protein ,” Biochemistry 36 (30 ): 9109 - 1919 , Jul. 132 (40 ): 14251 - 14260 , Jul. 2010 . 1997 . Barbe et al. , “ Highly Chemoselective Metal- Free Reduction of Kraulis et al. , “ Solution Structure and Dynamics of Ras p21 -GDP Tertiary Amides, ” J. Am . Chem . Soc . 130 :18 -19 , 2008 . Determined by Heteronuclear Three - and Four- Dimensional NMR Bégué et al ., “ lons a - Cetocarbenium . Influence De La Structure Sur Spectroscopy, ” Biochemistry 33 :3515 - 3531, 1994 . L ' Evolution Des Ions a - Cetocyclohexylcarbenium ,” Tetrahedron Lee et al. , “ The mutation spectrum revealed by paired genome 31( 20 ) :2205 -2511 , 1975 . ( English Abstract Only ). sequences from a lung cancer patient, ” Nature 465 :473 -477 , May Johnson et al. , “ The Chemistry of y -Bromopropionyl Isocyanate . I . 2010 . Synthesis of 1 - Aryldihydrouracils ,” The Journal of Organic Chem Lenzen et al. , “ [ 10 ] Analysis of Intrinsic and CDC25- Stimulated istry 24 ( 9 ): 1391- 1392 , Sep . 1959 . Guanine Nucleotide Exchange of p21" as — Nucleotide Complexes Jordan , “ Tamoxifen : A most unlikely pioneering medicine ,” Nature by Fluorescence Measurements ,” Methods in Enzymology 255 :95 Reviews 2 :205 - 213, Mar. 2003 . 109 , 1995 . Kelly et al. , “ Synthesis of Isomeric 3 - Piperidinyl and 3 -Pyrrolidinyl Li et al. , “ Substituted Quinazoline Compounds and Methods of Use Benzo [5 ,6 ]cyclohepta [1 , 2- b ]pyridines : Sulfonamido Derivatives as Thereof, ” U .S . Appl. No. 15 /093 ,951 , filed Apr. 8 , 2016 , 349 pages . Inhibitors of Ras Prenylation , ” Bioorganic & Medicinial Chemistry Malani et al. , “ Synthesis , characterization and in vitro screening on bacterial , fungal and malarial strain of piprazinyl cyano biphenyl 6 :673 -686 , 1998 . based compounds, ” Bioorganic Chemistry 51 : 16 - 23 , 2013 . Le Picard et al . , “ Design and Synthesis of Naphthalenic Derivatives Margarit et al. , “ Structural Evidence for Feedback Activation by as Potential Inhibitors of Hydroxyindole - O -methyltransferase , " Pharm . Ras GTP of the Ras - Specific Nucleotide Exchange Factor SOS, " Pharmacol. Commun . 5 : 183 - 188 , 1999 . Cell 112 :685 -695 , Mar . 2008 . Liansheng Li et al. , “ Inhibitors of Kras G12C Mutant Proteins, " Milburn et al. , “ Molecular switch for signal transduction : structural U .S . Appl . No. 14 / 866 ,147 , filed Sep . 25 , 2015 , 110 pages. differences between active and inactive forms of protooncogenic ras Liu et al. , “ Polygonatum cyrtonema lectin induces murine fibrosarcoma proteins, ” Science 247 ( 4945 ) :939 -945 , Feb . 1990 . L929 cell apoptosis and autophagy via blocking Ras- Raf and Pacold et al. , “ Crystal structure and functional analysis of Ras PI3K - Akt signaling pathways, ” Biochimie 92: 1934 - 1938 , 2010 . binding to its effector phosphoinositide 3 -kinase gamma, ” Cell Loboda et al ., “ A gene expression signature of RAS pathway 103 ( 6 ) :931 - 943 , Dec . 2000 . dependence predicts response to PI3K and RAS pathway inhibitors Palmioli et al ., “ First experimental identification of Ras- inhibitor and expands the population of RAS pathway activated tumors ,” binding interface using a water- soluble Ras ligand , ” Bioorganic and BMC Medical Genomics 3 ( 26 ) : 1 - 11, 2010 . Medicinal Chemistry 19 :4217 - 4222 , 2009 . Ostrem et al. , “ K -Ras (G12C ) inhibitors allosterically control GTP PubChem Compound , “ AKOSO24742141, " retrieved from http : // affinity and effector interactions, ” Nature 000 , 2013 , 14 pages . pubchem .ncbi . nim .nih . gov /compound / 49702158 # x304 on Nov . 27 , Palmioli et al ., " Selective cytotoxicity of a bicyclic Ras inhibitor in 2010 , CID 49702158 , 12 pages. cancer cells expressing K - RasG13D ," Biochemical and Biophysical Rensland et al. , " Substrate and Product Structural Requirements for Research Communications 386 ( 4 ) :593 - 597 , Sep . 2009 . Binding of Nucleotides to H - ras p21 : The Mechanism of Discrimi Pédeboscq et al. , " Synthesis and evaluation of apoptosis induction nation between Guanosine and Adenosine Nucleotides, ” Biochem of thienopyrimidine compounds on KRAS and BRAF mutated istry 34 ( 2 ) :593 - 599 , 1995 . colorectal cancer cell lines, ” Bioorganic & Medicinal Chemistry Sydor et al. , “ Transient Kinetic Studies on the Interaction of Ras and 20 :6724 -6731 , 2012 . the Ras- Binding Domain of c - Raf- 1 Reveal Rapid Equilibration of Peri et al. , “ Arabinose -derived bicyclic amino acids: synthesis , the Complex , ” Biochemistry 37 : 14292 - 14299 , 1998 . conformational analysis and construction of an a , Bz -selective RGD Taveras et al. , “ Ras Oncoprotein Inhibitors: The Discovery of peptide ," J . Am . Chem . Soc ., Perkins Trans 1 ( 5 ) :638 -644 , Feb . Potent, Ras Nucleotide Exchange Inhibitors and the Structural 2002 . Determination of a Drug - Protein Complex ,” Bioorganic and Medici Peri et al. , " Sugar- Derived Ras Inhibitors : Group Epitope Mapping nal Chemistry 5 ( 1 ): 125 - 133 , 1997 . by NMR Spectroscopy and Biological Evaluation ," Eur. J . Org . Vetter et al. , “ The Guanine Nucleotide -Binding Switch in Three Chem . 2006 ( 16 ): 3707 -3720 , Aug. 2006 . Dimensions, ” Science 294 ( 5545 ): 1299 - 1304 , Nov . 2001 . Peri et al. , “ Synthesis of bicyclic sugar azido acids and their Yang et al . , “ Fragment- Based Discovery of Nonpeptidic BACE - 1 incorporation in cyclic peptides, " Chem . Commun . 23 : 2303 -2304 , Inhibitors Using Tethering, ” Biochemistry 48 :4488 - 4496 , 2009 . Jan . 2000 . Banker et al . (eds .) , Modern Pharmaceutics , New York , Marcel Pingda Ren et al ., “ Covalent Inhibitors of KRAS G12C ,” U . S . Appl. Dekker, Inc ., 1996 , pp . 451 and 596 . ( 3 pages ). No. 14 /933 , 734 , filed Nov . 5 , 2015 , 355 pages. Duncan et al. , “ N -Dialkylaminoalkybiphenylamines as Antimalarial PubChem Compound , " ( 2S ,6R ) - hexahydrofuro [ 3 , 2 - b ] furan - 2 ,6 and Atischistosomal Agents ,” Journal ofMedicinal Chemistry 12 :25 diyl dicarbonochloridate : Compound Summary CID 53396983, " Oct. 29 , Jan . 1969 . 30 , 2011 , retrieved from http : // pubchem .ncbi . nlm .nih .gov /compound / Kumar et al. , “ Synthesis of 3 - Sulfonylamino Quinolines form 53396983 , 6 pages. 1 - ( 2 -Aminophenyl ) Propargyl Alcohols through a Ag (I ) - Catalyzed PubChem Compound , “ ( 4 -hydroxypiperidin - 1 - yl ) - pyridin - 4 Hydroamination , ( 2 + 3 ) Cycloaddition , and an Unusual Strain ylmethanone : AC1L5BNJ, ” retrieved on Feb . 17 , 2014 , from http: / / Driven Ring Expansion , ” Organic Letters 17 ( 9 ) :2226 -2229 , Apr. pubchem .ncbi . nlm .nih .gov / summary / summary .cgi ? CID = 76837 , Jul . 2015 . 8 , 2005 , 5 pages. Ohnmacht , Jr . et al. , " Antimalarials . 5 . a - Dibutylaminomethyl - and PubChem Compound , “ AKOSO24742141, " Nov . 27 , 2010 , retrieved a -( 2 - Piperidyl) - 3 - quinolinemethanols, ” Journalof Medicinal Chem from http : // pubchem .ncbi . nim .nih . gov / compound /49702158 # x304 , istry 14 ( 1 ) : 17 - 24 , 197 . CID 49702158 , 12 pages . US 10 ,111 ,874 B2 Page 4

( 56 ) References Cited Jones et al . , “ Increased frequency of the k -ras G12C mutation in MYH polyposis colorectal adenomas, " British Journal of Cancer OTHER PUBLICATIONS 90 : 1591 - 1593 , 2004 . Knochel et al. , “ Functionalization of heterocyclic compounds using PubChem Compound , “ Compound Summary for CID 21765509 : polyfunctional magnesium and zinc reagents ,” Beilstein Journal of Molecular Formula CsH2 N303, ” Dec . 5 , 2007 , retriieved from Organic Chemistry 7 : 1261 - 1277 , 2011 . http :/ / pubchem .ncbi . nlm .nih .gov / compound /21765509 , 4 pages . Li et al ., “ Methods and Compositions for Inhibition of RAS , ” U . S . PubChem Compound , “ Compound Summary for CID 21765511 : Appl. No . 15 /508 ,387 , filed Mar. 2 , 2017 , 145 pages . Molecular Formula C18H21N308, " Dec . 5 , 2007 , retrieved from Liang et al. , “ Parallel Synthesis and Screening of a Solid Phase http : // pubchem .ncbi . nlm .nih .gov /compound /21765511 , 4 pages. Carbohydrate Library ,” Science 274 : 1520 - 1522 , Nov . 1996 . PubChem Compound , “ Compound Summary for CID 60018735 : Lone et al. , “ A substrate - free activity -based protein profiling screen Molecular Formula C20H30013, " Aug. 20 , 2012 , retrieved from for the discovery of selective PREPL inhibitors ," J. Am Chem Soc . http : / /pubchem .ncbi . nlm .nih . gov /compound /60018735 # section = 133 ( 30 ) : 11665 - 11674 , Aug. 2011 , 20 pages . Top , 1 page . Long , “ Taxol: An important compound with an impressive struc PubChem Compound , “ Compound Summary for CID 72623693 : ture, ” Organic and General Chemistry at Flathead Valley Commu AGN - PC -OD8337 ," Jan . 9 , 2014 , retrieved from http :/ / pubchem . nity College, Sep . 10 , 2011, retrieved from https: / / longscience .com / ncbi. nlm .nih . gov / compound / 72623693 , 6 pages . 2011/ 09 / 10 / taxol -an - organic -compound -you - should -know -about / on PubChem Compound , “ Compound Summary for CID 9897840 : Feb . 22 , 2017 , 4 pages . Molecular Formula C50H46020 ," Oct. 25 , 2006 , retrieved from Maurer et al. , “ Small -molecule ligands bind to a distinct pocket in http : // pubchem .ncbi . nlm .nih . gov / compound / 9897840 , 6 pages . Ras and inhibit SOS- mediated nucleotide exchange activity, ” PNAS PubChem Compound , " SCHEMBL6674271 , " Dec . 1 , 2012 , retrieved 109 ( 14 ) :5299 -5304 , Apr . 3 , 2012 . from http : // pubchem .ncbi . nim .nih . gov / compound /69861127 # x304 , McMahon , “ VEGF Receptor Signaling in Tumor Angiogenesis, ” CID 69861127 , 12 pages. The Oncologist 5 ( suppl. 1 ) : 3 - 10 , 2000 . PubChem Compound , " SCHEMBL6797439 ," Dec . 1 , 2012 , retrieved Minto et al. , “ Pharmacokinetics and Pharmacodynamics of Nandrolone from http :/ / pubchem .ncbi . nim .nih . gov /compound / 69898605 # x304 , Esters in Oil Vehicle : Effects of Ester, Injection Site and Injection CID 69898605 , 12 pages. Volume, ” The Journal of Pharmacology and Experimental Thera Sasaki et al. , " Selective Formation of Stable Triplexes Including a peutics 281( 1 ): 93 - 102, 1997 . TA or a CG Interrupting Site with New Bicyclic Nucleoside Pathan et al. , “ Lead identification for the K - Ras protein : virtual Analogues (WNA ) ,” J. Am . Chem . Soc . 126 ( 2 ) :516 - 528 , Jan . 2004 . screening and combinatorial fragment- based approaches , ” OncoTargets Spiegel et al. , “ Small- molecule modulation of Ras signaling, " and Therapy 9 : 2575 - 2584 , 2016 . Nature Chemical Biology 10 :613 -622 , Aug . 2014 . Patricelli et al. , “ Selective Inhibition of Oncogenic KRAS Output Streuff et al. , “ First asymmetric aminohydroxylation of acrylamides, ” with Small Molecules Targeting the Inactive State , ” Cancer Dis Tetrahedron : Asymmetry 16 ( 21 ) :3492 - 3496 , Oct . 2005 . covery 6 ( 3 )316 - 329 , 2016 . Tsubaki et al. , “ Reduction of metastasis , cell invasion , and adhesion Pautsch et al . , “ Crystal structure of the C3bot -RalA complex reveals in mouse osteosarcoma by YM529 /ONO -5920 - induced blockade of a novel type of action of a bacterial exoenzyme, ” The EMBO the RAS /MEK /ERK and Ras / PI3K / Akt pathway, " Toxicology and Journal 24 : 3670 - 3680 , 2005 . Applied Pharmacology 259 ( 3 ) :402 -410 , Jan . 2012 . Pinedo et al. , “ Aggressive combination therapy to cure patients with Tulshian et al . , " Synthesis and Phosphodiesterase Activity of Car metastatic cancer, " The Lancet Oncology 1 :72 - 73 , Oct. 2000 . boxylic Acid Mimetics of Cyclic Guanosine 3 ' ,5 ' -Monophosphate , " Pinedo et al. , “ Translational Research : The Role of VEGF in Tumor J . Med . Chem . 36 ( 9 ) : 1210 - 1220 , Jan . 1993 . Angiogenesis , " The Oncologist 5 ( suppl. 1 ) : 1 - 2 , 2000 . Wolff, ( ed .) , Burger 's Medicinal Chemistry and Drug Discovery , PubChem Substance Record for SID 22405303 , Mar. 5, 2007 , CID Fifth Edition , vol. 1 : Principles and Practice, San Diego , California , 2579941 (MLS000416491 ) , retreived from https : // pubchem .ncbi . John Wiley & Sons, 1994 , pp . 975 - 977 . nlm .nih . gov/ substance /22405303 , on May 15 , 2017 , 7 pages . Wu et al. , “ Stereoselective synthesis of dioxabicycles from 1 - C PubChem Substance Record for SID 44253980 , Dec . 5 , 2007 , CID allyl- 2 - 0 -benzyl - glycosides - An intramolecular cyclization between 966800 ( 1 - BENZOYLPYRROLIDINE ) , retrieved from https: // 2 - 0 -benzyl oxygen and the allyl double bond , " Can . J . Chem . pubchem .ncbi . nlm .nih .gov / substance/ 44253980 # section = Top on May 84 ( 1 ) :597 -602 , Jan . 2006 . 11 , 2017 , 5 pages . Zenkl et al. , “ Sugar -Responsive Fluorescent Nanospheres, ” Macromol. Schubbert et al . , “ Biochemical and Functional Characterization of Biosci. 8 : 146 - 152 , 2008. Germ Line KRAS Mutations, ” Molecular and Cellular Biology Adibekian et al ., “ Optimization and characterization of a triazole 27 (22 ): 7765 -7770 , Nov. 2007. urea dual inhibitor for lysophosphlipase 1 (LYPLA1 ) and Vippagunta et al ., “ Crystalline solids, ” Advanced Drug Delivery lysophospholipase 2 (LYPLA2 ) , ” Probe Reports from the NIH Reviews 48: 3 - 26 , 2001. Molecular Libraries Program , 2011, 42 pages. Yan et al. , “ Discovery and characterization of small molecules that Al- Muhammed et al ., “ In - vivo studies on dexamethasone sodium target the GRPase Ral, " Nature 515 : 443- 447 , Nov . 2014 , 15 pages. phosphate liposomes ," J. Microencapsulation 13 (3 ): 293 -306 , 1996 . Bachovchin et al. , “ Identification of selective inhibitors of uncharacter Berge et al. , “ Pharmaceutical Salts , ” Journal of Pharmaceutical ized enzymes by high - throughput screening with fluorescent activity Sciences 66 ( 1 ) : 1 - 19 , 1977 . based probes ,” Nature Biotechnology 27 (4 ): 387 -394 , 2009 . (11 Chemcats Chemical Abstract, Accession No . 1301347730, Sep . 9 , pages ) . 2015 , 2 pages . CAS Registry No . 5530 -21 - 2 , “ 1 - Propanone , 1 [ 4 - [ 2 -( 2 -methoxy - 4 Chemocare , “ Taxol, ” retrieved from http : / /www . chemocare. com / propylphenoxy )acetyl ]- 1 - piperazinyl ] -, ” entered into STN Nov . 16 , chemotherapy /drug - info / Taxol. aspx on Feb . 22 , 2017 , 3 pages . 1984 , last updated Dec . 15 , 2008 , 6 pages . Cho et al. , “ An Unnatural Biopolymer, ” Science 261: 1303 - 1305 , Cox et al. , “ Drugging the undruggable RAS : Mission Possible ? , " Sep . 3 , 1993 Nature Reviews Drug Discovery 13 : 828 - 851 , 2014 . Chonn et al. , “ Recent advances in liposomal drug -delivery sys Pardin et al . , “ Synthesis and evaluation of peptidic irreversible tems, ” Current Opinion in Biotechnology 6 :698 -708 , 1995 . inhibitors of tissue transglutaminase , ” Bioorganic & Medicinal DeWitt et al . , “ Diversomers” : An approach to nonpeptide , Chemistry 14 :8379 - 8385 , 2006 . nonoligomeric chemical diversity , " Proc . Natl. Acad . Sci. 90 :6909 Pubchem , “ 1 -methoxy - 3 - tert -butyl - 1H - isoindole ,” Compound Sum 6913 , Aug. 1993 . mary for CID 10375614 , creation date Oct. 25 , 2006 , retrieved from Furka et al. , "General method for rapid synthesis of multicomponent https: / /pubchem . ncbi. nlm .nih .gov /compound / 10375614 , 9 pages. peptide mixtures, ” Int. J . Peptide Protein Res. 37 :487 -493 , 1991. Shima et al. , “ Discovery of Small -Molecule Ras Inhibitors that Hagihara et al. , “ Vinylogous Polypeptides : An Alternative Peptide Display Antitumor Activity by Interfering with RAS -GTP - Effector Backbone, ” J . Am . Chem . Soc . 114 :6568 -6570 , 1992 . Interaction ,” The Enzymes 34 : 1 -23 , 2013 . US 10 ,111 ,874 B2 Page 5

( 56 ) References Cited OTHER PUBLICATIONS Stefanachi et al. , “ 1 - , 3 -, and 8 - substituted - 9 -deazaxanthines as potent and selective antagonists at the human A2B adenosine recep tor, ” Bioorg Med Chem 16 ( 6 ) : 2852 - 2869, 2008 . Sun et al ., “ Discovery of Small Molecules that Bind to K - Ras and Inhibit Sos -Mediated Activation , ” Angew . Chem . Int. Ed . 51 :6140 6143 , 2012 Xu et al. , “ Design , Synthesis , and Biological Evaluation of 2 -Oxo 3 , 4 - dihydropyrimido [ 4 , 5 - d ]pyrimidinyl Derivatives as New Irre versible Epidermal Growth Factor Receptor Inhibitors with Improved Pharmacokinetic Properties, ” Journal ofMedicinal Chemistry 56 : 8803 8813 , 2013 Haggam et al. , “ Facile synthesis of some condensed 1 , 3 -thiazines and thiazoles under conventional conditions: antitumor activity , " Res. Chem . Intermed . 43 :6299 -6315 , 2017 . Janes et al ., “ Targeting KRAS Mutant Cancers with a Covalent G12C - Specific Inhibitor, " Cell 172 : 578 -589 , 2018 . Kuroyanagi et al. , “ Structure - Activity Relationships of 1 , 3 Benzoxazole - 4 -carbonitriles as Novel Antifungal Agents with Potent in Vivo Efficacy, ” Chem . Pharm . Bull . 59 ( 3) : 341 -352 , 2011 . * cited by examiner atent Oct. 30 , 2018 Sheet 1 of 16 US 10 , 111, 874 B2

Sustainedp-HER2. 00000 Sustainedp-EGERIA SustainedpoMET-2Highbasaland1 Sustainedp-STAT33 sustainedo.SRC DEGFRinduction-PAKTinduction? STRONG D-S6induction2p.86induction 1.FIG

WWW

POMETinduction-3

andHighbasaiabasalandactivation }sustainedhighbasalandp.SRCsustainedSRCand PERKinhibition-DERKinhibition1PERKinhibition" Sustained pAKT1,p.inductionAKT-2D'ABLinhibition sustainedp-SRCand3PSTAT3induction4D Exploratoryevidenceforsustainedand/orinducedpathwayssuggesttargetingwith:

DOMETinduction- PSTATU

NC1,358 -5inhibitionDOMET D-AKTinhibition? D.STAT3inhibition-2 Lowbasaland sustainedoSRC inhibitionERK'D inhibition56.0 EGFRIHER2.D induction DMSO U. S . Pateratent Oct. 30 , 2018 Sheet 2 of 16 US 10 , 111, 874 B2

(10uM P-ERK(T202/4204) ARSK(T359/S363) G12Cinhibitors Ø-S6(S235/6) D-AKT(S473) PARACieaved

] 1uM[ Paclitaxel * 158- 1 * 153 -1 *Gem 64- 11 GOC0941 * DMSO 158 -}

(5AM Erlotinib+ 64- 11 W DMSO B.A549(G12Scontrol) 158 - WW

OSWO wwwwwwwww

- FIG.2 PERK(T202/4204) O-RSK(T359/S363) D-AKT(5473) 5-S6(S235/6) PARPCleaved 1uM[ Paclitaxel 158- { momentun 2M 153- 1 +GDC0941 64- 11 678910111213 DMSO 158- { Erlotinib 15M 153 -1 DMSO 168 -1 345 A.NCI-H358(G120) 153 -1 64- 1 OMSO 12 U . S . Patent Oct. 30, 2018 Sheet 3 of 16 US 10, 111, 874 B2

Ertotinioalone(1or RangeofresponsetoTakol(0.54M}aloneas Rangeofresponseto Rangeofresponseto Rangeofresponseto positivecontrol Taxol(0.5uMalone 51M aspositivecontrol GOC0941alone gie CM}inge(?20 Att 20 NCH41 A375 A518 15 GOC0941response2UM*1-64dose HCT116 NCH4211 HCT116 A544 $ 10 11-64doseresponse ControlSyControlA375 10 iniustoru 5 ControlControl $ en mem meme me 0 laschen 0 .B D. FIG.3

Sito20

WCI-4398 NO1-H2122 NC1-12038 WCI-4358 NCI-62122 NOH-342039NO*1792 nhibkoJUM +G12C (*similarsynergisticresponsetoafatinib) 5 . . . . G12cG1202

ESCOLA

RLO( LiniaschiXS duction

A. atent Oct. 30 , 2018 Sheet 4 of 16 US 10 , 111, 874 B2

)100M (64 -11 + GDC0941 Averageresponseof4 NSCLClines: )GDC094150M (64 -11 + GDC0941 NCI-H2122 SW1573 )100M (64 -Il + Erlotinib NCKH1792 )Erlotinib501 (64 -Il + Erlotinib )10uM ( 64-11 WS )DMSO5uM ( 64 -11 Apoptosis %

(10-UM]

64: FIG.4 15M DNAcontent DMSO cells of

[2M) Single agent [5UM] A. theErlotinib +GDC0941 atent Oct. 30 , 2018 Sheet 5 of 16 US 10, 111, 874 B2

Combo wwwww

YOR

[1.5nM) Paclitaxel 14.3 DNAContent 11-64 [10UM]4 . 5 24.0 FIG.5

DMSO 3.20 Gatedpopulation-%ofsubdiploidapoptoticcells

72hr 72hr

1207 48 48

24 24

0 0 atent Oct. 30 , 2018 Sheet 6 of 16 US 10 , 111, 874 B2

Combo 27.2 51.2

Docetaxel [1nM) DNAContent (10UM]

24.0 FIG.6

DMSO 3.20 Gatedpopulation=%ofsubdiploidapoptoticcells

72hr 72hr 48 wer 48 24 24

0 0 U. S . Patentatent Oct. 30 , 2018 Sheet 7 of 16 US 10, 111, 874 B2

Combo 38.2

. www

[5nM]

SN38 12.0

. . . . . - , -, - ,- , - , - ,- , -, - ,- , - , - ,- , -, - ,- , -, - ,- , -, - ,- , -, ,- , ,- , , - , ,- , ,- , DNAContent [10UM]

9.36 7.FIG %ofsubdiploidapoptoticcells

DMSO 3.20 72hr 72hr

48 48 24 24 Gatedpopulation ??????????????????????????????????????????????????????????????????????????????????????? 0 www 0 atent Oct. 30 , 2018 Sheet 8 of 16 US 10, 111, 874 B2

Trametinib(200M) #+Dasatinib(1000M) worytem+Erlotinib(5UM) 1-272alone

10

W

1 YN.

Calu-1 0.1 w Comba

FIG.8 ) Glo - Caspase( Apoptosis % HighSRC activity

RTKarray -

H358 CALU-1CALU-1 atent Oct. 30 , 2018 Sheet 9 of 16 US 10 , 111, 874 B2

KRASC128)A549(

|-74

FIG.9

NCI-H358(KRASG120) atent Oct. 30 , 2018 Sheet 10 of 16 US 10 ,111 , 874 B2

SW1573 NSCLC (KRAS01200120 & PIK3CAKTIIN )

Cleaved PARP D -AKT (5473 ) AKT D -MEK (S217 /221 ) P -ERK ( T202 /4204 ) = = = = ERK P -RSK (T359 /S363 ) Cyclin 01 P - S6 (S235 / 6 ) P -4EBP1 (T37146 ) GST- RBD * * * KRAS -GTP atent Oct. 30 , 2018 Sheet 11 of 16 US 10 ,111 , 874 B2

NCI- H358 GDC-0941 (2 .50M ) erlotinib selumetinib RBD - PD : KRAS -GTP KRAS P -EGFR P -HER2 P -HER3 HER3 D -ERK D - AKT P -S6 c -caspase 3

FIG . Keanna11 atent Oct. 30 , 2018 Sheet 12 of 16 US 10, 111, 874 B2

CALU - 1 ( 24hr treatment)

wwwwwwwwwwwwwwwwwwww W 1- 272 1- 272

' . ' . ' . ' , . , . , Cleaved PARP P - SRC (Y416 ) D -AKT (S473 ) P - ERK P -RSK P -S6 (S235 / 6 ) HSP90 FIG . 12 atent Oct. 30 , 2018 Sheet 13 of 16 US 10 , 111, 874 B2

HSPOO Suro -272 - 1 WA 900 *727 -1 A549 272-1

*20 *212 -1 POR SW1573 272-3 inhibitionandSRClikelythroughmostinductionisApoptosis V

ooooooooooooooooooo isnotduetoapleitropiceffectofdasatinib'smultipletargets 272- 1 goingonano Sat 272- SRCicombinationveryeffective SW1463NCIH1792-CALU1 2. OSS 272-1 FIG.13 272- G12C+NSCLC&colon 9800* 212 - 272- Sarc* 272 -1 NCMM23 272-1

1-272 . 2

* NCI-H358 272-1 atent Oct. 30 , 2018 Sheet 14 of 16 US 10 ,111 , 874 B2

* * SW1573 @ @ CALUMI OQ NC - H1792 OB SW1463 NC - 123 O NCH - 4358 Foidinductionofapoptosis (Densitometryofcleaved-PARPimmunoboli) MA- PACA2 A549 A

272? DasatinibDasatinib +}-- 272 SarcatinibSarcatinib+ 1-2727

FIG . En14 atent Oct. 30 , 2018 Sheet 15 of 16 US 10, 111, 874 B2

. FIG.15

.

.

.

. C-PARP p-S6 P-ERK STAT3-D .

272- ( *Mome NCKH1792MIA-PACA2 Mome-MomelotinibCYT387=SUM 24hrtreatment

NCI-H358 atent Oct. 30 , 2018 Sheet 16 of 16 US 10, 111, 874 B2

16.FIG3 C-PARP STAT3-P p-TBK1 p-S6 272- 1 + Momelotinib

.:

.

Momelotinib * ...... F * 29 NCI-H23 Ruxolitirib .:

. mmmmmmmmmmmmmmmmmmmmmmmmmmmm combinationforinhibitionS6Synergisticp-.

STAT3-D P-S6 272- 1 * Momelotinib Momelotinib 272- 1 + Ruxoktinib Ruxoltirib US 10 , 111 , 874 B2

COMBINATION THERAPIES FOR lung ( ~ 35 % ) , with G12C being a common mutation ( gly TREATMENT OF CANCER cine - 12 to cysteine ). This translates into more than 150 , 000 newly diagnosed cases of KRAS driven cancer yearly in the BACKGROUND US alone . These patients have no effective treatment options 5 and their chances for long term survival are extremely low . Technical Field After many years of failed efforts , the direct targeting of KRAS was long considered to be impossible . More recently Embodiments of the present invention are generally an approach targeting a specific KRAS mutation , G12C , directed to combination therapies for treatment of cancers which accounts for nearly 50 % of KRAS mutant lung associated with mutations in the KRAS gene . cancers, has been reported (Ostrem et al. , Nature 2013, Description of the Related Art 503 :548 ) . We have refined this strategy to yield quite potent Ras represents a group of closely related monomeric inhibitors of KRAS G12C function in cells and in vivo . globular proteins of 189 amino acids ( 21 kDa molecular These compounds hold great promise for the treatment of mass ) which are associated with the plasma membrane and cancers harboring the KRAS G12C mutation . which bind either GDP or GTP . Ras acts as a molecular While KRAS is a critical driver mutation in many types switch . When Ras contains bound GDP, it is in the resting or 15 of cancer , its precise role in established tumors is the subject off position and is " inactive .” In response to exposure of the 01of some debate . KRAS mutated cancer cells show varied cell to certain growth promoting stimuli, Ras is induced to degrees of growth inhibition when mutant KRAS is exchange its bound GDP for a GTP. With GTP bound , Ras depleted , with some lines showing only modest effects is “ switched on ” and is able to interact with and activate (Singh et al. , Cancer Cell 2009 , 15 : 489 ) . Further, even in other proteins ( its “ downstream targets ” ) . The Ras protein 20 lines with clear growth dependence on mutant KRAS , itself has a very low intrinsic ability to hydrolyze GTP back depletion of KRAS does not lead to robust induction of cell to GDP, thus turning itself into the off state . Switching Ras death or apoptosis (Sunaga et al. , Mol Cancer Ther 2011 , off requires extrinsic proteins termed GTPase - activating 10 : 336 ; Young et al. , Cancer Discov 2013 , 3 : 112 ) . Thus , proteins (GAPs ) that interact with Ras and greatly accelerate despite the central role for mutant KRAS in tumorigenesis , the conversion ofGTP to GDP . Any mutation in Ras which 25 it is possible that inhibition of KRAS alone may not be affects its ability to interact with GAP or to convert GTP sufficient for a desirable clinical outcome. back to GDP will result in a prolonged activation of the Accordingly , while progress has been made in this field , protein and consequently a prolonged signal to the cell there remains a need in the art for improved methods for telling it to continue to grow and divide . Because these treatment of KRAS mutant cancers , for example combina signals result in cell growth and division , overactive Ras 30 tion therapies . The present invention fulfills this need and signaling may ultimately lead to cancer . provides further related advantages. Structurally , Ras proteins contain a G domain which is responsible for the enzymatic activity of Ras — the guanine BRIEF SUMMARY nucleotide binding and the hydrolysis (GTPase reaction ) . It also contains a C -terminal extension , known as the CAAX 35 In brief, the present invention provides methods for box , which may be post -translationally modified and is treatment of cancer, for example cancers associated with responsible for targeting the protein to the membrane . The G mutations in the KRAS gene . In one embodiment, the domain is approximately 21 -25 kDa in size and it contains disclosure provides a method for treating a KRAS , HRAS or a phosphate binding loop ( P -loop ). The P - loop represents the NRAS G12C mutant cancer, the method comprising admin pocket where the nucleotides are bound in the protein , and 40 istering an effective amount of a KRAS , HRAS or NRAS this is the rigid part of the domain with conserved amino G12C mutant modulating compound and an additional acid residues which are essential for nucleotide binding and therapeutic agent to a subject in need thereof. Exemplary hydrolysis (Glycine 12 , Threonine 26 and Lysine 16 ). The G cancers that can be treated by the disclosed method include , domain also contains the so called Switch I ( residues 30 - 40 ) but are not limited to , hematological cancers, pancreatic and Switch II ( residues 60 -76 ) regions, both ofwhich are the 45 cancer, MYH associated polyposis , colorectal cancer and /or dynamic parts of the protein which are often represented as lung cancer . the “ spring -loaded ” mechanism because of their ability to In a different embodiment, the disclosure provides a switch between the resting and loaded state . The key inter - method for inducing apoptosis in a cell population compris action is the hydrogen bonds formed by Threonine - 35 and ing a KRAS , HRAS or NRAS G12C mutant protein , the glycine - 60 with the y - phosphate of GTP which maintain 50 method comprising administering an effective amount of a Switch 1 and Switch 2 regions respectively in their active KRAS , HRAS or NRAS G12C mutant modulating com conformation . After hydrolysis of GTP and release of phos- pound and an additional therapeutic agent. phate , these two relax into the inactive GDP conformation . In still other embodiments , the disclosure is directed to a The most notable members of the Ras subfamily are method for inhibiting tumor metastasis in a subject having a HRAS , KRAS and NRAS, mainly for being implicated in 55 KRAS , HRAS or NRAS G12C mutant cancer, the method many types of cancer. However , there are many other comprising administering an effective amount of a KRAS , members including DIRAS1 ; DIRAS2 ; DIRAS3 ; ERAS ; HRAS or NRAS G12C mutant modulating compound and GEM ; MRAS ; NKIRAS1; NKIRAS2 ; NRAS ; RALA ; an additional therapeutic agent. RALB ; RAP1A ; RAP1B ; RAP2A ; RAP2B ; RAP2C ; Pharmaceutical compositions and kits for combination RASD1; RASD2; RASL10A ; RASL10B ; RASL11A ; 60 therapy of different cancers are also provided . RASL11B ; RASL12 ; REM1; REM2; RERG ; RERGL ; These and other aspects of the invention will be apparent RRAD ; RRAS and RRAS2 . upon reference to the following detailed description . Mutations in any one of the three main isoforms of RAS (HRAS , NRAS , or KRAS ) genes are among the most BRIEF DESCRIPTION OF THE DRAWINGS common events in human tumorigenesis . KRAS mutations 65 occur in more than 20 % of all human cancers with the In the figures, identical reference numbers identify similar highest levels in pancreatic (~ 90 % ), colorectal (~ 40 % ), and elements . The sizes and relative positions of elements in the US 10 , 111 , 874 B2 figures are not necessarily drawn to scale and some of these were pretreated with docetaxel for 24 hours and then treated elements are arbitrarily enlarged and positioned to improve with II -64 for an additional 48 hours (72 hours total) . The figure legibility . Further , the particular shapes of the ele - bottom row shows results from cells that were pretreated ments as drawn are not intended to convey any information with II -64 for 24 hours and then treated with docetaxel for regarding the actual shape of the particular elements , and 5 an additional 48 hours (72 hours total ). Apoptosis was have been solely selected for ease of recognition in the measured via flow cytometry . Gated populations = % of sub figures . diploid apoptotic cells . FIG . 1 provides western blots for identifying synergistic FIG . 7 depicts apoptosis in NCI- H358 cells treated with pathways for targeting in combination with KRAS G12C II -64 ( 10 uM ) , SN38 (5 nM ) , or a combination treatment inhibition . Shown are dot blot arrays for detection of phos - 10 ( 11 - 64 + SN38 ) . The top row shows results from cells that phorylated receptor tyrosine kinases ( p -RTK ) and phospho were pretreated with SN38 for 24 hours and then treated rylated signaling kinases ( ie . p - ERK , or p - AKT) for indi- with II - 64 for an additional 48 hours (72 hours total) . The cated cell lines treated with indicated K - Ras G12C inhibitor. bottom row shows results from cells that were pretreated Notable signaling targets and their respective pathways that with II - 64 for 24 hours and then treated with SN38 for an are induced or maintained following treatment are summa- 15 additional 48 hours (72 hours total ) . Apoptosis was mea rized for various cell lines . sured via flow cytometry . Gated populations = % of subdip FIG . 2 depicts western blot analysis of downstream tar- loid apoptotic cells . gets of K -Ras signaling . A ) NCI- H358 cells expressing the FIG . 8 depicts a tyrosine kinase activity array and caspase K - Ras G12C isoform were treated with a DMSO control or activity in Calu - 1 cells . A ) An RTK array was used to K - Ras G12C inhibitors II -64 , 1 - 153 , or 1 - 158 at a concen - 20 measure tyrosine kinase activity in NCI- H358 cells and tration of 10 uM ( lanes 1 - 4 ) . Cells were then treated with Calu - 1 cells . High SRC activity was detected in Calu - 1 cells . DMSO , II- 64 , 1- 153 , or 1 - 158 in combination with either the B ) Caspase activity was measured in Calu - 1 cells using a EGFR inhibitor erlotinib at 5 uM ( lanes 5 - 7 ) or the PI3K Caspase -Glo assay . Cells were treated for 48 hours with inhibitor GDC0941 at 2 uM ( lanes 8 - 12 ) . Paclitaxel was increasing concentrations of 1 - 272 alone , or I - 272 + dasatinib used as a positive control. The western blots were probed 25 (SRC inhibitor ; 100 nM ), 1- 272 + erlotinib ( 5 uM ), 1 - 272 + with antibodies for p - AKT, p -ERK , total ERK , P - RSK , P -S6 trametinib (20 nM ), or 1 -272 +GDC0941 (1 uM ). I -272 + and cleaved PARP. Cleaved PARP is indicative of apoptosis . dasatinib induced significantly increased apoptosis . B ) A549 cells that express the G12S isoform of K - Ras were FIG . 9 is western blot data for combinations of an used a control for K - Ras G12C inhibitor specificity . A549 exemplary KRAS G12C inhibitor with an EGFR , MEK or cells were treated as in A ) . Little to no PARP cleavage was 30 PI3K inhibitor. detected . FIG . 10 is another western blot showing data from com FIG . 3 depicts caspase activity in K -Ras G12C cell lines binations of an exemplary G12C inhibitor with PI3KPI3K and control cells lines treated with a K -Ras G12C inhibitor inhibition . alone , erlotinib alone , or a combination treatment. Taxol (0 .5 FIG . 11 provides data for combinations of a G12C inhibi UM ) was used as a positive control. Caspase activity was 35 tor with an EGFR , EGFR /HER2 or PI3K inhibitor in NCI evaluated by measuring luminescence from cleavable sub - H358 cells . strate in a caspase assay. A ) K -Ras G12C expressing cell FIG . 12 is Western blot data from experiments treating lines NCI- H358 , NCI- H2122 , and NCI- H2030 were treated CALU - 1 cells with an exemplary G12C inhibitor or Dasu with increasing doses of II -64 ( I ) , II - 64 + 1 uM erlotinib ( A ), natinib , or both . or II -64 + 5 um erlotinib ( V ) . B ) Control cell lines NCI - 40 FIG . 13 presents data for combinations of Dasatinib (Das ) H441, HCT116 , A375 , and A549 were treated as in A ) . C ) or Sarcatinib ( Sarc ) with an exemplary G12C inhibitor in K - Ras G12C expressing cell lines NCI- H358 , NCI- H2122 , various cell lines . NCI- H2030 , and NCI- H1792 were treated with increasing FIG . 14 is densitometry data for the gel of FIG . 14 . doses of II -64 ( I ) or II -64 + 2 UM GDC0941 ( A ) . D ) Control FIG . 15 is data for combinations of an exemplary G12C cell lines NCI- H441, HCT116 , A375 , and A549 were treated 45 inhibitor and momelotinib in various cell lines . as in C ) . FIG . 16 provides Western blot data for combinations of an FIG . 4 depicts the ability of the compounds disclosed exemplary G12C inhibitor and momelotinib or ruxolitinib in herein in inhibiting Ras -mediated cell cycle progression and various cell lines . induction of apoptosis . A ) Flow cytometry data demonstrat ing cell cycle progression in NCI-H358 cells treated with 50 DETAILED DESCRIPTION II -64 alone at 5 uM or 10 UM , II -64 + erlotinib ( 5 uM ) , or II -64 +GDC0941 ( 2 ?M ) . B ) The average apoptosis response In the following description , certain specific details are set of NCI- H358 , NCI-H1792 , NCI- H2122 , and SW1573 cell forth in order to provide a thorough understanding of various lines generated by flow cytometry as described in A ) . embodiments of the invention . However , one skilled in the FIG . 5 depicts apoptosis in NCI- H358 cells treated with 55 art will understand that the invention may be practiced II- 64 ( 10 UM ), paclitaxel ( 1 . 5 nM ) , or a combination treat without these details . ment ( II- 64 + paclitaxel) . The top row shows results from Unless the context requires otherwise , throughout the cells that were pretreated with paclitaxel for 24 hours and present specification and claims, the word " comprise” and then treated with II -64 for an additional 48 hours (72 hours variations thereof, such as , “ comprises” and “ comprising ” total ) . The bottom row shows results from cells that were 60 are to be construed in an open , inclusive sense , that is , as pretreated with II -64 for 24 hours and then treated with “ including , but not limited to ” . paclitaxel for an additional 48 hours (72 hours total) . Apop - Reference throughout this specification to " one embodi tosis was measured via flow cytometry . Gated popula ment ” or “ an embodiment” means that a particular feature , tions = % of subdiploid apoptotic cells . structure or characteristic described in connection with the FIG . 6 depicts apoptosis in NCI- H358 cells treated with 65 embodiment is included in at least one embodiment of the II -64 ( 10 uM ) , docetaxel ( 1 nM ), or a combination treatment present invention . Thus , the appearances of the phrases “ in ( II -64 + docetaxel) . The top row shows results from cells that one embodiment” or “ in an embodiment” in various places US 10 , 111, 874 B2 throughout this specification are not necessarily all referring twelve carbon atoms. “ Amidinylalkyloxy ” refers to an to the same embodiment. Furthermore , the particular fea - alkoxy group comprising at least one amidinyl substituent tures , structures, or characteristics may be combined in any on the alkyl group . “Guanidinylalkyloxy ” refers to an suitable manner in one or more embodiments. alkoxy group comprising at least one guanidinyl substituent Unless defined otherwise, all technical and scientific 5 on the alkyl group . “ Alkylcarbonylaminylalkyloxy ” refers to terms used herein have the same meaning as is commonly an alkoxy group comprising at least one alkylcarbonylami understood by one of skill in the art to which this invention nyl substituent on the alkyl group . “ Heterocyclylalkyloxy" belongs. As used in the specification and claims, the singular refers to an alkoxy group comprising at least one heterocy form “ a, ” “ an ,” and “ the” include plural references unless clyl substituent on the alkyl group . “Heteroarylalkyloxy ” the context clearly dictates otherwise . 10 refers to an alkoxy group comprising at least one heteroaryl “ Amidinyl ” refers to a radical of the form - ( C = NR , ) substituent on the alkyl group . “ Aminylalkyloxy ” refers to NR , R ., wherein Ra, R , and R . are each independently H or an alkoxy group comprising at least one substituent of the C -Co alkyl. form — NR , R , where R , and R , are each independently H " Amino ” refers to the — NH , radical. 15 or C . - C . alkyl, on the alkyl group . Unless stated otherwise “ Carboxy ” or “ carboxyl” refers to the CO H radical. specifically in the specification , an alkoxy, amidinylalky " Cyano ” refers to the — CN radical . loxy, guanidinylalkyloxy, alkylcarbonylaminyl, heterocy “ Guanidinyl ” refers to a radical of the form - NRd clylalkyloxy, heteroarlyalkyloxy and /or aminylalkyloxy ( C = NR .) NR R ., wherein R ., R , R . , and R , are each group is optionally substituted . independently H or C , -Co alkyl. 20 “ Alkoxyalkyl” refers to a radical of the formula — R OR , “ Hydroxy ” or “ hydroxyl ” refers to the OH radical . where R , is an alkyl radical as defined above containing one “ Imino ” refers to the = NH substituent. to twelve carbon atoms and Ry is an alkylene radical as “ Nitro ” refers to the — NO , radical. defined above containing one to twelve carbon atoms. “ Oxo ” refers to the = O substituent. Unless stated otherwise specifically in the specification , an “ Thioxo ” refers to the = S substituent. 25 alkoxyalkyl group is optionally substituted . “ Alkyl” refers to a straight or branched hydrocarbon chain “ Alkoxycarbonyl” refers to a radical of the formula radical consisting solely of carbon and hydrogen atoms, CCOOR , where R , is an alkyl radical as defined above which is saturated or unsaturated (i . e . , contains one or more containing one to twelve carbon atoms. Unless stated oth double and / or triple bonds ), having from one to twelve erwise specifically in the specification , an alkoxycarbonyl carbon atoms ( C -C12 alkyl) , preferably one to eight carbon 30 group is optionally substituted . atoms ( C1 - C , alkyl) or one to six carbon atoms ( C , - Co “ Aryloxy ” refers to a radical of the formula - OR , where alkyl) , and which is attached to the rest of the molecule by R , is an aryl radical as defined herein . Unless stated other a single bond , e . g . , methyl, ethyl, n -propyl , 1 -methylethyl wise specifically in the specification , an aryloxy group is ( iso -propyl ) , n -butyl , n -pentyl , 1 , 1 -dimethylethyl (t -butyl ) , optionally substituted . 3 -methylhexyl , 2 -methylhexyl , ethenyl, prop - 1 - enyl, but- 1 - 35 “ Alkylaminyl” refers to a radical of the formula — NHR , enyl, pent- 1 - enyl, penta - 1 ,4 -dienyl , ethynyl , propynyl, buty - or — NR , R , where each Rq is , independently , an alkyl nyl , pentynyl, hexynyl , and the like . Alkyl includes alkenyls radical as defined above containing one to twelve carbon ( one or more carbon - carbon double bonds ) and alkynyls atoms. A “ haloalkylaminyl ” group is an alkylaminyl group (one or more carbon - carbon triple bonds such as ethynyl and comprising at least one halo substituent on the alkyl group . the like ). “ Amidinylalkyl” refers to an alkyl group compris - 40 A “ hydroxylalkylaminyl” group is an alkylaminyl group ing at least one amidinyl substituent. “ Guanidinylalkyl” comprising at least one hydroxyl substituent on the alkyl refers to an alkyl group comprising at least one guanidinyl group. An " amidinylalkylaminyl” group is an alkylaminyl substituent. Unless stated otherwise specifically in the speci group comprising at least one amidinyl substituent on the fication , an alkyl, amidinylalkyl and / or guanidinylalkyl alkyl group . A “ guanidinylalkylaminyl” group is an alky group is optionally substituted . 45 laminyl group comprising at least one guanidinyl substituent " Alkylene” or “ alkylene chain ” refers to a straight or on the alkyl group . Unless stated otherwise specifically in branched divalent hydrocarbon chain linking the rest of the the specification , an alkylaminyl , haloalkylaminyl, hydroxy molecule to a radical group , consisting solely of carbon and lalkylaminyl, amidinylalkylaminyl and/ or guanidinylalky hydrogen , which is saturated or unsaturated ( i. e ., contains laminyl group is optionally substituted . one or more double and / or triple bonds ) , and having from 50 " Aminylalkyl” refers to an alkyl group comprising at least one to twelve carbon atoms, e . g . , methylene , ethylene , one aminyl substituent ( NR , R , wherein R , and R , are propylene, n - butylene, ethenylene , propenylene , n - bute - each independently H or CZ - C . alkyl) . The aminyl substitu nylene , propynylene , n -butynylene , and the like . The alky - ent can be on a tertiary , secondary or primary carbon . Unless lene chain is attached to the rest of the molecule through a stated otherwise specifically in the specification , an aminyl single or double bond and to the radical group through a 55 alkyl group is optionally substituted . single or double bond . The points of attachment of the “ Aminylalkylaminyl” refers to a radical of the formula alkylene chain to the rest of the molecule and to the radical — NR , R , wherein R , is H or C . - C . alkyl and R , is aminyl group can be through one carbon or any two carbons within alkyl. Unless stated otherwise specifically in the specifica the chain . Unless stated otherwise specifically in the speci- tion , an aminylalkylaminyl group is optionally substituted . fication , an alkylene chain is optionally substituted . 60 “ Alkylcarbonylaminyl” refers to a radical of the formula " Alkylcycloalkyl” refers to a radical of the formula — NH ( C = O )R , where R , is an alkyl radical as defined - R , R , where R , is cycloalkyl chain as defined herein and above containing one to twelve carbon atoms. Unless stated Rd is an alkyl radical as defined above. Unless stated otherwise specifically in the specification , an alkylcarbo otherwise specifically in the specification , an alkylcy - nylaminyl group is optionally substituted . An alkenylcarbo cloalkyl group is optionally substituted . 65 nylaminyl is an alkylcarbonylaminyl containing at least one “ Alkoxy ” refers to a radical of the formula OR , where carbon - carbon double bond. An alkenylcarbonylaminyl R , is an alkyl radical as defined above containing one to group is optionally substituted . US 10 , 111, 874 B2 " Alkylaminylalkyl ” refers to an alkyl group comprising at the ring . Unless otherwise stated specifically in the specifi least one alkylaminyl substituent . The alkylaminyl substitu - cation, a cycloalkyl (or cycloalkenyl ) group is optionally ent can be on a tertiary, secondary or primary carbon . Unless substituted . stated otherwise specifically in the specification , an alky - “ Cyanocycloalkyl” refers to a radical of the formula laminylalkyl group is optionally substituted . 5 R R where R , is cycloalkylene chain and R is a cyano " Aminylcarbonyl” refers to a radical of the formula group as defined above . Unless stated otherwise specifically -C O NH , . Unless stated otherwise specifically in the specification , an aminylcarbonyl group is optionally substi in the specification , a cyanocycloalkyl group is optionally tuted . substituted . “ Alkylaminylcarbonyl” refers to a radical of the formula 10 " Cycloalkylaminylcarbony?” refers to a radical of the - C ( = O )NR _ R ) , where R , and R , are each independently formula CEO) NR ,R ), where R , and R , are each inde H or alkyl, provided at least one of R , or R , is alkyl. Unless pendently H or cycloalkyl, provided at least one of R , or Ro stated otherwise specifically in the specification , an alky is cycloalkyl. Unless stated otherwise specifically in the laminylcarbonyl group is optionally substituted . specification , n cycloalkylaminylcarbonyl group is option " Aminylcarbonylalkyl” refers to a radical of the formula 15 ally substituted . - R C . O ) NR R ) , where R , and R are each indepen “ Cycloalkylalkyl” refers to a radical of the formula dently H or alkyl and R is alkylene . Unless stated otherwise — R R , where R , is an alkylene chain as defined above and specifically in the specification , an aminylcarbonylalkyl Ro is a cycloalkyl radical as defined above . Unless stated group is optionally substituted . otherwise specifically in the specification , a cycloalkylalkyl “ Aminylcarbonycycloalkylalkyl ” refers to a radical of the 20 group is optionally substituted . formula - R C O )NR , Ro, where R , and R , are each “ Fused ” refers to any ring structure described herein independently H or alkyl and R is cycloalkyl . Unless stated which is fused to an existing ring structure in the compounds otherwise specifically in the specification , an aminylcarbo of the invention . When the fused ring is a heterocyclyl ring nylcycloalkyl group is optionally substituted . or a heteroaryl ring , any carbon atom on the existing ring “ Aryl” refers to a hydrocarbon ring system radical com - 25 structure which becomes part of the fused heterocyclyl ring prising hydrogen , 6 to 18 carbon atoms and at least one or the fused heteroaryl ring is replaced with a nitrogen atom . aromatic ring . For purposes of this invention , the aryl radical “ Halo ” or “ halogen ” refers to bromo, chloro , fluoro or is a monocyclic , bicyclic , tricyclic or tetracyclic ring system , jodo . which may include fused or bridged ring systems. Aryl radicals include , but are not limited to , aryl radicals derived 30 + “ Haloalkyl” refers to an alkyl radical , as defined above , from aceanthrylene , acenaphthylene , acephenanthrylene , that is substituted by one or more halo radicals , as defined anthracene , azulene , benzene , chrysene, fluoranthene , fluo above , e . g ., trifluoromethyl , difluoromethyl, trichlorom rene , as - indacene , s - indacene , indane , indene , naphthalene , ethyl, 2 , 2 , 2 - trifluoroethyl, 1 , 2 - difluoroethyl , 3 - bromo - 2 phenalene, phenanthrene , pleiadene, pyrene, and triph fluoropropyl, 1, 2 -dibromoethyl , and the like . Unless stated enylene . Unless stated otherwise specifically in the specifi- 355 onotherwise specifically in the specification , a haloalkyl group cation , the termn “arul aryl"” or the prefix car“ ar -”» ( suchsuch as inin is optionally substituted . “ aralkyl” ) is meant to include aryl radicals that are option “ Halolkoxy ” refers to a radical of the formula — OR , ally substituted . where R , is a haloalkyl radical as defined herein containing “ Aralkyl” refers to a radical of the formula — R - R . one to twelve carbon atoms. Unless stated otherwise spe where R , is an alkylene chain as defined above and R is one 40 cifically in the specification , a haloalkoxy group is option or more aryl radicals as defined above , for example , benzyl, ally substituted . diphenylmethyl and the like. Unless stated otherwise spe- “ Heterocyclyl” or “ heterocyclic ring” refers to a stable 3 cifically in the specification , an aralkyl group is optionally to 18 -membered non -aromatic ring radical which consists of substituted . two to twelve carbon atoms and from one to six heteroatoms “ Carboxyalkyl” refers to a radical of the formula - R1 – 45 selected from the group consisting of nitrogen , oxygen and R . where R , is an alkylene chain as defined above and R . is sulfur. Unless stated otherwise specifically in the specifica a carboxy group as defined above . Unless stated otherwise tion , the heterocyclyl radical is a monocyclic , bicyclic , specifically in the specification , carboxyalkyl group is tricyclic or tetracyclic ring system , which may include fused optionally substituted . or bridged ring systems; and the nitrogen , carbon or sulfur “Cyanoalkyl ” refers to a radical of the formula — R - R 50 atoms in the heterocyclyl radical is optionally oxidized ; the where R , is an alkylene chain as defined above and R is a nitrogen atom is optionally quaternized ; and the heterocyclyl cyano group as defined above. Unless stated otherwise radical is partially or fully saturated . Examples of such specifically in the specification , a cyanoalkyl group is heterocyclyl radicals include, but are not limited to , dioxo optionally substituted . lanyl, thienyl[ 1 , 3 ]dithianyl , decahydroisoquinolyl, imida " Cycloalkyl ” or " carbocyclic ring ” refers to a stable 55 zolinyl , imidazolidinyl , isothiazolidinyl, isoxazolidinyl, non - aromatic monocyclic or polycyclic hydrocarbon radical morpholinyl, octahydroindolyl , octahydroisoindolyl, 2 - ox consisting solely of carbon and hydrogen atoms, which may opiperazinyl, 2 -oxopiperidinyl , 2 - oxopyrrolidinyl, oxazo include fused or bridged ring systems, having from three to lidinyl, piperidinyl, piperazinyl , 4 - piperidonyl, pyrrolidinyl, fifteen carbon atoms, preferably having from three to ten pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, carbon atoms, and which is saturated or unsaturated and 60 trithianyl , tetrahydropyranyl, thiomorpholinyl, thiamor attached to the rest of the molecule by a single bond . pholinyl, 1 - oxo - thiomorpholinyl, and 1 , 1 -dioxo - thiomor Monocyclic radicals include , for example , cyclopropyl, pholinyl. Unless stated otherwise specifically in the speci cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and fication . “ Heterocyclyloxy ” refers to a heterocyclyl group cyclooctyl. Polycyclic radicals include , for example , ada - bound to the remainder of the molecule via an oxygen bond mantyl, norbomyl, decalinyl , 7 , 7 - dimethyl- bicyclo [ 2 . 2 . 1 ] 65 60 ) . “ Heterocyclylaminyl” refers to a heterocyclyl heptanyl, and the like . A " cycloalkenyl” is a cycloalkyl group bound to the remainder of the molecule via a nitrogen comprising one ormore carbon -carbon double bonds within bond NR , - , where Ra is H or C1- C , alkyl ) . Unless US 10 , 111 , 874 B2 10 stated otherwise specifically in the specification , a hetero - be on a primary, secondary or tertiary carbon . Unless stated cyclyl, heterocyclyloxy and / or hetercyclylaminyl group is otherwise specifically in the specification , a hydroxylalkyl optionally substituted . group is optionally substituted . “ N -heterocyclyl ” refers to a heterocyclyl radical as “ Thioalkyl” refers to a radical of the formula — SR , defined above containing at least one nitrogen and where the 5 where R , is an alkyl radical as defined above containing one point of attachment of the heterocyclyl radical to the rest of to twelve carbon atoms. Unless stated otherwise specifically the molecule is through a nitrogen atom in the heterocyclyl in the specification , a thioalkyl group is optionally substi radical. Unless stated otherwise specifically in the specifi - tuted . cation , an N -heterocyclyl group is optionally substituted . The term “ substituted ” used herein means any of the “ Heterocyclylalkyl” refers to a radical of the formula 10 above groups (e .g . , alkyl, alkylene , alkylcycloalkyl, alkoxy , - R , R , where R , is an alkylene chain as defined above and alkoxyalkyl, alkoxycarbonyl, aryloxy , alkylaminyl, alkyl R , is a heterocyclyl radical as defined above, and if the carbonylaminyl , alkylaminylalkyl , aminylcarbonyl , alky heterocyclyl is a nitrogen -containing heterocyclyl, the het - laminylcarbonyl, aminylcarbonylalkyl, aminylcarbonycy erocyclyl is optionally attached to the alkyl radical at the cloalkylalkyl, thioalkyl, aryl, aralkyl , carboxyalkyl, nitrogen atom . Unless stated otherwise specifically in the 15 cyanoalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylaminyl specification , a heterocyclylalkyl group is optionally substi - carbonyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocy tuted . clyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N -het “ Heteroaryl” refers to a 5 - to 14 -membered ring system eroaryl and /or heteroarylalkyl) wherein at least one radical comprising hydrogen atoms, one to thirteen carbon hydrogen atom is replaced by a bond to a non - hydrogen atoms, one to six heteroatoms selected from the group 20 atoms such as, but not limited to : a halogen atom such as F , consisting of nitrogen , oxygen and sulfur , and at least one Cl, Br, and I ; an oxygen atom in groups such as hydroxyl aromatic ring . For purposes of this invention , the heteroaryl groups , alkoxy groups, and ester groups ; a sulfur atom in radical may be a monocyclic , bicyclic , tricyclic or tetracy - groups such as thiol groups , thioalkyl groups , sulfone clic ring system , which may include fused or bridged ring groups, sulfonyl groups , and sulfoxide groups ; a nitrogen systems; and the nitrogen , carbon or sulfur atoms in the 25 atom in groups such as amines , amides, alkylamines , dialky heteroaryl radical may be optionally oxidized ; the nitrogen lamines , arylamines , alkylarylamines , diarylamines , N -ox atom may be optionally quaternized . Examples include , but ides , imides, and enamines ; a silicon atom in groups such as are not limited to , azepinyl, acridinyl, benzimidazolyl, ben trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl zothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, ben - groups, and triarylsilyl groups ; and other heteroatoms in zooxazolyl, benzothiazolyl , benzothiadiazolyl, benzo [b ] [ 1 , 30 various other groups . “ Substituted ” also means any of the 4 ]dioxepinyl , 1 , 4 -benzodioxanyl , benzonaphthofuranyl, above groups in which one or more hydrogen atoms are benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, replaced by a higher -order bond (e . g. , a double - or triple benzopyranonyl, benzofuranyl, benzofuranonyl, benzothie - bond ) to a heteroatom such as oxygen in oxo , carbonyl , nyl (benzothiophenyl ) , benzotriazolyl , benzo [ 4, 6 ] imidazo carboxyl, and ester groups ; and nitrogen in groups such as [ 1, 2 - a ]pyridinyl , carbazolyl, cinnolinyl, dibenzofuranyl, 35 imines , oximes ,hydrazones , and nitriles . For example , “ sub dibenzothiophenyl , furanyl, furanonyl , isothiazolyl, imida - stituted ” includes any of the above groups in which one or zolyl, indazolyl, indolyl , indazolyl, isoindolyl, indolinyl, more hydrogen atoms are replaced with — NR Rn - NR C isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl , naphthy - FORh — NR CEO )NR Rh - NR CEO )OR , ridinyl , oxadiazolyl, 2 - oxoazepinyl, oxazolyl , oxiranyl, NR SO Rn O?EO )NR Rn - OR , SR , SORG, 1 -oxidopyridinyl , l -oxidopyrimidinyl , 1 -oxidopyrazinyl , 40 _ SOR OSOR , ŠO ,OR , = NSOR , and 1 -oxidopyridazinyl , 1 - phenyl- 1H -pyrrolyl , phenazinyl, phe SONR Rn " Substituted also means any of the above nothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl , purinyl, groups in which one or more hydrogen atoms are replaced pyrrolyl , pyrazolyl , pyridinyl, pyrazinyl, pyrimidinyl, with COR , CEO) OR , CO)NR Rn. pyridazinyl, quinazolinyl, quinoxalinyl , quinolinyl, quinu CH _ SOZR , CH SO NR R . In the foregoing, R , and clidinyl , isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thia - 45 R , are the same or different and independently hydrogen , diazolyl, triazolyl, tetrazolyl , triazinyl , and thiophenyl ( i. e . alkyl, alkoxy, alkylaminyl , thioalkyl, aryl, aralkyl, thienyl) . “ Heteroaryloxy ” refers to a heteroaryl group bound cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N -het to the remainder of the molecule via an oxygen bond erocyclyl, heterocyclylalkyl, heteroaryl, N -heteroaryl and / or 10 ) . “ Heteroarylaminy?” refers to a heteroaryl group heteroarylalkyl. “ Substituted ” further means any of the bound to the remainder of the molecule via a nitrogen bond 50 above groups in which one or more hydrogen atoms are ( NR , — , where R , is H or C . - C . alkyl) . Unless stated replaced by a bond to an aminyl, cyano , hydroxyl, imino , otherwise specifically in the specification , a heteroaryl, nitro , oxo , thioxo , halo , alkyl, alkoxy , alkylaminyl, thio heteroaryloxy and / or heteroarylaminyl group is optionally alkyl, aryl, aralkyl , cycloalkyl, cycloalkylalkyl, haloalkyl, substituted . heterocyclyl, N -heterocyclyl , heterocyclylalkyl, heteroaryl, “ N -heteroaryl ” refers to a heteroaryl radical as defined 55 N -heteroaryl and / or heteroarylalkyl group . In addition , each above containing at least one nitrogen and where the point of the foregoing substituents may also be optionally substi of attachment of the heteroaryl radical to the rest of the tuted with one or more of the above substituents . molecule is through a nitrogen atom in the heteroaryl “ Electrophile ” or “ electrophilic moiety ” is any moiety radical. Unless stated otherwise specifically in the specifi - capable of reacting with a nucleophile ( e. g ., a moiety having cation , an N -heteroaryl group is optionally substituted . 60 a lone pair of electrons , a negative charge , a partial negative “ Heteroarylalkyl” refers to a radical of the formula charge and / or an excess of electrons , for example a — SH - RR where R is an alkylene chain as defined above and group ). Electrophiles typically are electron poor or comprise Ry is a heteroaryl radical as defined above. Unless stated atoms which are electron poor. In certain embodiments an otherwise specifically in the specification , a heteroarylalkyl electrophile contains a positive charge or partial positive group is optionally substituted . 65 charge , has a resonance structure which contains a positive “ Hydroxylalkyl” refers to an alkyl group comprising at charge or partial positive charge or is a moiety in which least one hydroxyl substituent. The OH substituent may delocalization or polarization of electrons results in one or US 10 , 111 , 874 B2 12 more atom which contains a positive charge or partial 10 - sulfonic acid , capric acid , caproic acid , caprylic acid , positive charge . In some embodiments , the electrophiles carbonic acid , cinnamic acid , citric acid , cyclamic acid , comprise conjugated double bonds, for example an a , ß dodecylsulfuric acid , ethane -1 ,2 -disulfonic acid , ethanesul unsaturated carbonyl or a ,ß -unsaturated thiocarbonyl com fonic acid , 2 -hydroxyethanesulfonic acid , formic acid , pound . 5 fumaric acid , galactaric acid , gentisic acid , glucoheptonic The term “ effective amount” or “ therapeutically effective acid , gluconic acid , glucuronic acid , glutamic acid , glutaric amount” refers to that amount of a compound described acid , 2 -oxo - glutaric acid , glycerophosphoric acid , glycolic herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined acid , hippuric acid , isobutyric acid , lactic acid , lactobionic below . The therapeutically effective amount may vary 10 acid , lauric acid , maleic acid , malic acid , malonic acid , depending upon the intended treatment application ( in vivo ) , mandelic acid , methanesulfonic acid , mucic acid , naphtha or the subject and disease condition being treated , e . g ., the lene - 1 , 5 - disulfonic acid , naphthalene - 2 - sulfonic acid , 1 -hy weight and age of the subject, the severity of the disease droxy - 2 - naphthoic acid , nicotinic acid , oleic acid , orotic condition , the manner of administration and the like , which acid , oxalic acid , palmitic acid , pamoic acid , propionic acid , can readily be determined by one of ordinary skill in the art. 15 pyroglutamic acid , pyruvic acid , salicylic acid , 4 - aminosali The term also applies to a dose that will induce a particular cylic acid , sebacic acid , stearic acid , succinic acid , tartaric response in target cells , e . g . reduction of platelet adhesion acid , thiocyanic acid , p - toluenesulfonic acid , trifluoroacetic and / or cell migration . The specific dose will vary depending acid , undecylenic acid , and the like . on the particular compounds chosen , the dosing regimen to “ Pharmaceutically acceptable base addition salt” refers to be followed , whether it is administered in combination with 20 those salts which retain the biological effectiveness and other compounds , timing of administration , the tissue to properties of the free acids , which are not biologically or which it is administered , and the physical delivery system in otherwise undesirable . These salts are prepared from addi which it is carried . tion of an inorganic base or an organic base to the free acid . As used herein , “ treatment” or “ treating” refers to an Salts derived from inorganic bases include , but are not approach for obtaining beneficial or desired results with 25 limited to , the sodium , potassium , lithium , ammonium , respect to a disease , disorder or medical condition including calcium , magnesium , iron , zinc , copper, manganese , alumi but not limited to a therapeutic benefit and /or a prophylactic num salts and the like . Preferred inorganic salts are the benefit. By therapeutic benefit is meant eradication or ame ammonium , sodium , potassium , calcium , and magnesium lioration of the underlying disorder being treated . Also , a salts . Salts derived from organic bases include , but are not therapeutic benefit is achieved with the eradication or ame - 30 limited to , salts of primary , secondary , and tertiary amines , lioration of one or more of the physiological symptoms substituted amines including naturally occurring substituted associated with the underlying disorder such that an amines , cyclic amines and basic ion exchange resins, such as improvement is observed in the subject , notwithstanding ammonia , isopropylamine , trimethylamine , diethylamine , that the subject may still be afflicted with the underlying triethylamine, tripropylamine , diethanolamine, etha disorder . In certain embodiments , for prophylactic benefit , 35 nolamine , deanol, 2 - dimethylaminoethanol, 2 - diethylamin the compositions are administered to a subject at risk of oethanol, dicyclohexylamine , lysine , arginine , histidine , caf developing a particular disease , or to a subject reporting one feine, procaine , hydrabamine , choline , betaine , or more of the physiological symptoms of a disease , even benethamine , benzathine , ethylenediamine, glucosamine , though a diagnosis of this disease may not have been made . methylglucamine , theobromine , triethanolamine , trometh A “ therapeutic effect, " as that term is used herein , encom - 40 amine, purines , piperazine , piperidine , N - ethylpiperidine, passes a therapeutic benefit and / or a prophylactic benefit as polyamine resins and the like . Particularly preferred organic described above . A prophylactic effect includes delaying or bases are isopropylamine , diethylamine , ethanolamine , trim eliminating the appearance of a disease or condition , delay - ethylamine, dicyclohexylamine, choline and caffeine . ing or eliminating the onset of symptoms of a disease or The terms “ antagonist ” and “ inhibitor” are used inter condition , slowing , halting , or reversing the progression of 45 changeably , and they refer to a compound having the ability a disease or condition , or any combination thereof. to inhibit a biological function of a target protein , whether by The term “ co -administration ," " administered in combina - inhibiting the activity or expression of the protein , such as tion with , " and their grammatical equivalents , as used KRAS , HRAS or NRAS G12C . Accordingly , the terms herein , encompass administration of two or more agents to " antagonist ” and “ inhibitors” are defined in the context of an animal, including humans , so that both agents and /or their 50 the biological role of the target protein . While preferred metabolites are present in the subject at the same time. antagonists herein specifically interact with ( e . g . bind to ) the Co - administration includes simultaneous administration in target , compounds that inhibit a biological activity of the separate compositions , administration at different times in target protein by interacting with other members of the separate compositions, or administration in a composition in signal transduction pathway of which the target protein is a which both agents are present. 55 member are also specifically included within this definition . “ Pharmaceutically acceptable salt” includes both acid and A preferred biological activity inhibited by an antagonist is base addition salts . associated with the development, growth , or spread of a “ Pharmaceutically acceptable acid addition salt” refers to tumor. those salts which retain the biological effectiveness and The term “ agonist ” as used herein refers to a compound properties of the free bases , which are not biologically or 60 having the ability to initiate or enhance a biological function otherwise undesirable , and which are formed with inorganic of a target protein , whether by inhibiting the activity or acids such as , but are not limited to , hydrochloric acid , expression of the target protein . Accordingly , the term hydrobromic acid , sulfuric acid , nitric acid , phosphoric acid “ agonist " is defined in the context of the biological role of and the like , and organic acids such as , but not limited to , the target polypeptide . While preferred agonists herein spe acetic acid , 2 ,2 -dichloroacetic acid , adipic acid , alginic acid , 65 cifically interact with (e . g . bind to ) the target, compounds ascorbic acid , aspartic acid , benzenesulfonic acid , benzoic that initiate or enhance a biological activity of the target acid , 4 -acetamidobenzoic acid , camphoric acid , camphor - polypeptide by interacting with othermembers of the signal US 10 , 111, 874 B2 13 14 transduction pathway of which the target polypeptide isa e ritoneal, intravesical , subcutaneous, transdermal, buccal , or member are also specifically included within this definition . inhalation or in the form of a suppository . As used herein , “ agent” or “ biologically active agent” “ Prodrug ” is meant to indicate a compound that may be refers to a biological, pharmaceutical, or chemical com - converted under physiological conditions or by solvolysis to pound or other moiety . Non - limiting examples include a 5 a biologically active compound described herein ( e . g . , com simple or complex organic or inorganic molecule, a peptide , pound of structure ( I ) ) . Thus, the term “ prodrug ” refers to a a protein , an oligonucleotide, an antibody, an antibody precursor of a biologically active compound that is pharma derivative , antibody fragment, a vitamin derivative, a car ceutically acceptable . In some aspects , a prodrug is inactive bohydrate , a toxin , or a chemotherapeutic compound . Vari - when administered to a subject, but is converted in vivo to ous compounds can be synthesized , for example , small 10 an active compound , for example , by hydrolysis . The pro molecules and oligomers (e . g. , oligopeptides and oligo drug compound often offers advantages of solubility , tissue nucleotides ) , and synthetic organic compounds based on compatibility or delayed release in a mammalian organism various core structures . In addition , various natural sources ( see, e . g . , Bundgard , H ., Design of Prodrugs ( 1985 ) , pp . 7 - 9 , can provide compounds for screening , such as plant or 21- 24 (Elsevier , Amsterdam ). A discussion of prodrugs is animal extracts , and the like . 15 provided in Higuchi, T . , et al. , “ Pro - drugs as Novel Delivery " Signal transduction ” is a process during which stimula - Systems, ” A . C .S . Symposium Series, Vol. 14 , and in Bior tory or inhibitory signals are transmitted into and within a eversible Carriers in Drug Design , ed . Edward B . Roche , cell to elicit an intracellular response . A modulator of a American Pharmaceutical Association and Pergamon Press , signal transduction pathway refers to a compound which 1987 , both of which are incorporated in full by reference modulates the activity of one or more cellular proteins 20 herein . The term “ prodrug ” is also meant to include any mapped to the same specific signal transduction pathway . A covalently bonded carriers , which release the active com modulator may augment (agonist ) or suppress ( antagonist) pound in vivo when such prodrug is administered to a the activity of a signaling molecule . mammalian subject. Prodrugs of an active compound , as An “ anti- cancer agent" , " anti - tumor agent” or “ chemo - described herein , are typically prepared by modifying func therapeutic agent” refers to any agent useful in the treatment 25 tional groups present in the active compound in such a way of a neoplastic condition . One class of anti - cancer agents that the modifications are cleaved , either in routine manipu comprises chemotherapeutic agents . " Chemotherapy" lation or in vivo , to the parent active compound . Prodrugs means the administration of one or more chemotherapeutic include compounds wherein a hydroxy , amino or mercapto drugs and / or other agents to a cancer patient by various group is bonded to any group that, when the prodrug of the methods , including intravenous, oral, intramuscular, intrap - 30 active compound is administered to a mammalian subject , eritoneal, intravesical, subcutaneous, transdermal, buccal, or cleaves to form a free hydroxy, free amino or free mercapto inhalation or in the form of a suppository . group , respectively . Examples of prodrugs include, but are The term " cell proliferation ” refers to a phenomenon by not limited to , acetate , formate and benzoate derivatives of which the cell number has changed as a result of division . a hydroxy functional group , or acetamide , formamide and This term also encompasses cell growth by which the cell 35 benzamide derivatives of an amine functional group in the morphology has changed ( e . g . , increased in size ) consistent active compound and the like . with a proliferative signal. The term " in vivo ” refers to an event that takes place in The term " selective inhibition ” or “ selectively inhibit ” a subject ’s body. refers to a biologically active agent refers to the agent' s The invention disclosed herein is also meant to encom ability to preferentially reduce the target signaling activity as 40 pass all pharmaceutically acceptable compounds of structure compared to off - target signaling activity , via direct or indi- (I ) being isotopically - labelled by having one or more atoms rect interaction with the target . replaced by an atom having a different atomic mass or mass “ Subject” refers to an animal, such as a mammal, for number . Examples of isotopes that can be incorporated into example a human . The methods described herein can be the disclosed compounds include isotopes of hydrogen , useful in both human therapeutics and veterinary applica - 45 carbon , nitrogen , oxygen , phosphorous , fluorine, chlorine, tions . In some embodiments , the subject is a mammal , and and iodine, such as 2H , PH , C , 130 , 14C , 13N , 15N , 150 , 170 , in some embodiments , the subject is human . 180 , 310 , 32P, 35S , 18F , 36C1 , 1231, and 1251, respectively . “ Mammal” includes humans and both domestic animals These radiolabelled compounds could be useful to help such as laboratory animals and household pets ( e . g ., cats , determine or measure the effectiveness of the compounds , dogs , swine, cattle , sheep , goats, horses , rabbits ) , and non - 50 by characterizing , for example , the site or mode of action , or domestic animals such as wildlife and the like. binding affinity to pharmacologically important site of “ Radiation therapy ” means exposing a subject , using action . Certain isotopically - labelled compounds of structure routine methods and compositions known to the practitioner , ( I ) , for example , those incorporating a radioactive isotope , to radiation emitters such as alpha -particle emitting radio are useful in drug and /or substrate tissue distribution studies. nuclides ( e . g . , actinium and thorium radionuclides ) , low 55 The radioactive isotopes tritium , i .e . ” H , and carbon - 14 , i .e . linear energy transfer (LET ) radiation emitters ( i. e . beta 14C , are particularly useful for this purpose in view of their emitters ) , conversion electron emitters ( e . g . strontium -89 ease of incorporation and ready means of detection . and Samarium - 153 -EDTMP , or high - energy radiation , Substitution with heavier isotopes such as deuterium , i . e . including without limitation X - rays , gamma rays, and neu - ? H , may afford certain therapeutic advantages resulting from trons. 60 greater metabolic stability , for example , increased in vivo An " anti - cancer agent" , " anti - tumor agent” or “ chemo - half- life or reduced dosage requirements , and hence are therapeutic agent” refers to any agent useful in the treatment preferred in some circumstances. of a neoplastic condition . One class of anti- cancer agents Substitution with positron emitting isotopes , such as 11C , comprises chemotherapeutic agents . " Chemotherapy ” 18F , 150 and 13N , can be useful in Positron Emission means the administration of one or more chemotherapeutic 65 Topography ( PET ) studies for examining substrate receptor drugs and / or other agents to a cancer patient by various occupancy . Isotopically -labeled compounds of structure (I ) methods, including intravenous, oral, intramuscular , intrap can generally be prepared by conventional techniques US 10 , 111 , 874 B2 16 known to those skilled in the art or by processes analogous pure forms. Optically active ( + ) and ( - ) , ( R ) - and (S ) -, or to those described in the Preparations and Examples as set (D )- and ( L )- isomers may be prepared using chiral synthons out below using an appropriate isotopically -labeled reagent or chiral reagents, or resolved using conventional tech in place of the non - labeled reagent previously employed . niques, for example, chromatography and fractional crystal The invention disclosed herein is also meant to encom - 5 lization . Conventional techniques for the preparation / isola pass the in vivo metabolic products of the disclosed com - tion of individual enantiomers include chiral synthesis from pounds. Such products may result from , for example , the a suitable optically pure precursor or resolution of the oxidation , reduction , hydrolysis , amidation , esterification , racemate ( or the racemate of a salt or derivative ) using , for and the like of the administered compound , primarily due to example , chiral high pressure liquid chromatography enzymatic processes . Accordingly , the invention includes 10 (HPLC ) . When the compounds described herein contain compounds produced by a process comprising administering olefinic double bonds or other centers of geometric asym a compound of this invention to a mammal for a period of metry , and unless specified otherwise , it is intended that the time sufficient to yield a metabolic product thereof. Such compounds include both E and Z geometric isomers. Like products are typically identified by administering a radiola - wise , all tautomeric forms are also intended to be included . belled compound of the invention in a detectable dose to an 15 The present invention includes all manner of rotamers and animal, such as rat, mouse , guinea pig , monkey , or to human , conformationally restricted states of a compound of the allowing sufficient time for metabolism to occur, and iso invention . lating its conversion products from the urine , blood or other A “ stereoisomer” refers to a compound made up of the biological samples . same atoms bonded by the same bonds but having different " Stable compound ” and “ stable structure ” are meant to 20 three - dimensional structures , which are not interchangeable . indicate a compound that is sufficiently robust to survive The present invention contemplates various stereoisomers isolation to a useful degree of purity from a reaction mixture , and mixtures thereof and includes " enantiomers ” , which and formulation into an efficacious therapeutic agent . refers to two stereoisomers whose molecules are non -super Often crystallizations produce a solvate of the compound imposable mirror images of one another. of the invention . As used herein , the term “ solvate ” refers to 25 A “ tautomer ” refers to a proton shift from one atom of a an aggregate that comprises one or more molecules of a molecule to another atom of the same molecule . The present compound of the invention with one or more molecules of invention includes tautomers of any said compounds. solvent. In some embodiments , the solvent is water, in which The chemical naming protocol and structure diagrams case the solvate is a hydrate . Alternatively , in other embodi- used herein are a modified form of the I. U .P . A .C . nomen ments , the solvent is an organic solvent. Thus , the com - 30 clature system , using the ACD /Name Version 9 .07 software pounds of the present invention may exist as a hydrate , program and / or ChemDraw Ultra Version 11 . 0 . 1 software including a monohydrate , dihydrate , hemihydrate , sesqui- naming program ( CambridgeSoft) . For complex chemical hydrate , trihydrate , tetrahydrate and the like , as well as the names employed herein , a substituent group is typically corresponding solvated forms. In some aspects, the com - named before the group to which it attaches . For example , pound of the invention is a true solvate , while in other cases, 35 cyclopropylethyl comprises an ethyl backbone with a cyclo the compound of the invention merely retains adventitious propyl substituent. Except as described below , all bonds are water or is a mixture of water plus some adventitious identified in the chemical structure diagramsherein , except solvent. for all bonds on some carbon atoms, which are assumed to “ Optional” or “ optionally ” means that the subsequently be bonded to sufficient hydrogen atoms to complete the described event of circumstances may or may not occur, and 40 valency . that the description includes instances where said event or A . Treatment Methods circumstance occurs and instances in which it does not . For The present disclosure is generally directed to methods example , " optionally substituted aryl” means that the aryl for treatment of various cancers . The present inventors have radical may or may not be substituted and that the descrip - discovered that a combination of mutant specific KRAS , tion includes both substituted aryl radicals and aryl radicals 45 NRAS or HRAS G12C inhibitory molecules with clinically having no substitution . relevant molecular targeted drugs and / or chemotherapy A " pharmaceutical composition ” refers to a formulation agents is a surprisingly effective method for treatment of of a compound of the invention and a medium generally certain cancers , for example cancers associated with KRAS , accepted in the art for the delivery of the biologically active NRAS or HRAS G12C mutant proteins ( a “ KRAS , HRAS compound to mammals , e . g ., humans. Such a medium 50 or NRAS G12C mutant cancer” ). In various embodiments , includes all pharmaceutically acceptable carriers , diluents or inhibition of mutant KRAS dramatically sensitizes cancer excipients thereforfor . cells to the described combination therapies, leading to “ Pharmaceutically acceptable carrier, diluent or excipi- robust cell death . Such combination methods have the ent” includes without limitation any adjuvant, carrier, possibility to greatly improve the outcomes for patients with excipient, glidant, sweetening agent, diluent, preservative , 55 tumors harboring the KRAS, NRAS or HRAS G12C muta dye / colorant , flavor enhancer , surfactant, wetting agent, dis - tion . persing agent, suspending agent, stabilizer, isotonic agent, Example 1 describes a strategy for identifying and assess solvent, or emulsifier which has been approved by the ing potential targets that would benefit from a combination United States Food and Drug Administration as being treatment including a KRAS G12C inhibitor and a second acceptable for use in humans or domestic animals . 60 agent that would inhibit any cell signaling pathway that was The compounds of the invention , or their pharmaceuti - hyperactivated or maintained following KRAS G12C inhi cally acceptable salts may contain one or more asymmetric bition . Exemplary targets identified include RTK , PI3K , centers and may thus give rise to enantiomers , diastereom - mTOR , SRC , and JAK /STAT . ers , and other stereoisomeric forms that are defined , in terms Examples 2 - 10 describe additional data obtained in sup of absolute stereochemistry , as (R )- or ( S )- or, as ( D )- or (L )- 65 port of certain embodiments of the present invention . In for amino acids . The present invention is meant to include all Example 2 , a combination of an exemplary KRAS G12C such possible isomers , as well as their racemic and optically inhibitor was used with one of an RTK , a PI3K , an mTOR , US 10V9 , 1111 ,874 B2 17 18 an SRC , or a JAK inhibitor. The synergistic effect of the a KRAS, HRAS or NRAS G12C mutant modulating com combination was assessed by monitoring both cell prolif pound and an additional therapeutic agent to a subject in eration and apoptosis in the presence of each agent alone and need thereof. In certain embodiments , the cancer is a KRAS in the presence of the combination . This example was G12C mutant cancer . The KRAS , HRAS or NRAS G12C carried out on a variety of mutant cell lines (H358 , H1792 , 5 mutant modulating compound is not particularly limited Calu - 1 , SW1463 , SW1573 , MiaPaca2 , NCI- H23 ) or control provided the compound modulates ( e . g . , inhibits ) the activ cell line (A549 ) . The proliferation data was combined with ity of the KRAS , HRAS or NRAS G12C mutant. Exemplary apoptosis data to assess the synergistic effect of the com compounds for this purpose are described herein in the pounds used in combination . section entitled “ Compounds. " In Example 3 , multiple KRAS G12C cell lines were 10 In various embodiments of the method , the additional evaluated for evidence of apoptosis induction in the pres therapeutic agent is an epidermal growth factor receptor ence of KRAS G12C inhibitors alone , or in combination with targeted agents (EGFR , PI3K , IGF1R , and MEK inhibi ( EGFR ) inhibitor, phosphatidylinositol kinase (PI3K ) tors ) or chemotherapeutic agents ( Taxol , Docetaxel , SN38 inhibitor, insulin - like growth factor receptor ( IGF1R ) inhibi ( active ingredient in Irinotecan ) ) . In similar fashion . 15 tor, Janus kinase ( JAK ) inhibitor, a Met (MET ) kinase Examples 4 - 10 each show an evaluation of a KRAS G12C inhibitor, a SRC family kinase (SFK ) inhibitor, a mitogen inhibitor used in combination with one of many different activated protein kinase (MEK ) inhibitor, an extracellular types of inhibitors ( e . g ., EGFR , PI3K , MEK , SRC , JAK ) for signal- regulated kinase ( ERK ) inhibitor, mechanistic target synergistic pathway inhibition or induction of apoptosis in of rapamycin (mTOR ) inhibitor, a topoisomerase inhibitor relevant cancer cell lines . 20 ( such as irinotecan , or such as etoposide , or such as doxo Synergistic apoptosis induction was observed with treat- rubicin ), taxanes ( such as anti- microtubule agents including ment of KRAS G12C mutated cell lines with combinations paclitaxel and docetaxel) , anti- metabolite agents (such as of a KRAS G12C inhibitor and selected targeted and che - 5 -FU or such as gemcitabine ), alkylating agents ( such as motherapeutic agents . In many cases , the levels of apoptosis cisplatin or such as cyclophosphamide ) , or a taxane . induced by these combinations rivaled what is seen with 25 In some other embodiments of the method , the additional high dose staurosporine or Taxol. As with the single agent therapeutic agent is an epidermal growth factor receptor treatments , the effects varied by cell -type and by the precise ( EGFR ) inhibitor , phosphatidylinositol kinase (PI3K ) combination . The greatest synergy was observed when a inhibitor , insulin - like growth factor receptor ( IGF1R ) inhibi KRAS G12C inhibitor was combined with an EGFR inhibi tor, Janus kinase (JAK ) inhibitor, a Met (MET ) kinase tor ( e . g . , erlotinib and afatinib ) , a PI3K inhibitor ( e . g ., 30 inhibitor , a SRC family kinase (SFK ) inhibitor, a mitogen GDC0941 , BYL - 719 ) , or the chemotherapeutic agent SN38 activated protein kinase (MEK ) inhibitor, an extracellular ( active ingredient in Irinotecan ) . Some positive results were signal- regulated kinase (ERK ) inhibitor, a topoisomerase also seen with MEK inhibitors , IGFIR inhibitors , JAK inhibitor ( such as irinotecan , or such as etoposide , or such as inhibitors , SRC inhibitors , and the chemotherapeutic agents doxorubicin ), taxanes ( such as anti -microtubule agents Taxol, Docetaxel , and Paclitaxel. 35 including paclitaxel and docetaxel) , anti -metabolite agents Overall the data support that inhibition ofmutant KRAS ( such as 5 -FU or such as gemcitabine ), alkylating agents activity can dramatically alter the sensitivity of KRAS (such as cisplatin or such as cyclophosphamide ), or a taxane . mutant cell lines to both targeted cancer therapies and , more In some embodiments , the additional therapeutic agent is broadly , active chemotherapies . The levels of apoptosis an epidermal growth factor receptor ( EGFR ) inhibitor, such observed with optimal combinations are equal to potent 40 as erlotinib or such as afatinib . In some embodiments the apoptosis inducers and suggest that nearly 100 % cell killing additional therapeutic agent is Iressa . In some embodiments is possible . In a clinical setting this type of behavior should the additional therapeutic agent is a monoclonal antibody allow for optimal therapeutic combinations to lead to dra - such as cetuximab ( Erbitux ) or panitumumab (Vectibix ) . In matic tumor regression . some embodiments the GFR inhibitor is a dual or pan -HER The effectiveness of different combinations varied with 45 inhibitor . In other embodiments , the additional therapeutic the different cell lines despite sharing the KRAS G12C agent is a phosphatidylinositol- 3kinase (PI3K ) inhibitor, mutation . While not wishing to be bound by theory , this is such as GDC0941 , MLN1117 , BYL719 ( Alpelisib ) or may be related to differences in the genetic background and BKM120 (Buparlisib ). GDC0941 refers to 2 - 1H - indazol varied oncogene addictions in each of these lines . FIG 9. 4 -yl ) - 6 - ( 4 -methanesulfonyl - piperazin - 1 - ylmethyl) - 4 -mor provides data for an effective combination strategy for 50 pholin - 4 -yl - thieno[ 3 ,2 - d ]pyrimidine or a salt thereof ( e . g . , Calu - 1 cells. Calu - 1 cells were generally resistant to single bismesylate salt ) . agent KRAS G12C treatment as well as combinations with In still different embodiments , the additional therapeutic targeted kinase inhibitors . Comparison of tyrosine kinase agent is an insulin - like growth factor receptor ( IGF1R ) phosphorylation levels between H358 and Calu - 1 cells inhibitor . For example , in some embodiments the insulin revealed that Calu - 1 cells have high levels of C - SRC phos - 55 like growth factor receptor ( IGF1R ) inhibitor is NVP phorylation (FIG . 9A ). Combination treatment of Calu - 1 AEW541. In other embodiments , the additional therapeutic cells with a KRAS G12C inhibitor and a SRC inhibitor agent is IGOSI- 906 (Linsitinib ) , BMS- 754807, or in other (Dasatinib ) revealed a strong synergistic induction of apop embodiments the additional therapeutic agent is a neutral tosis (FIG . 9B ). izing monoclonal antibodies specific to IGFIR such as Given that KRAS is a centrally important oncogene that 60 AMG -479 ( ganitumab ) , CP - 751, 871 ( figitumumab ), IMC universally leads to treatment- resistant cancer , we anticipate A12 ( cixutumumab ) , MK -0646 (dalotuzumab ) , and R - 1507 that eliminating the oncogenic KRAS signaling will uncover ( robatumumab ). enhanced sensitivities to a broad range of cancer therapeu In some other embodiments , the additional therapeutic tics beyond what has been examined here . agent is a Janus kinase ( JAK ) inhibitor. In some embodi Accordingly , in one embodiment a method for treating a 65 ments , the additional therapeutic agent is CYT387 , KRAS , HRAS or NRAS G12C mutant cancer is provided , GLPG0634 , Baricitinib , Lestaurtinib , momelotinib , Pacri the method comprising administering an effective amount of tinib , Ruxolitinib or TG101348 US 10V91 , 111 1 , 874 B2 20 In some other embodiments the additional therapeutic While not wishing to be bound by theory , it is believed agent is an MET kinase inhibitor, such as Crizotinib , tivan - that the effectiveness of the presently described combination tinib , AMG337 , cabozantinib , foretinib . In other embodi therapies is related , at least in part , to the synergistic ability ments the additional therapeutic agent is a neutralizing of the individual components to induce apoptosis in cells monoclonal antibody to MET such as onartuzumab . 5 comprising KRAS , HRAS or NRAS G12C mutant protein . In more embodiments , the additional therapeutic agent is Accordingly , in certain embodiments a method for inducing a SRC family non -receptor tyrosine kinase inhibitor. For apoptosis in a cell population comprising a KRAS, HRAS or NRAS G12C mutant protein is provided , the method com example in some embodiments the additional therapeutic prising administering an effective amount of a KRAS , agent is an inhibitor of the subfamily of SRC family non 10 HRAS or NRAS G12C mutant modulating compound and receptor tyrosine kinases. Exemplary inhibitors in this an additional therapeutic agent. Compounds and additional respect include Dasatinib . Other examples in this regard therapeutic agents useful in such methods include any of include Ponatinib , sarcatinib , and bosutinib these described herein . In yet different embodiments , the additional therapeutic The described methods also find utility for inhibiting agent is a mitogen - activated protein kinase (MEK Ek )) inhibitor. 15 tumor metastasis , and in some embodiments , a method for In some of these embodiments , the mitogen - activated pro inhibiting tumor metastasis in a subject having a KRAS , tein kinase (MEK ) inhibitor is trametinib , selumetinib , cobi HRAS or NRAS G12C mutant cancer is provided , the metinib , PD0325901 , or RO5126766 . In other embodiments method comprising administering an effective amount of a the MEK inhibitor is GSK - 1120212, also known as tram KRAS , HRAS or NRAS G12C mutant modulating com etinib . 20 pound and an additional therapeutic agent. Compounds and In yet different embodiments , the additional therapeutic additional therapeutic agents useful for inhibiting tumor agent is an extracellular- signal - regulated kinase ( ERK ) metastasis include any of these described herein . inhibitor. In some of these embodiments , the extracellular - The described methods are generally applicable to any signal- regulated kinase ( ERK ) inhibitor is SCH722984 or type of cancer. In certain embodiments the cancer is asso GDC - 0994 . 25 ciated with a KRAS , HRAS or NRAS G12C mutant protein . In other embodiments , the additional therapeutic agent is In somemore specific embodiments , the cancer is associated a protein kinase inhibitor, such as Staurosporine or with a KRAS , HRAS or NRAS G12C mutant protein . While Midostaurin . In other embodiments the protein kinase many cancers are can be treated according to the disclosed inhibitor is Afatinib , Axitinib , Bevacizumab , Bostutinib , methods, some embodiments are directed to treatment of Cetuximab , Crizotinib , Dasatinib , Erlotinib , Fostamatinib , 30 hematological cancer, pancreatic cancer, MYH associated Gefitinib , Imatinib , Lapatinib , Lenvatinib , Ibrutinib , Nilo - polyposis , colorectal cancer or lung cancer. tinib , Panitumumab , Pazopanib , Pegaptanib , Ranibizumab , KRAS , HRAS or NRAS G12C mutations have also been Ruxolitinib , Sorafenib , Sunitinib , SU6656 , Trastuzumab , identified in hematological malignancies ( e . g . , cancers that Tofacitinib , Vandetanib , or Vemurafenib . In still more affect blood , bone marrow and /or lymph nodes ) . Accord embodiments , the additional therapeutic agent is a topoi- 35 ingly , certain embodiments of the methods are directed to somerase inhibitor. In some of these embodiments , the treatment of a hematological malignancy . Such malignan topoisomerase inhibitor is Irinotecan . In some more embodi- cies include , but are not limited to leukemias and lympho ments , the additional therapeutic agent is a taxane . Exem - mas . For example , the presently disclosed combination plary taxanes include Taxol and Docetaxel. therapy can be used for treatment of diseases such as Acute In still different embodiments , wherein the additional 40 lymphoblastic leukemia (ALL ), Acute myelogenous leuke therapeutic agent is an mTOR inhibitor, such as Rapamycin mia ( AML ) , Chronic lymphocytic leukemia ( CLL ) , small or MLN0128 . lymphocytic lymphoma (SLL ) , Chronic myelogenous leu The exact method for administering the compound and kemia ( CML ), Acute monocytic leukemia (AMOL ) and /or the additional therapeutic agent will be apparent to one of other leukemias. In other embodiments , the methods are ordinary skill in the art . In some exemplary embodiments the 45 useful for treatment of lymphomas such as all subtypes of compound and the additional therapeutic agent are co - Hodgkin ' s lymphoma or non -Hodgkin ' s lymphoma. administered . In other embodiments , the compound and the Determining whether a tumor or cancer comprises a additional therapeutic agent are separately administered . G12C KRAS, HRAS or NRAS mutation can be undertaken In some embodiments, the compound and the additional by assessing the nucleotide sequence encoding the KRAS , therapeutic agent are administered with the second agent 50 HRAS or NRAS protein , by assessing the amino acid simultaneously or separately . This administration in combi - sequence of the KRAS , HRAS or NRAS protein , or by nation can include simultaneous administration of the two assessing the characteristics of a putative KRAS , HRAS or agents in the same dosage form , simultaneous administra - NRAS mutant protein . The sequence of wild -type human tion in separate dosage forms, and separate administration . KRAS , HRAS or NRAS is known in the art, ( e . g ., Accession That is , the compound and any of the additional therapeutic 55 No. NP203524 ) . agents described herein can be formulated together in the Methods for detecting a mutation in a KRAS , HRAS or same dosage form and administered simultaneously . Alter - NRAS nucleotide sequence are known by those of skill in natively , the compound and any of the additional therapeutic the art . These methods include, but are not limited to , agents described herein can be simultaneously administered , polymerase chain reaction - restriction fragment length poly wherein both the agents are present in separate formulations. 60 morphism ( PCR -RFLP ) assays , polymerase chain reaction In another alternative , the compound can be administered single strand conformation polymorphism (PCR - SSCP ) just followed by and any of the additional therapeutic agents assays, real -time PCR assays , PCR sequencing , mutant described herein , or vice versa . In some embodiments of the allele -specific PCR amplification (MASA ) assays , direct separate administration protocol, the compound and any of sequencing, primer extension reactions , electrophoresis , oli the additional therapeutic agents described herein are admin - 65 gonucleotide ligation assays , hybridization assays , TaqMan istered a few minutes apart, or a few hours apart, or a few assays, SNP genotyping assays, high resolution melting days apart . assays and microarray analyses. In some embodiments , US 10 , 111 , 874 B2 21 22 samples are evaluated for G12C KRAS , HRAS or NRAS syndromes, myelodysplastic /myleoproliferative neoplasms, mutations by real- time PCR . In real- time PCR , fluorescent multiple myeloma, merkel cell carcinoma , malignant meso probes, specific for the KRAS , HRAS or NRAS G12C thelioma , malignant fibrous histiocytoma of bone and osteo mutation , are used . When a mutation is present, the probe sarcoma, nasal cavity and paranasal sinus cancer, nasopha binds and fluorescence is detected . In some embodiments , 5 ryngeal cancer, neuroblastoma, non -Hodgkin ' s lymphoma, the KRAS , HRAS or NRAS G12C mutation is identified non - small cell lung cancer (NSCLC ) , oral cancer , lip and using a direct sequencing method of specific regions ( e . g . , oral cavity cancer , oropharyngeal cancer, ovarian cancer, exon 2 and / or exon 3 ) in the KRAS , HRAS or NRAS gene . pancreatic cancer, papillomatosis , paraganglioma, paranasal This technique will identify all possible mutations in the sinus and nasal cavity cancer , parathyroid cancer, penile region sequenced . 10 cancer, pharyngeal cancer, pleuropulmonary blastoma , pri Methods for detecting a mutation in a KRAS , HRAS or mary central nervous system (CNS ) lymphoma, prostate NRAS protein are known by those of skill in the art. These cancer, rectal cancer, transitional cell cancer, retinoblas methods include , but are not limited to , detection of a toma , rhabdomyosarcoma , salivary gland cancer, skin can KRAS, HRAS or NRAS mutant using a binding agent ( e . g ., cer, stomach ( gastric ) cancer, small cell lung cancer, small an antibody ) specific for the mutant protein , protein elec - 15 intestine cancer, soft tissue sarcoma, T -Cell lymphoma, trophoresis and Western blotting, and direct peptide testicular cancer, throat cancer, thymoma and thymic carci sequencing . noma, thyroid cancer, transitional cell cancer of the renal Methods for determining whether a tumor or cancer pelvis and ureter, trophoblastic tumor, unusual cancers of comprises a G12C KRAS , HRAS or NRAS mutation can childhood , urethral cancer, uterine sarcoma, vaginal cancer, use a variety of samples . In some embodiments , the sample 20 vulvar cancer, or Viral- Induced cancer . In some embodi is taken from a subject having a tumor or cancer. In some ments , said method relates to the treatment of a non embodiments , the sample is taken from a subject having a cancerous hyperproliferative disorder such as benign hyper cancer or tumor. In some embodiments, the sample is a fresh plasia of the skin ( e . g ., psoriasis ), restenosis , or prostate ( e . tumor/ cancer sample. In some embodiments , the sample is a g ., benign prostatic hypertrophy (BPH ) ) . frozen tumor / cancer sample . In some embodiments , the 25 In certain particular embodiments , the invention relates to sample is a formalin - fixed paraffin -embedded sample . In methods for treatment of lung cancers, the methods com some embodiments , the sample is processed to a cell lysate . prise administering an effective amount of a KRAS , HRAS In some embodiments , the sample is processed to DNA or or NRAS G12C mutant modulating compound and an RNA . additional therapeutic agent to a subject in need thereof. In In some embodiments, the disclosed methods are for 30 certain embodiments the lung cancer is a non -small cell lung treating a hyperproliferative disorder in a subject that com - carcinoma (NSCLC ), for example adenocarcinoma , prises administering to said subject a therapeutically effec squamous -cell lung carcinoma or large -cell lung carcinoma . tive amount of a KRAS, HRAS or NRAS G12C mutant In other embodiments , the lung cancer is a small cell lung modulating compound and an additional therapeutic agent to carcinoma. Other lung cancers treatable with the disclosed a subject in need thereof . The compounds and additional 35 compounds include , but are not limited to , glandular tumors , therapeutic reagents useful in this regard include any of carcinoid tumors and undifferentiated carcinomas. those described herein . In some embodiments , said method Subjects that can be treated with the methods of this relates to the treatment of cancer such as acute myeloid invention include , for example , subjects that have been leukemia , cancer in adolescents , adrenocortical carcinoma diagnosed as having acute myeloid leukemia , acute myeloid childhood , AIDS - related cancers ( e . g . Lymphoma and 40 leukemia , cancer in adolescents , adrenocortical carcinoma Kaposi ' s Sarcoma ) , anal cancer , appendix cancer, astrocy - childhood , AIDS -related cancers ( e . g . Lymphoma and tomas, atypical teratoid , basal cell carcinoma, bile duct Kaposi' s Sarcoma) , anal cancer , appendix cancer , astrocy cancer, bladder cancer , bone cancer, brain stem glioma, tomas , atypical teratoid , basal cell carcinoma, bile duct brain tumor, breast cancer, bronchial tumors, burkitt lym cancer, bladder cancer, bone cancer , brain stem glioma, phoma, carcinoid tumor, atypical teratoid , embryonal 45 brain tumor , breast cancer , bronchial tumors , burkitt lym tumors , germ cell tumor, primary lymphoma , cervical can - phoma, carcinoid tumor , atypical teratoid , embryonal cer , childhood cancers , chordoma, cardiac tumors , chronic tumors , germ cell tumor, primary lymphoma, cervical can lymphocytic leukemia (CLL ) , chronic myelogenous leuke cer , childhood cancers , chordoma, cardiac tumors , chronic mia (CML ) , chronic myleoproliferative disorders , colon lymphocytic leukemia (CLL ), chronic myelogenous leuke cancer , colorectal cancer, craniopharyngioma, cutaneous 50 mia (CML ) , chronic myeloproliferative disorders , colon T - cell lymphoma , extrahepatic ductal carcinoma in situ cancer, colorectal cancer, craniopharyngioma, cutaneous (DCIS ) , embryonal tumors , CNS cancer , endometrial can - T - cell lymphoma, extrahepatic ductal carcinoma in situ cer , ependymoma, esophageal cancer , esthesioneuroblas - (DCIS ) , embryonal tumors , CNS cancer, endometrial can toma, ewing sarcoma, extracranial germ cell tumor, extrago cer , ependymoma, esophageal cancer, esthesioneuroblas nadal germ cell tumor, eye cancer, fibrous histiocytoma of 55 toma , Ewing ' s sarcoma , extracranial germ cell tumor, bone, gall bladder cancer, gastric cancer , gastrointestinal extragonadal germ cell tumor, eye cancer , fibrous histiocy carcinoid tumor, gastrointestinal stromal tumors (GIST ) , toma of bone, gall bladder cancer, gastric cancer, gastroin germ cell tumor , gestational trophoblastic tumor, hairy cell testinal carcinoid tumor , gastrointestinal stromal tumors leukemia , head and neck cancer , heart cancer, liver cancer, (GIST ) , germ cell tumor, gestational trophoblastic tumor, Hodgkin ' s lymphoma, hypopharyngeal cancer, intraocular 60 hairy cell leukemia , head and neck cancer , heart cancer, liver melanoma , islet cell tumors , pancreatic neuroendocrine cancer , Hodgkin ' s lymphoma, hypopharyngeal cancer , tumors , kidney cancer, laryngeal cancer , lip and oral cavity intraocular melanoma, islet cell tumors , pancreatic neuroen cancer, liver cancer, lobular carcinoma in situ (LCIS ), lung docrine tumors , kidney cancer , laryngeal cancer , lip and oral cancer , lymphoma, metastatic squamous neck cancer with cavity cancer, liver cancer , lobular carcinoma in situ (LCIS ) , occult primary , midline tract carcinoma, mouth cancer mul- 65 lung cancer, lymphoma, metastatic squamous neck cancer tiple endocrine neoplasia syndromes , multiple myeloma with occult primary , midline tract carcinoma, mouth cancer plasma cell neoplasm , mycosis fungoides, myelodysplastic multiple endocrine neoplasia syndromes , multiple myeloma/ US 10 , 111 ,874 B2 23 24 plasma cell neoplasm , mycosis fungoides, myelodysplastic additional therapeutic agent sufficient to inhibit the activity syndromes, myelodysplastic /myeloproliferative neoplasms, ofKRAS , HRAS or NRAS G12C in said organism . In some multiple myeloma, merkel cell carcinoma , malignant meso - embodiments , the invention provides methods of inhibiting thelioma, malignant fibrous histiocytoma of bone and osteo KRAS, HRAS or NRAS G12C activity in an animal by sarcoma, nasal cavity and paranasal sinus cancer, nasopha - 5 contacting said animal with an amount of a KRAS , HRAS ryngeal cancer , neuroblastoma, non -Hodgkin ' s lymphoma, or NRAS G12C mutant modulating compound and an non - small cell lung cancer (NSCLC ) , oral cancer, lip and additional therapeutic agent sufficient to inhibit the activity oral cavity cancer , oropharyngeal cancer , ovarian cancer , of KRAS , HRAS or NRAS G12C in said animal. In some pancreatic cancer, papillomatosis , paraganglioma, paranasal embodiments , the invention provides methods of inhibiting sinus and nasal cavity cancer, parathyroid cancer, penile 10 KRAS , HRAS or NRAS G12C activity in a subject by cancer , pharyngeal cancer, pleuropulmonary blastoma, pri contacting said subject with an amount of a KRAS, HRAS mary central nervous system (CNS ) lymphoma, prostate or NRAS G12C mutant modulating compound and an cancer, rectal cancer , transitional cell cancer, retinoblas - additional therapeutic agent sufficient to inhibit the activity toma, rhabdomyosarcoma, salivary gland cancer, skin can of KRAS , HRAS or NRAS G12C in said subject. In some cer , stomach (gastric ) cancer , small cell lung cancer, small 15 embodiments , the invention provides methods of inhibiting intestine cancer, soft tissue sarcoma, T -Cell lymphoma, KRAS , HRAS or NRAS G12C activity in a human by testicular cancer, throat cancer, thymoma and thymic carci contacting said human with an amount of a KRAS, HRAS noma, thyroid cancer , transitional cell cancer of the renal or NRAS G12C mutant modulating compound and an pelvis and ureter, trophoblastic tumor, unusual cancers of additional therapeutic agent sufficient to inhibit the activity childhood , urethral cancer, uterine sarcoma, vaginal cancer, 20 of KRAS , HRAS or NRAS G12C in said human . The vulvar cancer, or Viral- Induced cancer . In some embodi- present invention provides methods of treating a disease ments subjects that are treated according to the methods of mediated by KRAS , HRAS or NRAS G12C activity in a the invention include subjects that have been diagnosed as subject in need of such treatment. having a non - cancerous hyperproliferative disorder such as The additional therapeutic agent can be selected from any benign hyperplasia of the skin ( e . g ., psoriasis ) , restenosis , 25 number of therapeutic agents useful for treating cancer . Such or prostate ( e . g ., benign prostatic hypertrophy ( BPH ) ) . therapeutic agents can be approved for use in humans or The invention further provides methods of modulating a experimental . In some embodiments , the additional thera G12C Mutant KRAS , HRAS or NRAS protein activity by peutic agent is selected from the group consisting of mitotic contacting the protein with an effective amount of a KRAS , inhibitors , alkylating agents , anti -metabolites , intercalating HRAS or NRAS G12C mutant modulating compound and 30 antibiotics , growth factor inhibitors, cell cycle inhibitors , an additional therapeutic agent. Modulation can be inhibit - enzymes, topoisomerase inhibitors , biological response ing or activating protein activity . In some embodiments , the modifiers, anti -hormones , angiogenesis inhibitors, and anti invention provides methods of inhibiting protein activity by androgens . contacting the G12C Mutant KRAS, HRAS or NRAS pro - In addition to the above examples, other non - limiting tein with an effective amount of a KRAS , HRAS or NRAS 35 examples of additional therapeutic agents useful in the G12C mutant modulating compound and an additional described methods are chemotherapeutic agents, cytotoxic therapeutic agent in solution . In some embodiments , the agents , and non -peptide small molecules such as Gleevec® invention provides methods of inhibiting the G12C Mutant ( Imatinib Mesylate ) , Velcade® ( bortezomib ) , Casodex (bi KRAS , HRAS or NRAS protein activity by contacting a calutamide ) , Iressa® (gefitinib ) , and Adriamycin as well as cell, tissue , organ that express the protein of interest with a 40 a host of chemotherapeutic agents . Non - limiting examples KRAS , HRAS or NRAS G12C mutant modulating com - of chemotherapeutic agents include alkylating agents such pound and an additional therapeutic agent. In some embodi- as thiotepa and cyclosphosphamide (CYTOXANTM ) ; alkyl ments, the invention provides methods of inhibiting protein sulfonates such as busulfan , improsulfan and piposulfan ; activity in subject including but not limited to rodents and aziridines such as benzodopa , carboquone , meturedopa , and mammal ( e . g . , human ) by administering into the subject an 45 uredopa ; ethylenimines and methylamelamines including effective amount of a KRAS , HRAS or NRAS G12C mutant altretamine , triethylenemelamine , triethylenephosphor modulating compound and an additional therapeutic agent. amide, triethylenethiophosphaoramide and trimethylolom In some embodiments , the percentage modulation exceeds elamine ; nitrogen mustards such as chlorambucil , chlornap 25 % , 30 % , 40 % , 50 % , 60 % , 70 % , 80 % , or 90 % . In some hazine , cholophosphamide , estramustine , ifosfamide , embodiments , the percentage of inhibiting exceeds 25 % , 50 mechlorethamine , mechlorethamine oxide hydrochloride , 30 % , 40 % , 50 % , 60 % , 70 % , 80 % , or 90 % . melphalan , novembichin , phenesterine , prednimustine , tro In some embodiments , the invention provides methods of fosfamide , uracil mustard ; nitrosureas such as carmustine , inhibiting KRAS , HRAS or NRAS G12C activity in a cell chlorozotocin , fotemustine , lomustine , nimustine , rani by contacting said cell with an amount of a KRAS , HRAS mustine; antibiotics such as aclacinomysins, actinomycin , or NRAS G12C mutant modulating compound and an 55 authramycin , azaserine , bleomycins, cactinomycin , cali additional therapeutic agent sufficient to inhibit the activity cheamicin , carabicin , carminomycin , carzinophilin , Caso of KRAS , HRAS or NRAS G12C in said cell . In some dexTM , chromomycins, dactinomycin , daunorubicin , detoru embodiments , the invention provides methods of inhibiting bicin , 6 - diazo - 5 - oxo - L -norleucine , doxorubicin , epirubicin , KRAS , HRAS or NRAS G12C activity in a tissue by esorubicin , idarubicin , marcellomycin , mitomycins, myco contacting said tissue with an amount of a KRAS , HRAS or 60 phenolic acid , nogalamycin , olivomycins, peplomycin , pot NRAS G12C mutant modulating compound and an addi- firomycin , puromycin , quelamycin , rodorubicin , streptoni tional therapeutic agent sufficient to inhibit the activity of grin , streptozocin , tubercidin , ubenimex , zinostatin , KRAS , HRAS or NRAS G12C in said tissue . In some zorubicin ; anti -metabolites such as methotrexate and 5 - fluo embodiments , the invention provides methods of inhibiting rouracil ( 5 - FU ) ; folic acid analogues such as denopterin , KRAS , HRAS or NRAS G12C activity in an organism by 65 methotrexate , pteropterin , trimetrexate ; purine analogs such contacting said organism with an amount of a KRAS , HRAS as fludarabine, 6 -mercaptopurine , thiamiprine , thioguanine ; or NRAS G12C mutant modulating compound and an pyrimidine analogs such as ancitabine , azacitidine , 6 -azau US 10 , 111 , 874 B2 25 26 ridine , carmofur, cytarabine , dideoxyuridine , doxifluridine , niques for administering radiation therapy are known in the enocitabine, floxuridine, androgens such as calusterone, art , and these techniques can be used in the combination dromostanolone propionate , epitiostanol, mepitiostane, tes therapy described herein . The administration of the a KRAS , tolactone ; anti -adrenals such as aminoglutethimide , mito HRAS or NRAS G12C mutant modulating compound and tane , trilostane; folic acid replenisher such as frolinic acid ; 5 an additional therapeutic agent in this combination therapy aceglatone ; aldophosphamide glycoside ; aminolevulinic can be determined as described herein . acid ; amsacrine ; bestrabucil ; bisantrene ; edatraxate ; defo - Radiation therapy can be administered through one of famine ; demecolcine ; diaziquone ; elfomithine ; elliptinium several methods, or a combination of methods, including acetate ; etoglucid ; gallium nitrate ; hydroxyurea ; lentinan ; without limitation external -beam therapy , internal radiation lonidamine; mitoguazone ; mitoxantrone ; mopidamol; nitra - 10 therapy , implant radiation , stereotactic radiosurgery , sys crine ; pentostatin ; phenamet ; pirarubicin ; podophyllinic temic radiation therapy, radiotherapy and permanent or acid ; 2 -ethylhydrazide ; procarbazine ; PSK® ; razoxane ; temporary interstitial brachytherapy. The term “ brachy sizofiran ; spirogermanium ; tenuazonic acid ; triaziquone ; therapy , " as used herein , refers to radiation therapy delivered 2 , 2 ', 2 " - trichlorotriethylamine ; urethan ; vindesine ; dacarba - by a spatially confined radioactive material inserted into the zine ; mannomustine ; mitobronitol; mitolactol; pipobroman ; 15 body at or near a tumor or other proliferative tissue disease gacytosine ; arabinoside (“ Ara - C ” ) ; cyclophosphamide; thio site . The term is intended without limitation to include tepa; taxanes , e .g . paclitaxel ( TAXOLTM , Bristol- Myers exposure to radioactive isotopes (e .g . At- 211 , 1 -131 , 1- 125, Squibb Oncology, Princeton , N .J .) and docetaxel ( TAXO Y -90 , Re - 186 , Re - 188 , Sm - 153 , Bi- 212 , P - 32 , and radioac TERETM , Rhone -Poulenc Rorer , Antony , France ) ; retinoic tive isotopes of Lu ) . Suitable radiation sources for use as a acid ; esperamicins ; capecitabine ; and pharmaceutically 20 cell conditioner of the present invention include both solids acceptable salts , acids or derivatives of any of the above . and liquids . By way of non - limiting example , the radiation Also included as suitable chemotherapeutic cell condi source can be a radionuclide , such as 1 - 125 , 1- 131 , Yb - 169, tioners are anti -hormonal agents that act to regulate or Ir - 192 as a solid source , 1 - 125 as a solid source, or other inhibit hormone action on tumors such as anti -estrogens radionuclides that emit photons , beta particles , gamma including for example tamoxifen , (NolvadexTM ) , raloxifene , 25 radiation , or other therapeutic rays . The radioactive material aromatase inhibiting 4 ( 5 ) - imidazoles , 4 -hydroxytamoxifen , can also be a fluid made from any solution of radionuclide trioxifene , keoxifene, LY 117018 , onapristone , and tore - ( s ) , e . g . , a solution of I- 125 or 1 - 131 , or a radioactive fluid mifene (Fareston ); and anti -androgens such as flutamide , can be produced using a slurry of a suitable fluid containing nilutamide , bicalutamide , leuprolide , and goserelin ; small particles of solid radionuclides , such as Au - 198 , Y - 90 . chlorambucil ; gemcitabine ; 6 - thioguanine; mercaptopurine ; 30 Moreover , the radionuclide( s ) can be embodied in a gel or methotrexate ; platinum analogs such as cisplatin and carbo - radioactive micro spheres . platin ; vinblastine; platinum ; etoposide ( VP - 16 ) ; ifosfamide ; Without being limited by any theory , the methods of the mitomycin C ; mitoxantrone ; vincristine ; vinorelbine ; navel present invention can render abnormal cells more sensitive bine ; novantrone; teniposide; daunomycin ; aminopterin ; to treatment with radiation for purposes of killing and /or xeloda ; ibandronate ; camptothecin - 11 (CPT - 11 ) ; topoi- 35 inhibiting the growth of such cells . Accordingly , this inven somerase inhibitor RFS 2000 ; difluoromethylornithine tion further relates to a method for sensitizing abnormal cells (DMFO ) . Where desired , the compounds or pharmaceutical in a subject to treatment with radiation which comprises composition of the present invention can be used in com - administering to the subject an amount of a KRAS , HRAS bination with commonly prescribed anti -cancer drugs such or NRAS G12C mutant modulating compound and an as Herceptin® , Avastin , Erbitux® , Rituxan® , Taxol® , 40 additional therapeutic agent, which amount is effective is Arimidex® , Taxotere® , ABVD , AVICINE , Abagovomab , sensitizing abnormal cells to treatment with radiation . The Acridine carboxamide , Adecatumumab , 17 - N - Allylamino amount of the KRAS, HRAS or NRAS G12C mutant 17 - demethoxygeldanamycin , Alpharadin , Alvocidib , modulating compound and an additional therapeutic agent in 3 - Aminopyridine - 2 - carboxaldehyde thiosemicarbazone , this method can be determined according to the means for Amonafide, Anthracenedione , Anti -CD22 immunotoxins, 45 ascertaining effective amounts known in the art . Antineoplastic , Antitumorigenic herbs , Apaziquone , Atipri- In other embodiments , the additional therapeutic agent is mod , Azathioprine, Belotecan , Bendamustine , BIBW 2992 , selected from anti -angiogenesis agents , signal transduction Biricodar , Brostallicin , Bryostatin , Buthionine sulfoximine , inhibitors , antiproliferative agents , glycolysis inhibitors , or CBV (chemotherapy ), Calyculin , cell - cycle nonspecific autophagy inhibitors . antineoplastic agents , Dichloroacetic acid , Discodermolide , 50 Anti- angiogenesis agents , such as MMP - 2 (matrix -met Elsamitrucin , Enocitabine , Epothilone, Eribulin , Everoli - alloproteinase 2 ) inhibitors , MMP - 9 (matrix -metalloprotei mus, Exatecan , Exisulind , Ferruginol, Forodesine , Fosfe nase 9 ) inhibitors , and COX - 11 ( cyclooxygenase 11 ) inhibi strol, ICE chemotherapy regimen , IT- 101, Imexon , Imiqui tors, can be used as the additional therapeutic agent in the mod , Indolocarbazole , Irofulven , Laniquidar, Larotaxel, methods described herein . Anti- angiogenesis agents include, Lenalidomide , Lucanthone, Lurtotecan , Mafosfamide, 55 for example , rapamycin , temsirolimus ( CCI- 779 ) , everoli Mitozolomide, Nafoxidine , Nedaplatin , Olaparib , Ortataxel , mus (RAD001 ) , sorafenib , sunitinib , and bevacizumab . PAC - 1 , Pawpaw , Pixantrone, Proteasome inhibitor, Rebec Examples of useful COX - II inhibitors include CEL camycin , Resiquimod , Rubitecan , SN - 38 , Salinosporamide EBREXTM ( alecoxib ) , valdecoxib , and rofecoxib . Examples A , Sapacitabine, Stanford V , Swainsonine , Talaporfin , Tariq - of useful matrix metalloproteinase inhibitors are described uidar, Tegafur- uracil , Temodar, Tesetaxel, Triplatin tetrani- 60 in WO 96 /33172 (published Oct . 24 , 1996 ) , WO 96 / 27583 trate , Tris ( 2 - chloroethyl) amine , Troxacitabine , Uramustine , (published Mar. 7 , 1996 ) , European Patent Application No . Vadimezan , Vinflunine , ZD6126 or Zosuquidar. 97304971 . 1 ( filed Jul. 8 , 1997 ) , European Patent Applica This invention further relates to a method for using a tion No . 99308617 . 2 ( filed Oct. 29, 1999 ), WO 98 /07697 KRAS , HRAS or NRAS G12C mutant modulating com (published Feb . 26 , 1998 ), WO 98 /03516 (published Jan . 29 , pound and an additional therapeutic agent, in combination 65 1998 ), WO 98 / 34918 (published Aug. 13 , 1998 ) , WO with radiation therapy for inhibiting abnormal cell growth or 98 /34915 (published Aug . 13 , 1998 ) , WO 98 / 33768 (pub treating the hyperproliferative disorder in the subject . Tech - lished Aug . 6 , 1998 ), WO 98 / 30566 ( published Jul. 16 , US 10 , 111, 874 B2 27 28 1998 ), European Patent Publication 606 ,046 (published Jul. protein activity ) . Examples of compounds useful in certain 13 , 1994 ) , European Patent Publication 931, 788 (published embodiments of the methods are provided in PCT Pub . Nos. Jul. 28 , 1999 ), WO 90 / 05719 (published May 31 , 1990 ) , WO 2013 / 155223 and 2015 /054572 , the compounds and WO 99 / 52910 (published Oct . 21 , 1999 ) , WO 99 /52889 methods of which are incorporated herein by reference in ( published Oct. 21 , 1999 ), WO 99 / 29667 ( published Jun . 17 , 5 their entirety . Other compounds useful in different embodi 1999 ) , PCT International Application No . PCT / IB98 / 01113 ments of the method are provided herein below . ( filed Jul. 21, 1998 ), European Patent Application No . 1 . Compounds of Structure ( I ) 99302232 .1 ( filed Mar. 25 , 1999 ) , Great Britain Patent As noted above , in one embodiment of the present inven Application No. 9912961. 1 ( filed Jun . 3 , 1999 ) , U . S . Pro tion , compounds having activity as modulators of a G12C visional Application No. 60 / 148 , 464 ( filed Aug . 12 , 1999 ) , 10 mutant KRAS, HRAS or NRAS protein are provided , the U . S . Pat. No . 5 , 863, 949 ( issued Jan . 26 , 1999 ) , U . S . Pat. No . 5 , 861, 510 ( issued Jan . 19 , 1999 ) , and European Patent compounds have the following structure ( I) : Publication 780 ,386 (published Jun . 25 , 1997 ) , all of which are incorporated herein in their entireties by reference . Preferred MMP -2 and MMP - 9 inhibitors are those that have 15 little or no activity inhibiting MMP -1 . More preferred , are Q - 12- F those that selectively inhibit MMP - 2 and / or AMP - 9 relative n2 to the other matrix -metalloproteinases (i . e. , MAP - 1, MMP X GL 3 , MMP - 4 , MMP - 5 , MMP- 6 , MMP - 7 , MMP - 8 , MMP- 10 , RP MMP- 11 , MMP - 12 , and MMP - 13 ) . Some specific examples 20 TR46 of MMP inhibitors useful in the invention are AG - 3340 , RO 32 - 3555 , and RS 13 -0830 . Autophagy inhibitors include , but are not limited to or a pharmaceutically acceptable salt, tautomer , prodrug or chloroquine , 3 -methyladenine , hydroxychloroquine stereoisomer thereof, wherein : ( PlaquenilTM ) , bafilomycin A1, 5 - amino - 4 - imidazole car- 25 A is CR ' , CR25 , NR or S ; boxamide riboside (AICAR ), okadaic acid , autophagy - sup B is a bond , CR or CR20 pressive algal toxins which inhibit protein phosphatases of G and G2 are each independently N or CH ; type 2 or type 1 , analogues of cAMP, and drugs which W , X and Y are each independently N , NRS or CR “ ; elevate CAMP levels such as adenosine, LY204002 , N6 -mer Z is a bond , N or CRO ; captopurine riboside , and vinblastine . In addition , antisense 30L is a bond or NR ' ; or siRNA that inhibits expression of proteins including but L ’ is a bond or alkylene ; not limited to ATG5 (which are implicated in autophagy ), R is H , cyano , halo , C7 -Cgalkyl , C . -Coalkylaminyl , may also be used . Cz- Cg cycloalkyl, C , -Coalkenyl or Cz - Cocycloalkenyl, het B . Compounds erocyclyl , heteroaryl, aryloxy or aryl; As noted above , embodiments of the present methods 35 R24 , R2b and R2C are each independently H , halo , include administration of a KRAS , HRAS or NRAS G12C hydroxyl , CZ -C6 alkyl, C1- C6 haloalkyl, C7 - C alkoxy , mutant modulating compound (“ compound ” ) . The com Cz - Cg cycloalkyl or aryl; pounds have activity as modulators of KRAS , HRAS or R3a and R35 are, at each occurrence, independently H , NRAS G12C mutant protein activity . In some embodiments , OH , - NH2, CO , H , halo , cyano , C , - C6 alkyl, C . - C . the compound is a KRAS, HRAS or NRAS G12C mutant 40 alkynyl , hydroxylalkly , aminylalkyl, alkylaminylalkyl , cya modulating compound . In an aspect , the compounds are noalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbo capable of selectively binding to and/ or modulating a G12C nyl; or R3a and R35 join to form a carbocyclic or heterocyclic mutant KRAS , HRAS or NRAS protein . The compounds ring ; or R3a is H , OH , - NH2, CO , H , halo , cyano , may modulate the G12C mutant KRAS , HRAS or NRAS C .- C . alkyl , C7 -C6 alkynyl, hydroxylalkly , aminylalkyl , protein by reaction with an amino acid . While not wishing 45 alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbo to be bound by theory , the present applicants believe that, in nylalkyl or aminylcarbonyl, and R36 joins with Rºb to form some embodiments , the compounds selectively react with a carbocyclic or heterocyclic ring ; the G12C mutant KRAS , HRAS or NRAS proteins by R4a and R45 are , at each occurrence , independently H , forming a covalent bond with the cysteine at the 12 position OH , — NH , , - CO , H , halo , cyano , C , - C alkyl, C , -Co of a G12C mutant KRAS , HRAS or NRAS protein . By 50 alkynyl, hydroxylalkly , aminylalkyl, alkylaminylalkyl, cya binding to the Cystine 12 , the compounds may lock the noalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbo switch II of the G12C mutant KRAS , HRAS or NRAS into nyl ; or R4a and R4h join to form a carbocyclic or heterocyclic an inactive stage. This inactive stage may be distinct from ring ; or R4a is H , OH , - NH2, CO , H , halo , cyano , those observed for GTP and GDP bound KRAS, HRAS or C , - C , alkyl , C . - C . alkynyl, hydroxylalkly , aminylalkyl, NRAS . Some of the compounds may also be able to perturb 55 alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbo the switch I conformation . Some of the compounds may nylalkyl or aminylcarbonyl , and R46 joins with R36 to form favor the binding of the bound KRAS , HRAS or NRAS to a carbocyclic or heterocyclic ring ; GDP rather than GTP and therefore sequester the KRAS, R is , at each occurrence , independently H , C1 - C . alkyl or HRAS or NRAS into an inactive KRAS , HRAS or NRAS a bond to L ; GDP state . Because effector binding to KRAS , HRAS or 60 Ró is , at each occurrence , independently H , oxo , cyano , NRAS is highly sensitive to the conformation of switch I and cyanoalkyl, amino , aminylalkyl , aminylalkylaminyl, ami II , the irreversible binding of these compounds may disrupt nylcarbonyl, alkylaminyl, haloalkylaminyl, hydroxylal KRAS , HRAS or NRAS downstream signaling. kyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalky The present methods are not limited by the exact structure laminyl, guanidinylalkyl, guanidinylalkoxy , of the KRAS , HRAS or NRAS G12C mutant modulating 65 guanidinylalkylaminyl, C . - C . alkoxy, aminylalkoxy, alkyl compound , provided it has the above noted functionality carbonylaminylalkoxy, C . - C . alkyl, heterocyclyl, heterocy ( e . g . , modulating KRAS , HRAS or NRAS G12C mutant clyloxy , heterocyclylalkyloxy, heterocyclylaminyl, hetero US 10 , 111, 874 B2 29 30 cyclylalkylaminyl, heteroaryl , heteroaryloxy, R is , at each occurrence , independently H , oxo , cyano , heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylami cyanoalkyl, amino , aminylalkyl, aminylalkylaminyl, amin nyl, aryl, aryloxy, arylamino , arylalkylamino , arylalkyloxy ocarbonyl, alkylaminyl, haloalkylamino , hydroxylal or a bond to L ' ; kyamino , amindinylalkyl, amidinylalkoxy , amindinylalky R ? is H or C . -C . alkyl ; 5 laminyl, guanidinylalkyl, guanidinylalkoxy , m and m² are each independently 1 , 2 or 3 ; guanidinylalkylaminyl , C - C . alkoxy , aminylalkoxy , alkyl - - - - - indicates a single or double bond such that all carbonylaminylalkoxy, C1- C6 alkyl, heterocyclyl , heterocy valences are satisfied ; and clyloxy , heterocyclylalkyloxy , heterocyclylamino , heterocy E is an electrophilic moiety capable of forming a covalent clylalkylamino , heteroaryl, heteroaryloxy , bond with the cysteine residue at position 12 of a KRAS, 10 heteroarylalkyloxy, heteroarylamino , heteroarylalkylamino , HRAS or NRAS G12C mutant protein , aryl, aryloxy, arylamino , arylalkylamino , arylalkyloxy or a wherein at least one of W , X , Y or Z is CR where Róis bond to L ' ; a bond to L ?. Róa is H , alkyl or a bond to L ' ; In some embodiments when R ', R24 , R26 and R2C are all R ? is H or C . -C . alkyl independently selected from H and halo , then X and Z are 15m ' and m “ are each independently 1 , 2 or 3 ; both N and at least one of R3a , R35 , R4a or R4b is not H , and - - - -- indicates a single or double bond such that all provided that at least one of R20 , R25 or R2° is not H when valences are satisfied ; and Rl is pyridyl. E is an electrophilic moiety capable of forming a covalent In other embodiments, the compound has the following bond with the cysteine residue at position 12 of a KRAS , 20 HRAS or NRAS G12C mutant protein , wherein at least one structure ( I ) : of W , X , Y or Z is CR where R is a bond to L ' or at least one of W , X or Y is NR ” , wherein RS is a bond to L ' . In some embodiments of the compound of structure ( I ) , R30 R36 E the bond between Wand X is a double bond . In other R3a Î m2 2 -12 25 embodiments , the bond between Y and Z is a double bond . In more embodiments , the bond between A and B is a double bond . In still more embodiments, the bonds between W and R2 – 11- X , Y and Z and A and B are each double bonds . Rta R4 In somemore embodiments of the foregoing compound of 30 structure ( 1 ) : A is CRP, CR2b, NR ? or S ; or a pharmaceutically acceptable salt , tautomer , prodrug or B is a bond , CR or CR2C stereoisomer thereof, wherein : G and G are each independently N or CH ; A is CR ', CR26, NR7 or S ; W , X and Y are each independently N , NR or CR " ; B is a bond , CR1 or CR20 35 Z is a bond , N or CRO ; G and G ? are each independently N or CH ; L ' is a bond or NR ?; W , X and Y are each independently N , NR or CRO; L2 is a bond or alkylene ; Z is a bond , N or CR?a or Z is NH when Y is C = 0 ; R is H , cyano , halo , heterocyclyl, heteroaryl, aryloxy or L ' is a bond or NR7; aryl; L2 is a bond or alkylene ; 40 R24 , R26 and R2C are each independently H , halo , Rl is H , cyano , halo , heterocyclyl , heteroaryl , aryloxy or hydroxyl , C ,- C6 alkyl, C . -C . haloalkyl C3 -C , cycloalkyl or aryl; aryl; R24 , R26 and 2C are each independently H , halo , R3a and R35 are , at each occurrence, independently H , hydroxyl, C . -C . alkyl, C1- C6 haloalkyl, C1- C6 alkoxy, OH , - NH2, CO2H , halo , cyano , C , - C . alkyl, C . - C . Cz - C , cycloalkyl or aryl; 45 alkynyl, hydroxylalkly , aminylalkyl, alkylaminylalkyl, cya R3a and R3b are , at each occurrence , independently H , noalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbo - OH , - NH2, CO , H , halo , cyano , CZ - C6 alkyl, CZ - C6 nyl; or R3a and R3h join to form a carbocyclic or heterocyclic alkynyl, hydroxylalkly , aminylalkyl, alkylaminylalkyl, cya - ring ; or R3a is H , OH , - NH2, CO2H , halo , cyano , noalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbo - C -C6 alkyl, C , -C6 alkynyl, hydroxylalkly , aminylalkyl , nyl ; or R3a and R36 join to form a carbocyclic or heterocyclic 50 alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbo ring; or R3a is H , OH , - NH2, CO2H , halo , cyano , nylalkyl or aminylcarbonyl, and R3h joins with R45 to form C . - C . alkyl, C , -C6 alkynyl, hydroxylalkly , aminoalkyl, a carbocyclic or heterocyclic ring ; alkylaminylalkyl , cyanoalkyl, carboxyalkyl, aminylcarbo - R4a and R46 are, at each occurrence , independently H , nylalkyl or aminylcarbonyl, and R36 joins with R4h to form OH , - NH2, CO2H , halo , cyano , C . - C . alkyl , C . -C6 a carbocyclic or heterocyclic ring; 55 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cya R4a and R46 are , at each occurrence , independently H , noalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbo - OH , - NH2, CO2H , halo , cyano , C ,- C6 alkyl, C .- Co nyl; or R4a and R4h join to form a carbocyclic or heterocyclic alkynyl , hydroxylalkly , aminylalkyl, alkylaminylalkyl , cya - ring; or R?a is H , OH , - NH2, CO2H , halo , cyano , noalkyl , carboxyalkyl, aminocarbonylalkyl or aminocarbo - C1 -C6 alkyl, C1- C6 alkynyl, hydroxylalkly , aminylalkyl , nyl; or R40 and R46 join to form a carbocyclic or heterocyclic 60 alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbo ring ; or R4a is H , OH , NH2, CO , H , halo , cyano , nylalkyl or aminylcarbonyl, and R4h joins with R36 to form C1- C6 alkyl, C . - C . alkynyl, hydroxylalkly , aminylalkyl, a carbocyclic or heterocyclic ring ; alkylaminoalkyl, cyanoalkyl, carboxyalkyl , aminylcarbo R $ and R ? are each independently H or C . - C . alkyl; nylalkyl or aminylcarbonyl, and R4h joins with R35 to form R? is , at each occurrence , independently H , oxo , cyano , a carbocyclic or heterocyclic ring ; 65 cyanoalkyl, amino , aminylcarbonyl, alkylaminyl, C / -C6 R is , at each occurrence , independently H , C . - C . alkyl or alkoxy , C , - C alkyl or a bond to L ' ; a bond to L ' ; m and m ’ are each independently 1 , 2 or 3 ; US 10 , 111, 874 B2 31 32 - - - - - indicates a single or double bond such that all charge , partial positive charge or a polarized bond . In other valences are satisfied ; and embodiments , E comprises one or more bonds wherein the E is an electrophilic moiety capable of forming a covalent electronegativity of the two atoms forming the bonds is bond with the cysteine residue at position 12 of a KRAS, sufficiently different such that a partial positive charge ( e. g. , HRAS or NRAS G12C mutant protein , 5 by polarization of the bond ) resides on one of the atoms, for wherein at least one of W , X , Y or Z is CR where Róis example on a carbon atom . E moieties comprising carbon a bond to L ' , and provided that when R1, R20 , R25 and R2e are all indepen halogen bonds, carbon - oxygen bonds or carbon bonds to dently selected from H and halo , then X and Z are both N various leaving groups known in the art are examples of and at least one of R34 , R35 , R4a or R46 is not H , and 10 such E moieties. provided that at least one of R20 , R25 or R2° is not H when In certain embodiments of the foregoing , E has the R is pyridyl. following structure : In some other embodiments of the foregoing compound of structure ( I ) : A is CR ? b , NR ? or S ; 15 B is a bond or CR2C R10 G1 and G2 are each independently N or CH ; mm W , X and Y are each independently N , NR or CRO ; Z is a bond , N or CR ; L ' is a bond or NR " ; 20 wherein : L2 is a bond or alkylene ; R ! is cyano , C . - Cgalkyl, C . - Cgalkylaminyl, C3 -C , = represents a double or triple bond ; cycloalkyl, C7- Cgalkenyl or Cz -Cg cycloalkenyl, heterocy is –CO ) , CNRP') — , - NR CO$ ) , clyl or aryl; S ( 0 ) 2 - or - NR S 02— ; R29 , R26 and R2C are each independently H , halo , C -C6 25 R8 is H , C7 -Cgalkyl or hydroxylalkyl ; alkyl or C3 - C cycloalkyl; Ra and R3b are , at each occurrence , independently H , RS' is H , OH , CN or C - Coalkyl ; and - OH , - NH2, CO2H , halo , cyano , hydroxylalkly , ami when = = is a double bond then Rº and R10 are each nylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl; or independently H , cyano , carboxyl, C , -Cgalkyl , alkoxycar R3a and R3b join to form a carbocyclic or heterocyclic ring ; 30 bonyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or or R $ a is H , OH , - NH2, CO , H , halo , cyano , hydroxy - R and Rº join to form a carbocyclic or heterocyclic ring ; lalkly , aminylalkyl , cyanoalkyl , carboxyalkyl or aminylcar bonyl, and R3h joins with R4h to form a carbocyclic or when = = - is a triple bond ; then Rº is absent and R10 is H , heterocyclic ring ; C -Cgalkyl , aminylalkyl, alkylaminylalkyl or hydroxylalkyl. R4a and R4b are , at each occurrence , independently H . 35 In certain embodiments when = is a double bond then - OH . — NH , - CO , H , halo , cyano , hydroxylalkly, ami- R and R " are each independently H , cyano , C , -Cgalkyl , nylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl; or aminylalkyl, alkylaminylalkyl , or hydroxylalkyl or Rº and R44 and R46 join to form a carbocyclic or heterocyclic ring ; Rº join to form a carbocyclic or heterocyclic ring. or R4a is H , OH , - NH2, CO2H , halo , cyano ,hydroxy - In some of the foregoing embodiments , Q is — CEO) , lalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcar - 40 - NR8C ( = O ) - , - S (= O ), — or NR°S (= O ), bonyl, and R4h joins with R3b to form a carbocyclic or heterocyclic ring ; In some other of the foregoing embodiments , Qis R and R ’ are each independently H or C2 -Coalkyl ; CENR8' ) , wherein RS' is H , OH , CN or Rºis , at each occurrence , independently H , cyano , amino , C , - C alkyl. For example , in some embodiments Rºis H . In alkylaminyl , C , -Coalkoxy , C7 -Coalkyl or a bond to L "; y45 other. embodiments , R8' is CN . In other embodiments , R8' m ' and m² are each independently 1 , 2 or 3 ; is OH . - - - - - indicates a single or double bond such that all In some embodiments , the compound has the following valences are satisfied ; and structure ( I' ) : E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, 50 HRAS or NRAS G12C mutant protein , (1') wherein at least one of W , X or Y is CR where R is a 72_ E, bond to L '. m22 -12 12 - E, In still other embodiments of the foregoing compound of structure (I ) , R ' is H , cyano , halo , heterocyclyl, heteroaryl, 55 ml aryloxy or aryl. R46 The structure of E is not particularly limited provided it is capable of forming a covalent bond with a nucleophile , such as the cysteine residue at position 12 of a KRAS , HRAS or NRAS G12C mutant protein . Accordingly , moieties which 60 are capable of reaction with ( e . g . , by covalent bond forma tion ) a nucleophile are preferred . In certain embodiments , E R20 is capable of reacting in a conjugate addition manner ( e . g ., 1 . 4 -conjugate addition ) with an appropriately reactive nucleophile . In some embodiments , E comprises conjugatedated 65 Whereinwherein R ' isis R and R " is R2C or R ' is H and R " is R ' . pi bonds such that delocalization of electrons results in at In other embodiments , the compound has the following least one atom ( e . g . , a carbon atom ) having a positive structure ( I' a ): US 10 , 111, 874 B2 33 34 -continued (I ' a ) (I 'c ) R3a R33 2 RIO ä R 10 . G2 SL pe I R46 R9 Nim1 R46 L1 R4a R4a R41 X

RI R20 R26

( I 'd ) wherein : 0 represents a double or triple bond ; R 10 Q is CFO , CENR8' ) — , - NR CO$ ) , S ( = O ) 2 - or - NR?S ( = O ) 2 — ; R® is H , C7 - Cgalkyl or hydroxylalkyl ; 25 R46 R4a or

R $ ' is H , OH , CN or C .- C alkyl; x when = is a double bond then Rº and R1° are each independently H , cyano , carboxyl, C , - C alkyl, alkoxycar bonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or 30 2 hydroxylalkyl or Rº and Rlº join to form a carbocyclic or R? heterocyclic ring; when - - - is a triple bond then Rº is absent and R10 is H , C -Coalkyl , aminylalkyl, alkylaminylalkyl or hydroxylal- 35 kyl; and R ' is R1 and R " is R2C or R ' is H and R " is R '. ( Ile ) In some of the foregoing embodiments of compound ( I' a ) , 2 R10 Q is Q is — CEO) - , - NR CEO) - , - S ( = O ) 2 - or 40 - NR S ( 0 ) 2 — In some other of the foregoing embodiments of compound R46 ( I' a ), Q is Ce= NR8' ) — , wherein R8' is H , OH , CN or Rta CZ - Coalkyl. For example , in some embodiments RS' is H . In other embodiments , R ' ' is CN . In other embodiments , R8' 45 isOH . In still more embodiments of the foregoing compounds, the compound has one of the following structures (I ' b ), (I ' c ), R20 (I ' d ) or (I ' e ): 50 In still more embodiments , the compound has one of the following structures (I ' f ) , ( l' g ), ( I' h ) or (I ' i ) : (I ' b ) R3a ( I' f) LR30 55 CL? Y RIU R3a R9 R36 LR36 129 RIO. R4a . - N LR4 R46 R41

R 26 R2b US 10 , 111, 874 B2 35 36 -continued - continued ( I' k ) R3 R3a R38 A LR3N - 12 R10, R 35 v - 12 R10; IR40 R R32 Rº R4 1 ~ 24 R 46 R 45 X 10 R25

Rc RTR R20 (I' h ) 15 R3 R32 ( I ' l ) R10 or Rze R3 Po RIO 19 R46 N R4a 1 R 45 R2a R4a or Y R20 R 26 R26 RE R38 ( I' m ) RIO Rze R33 R9 *R10 IR45 R4a R ! Rita R48 R2a R20 R25 R 25

In some embodiments of the compounds of structures In some embodiments of the compounds of structures ( I 'j ) , ( l' k ) , ( I' l ) or ( I 'm ) , R is aryl and Ra andR are ( l' f ) , (I ' g ), (I ' h ) or (I ' i ) , R1 is aryl and R2C and R25 are 45 independently selected from H and halo , for example in independently selected from H and halo , for example in some further embodiments Rl is aryl and R2a and R25 are some further embodiments Rl is aryl and R2C and R26 are independently selected from halo . independently selected from halo . In other embodiments , the compound has the following In different embodiments , the compound has one of the 50 structure (1 " ): following structures ( I' ]) , ( I' k ), ( I 'l ) or ( I' m ) :

R3a RB R35 LR360 55 Nim2 R3Bv R10 , R9 R46 R3a R4a R41 60 R2a R46 R 25

RI 65 wherein R ' is R and R " is R2C or R ' is H and R " is R1. For R20 example , in some embodiments the compound has the following structure ( Ika ) : US 10 , 111, 874 B2 37 US 10, 111 ,874 B2 38 - continued (I “ a ) ( I" d ) R36 R10 REBENm 2 -12 5 RIO Nim1 R46 or R4a Rio eta lo R Rua R26 R25 ( I" e ) wherein : = represents a double or triple bond ; Qis CO) CNRS' ) - NRCO ) , R10 - S ( O ) 2 - or - NR ' S ( 0 ) 2 — ; RO R8 is H , C , - C alkyl or hydroxylalkyl; RS' is H , OH , — CN or C , - Coalkyl; 20 R46 when = is a double bond then Rº and R1° are each R4a independently H , cyano , carboxyl , C7 - C alkyl, alkoxycar bonyl, aminylalkyl , alkylaminylalkyl , heteroaryl or hydroxylalkyl or R and Riº join to form a carbocyclic or R 25 heterocyclic ring ; when = is a triple bond then Rº is absent and R10 is H , C -Coalkyl , aminylalkyl, alkylaminylalkyl or hydroxylal In other embodiments , the compound has one of the kyl; and following structures (I " f ) , ( I " g ) , (I " h ) or ( I" i ) : R ' is R1 and R " is R2C or R ' is H and R " is R1. In some of the foregoing embodiments of compound 30 (Ita ) , Q is Q is — CEO) - , - NR C$ 0 — , - S ( O )2 — (I " f) or - NR8S ( = O ) 2 — . In some other of the foregoing embodiments of compound ( I a ), Q is C ( = NR8') , wherein R & ' is H , OH , CN R3bL - L - Q R10. or C , -Coalkyl . For example , in some embodiments RS' is H . RI In other embodiments , Re' is — CN . In other embodiments , Re' is - OH . RU -11 R4a | In other embodiments , the compound has one of the R46 following structures (I " b ) , ( I" C ), (I " d ) or (I " e ): 40 (I " b ) R26 R3 LR30 R36 K (2 - 0 R10. 45 LR36 R32 LR46 R9 R36 < _ 12- ya il' R4a X R46 50 R -11 R41 R 46 R2 R 25 (I" c) 55 R 25 R3 ( I " h ) plo. _ Q LR36 Rze R32 R 10 Rº LR46 60 P9 11 `pta R4T TR46 or ER42 Rta og R2 R 25 R 26 US 10 , 111, 874 B2 39 40 - continued In other various embodiments , the compound has the (I " i) following structure ( I' " ) : Yö RIOpios ^ R36 Rza î L TR46 22- 12 -

10 R20 R21 In some different embodiments , the compound has one of 15 the following structures ( I" j ) , ( I " k ) , ( I ' l ) or ( I' m ) : wherein A is NH or S . (I " j ) For example , in some embodiments , the compound has 20 the following structure ( I' " a ): 1 R35 N - 12 R10. IR46 Rº (I '" a ) R20 'R4a 25 R4- 7 m2 12 RIO R45 G44ml

R 25 30 ( I " k )

LR36 R10; N- 12 35 LR40 R Ra 11 YR4a R47R43 wherein : 40 = = represents a double or triple bond ; Qis Ce= ) , Ce= NR8' ) — , NR $ CEO ) , R 25 - S ( O ) 2 - or - NR®S ( 0 ) 2 — ; (I" 1 ) R® is H , C7 -Coalkyl or hydroxylalkyl ; . R 36 DRze K 10 45 R8' is H , OH , CN or CZ -Cgalkyl ; and 12 when = is a double bond then Rº and Riº are each independently H , cyano , carboxyl, C , -C alkyl, alkoxycar R2a bonyl, aminylalkyl , alkylaminylalkyl , heteroaryl or LIN R46 or* 50 hydroxylalkyl or R? and Rlº join to form a carbocyclic or Rta heterocyclic ring ; >= -= when = is a triple bond then Rº is absent and R10 is H , R2: C - Coalkyl, aminylalkyl, alkylaminylalkyl or hydroxylal (I ' m ) 55 kyl; and A isis NENH or S . Rze R3 2 RIO In some of the foregoing embodiments of compound R10 (I '" a ), eis eis C ( O ) - , - NR $ CEO) , RO - S ( O ) 2 - or - NR 'S ( 0 ) 2 — . R2a R46 60 In some other of the foregoing embodiments of compound Rta (I ' " a ) , Q is CENR $' ) — , wherein R8 is H , OH , CN or C2 -Coalkyl . For example , in some embodiments RS' is H . P / In other embodiments , RS' is CN . In other embodiments , Re' is OH . In other embodiments , the compound has one of the following structures ( I' " b ) , ( I' " C ) , ( I' " d ) or ( I' " e ) : US 10 , 111, 874 B2 42 -continued ( I' ' g ) ( I' b ) R3a LR I R36 R36 - 12 R10. R36 R10; LR46 R9 R3a LR40 R41 R4a R41X R4a R 46 10 R46 R2a R2 ( I' ' h ) R3a (I' N' C ) 15 R35 R36 R 10. ZR10 R9 29 N 20 R46 or R4 R ! R4 R46 R2

R20 A 25 ( I' d ) (I '" i) 12 n R10 R10 R9 30 NR or

R20 35 A R2 (I ' ' le ) R10 In certain embodiments of any of the foregoing , at least 41 one of G or G is N . In other embodiments , at least one of W , X or Y is N or NR . In other embodiments , at least one of W , X or Y is N and at least one of W , X or Y is CR®. For example , in some embodiments two of W , X and Y are N and 45 one of W , X and Y is CRO . In some embodiments , at least one of W , X or Y is N or Rua NR ” , wherein RS is a bond to L . In some other embodi ments, at least one of W , X or Y is N or CR " , wherein Róis a bond to L ' . In still more embodiments , the compound has one of the 50 For example , in some different embodiments , the com following structures (I '" f ), (I '" g ) , ( I' " h ) or (Il " i ) : pound has one of the following structures :

R3a (I ' " f) 55 R32 (I ' n ) Rze LR3 V R 10 . 2G2 - 12 RIO MO 1 R46 R $ RtN 11 `R4 R46 R41 R20 R 46 R2a YN RO R26 US 10 , 111, 874 B2 43 44 - continued ( I' o ) ( I ' a ) @ Rze R38 Rze R3 (2 VAD10 - 12 R10 Nm292 TR4 Rta R48 or Rita R4 or R20 po R ! Y N NH RG R 26 R2b ( I' !! b ) R3 R36 m2 2 RIOR ( I' p ) Ger R9

v2 RIOK . R45 G R2a Nim1

R20 Rua RP8 R 26

wherein : R 26 30 = represents a double or triple bond ; Qis C40 ) , CNRS ) — , - NR8C40 ) , - S ( O ) 2 - or - NR?S ( 0 ) 2 — ; R® is H , C . - Cgalkyl or hydroxylalkyl; RS' is H , OH , CN or CZ - Coalkyl; 35 when = is a double bond then Rº and R10 are each independently H , cyano , carboxyl, C7 -Cgalkyl , alkoxycar wherein : bonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or = represents a double or triple bond ; hydroxylalkyl or R9 and R10 join to form a carbocyclic or Qis —CO ) , CE= NR ') — , - NR CO$ ) , heterocyclic ring ; and - S ( = O )2 - or - NR?S ( 0 ) 2 = ; 40 when == a triple bond then Rº is absent and R10 is H , R8 is H , C , -Calkyl or hydroxylalkyl ; C .- Calkyl , aminylalkyl, alkylaminylalkyl or hydroxylalkyl . In some embodiments of the compounds of structures RS' is H , OH , CN or C ,- Coalkyl ; ( I' " ' " a ) or ( I '" " b ) , R is aryl or heteroaryl and R2a and R2b are when == is a double bond then Rº and R10 are each independently selected from H and halo , for example in independently H , cyano , carboxyl , C . - C alkyl, alkoxycar- 45 some further embodiments Rl is aryl or heteroaryl and R2a bonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or and R26 are independently selected from halo , such as chloro hydroxylalkyl orR and Rlº join to form a carbocyclic or and fluoro . In some embodiments , Rl is aryl or heteroaryl, heterocyclic ring ; and R20 is chloro and R2b is fluoro . In other embodiments R ' is when = is a triple bond then Rº is absent and R10 is H , so aryl or heteroaryl , one of R2a or R2b is halo , such as chloro C1- Calkyl , aminylalkyl, alkylaminylalkyl or hydroxylalkyl. or fluoro , and the other one of R2a or R26 is H . In other In some embodiments of the compounds of structures embodiments of the foregoing, Rºis H , cyano , cyanoalkyl , ( I' n ) , (I ' o ) or ( I' p ), Rl is aryl or heteroaryl and R2a and R26 amino , or C -Co alkyl. are independently selected from H and halo , for example in In yet more of any of the foregoing embodiments , E has some further embodiments Rl is aryl or heteroaryl and R2a 55 the following structure : and R25 are independently selected from halo , such as chloro and fluoro . In some embodiments , R ' is aryl or heteroaryl, R24 is chloro and R25 is fluoro . In other embodiments Rl is aryl or heteroaryl, one of R2a or R26 is halo , such as chloro R10 or fluoro , and the other one of R2a or R26 is H . In other 60 R9 embodiments of the foregoing , R is H , cyano , cyanoalkyl, amino , or C1 - C6 alkyl . wherein : In other different embodiments , the bond between W and Q is =C O ) , CENR8' ) — , NR $ C = 0 ) ; X Y and Z are both single bonds. For example , in some 65 S ( O ) 2 - or - NR8S 0 )2 — ; embodiments the compound has one of the following struc R® is H , C7 - Coalkyl or hydroxylalkyl; tures (I ' " " a ) or (I "" " b ): RS" is H , OH , CN or C , -Cgalkyl ; and US 10 , 111, 874 B2 45 46 R and R10 are each independently H , cyano , C7 -Cgalkyl , other more specific embodiments , the substituents are aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R9 and selected from fluoro , chloro , bromo, hydroxyl, methoxy and R10 join to form a carbocyclic or heterocyclic ring . cyclopropyl . In some of the foregoing embodiments , Qis - C = O ) - , In other embodiments , the R1 substituents are selected - NR $ CEO) - , - S ( O ) 2 - or - NR S 02— 5 from halo , cyano , cyano - C alkyl. cvanoC .- C .cycloalkyl . is hydroxyl, C , - Cgalkyl, C7 -Coalkylcycloalky , C2- Coalkynyl, - CENR $' ) — , wherein R8 is H , OH , CNIN or CZC1 - C606 ?C ,. - C alkoxy, C . - Cohaloalkoxy, C . - Cgalkylaminyl, alkyl. For example , in some embodiments R is H . In other C2 -Cgalkylcarbonylaminyl , C , Cohydroxylalkyl, embodiments , Re' is CN . In other embodiments , R ' is 10 C / - Cohaloalkyl, C / -C alkoxyalkyl, aminylsulfone , aminyl — OH . carbonyl, aminylcarbonylC , -Coalkyl , aminylcarbonylC3 In still other of any of the foregoing embodiments , E has Cecycloalkyl, C , - Coalkylaminylcarbonyl , the following structure : C3 - C cycloalkylaminylcarbonyl, C3 - C cycloalkylalkyl and C3 -Cycycloalkyl , C3 -Cgfusedcycloalkyl and heteroaryl. 15 In still other embodiments , the R ? substituents are selected from fluoro , chloro , bromo, cyano , hydroxyl, hydroxylmethyl, methoxy , methoxymethyl , ethyl, isopropyl, mi trifluoromethyl, aminylcarbonyl and cyclopropyl. 20 In still more embodiments , the Ri substituents are wherein : selected from fluoro , chloro , bromo, cyano , hydroxyl, Qis — CEO) — , - NRCO ) - , - S ( = O ) 2 - or hydroxylmethyl, methoxy, methoxymethyl, methyl, ethyl, - NR?S ( = O ) 2 = ; isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl R® is H , C1- Cgalkyl or hydroxylalkyl ; and and cyclopropyl. R " is H , C , -Cgalkyl , aminylalkyl, alkylaminylalkyl or 25 In certain embodiments . Rl has one of the following hydroxylalkyl. In some embodiments m ' is 1 . In other embodiments m ? structures : is 2 . In still more embodiments ,m is 3 . In different embodiments , m ’ is 1 . In some other embodiments , ma is 2 . Cl In yet still more embodiments , m ? is 3 . 30 In some other particular embodiments of any of the foregoing compounds , m ' is 1 , and mº is 1 . In other embodi ments , m ' is 1 and , m ? is 2 . In still other embodiments m ' is 2 , and m ? is 2 . In more embodiments , m ' is 1 , and m² is 3 . 35 In any of the foregoing embodiments , G and G2 are each independently selected from N and CH . In some embodi ments , at least one of G or G is N . In some embodiments , each of G1 and G ? are N . In some embodiments , each of G1 and Gº are N and m ' and m² are each 2 . In some other 40 win embodiments , at least one of G ? or G² is CH . In other embodiments , each of G ' and G ? are CH . Without wishing to be bound by theory , Applicants believe correct selection of the Ri substituent may play a part in the compounds ' inhibitory activity ( e . g ., against 45 KRAS , HRAS or NRAS G12C ) . In some embodiments , R is aryl or heterocyclyl ( e . g . , heteroaryl or aliphatic hetero cyclyl) , each of which is optionally substituted with one or CN more substituents. In some embodiments , Rl is capable of reversible interaction with KRAS , HRAS or NRAS G12C 50 NC mutant protein . In some embodiments Rl has high affinity towards KRAS , HRAS or NRAS and is highly specific towards G12C KRAS , HRAS or NRAS . In some embodi ments R ' is capable of hydrophobic interaction with KRAS , min HRAS or NRAS G12C . In some embodiments Rl is able to 55 CN form hydrogen bonds with various residues ofG12C KRAS , HRAS or NRAS protein . In other of the foregoing embodiments , R is heterocyclyl, heteroaryl or aryl. In certain embodiments of any of the foregoing , R is aryl. 60 For example , in some embodiments R is phenyl. In other V embodiments , R ' is naphthyl . In some of these embodi ments , R ' is unsubstituted aryl, such as unsubstituted phenyl or unsubstituted naphthyl. In other embodiments , R is substituted with one or more substituents . In some of these 65 HO embodiments , the substituents are selected from halo , cyano , hydroxyl, C . - Cgalkyl, C7 - C alkoxy and C3- Cycycloalkyl. In wenn US 10 ,111 , 874 B2 47 48 - continued - continued ?? ?? , ??

?? OCH3 OCH ???? ????? F . ? ?????? 10

?? NH : ; 15 OCHZ OCH3 OH

? 20 ??? Bry

?? 25 , , ??, ? , 30 , 35 N

Ima 3 ; NH2; ??S 40 ?? ???? ?? ? . 45 - ? ?? CI HO?? . 50 ?? Faco ????

55 ?

? ?, ?. ?????????? NH2 ?????? 60 NO ?? ?? ???? 65 ? ? US 10 ,111 , 874 B2 49 50 - continued

??? ??? h, ??????

z

— 10 H2N ??????? ???????? NH2 ?

20 NCN .

25 HN .

NH2; ? ???? 30 NH

UH

35 ??

??) .

" S ?, ? 40 ??

HN ??????? ?? ?? OH {

50

?? or ??????55 In still other embodiments , R has one of the following structures: ???????? ????? 60 CH3 ??.

65 In other of the foregoing embodiments , R ' has one of the following structures : ???, US 10 ,111 , 874 B2 51 52 -continued -continued

4. ?????

— CN

min CN NC ??????? ????? F ,

??

25 CF3 HO

30 FCO

?? HO ?? ?? ?? 35 ?????? ?? OH ?? ?? 40 ?? , ???3 ?? , ????????

45

HO HO ??? OCHZ OCH ; NH2; 50 ?? ??

?? 55 ?? CN

60 Bry

65 ??? ??, ?OCH ;, OCH ;, ?? , US 10, 111 , 874 B2 53 54 - continued -continued OH F2HC NH2 wwwww wwwwww

10

www HN

15 ma ON NHA; NH wwwwwww 20

N 25 F ; NH) ; CF3 HN 30 wwwwwww ? - /

OH

OH 35 www www 4 )

45 wwwxnx HO

OS wwwww ? 55 F HC

% % OH % %

H2N wwwwww HO US 10 , 111, 874 B2 55 56 - continued - continued HN

HN M min HO 10 O :

or

?? " alam 15 ULI13 mohad N

In some different embodiments of any of the foregoing, N R ! is heteroaryl. In certain embodiments , Rl comprises 20 N mm oxygen , sulfur, nitrogen or combinations thereof . In some of HN these embodiments , R ' comprises sulfur or nitrogen . In certain embodiments , R ' is thiophenyl, pyridinyl, pyridi nonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzo H?N CN dioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, 25 dihydroquinolinonyl , tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodi N oxinyl. In some embodiments , R ' is substituted or unsubstituted 30 indazolyl. In some of these embodiments the indazolyl is substituted with one or more C .- C . alkyl, C .- C . alkoxy and / or halo groups. For example , in some embodiments , the indazolyl is substituted with one or more methyl ,methoxy , mu chloro and / or fluoro groups . 35 HN For example , in some embodiments Rl is pyridinyl . In some embodiments R1 is unsubstituted pyridinyl, for IN example unsubstituted pyridin - 4 - yl or unsubstituted pyridin 3 - yl. In other embodiments R ! is thiophenyl. In some embodiments R is unsubstituted thiophenyl, for example unsubstituted thiophen - 2 - yl. min In other embodiments , Rl is substituted with one or more HN HN HN N substituents . For example , in some embodiments, the sub stituents are selected from halo , C . - Cgalkyl, C . - C alkoxy, or 45 C2 -Coalkenylcarbonylaminyl . In some of these embodi ments , the substituents are selected from halo and C , - C alkyl. In other embodiments , the substituents are selected from fluoro , chloro , amino and methyl. For example , in more specific embodiments, the substituents are 50 HNN HNN ON selected from chloro and methyl. In other embodiments at least one R1 substituent is fluoro . NH2; In some embodiments , R has one of the following structures : 55 nu OCH3 H3C7 N

NH NH

65 \ US 10 , 111 ,874 B2 57 58 - continued - continued N or NH ; NH ; NH

10) NH2 In certain embodiments , R has one of the following ?? N ??HN structures?? : N ; 15 ???????? H , C 20 HN ???Cl ?? 25 ?? HN . 3 ) ??????? HN ??????? 35 ; N 0 ;

HN HN 4 { ?????? 45 ??? H2N .

HgNN 50)

NA

HN N HO mir 55 ???? ???????

66) HN ??? N NH

N

?????? 65 US 10 , 111, 874 B2 59 60 - continued oxygen and /or nitrogen . In some further embodiments , R ' is HNN HNN morpholinyl. For example , in some embodiments R has the I NH2; following structure :

10

HN In various embodiments of the foregoing, R is unsubsti NH ; > ; tuted . 15 In some of the foregoing embodiments , R2a is H . In other embodiments , R2a is halo , for example in some embodi ments R2a is chloro or fluoro . In still other embodiments of the foregoing, R2a is C , - C alkyl. For example , in some embodiments R24 is Cz- Cg cycloalkyl, such as cyclopropyl . to 20 NH2; In other embodiments of the foregoing compounds , R25 and R C , when present, are H . In different embodiments , R25 HN and R2C, when present, are each independently halo . In yet other embodiments , R25 , when present, is halo . In more 25 embodiments , R2 , when present, is halo . In certain of the foregoing embodiments , halo is chloro or fluoro . The Q moiety is typically selected to optimize the reac min tivity (i . e. , electrophilicity ) of E . In certain of the foregoing embodiments , Qis CEO) . In other embodiments, Qis - S ( O ) 2 - In still more embodiments , Q is — NRC ( O ) . In still more different embodiments, Q is — NRS FO) 2 — HN In some of the immediately foregoing embodiments , R is 35 H . In other of these embodiments , R is hydroxylalkyl, for example in some embodiments the hydroxylalkyl is 2 - hy droxylalkyl. In some embodiments , Q is CENR8') — , wherein RS" wis H , — OH , CN or C -Cgalkyl . For example , in some or 20 . embodiments RS' is H . In other embodiments , RS' is CN . HN In other embodiments , R8 is OH . NH In some of any one of the foregoing embodiments , at least one of RP or R10 is H . For example , in some embodiments min 45 each ofRand R10 are H . In other of the foregoing embodiments , R1° is alkylami nylalkyl . In some of these embodiments , Riº has the fol lowing structure : In some of the foregoing embodiments , R has one of the 50 following structures:

55 ??? In other embodiments, Riº is hydroxylalkyl, such as 2 -hydroxylalkyl . In some other different embodiments of the foregoing embodiments , Rº and R10 join to form a carbocyclic ring . For example , in some of these embodiments the carbocyclic ??? or ring is a cyclopentene , cyclohexene or phenyl ring . In other mu embodiments , the carbocyclic ring is a cyclopentene or 65 cyclohexene ring . In other embodiments , the carbocyclic In still other embodiments , R1 is aliphatic heterocyclyl. In ring is a phenyl ring , for example a phenyl ring having the some embodiments the aliphatic heterocyclyl comprises following structure : US 10 , 111, 874 B2 62 - continued

OH VMW manm mu In some of any of the foregoing embodiments E is an 10 NH2 electrophile capable of bonding with a KRAS , HRAS or NRAS protein comprising G12C mutation . In some embodi ments, the electrophile E is capable of forming an irrevers mh ible covalent bond with a G12C mutant KRAS , HRAS or 15 O NRAS protein . In some cases , the electrophile E may bind = with the cysteine residue at the position 12 of a G12C mutant Or KRAS , HRAS or NRAS protein . In various embodiments of www any of the foregoing , E has one of the following structures: . LOH 20

NH 25 XXXHIn other embodiments of any of the foregoing , E has one ! w of the following structures:

mun 30

...... men ZIOS tita 35 XXL

.

40

CN CN mu CN CN 45

w Ci

CN 50 CN

) ) mun 55 N OH ; WA ni

60

OH N OH ;

65 nim stOH US 10 , 111, 874 B2 63 64 wherein : - continued R8 is H or C . -Cgalkyl ; Rºis H , cyano or C -Coalkyl , or Rº joins with R1° to form a carbocycle ;

4 5 R10 is H or CZ -Coalkyl or R10 joins with Rº to form a 1 carbocycle and R10a is H or CZ - Cgalkyl. In some embodiments E is

or 10 ...... OH N In different embodiments , E has one of the following structures : In some embodiments E is

20 NH tiw min In some embodiments E is

C1 www . nim mt 30 N In some of any of the foregoing embodiments , L is a bond . In other embodiments , L ' is NR ?. For example , in some of these embodiments , R ’ is C , -Coalkyl . In other 35 embodiments , L ' is NH . L can be selected to provide proper spacing and / or N . ?? : orientation for the E group to form a bond with the KRAS, HRAS or NRAS protein . In some of the foregoing embodi ments , L2 is a bond . In other of the foregoing embodiments , OH 40 L is alkylene . In some embodiments, the alkylene is sub stituted . In other embodiments the alkylene is unsubstituted . For example , in some embodiments L² is CH , or CH2CH2 or In certain embodiments , R3a and R35 are, at each occur rence , independently H , OH , — NH , , — CO , H , halo , 45 cyano , hydroxylalkly, aminylalkyl, cyanoalkyl, carboxy alkyl or aminylcarbonyl, and R4a and Rºb are , at each occurrence, independently H , OH , - NH2, CO , H , halo , In some cases E has one of the following structures : cyano , hydroxylalkly , aminylalkyl, cyanoalkyl , carboxy alkyl or aminylcarbonyl. 50 In other of the foregoing embodiments, R3a and R4a are, at each occurrence, independently H , OH , hydroxylalkly , cyano , or aminylcarbonyl and R36 and R45 aleare H . R10 . 2- - R10 ; In certain other embodiments , R3a and R4a are H and R36 and R46 are , at each occurrence , independently H , OH , 55 — NH2, CO2H , halo , cyano , hydroxylalkly , aminylalkyl, 2 cyanoalkyl, carboxyalkyl or aminylcarbonyl. In any of the foregoing embodiments , at least one of R3a , R35 ,R4a orR46 is H . In some embodiments , each ofR34 ,R35 , R10 ; AR10 ; R4a and R4b are H . R9 60 In some embodiments , R3a is - OH , - NH2, CO , H , halo , cyano , hydroxylalkly , aminylalkyl, cyanoalkyl, car boxyalkyl or aminylcarbonyl, and R35 , R4a and R4h are H . In other embodiments , R4a is — OH , NH2, CO , H , www...... halo , cyano , hydroxylalkly , aminylalkyl , cyanoalkyl, car R 10a or R102 65 boxyalkyl or aminylcarbonyl, and R3a , R35 and R46 are H . In other embodiments , R3a is H , OH , - NH2, CO2H , halo , cyano , hydroxylalkly , aminylalkyl, cyanoalkyl, car US 10 , 111 , 874 B2 65 66 boxyalkyl or aminylcarbonyl , and R3h joins with R46 to form a carbocyclic or heterocyclic ring ; In still more embodiments , R4a is H , OH , - NH2, NR - CO2H , halo , cyano , hydroxylalkly , aminylalkyl, cyano alkyl, carboxyalkyl or aminylcarbonyl , and R4h joins with 5 R3b to form a carbocyclic or heterocyclic ring . In other embodiments , R3a and R36 join to form a carbo wherein X is a bond , O or NR — ; each R is inde cyclic or heterocyclic ring . In other embodiments , R4a and pendently H or C -Cgalkyl and n is an integer from 0 to 6 . R4h join to form a carbocyclic or heterocyclic ring . o In other embodiments , R is amindinylalkyl , amidinylal In still other embodiments , R3a or R4a is aminylcarbonyl. koxy , amindinylalkylaminyl, guanidinylalkyl, guanidinylal For example , in certain embodiments , the aminylcarbonyl is koxy or guanidinylalkylaminyl. For example , in some embodiments Ró has one of the following structures :

15

NH2 or NH2 In other embodiments , R3a or R4a is cyano . In other embodi - 20 ments , R3a or R4a is — OH . In other embodiments , R3a or R4a is hydroxylalkyl, for example hydroxylmethyl. N CNH , In some embodiments , R is , at each occurrence , inde pendently H , oxo , cyano , cyanoalkyl, aminyl, aminylalkyl, os aminylalkylaminyl, aminylcarbonyl, alkylaminyl, haloalky laminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylal- wherein X is a bond , - O or — NR — ; each R is inde koxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylal - pendently H or C1- C alkyl and n is an integer from 0 to 6 . koxy , guanidinylalkylaminyl, C , - C6 alkoxy , aminylalkoxy, In other embodiments , Ró is heterocyclyl, heterocycly alkylcarbonylaminylalkoxy, C1 -C . alkyl, heterocyclyl, het- 30 loxy , heterocyclylalkyloxy, heterocyclylaminyl, heterocy erocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy , het clylalkylaminyl , heteroaryl, heteroaryloxy, heteroarylalky eroarylalkyloxy , heteroarylaminyl, heteroarylalkylaminyl, loxy , heteroarylaminyl or heteroarylalkylaminyl. For aryl, aryloxy, arylamino , arylalkylamino , arylalkyloxy or a example , in some embodiments R has one of the following bond to L . structures: Each of the foregoing R? moieties may be substituted with 35 one or more substituents . For example, in some embodi ments the one or more substituents are aminyl ( e . g . , substi tuted or substituted ) , alkylcarbonyl aminyl, hydroxyl, haloalkyl or heterocycyclyl ( e . g . , substituted or substituted a M NH VVV NH aliphatic heterocycle or substituted or substituted het 40 eroaryl) . For example , in some embodiments , the Rºmoiety is C . - C . alkyl, C . - C . alkoxy or alkylaminyl, which is further mu N - R substituted with alkylcarbonylaminyl, hydroxyl, — CN or haloalkyl. For example , in some embodiments , R has one of 4 the following structures: min F xx xx. .50 xoxo CFz; or What ,55 tato wherein X is a bond , O — or NR — ; each R is inde pendently H or C1- Cgalkyl and n is an integer from 0 to 6 . Various different Rº moieties are included in the scope of 60 the compounds . For example , in various embodiments , R is H . In other F F embodiments , RÓ is CN . In more embodiments , R “ is methoxy . In various other embodiments , R is aminylalkyl, aminyl- 65 alkyloxy or aminylalkyaminyl. For example , in some embodiments Rº has the following structures : US 10 , 111, 874 B2 67 68 -continued -continued

or mi A

A

10

- R wherein X is a bond , O — or — NR — ; each R is inde NH pendently H or CZ -Coalkyl and n is an integer from 0 to 6 . In some of the foregoing embodiments , X is N . in other of the foregoing embodiments , X is N . In other of the foregoing embodiments , Z is N . In still more embodiments , X is N and Z is N . In some embodiments , Z is N and Y is N . In other non embodiments , X is N , Z is N , Y is CR , wherein Ris H and W is CR®, wherein R is a bond to L ' . In different embodi ments , Z is N and Y is CR ", wherein R is H , W is CR ", wherein R™ is a bond to L and X is CR , wherein R™ is cyano , methoxy or amino . 25 In other embodiments , Z is N , X is CR and Rois cyano , Y is CR ", wherein Ris H and W is CR ", wherein R is a bond to L '. w In other embodiments , Y is N , Z is N , W is CR6, wherein RÓ is a bond to L ' and X is CR " , wherein R™ is H . 30 In other of the foregoing embodiments , Z is a bond . In certain embodiments , Y is NRS. In some of these embodiments , RS is C , -Cgalkyl . In other embodiments , RS is H . mo 35 In still other embodiments , X or Y is CR “. In some of these embodiments , R? is , at each occurrence, independently H , cyano , amino , C1- C alkoxy or a bond to L ' . In some other of these embodiments , R is H . In other embodiments , R is C . - Cgalkoxy . In other embodiments , R is cyano . In 40 more embodiments , R is methoxy . In other embodiments , Rºis amino . R ; In various different embodiments , the compound has one of the structures set forth in Table 1 below : TABLE 1 Exemplary Compounds of Structure (I )

No . Structure Name Method [M + H ]*

T - 1 1 - ( 4 - ( 7 -chloro - 6 - ( 2 A 413 . 20 chlorophenyl) quinazolin 4 - yl) piperazin - 1 -yl )prop 2 - en - 1 - one US 10 , 111 , 874 B2 69 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [ M + H ] + I - 2 1 - ( 4 - ( 7 - chloro - 6 - ( 2 427 . 25 chlorophenyl) quinazolin 4 -ylamino )piperidin - 1 yl) prop - 2 - en - 1 - one

HN

I - 3 1 - ( 4 - ( 6 - chloro - 5 - ( 2 401. 20 chlorophenyl ) - 1H indazol- 3 - yl) piperazin - 1 yl )prop - 2 - en - 1 - one

N 1 - 4 1 - ( 4 - ( 7 - chloro - 6 - ( 4 413 .25 chlorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl ) prop 2 - en - 1 - one

1 - 5 1 - ( 4 - ( 7 -chloro - 6 - ( 3 413. 20 chlorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl ) prop 2 - en - 1 - one

1 - 6 1 - ( 4 - 7 - chloro - 6 - ( 2 , 4 447 . 204 dichlorophenyl ) quinazolin 4 - yl) piperazin - 1 yl) prop - 2 -en - 1 -one US 10 , 111 , 874 B2 71 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [ M + H ] + 1 - 7 1 - ( 4 - ( 7 - chloro - 6 - ( 3 , 4 449 . 15 dichlorophenyl ) quinazolin 4 -yl )piperazin - 1 yl) prop - 2 -en - 1 -one

I - 8 2 - ( 4 - (4 - acryloylpiperazin B 404 . 1 1 - yl ) - 7 - chloroquinoazlin 6 - yl )benzonitrile

CN

I - 9 1 - ( 4 - ( 7 - chloro - 6 - ( 2 , 5 B 448 . 45 dichlorophenyl) quinazolin 4 - yl) piperazain - 1 yl) prop - 2 - en - 1 - one

1/

1 - 10 1 - ( 4 - ( 7 - chloro - 6 - (5 B 429 . 25 hydroxyphenylchloro ) -quinazolin 2 4 -yl ) piperazin - 1 yl) prop - 2 - en - 1 -one

OH

A

1 - 11 1 - ( 4 - ( 7 - chloro - 6 - ( 4 B 429 . 25 chloro - 2 hydroxyphenyl ) quinoazlin 4 - yl )piperazin - 1 - 2 - en - 1 - one

OH US 10 , 111 , 874 B2 73 74 TABLE 1 -continued Exemplary Compounds of Structure ( I ) No. Structure Name Method [ M + H ] + 1 - 12 1 - ( 4 - ( 7 -chloro - 6 - ( 4 395 . 25 hydroxyphenyl) quinazolin 4 - yl) piperazin - 1 yl) prop - 2 -en - 1 - one

HO .

I - 13 1 -( 4 -( 7 -chloro -6 -( 4 B 443. 30 chloro - 2 methoxyphenyl )quinoazlin 4 -yl ) piperazin - 1 yl) prop - 2 -en - 1 - one LOCH3

A I - 14 1 - ( 4 - ( 7 - chloro - 6 - ( 3 B 395 . 25 hydroxyphenyl ) quinazolin 4 - yl )piperazin - 1 yl )prop - 2 - en - 1 -one OH

1 - 15 1 - ( 4 - ( 7 -chloro - 6 -( 2 B 395 . 25 hydroxyphenyl) quinoazlin 4 - yl) piperazin - 1 yl) prop - 2 - en - 1 -one

OH

1 - 16 4 - ( 4 - (4 -acryloylpiperazin B 404 . 3 1 - yl) - 7- chloroquinazolin 6 - yl) benzonitrile

NC . US 10 , 111 , 874 B2 75 TABLE 1 -continued | Exemplary Compounds of Structure (I ) No. Structure Name Method ( M + H ] + I - 17 1 - ( 4 - 7 -chloto - 6 - ( pyridin B 380 . 25 4 - yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 18 1 - ( 4 - 7 - chloro - 6 B 379 . 25 phenylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 19 3 - ( 4 - ( 4 - acryloylpiperazin B 404 . 25 1 -yl ) - 7 - chloroquinazolin 6 -yl ) benzonitrile

N

I - 20 1 - 4 - 1- chloro - 6 - ( pyridin B 380 . 25 3 - yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 21 1 - 4 - 7 - chloro - 6 B 385 . 25 ( thiophen - 2 yl) quinazolin - 4 Z yl) piperazin - 1 - yl )prop - 2 XXXXXXX| en - 1 - one US 10 , 111 , 874 B2 77 78 TABLE 1 -continued Exemplary Compounds of Structure (1 )

No . Structure Name Method [ M + H ] +

I - 22 1 - ( 4 - ( 5 - ( 2 - chlorophenyl) 4a ,7a - dihydrothieno [ 2 , 3 B 385 .20 d ]pyrimidin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 23 1 - ( 4 - ( 7 - chloro - 6 - ( 2 B 431 . 20 chloro - 5 fluorophenyl ) quinazolin 4 -yl ) piperazin - 1 -yl )prop 2 - en - 1 - one

1 - 24 1 - ( 4 - (6 - chloro - 7 -( 2 ? . 412 . 20 chlorophenyl) isoquinolin 1 -yl )piperazin - 1 -yl ) prop 2 - en - 1 - one

1 - 25 ( E ) - 1 - ( 4 - ( 7 - chloro - 6 - ( 2 A 470 .35 chlorophenyl) quinazolin 4 - yl ) piperazin - 1 -yl ) - 4 ( dimethylamino )but - 2 - en 1 - one US 10 , 111 , 874 B2 79 TABLE 1 -continued Exemplary Compounds of Structure ( I ) No . Structure Name Method [ M + H ]+ 1 - 26 1 - ( 4 - ( 7 -chloro - 6 - ( 5 B 399. 20 methylthiophen - 2 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 -one

H3C

1 - 27 1 - ( 4 - 7 - chloro - 6 - ( 2 E 412 . 20 chlorophenyl ) quinolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 28 1 - ( 4 - ( 5 - ( 2 -chlorophenyl ) 368 . 25 7 ,7a - dihydro - 4aH pyrrolo [ 2 , 3 - d ]pyrimidin 4 - yl) piperazin - 1 - yl) prop 2 - en - 1 - one

1 - 29 N - ( 1 -( 7 -chloro - 6 - ( 2 B 399 .20 chlorophenyl) quinazolin 4 -yl )azetidin - 3 HN yl) acrylamide

I - 30 1 - ( 3 - ( 7 - chloro - 6 - ( 2 399 . 20 chlorophenyl) quinazolin 4 - ylamino )azetidin - 1 yl )prop - 2 - en - 1 -one

HN US 10 , 111 , 874 B2 81 82 TABLE 1 -continued Exemplary Compounds of Structure (1 )

No . Structure Name Method [ M + H ] +

1 - 31 1 - ( 4 - ( 6 -chloro - 5 -( 2 413 . 40 + chlorophenyl) - 1H indazol- 3 ylamino )piperidin - 1 HN yl) prop - 2 - en - 1 -one

IZ.

1 - 32 1 - ( 4 - ( 7 - chloro - 6 L 388 . 25 morpholinoquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

A

1 - 33 1 - ( 4 - ( 6 - ( 2 - chlorophenyl) B 397 . 20 7 - fluoroquinazolin - 4 yl) piperazin - 1 - yl )prop - 2 en - 1 - one

1- 34 1 - ( 4 - ( 7 - chloro - 6 - ( 5 419 . 15 chlorothiophen - 2 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 35 1 - ( 4 - ( 8 - ( 2 379 . 1 chlorophenyl) quinazolin 2 -yl ) piperazin - 1 - yl) prop 2 - en - 1 - one US 10 , 111 , 874 B2 83 84 TABLE 1 -continued Exemplary Compounds of Structure ( I) No . Structure Name Method [M + H ] + 1 - 36 1 - ( 4 - ( 7 - chloro - 6 - ( 2 410 . 35 + chlorophenyl) quinazolin 4 - yl) piperidin - 1 -yl )prop 2 - en - 1 - one

I - 37 1 - ( 4 - (6 -chloro - 7 - ( 4 412 . 20 chlorophenyl) isoquinolin 1 -yl ) piperazin - 1- yl) prop 2 - en - 1 -one

I - 38 1 - ( 4 - 6 - chloro - 7 - ( 4 D 428 . 25 chloro - 23 hydroxyphenyl ) isoquinolin 1 - yl) piperazin - 1 yl )prop - 2 - en - 1 -one ??

1 - 39 1 - ( 4 - ( 2 - amino - 7 -chloro 428 . 3 6 - ( 4 chlorophenyl )quinazolin 4 -yl ) piperazin - 1 -yl ) prop 2 - en - 1 - one

' N NH2 1 - 40 1 -( 4 - (6 - (4 - bromophenyl) 459 . 25 7 - chloroquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

BI US 10 , 111 , 874 B2 85 86 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . StructureStructure Name Method [ M + H ] + 1 -41 1 - ( 4 - 7 - cyclopropyl- 6 - ( 4 - B 425 . 25 cyclopropylphenyl ) quinazolin 4 - yl) piperazin - 1 yl) prop - 2 -en - 1 - one

1 - 42 4 - ( 4 -acryloylpiperazin - 1 437 . 25 yl) - 7 -chloro - 6 - ( 4 chlorophenyl) quinoline 3 - carbonitrile

- CN

1 -43 1 - ( 4 - ( 7 -chloro - 6 - ( 4 465 . 30 * chlorophenyl ) - 2 methoxyquinazolin - - 4 yl) piperazin - 1 -yl )prop - 2 en - 1 - one

OCH3

1 - 44 1 - acryloyl- 4 - ( 7 -chloro - 6 454 . 35 + ( 4 chlorophenyl) quinazolin 4 - yl) piperazin - 2 HN carboxamide US 10 , 111 , 874 B2 87 88 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [M + H ]* 1 - 45 7 - chloro -6 - (4 A 449 . 25 chlorophenyl ) -4 - ( 4 (vinylsulfonyl ) piperazin 1 -yl )quinazoline

1 - 46 1 - ( 4 - ( 7 - chloro - 6 - ( 4 443. 30 chlorophenyl )quinazolin 4 -yl ) - 2 (hydroxymethyl )piperazin HO 1 - yl) prop - 2 - en - 1 - one

1 - 47 1 - acryloyl- 4 - (7 - chloro -6 A 438 . 25 ( 4 chlorophenyl) quinazolin NC N 4 - yl) piperazine - 2 carbonitrile

1 - 48 1 -acryloyl - 4 - ( 7 328 . 2 chloroquinazolin - 4 yl )piperazine - 2 carbonitrile

1 - 49 1 - acryloyl- 4 - ( 6 -bromo - 7 408 . 20 chloroquinazolin - 4 yl) piperazine - 2 NC , N carbonitrile

BI US 10 , 111 , 874 B2 89 90 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [ M + H ] +

1 - 50 1 - ( 4 - ( 7 -chloro - 6 - ( 4 M 427 . 35 chlorophenyl) - 2 methylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 51 1 - acryoyl- 4 - ( 7 - chloro - 6 A 410 . 30 ( thiophen - 2 yl) quinazaolin - 4 NC yl) piperazine - 2 carbonitrile

1 - 52 1 -acryloyl - 4 - ( 7 -chloro - 6 A 404 . 35 izolin - 4 yl) piperazine- 2 NC carbonitrile

1 - 53 4 - (4 - acryloyl- 3 B 353 . 20 cyanopiperazin - 1 - yl ) - 7 chloroquinazoline - 6 NC carbonitrile

NC

1 - 54 ( S ) - 1 - acryloyl -4 - 07 456 . 30 chloro - 6 - ( 4 chlorophenyl) quinazolin 4 - yl )piperazine - 2 .. . AHIM NH2 carboxamide US 10 , 111 , 874 B2 91 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [ M + H ] + 1 - 55 1 -acryoyl - 4 - ( 7 - chloro - 6 368 . 25 cyclopropylquinazolin - 4 yl) piperazin - 2 NC . carbonitrile

1 - 56 1 - acryloyl- 4 - ( 7 -chloro - 6 M 452 . 30 ( 4 - chlorophenyl) - 2 methylquinazolin - 4 NC yl) piperazine - 2 carbonitrile

N

I- 57 1 - acryloyl- 4 -( quinazolin - A 294 . 20 4 - yl) piperazine - 2 carbontrile NO

1 - 58 ( R ) - 1 -acryloyl - 4 - ( 7 A 438 . 20 chloro - 6 - ( 4 chlorophenyl) quinazolin NCH N . 4 - yl) piperazine - 2 carbonitrile

1 - 59 ( S )- 1 -acryloyl - 4 -( 7 A 438. 25 chloro - 6 - ( 4 chlorophenyl) quinazolin NC N 4 - yl) piperazine - 2 carbonitrile US 10 , 111 , 874 B2 93 94 TABLE 1 -continued Exemplary Compounds of Structure (I ) No. Structure Name Method [ M + H ] + 1 - 60 1 - ( 4 - ( 7 - chloro - 6 - ( 4 470 . 35 chlorophenyl) quinazolin 4 - yl) - 2 ( (dimethylamino )methyl ) piperazin - 1 - yl )prop - 2 -en - 1 -one

1 - 61 1 -acryloyl - 4 - ( 6 ? . 327 .20 chloroisoquinolin - 1 yl) piperazine - 2 NC . N . carbonitrile

1 -62 1 - ( 4 - ( 7 - chloro - 6 - ( 4 A 457 . 35 chlorophenyl) quinazolin 4 -yl ) - 2 - (2 OH hydroxyethyl) piperazin 1 -yl ) prop - 2 -en - 1 -one

1 -63 ( S ) - 1 - ( 4 - ( 7 -chloro - 6 - ( 4 chlorophenyl) quinazolin A 443 . 30 4 - yl) - 2 (hydroxymethyl ) piperazin OH 1 - yl )prop - 2 - en - 1 -one

1 - 64 ( R ) - 1 - acryloyl- 4 - ( 7 A 456 . 30 chloro - 6 - ( 4 chlorophenyl) quinazolin IT! 4 - yl) piperazine - 2 HON carboxamide US 10, 111 , 874 B2 95 96 TABLE 1 -continued Exemplary Compounds of Structure (1 )

No . Structure Name Method [ M + H ] + I - 65 ( R ) - 1- ( 4- ( 7 - chloro - 6 - ( 4 A 443. 35 chlorophenyl) quinazolin 4- yl) - 2 (hydroxymethyl ) piperazin OH 1 - ylprop - 2 -en - 1 - one

I - 66 ( E ) - 4 - ( 7 - chloro- 6 - ( 4 . 495 . 40 chlorophenyl) quinazolin 4 - yl) - 1 - ( 4 (dimethylamino ) but- 2 enoyl) piperazine - 2 carbonitrile

I - 67 1 - ( 4 - ( 6 - chloro- 7 B 379 30 phenylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 , en - 1 - one

I - 68 1 - ( 4 - 6 -chloro - 7 A 343 . 25 cyclopropylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 , en - 1 - one US 10 , 111 , 874 B2 97 98 TABLE 1 -continued Exemplary Compounds of Structure (1 )

No . Structure Name Method [ M + H ] + 1 -69 2- ( 1 - acryloyl- 4 - (7 - chloro A 470. 35 6 - (4 chlorophenyl) quinazolin NH2 4 - yl) piperazin - 2 yl )acetamide

A

1 - 70 2 - ( 1- acryloyl - 4 - ( 7- chloro A 452 . 35 6- ( 4 chlorophenyl )quinazolin 4 - yl) piperazin - 2 CN yl) acetonitrile

1 - 71 1 - ( 4 - ( 6 - ( 4 379 . 30 chlorophenyl) quinazolin 4 - yl ) piperazin - 1 - yl) prop 2 - en - 1 - one

1 - 72 1 - ( 4 - ( 6 - chloro - 7 - ( 2 chlorophenyl) quinazolin A 413. 25 4 -yl ) piperazin - 1 -yl )prop 2 - en - 1 - one US 10 , 111 , 874 B2 99 100 TABLE 1 -continued Exemplary Compounds of Structure (I ) No. Structure Name Method [M + H ] " I - 73 1 - ( 4 - ( 6 - chloro - 7 - ( 3 chlorophenyl) quinazolin A 413 .3 4 -yl ) piperazin - 1 -yl ) prop 2 - en - 1 - one

1 - 74 1 - ( 4 - (6 - chloro - 7 - ( 2 395 . 25 hydroxyphenyl) quinazolin 4 - yl) piperazin - 1 yl) prop - 2 -en - 1 - one

OH

I - 75 1 - ( 4 - ( 6 - chloro - 7 - ( 3 395 . 25 hydroxyphenyl ) quinazolin 4 - yl) piperazin - 1 yl) prop - 2- en - 1 -one

OH

I - 76 1 - ( 4 - (6 - chloro - 7 L 395 . 25 phenoxyquinazolin - 4 yl) piperazin - 1 - yl ) prop - 2 en - 1 - one US 10 , 111 , 874 B2 101 102 TABLE 1 -continued ExemplaryExemplary CompoundsCompounds ofof StructureStructure ( (1 I ) No . Structure Name Method [ M + H ] *

1 - 77 1 - ( 4 - (6 -chloro - 7 - ( 2 - A 407 .75 ethylphenyl) quinazolin - 4 ethylpyl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 78 1 - ( 4 - (6 -chloro - 7 - ( 4 A 413 . 25 chlorophenyl) quinazolin 4 -yl ) piperazin - 1 -yl ) prop 2 - en - 1 - one

I - 79 1 - ( 4 - ( 6 - chloro - 7 - ( 3 407 . 30 ethylphenyl) quinazolin - 4 yl )piperazin - 1 - yl) prop - 2 BosBoxBoxy en - 1 - one

1 - 80 1 - ( 4 - ( - chloro - 7 L 387. 25 (piperazin - 1 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 -one US 10 , 111 , 874 B2 103 104 TABLE 1 -continued Exemplary Compounds of Structure ( 1) No . Structure Name Method [M + H ] + 1 - 81 1 - ( 4 - ( 6 - chloro - 7 - ( 2 397 . 25 fluorophenyl )quinazolin 4 -yl ) piperazin - 1 - yl ) prop 2 - en - 1 - one

I - 82 ( E ) - 1 - ( 4 - (6 - chloro - 7 A 436 . 40 phenylquinazolin - 4 yl) piperazin - 1 -yl ) - 4 (dimethylamino ) but- 2 -en 1 - one

1 - 83 1 - ( 4 - ( 6 - chloro - 7 - ( 4 397 . 25 fluorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl) prop 2 - en - 1 -one

I - 84 1 - ( 4 - ( 6 - chloro - 7 - ( 3 397 . 25 fluorophenyl) quinazolin 4 -yl )piperazin - 1 - yl) prop 2 - en - 1 - one

. A US 10 , 111 , 874 B2 105 106 TABLE 1 -continued Exemplary Compounds of Structure ( I )

No . Structure Name Method [ M + H ] *

1 - 85 2 - ( 1- acryloyl- 4 - (6 -chloro A 418 .30 7 -phenylquinazolin - 4 yl) piperazin - 2 yl )acetonitrile CN

I

1 - 86 1 -( 4 -( 6 - cyclopropyl- 7 ? 385 . 75 phenylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 -one

1 - 87 1 - ( 4 - 97 -phenylquinazolin B 345 .20 4 -yl )piperazin - 1 -yl ) prop 2 - en - 1 - one

1 - 88 1 - ( 4 - ( 7 - chloro - 6 D 378 . 20 phenylisoquinolin - 1 yl) piperazin - 1 - yl) prop - 2 en - 1 - one US 10 , 111 , 874 B2 107 108 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ] " 1 - 89 N - ( 1 - ( 6 -chloro - 7 B 393 . 25 phenylquinazolin - 4 yl) piperidin - 4 NH yl) acrylamide

N

1 - 90 1 - ( 4 - ( 6 - chloro - 7 - (pyridin 380 . 25 3 - yl) quinazolin -4 yl) piperazain - 1 -yl )prop - 2 en - 1 - one

1 - 91 1 - ( 4 - ( 6 - chloro - 7 ? 378 . 20 phenylquinolin -4 yl) piperazin - 1- yl) prop - 2 en - 1 - one

I - 92 1 - ( 4 - ( 6 - chloro - 7 - (pyridin ? 380 . 25 2 - yl) quinazolin - 4 yl) piperazin - 1 - yl ) prop - 2 en - 1 - one US 10 , 111 , 874 B2 109 110 TABLE 1 -continued Exemplary Compounds of Structure (1 )

No . Structure Name Method [ M + H ] +

I - 93 1 - (4 -( 6 - ethyl- 7 phenylquinazolin - 4 B 373 .75 yl) piperazin - 1 - yl )prop - 2 en - 1 - one

I - 94 1 - (4 - ( 6 - chloro - 2 409 . 30 methoxy - 7 phenylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 95 1 - ( 4 - (6 - chloro - 2 -methyl M 393 . 70 7 -phenylquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

. A

1 - ( 6 1 - ( 3 - ( 6 - chloro - 7 A 365 . 20 phenylquinazolin - 4 ylamino )azetidin - 1 yl) prop - 2 -en - 1 - one

' NH US 10 , 111 , 874 B2 111 112 TABLE 1 -continued Exemplary Compounds of Structure (I ) No. Structure Name Method [M + H ]* I - 97 1 - ( 4 - (6 -chloro - 7 - ( 2 409 . 7 methoxyphenyl) quinazolin 4 -yl ) piperazin - 1 yl) prop - 2 -en - 1 - one

1 - 98 2 - ( 4 - ( 4 - acryloylpiperazin B 422 . 30 1 -yl ) - 6 - chloroquinazolin 7 -yl )benzamide

- NH2

I - 99 1 - ( 4 - ( 6 -chloro - 7 - ( 2 B 421. 35 isopeopylphenyl )quinazolin 4 - yl) piperazin - 1 yl) prop - 2 - en - 1 -one

1 - 100 1 - ( 4 - ( 6 - chloro - 7 - ( 2 B 447 . 80 ( trifluoromethyl) phenyl ) quinazolin - 4 - yl) piperazin 1 - yl) prop - 2 -en - 1 - one

CF3 US 10 , 111 , 874 B2 113 114 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [M + H ] * I - 101 1 - ( 4 - ( 6 -chloro - 7 - ( 2 ,5 dichlorophenyl ) quinazolin B 447. 25 4 -yl ) piperazin - 1 yl) prop- 2 -en - 1 - one

I - 102 1 - ( 4 - ( 6 - chloro - 7 - ( 2 , 4 B 447. 30 dichlorophenyl) quinazolin 4 -yl ) piperazin - 1 yl) prop - 2 -en - 1 - one

1 - 103 1 - ( 4 - ( 6 - chloro - 7 - ( 2 B 423 . 35 (methoxymethyl ) phenyl ) quinazolin - 4 -yl ) piperazin 1 -yl )prop - 2 - en - 1 -one

A

I - 104 1 - acryloyl- 4 - ( 6 - chloro - 7 B 422 . 35 phenylquinazolin -4 yl) piperazine - 2 carboxamide H2N US 10 , 111 , 874 B2 115 116 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [M + H ] * I - 105 2- ( 4 -( 4 - acryloylpiperazin ? 405. 20 1 -yl ) - 6 -chloroquinazolin 7 - yl) benzonitrile

CN

I - 106 2 - ( 1 - acryloyl- 4 - ( 6 - chloro B 437 . 30 7 - ( 2 fluorophenyl) quinazolin 4 - yl) piperazin - 1 NC yl) acetonitrile

1 - 107 2- ( 1 - acryloyl- 4 - (6 - chloro ? 446 . 35 ethylphenyl7 -) quinazolin ( 2 -4 ylpiperazin -2 NC yl acetonitrile

A

I - 108 1 - ( 4 - ( 6 - chloro - 7 - ( 2 B 409 . 30 (hydroxymethyl ) phenyl ) quinazolin - 4 - yl) piperazin 1 - yl) prop - 2 - en - 1 -one

LOH US 10 , 111 , 874 B2 117 118 TABLE 1 -continued Exemplary Compounds of Structure ( 1) No . Structure Name Method [M + H ] *

I - 109 2- (1 - acryloyl 7 - (- 2 4 - ( 6 - chloro - B 452. 30 chlorophenyl )quinazolin 4 -yl ) piperazin - 2 NC yl) acetonitrile

1 - 110 2 - ( 1- acryloyl- 4 - (6 -chloro B 452 . 25 chlorophenyl7 - ( 4) quinazolin 4 -yl )piperazin - 2 NC yl )acetonitrile

I - 111 2 - ( 1 -acryloyl - 4 - (6 -chloro B 452 . 25 7 - ( 4 chlorophenyl) quinazolin 4 - yl) piperazin - 2 NC yl) acetonitrile

>

415 . 0 I - 112 difluorophenyl1 - ( 4 - ( 6 - chloro) quinazolin - 7 - ( 2 ,4 4 -yl ) piperazin - 1 - yl) prop 2 - en - 1 - one

F US 10 , 111 , 874 B2 119 120 TABLE 1- continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ] * 1 - 113 1 - ( 4 - ( 6 - chloro - 7 - ( 2 , 5 - B 415. 10 difluorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl )prop 2 - en - 1 - one

F

I - 114 1 - ( 4 - ( 6 - chloro - 7 - ( 4 B 431 .05 chloro - 2 fluorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl )prop 2 - en - 1 -one

1 - 115 1 - ( 4 - ( 6 - chloro - 7 - ( 5 ? 431 . 05 chloro - 2 fluorophenyl) quinazolin 4 - yl ) piperazin - 1 - yl) prop 2 - en - 1 - one

1 - 116 1 - ( 4 - 6 - chloro - 7 B 409 . 25 phenylquinazolin - 4 - yl) - 2 (hydroxymethyl ) piperazin 1- yl) prop - 2 - en - 1 -one OH US 10 , 111 , 874 B2 121 122 TABLE 1 -continued Exemplary Compounds of Structure ( I ) No . StructureStructure Name Method [ M + H ] " I - 117 1 - ( 4 - ( 6 - chloro - 7 - ( 4 429 . 35 chloro - 2 hydroxyphenyl ) quinazolin 4 - yl) piperazin -1 yl) prop - 2 - en - 1 - one

OH

I - 118 1 - ( 4 - ( 6 - chloro - 7 - ( 5 429 . 30 hydroxyphenylchloro) - quinazolin 2 4 - yl) piperazin - 1 yl) prop - 2 - en - 1 -one

OH

I - 119 1 - ( 4 -( 6 -chloro - 7 - ( 4 B 465 . 35 fluoro - 2 ( trifluoromethyl) phenyl ) quinazolin - 4 - yl) piperazin 1 - yl) prop - 2 -en - 1 - one

I - 120 1 - acryloyl- 4 - (6 - chloro - 7 - B 440 . 30 ( 2 fluorophenyl) quinazolin 4 -yl ) piperazine - 2 carboxamide US 10 , 111 , 874 B2 123 124 TABLE 1 -continued Exemplary Compounds of Structure ( I )

No . Structure Name Method [ M + H ] " I - 121 1 - acryloyl -4 - ( 6 - chloro - 7 - B 490 . 40 ( 2 ( trifluoromethyl) phenyl ) quinazolin - 4 - yl) piperazine 2 - carboxamide

CH3

I - 122 1- ( 4 - (6 -chloro - 7 - (5 413 . 30 hydroxyphenylfluoro )- 2quinazolin 4 -yl ) piperazin - 1 yl) prop - 2 - en - 1 -one

OH

I - 123 1 - ( 4 - ( 6 - chloro - 7 429 . 35 ( naphthalen - 1 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 124 1 - ( 4 - ( 6 - chloro - 7 - ( 2 461 . 35 ( trifluoromethyl) phenyl) quinazolin - 4 -yl ) - 2 methylpiperazin - 1 yl) prop - 2 - en - 1 -one

CF3 US 10 , 111 , 874 B2 125 126 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [ M + H ] I - 125 2- ( 1 - acryloyl- 4 -( 6 - chloro 486 . 40 7 - ( 2 (trifluoromethyl ) phenyl) quinazolin - 4 -yl ) piperazin NC 2 - yl )acetonitrile

A

I - 126 1 - ( 4 - ( 6 -chloro - 7 - ( 2 419 . 20 cyclopropylphenyl) quinazolin 4 - yl )piperazin - 1 yl) prop - 2 -en - 1 - one

N

I - 127 4 -( 4 -acryloylpiperazin - 1 421. 30 fluorophenylyl) - 6 -chloro )quinazolin -7 -( 2 - 3 carbonitrile

CI

I - 128 1 - ( 4 - (6 - chloro - 7 - ( 2 B 430 . 10 chloro - 5 hydroxyphenyl) quinazolin 4 -yl ) piperazin - 1 yl) prop - 2 -en - 1 -one

HU US 10 , 111 , 874 B2 127 128 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No. StructureStructure Name Method [ M + H ] + 1 - 129 1 - ( 4 - ( 7 - (benzo [ d ]oxazol B 420 .10 7 -yl ) - 6 -chloroquinazolin 4 -yl )piperazin - 1 - yl) prop 2 - en - 1 - one

I - 130 3 -( 4 - ( 4 -acryloylpiperazin - B 404 . 10 1 -yl ) - 6 - chloroquinazolin 7 - yl) benzonitrile

CN

I - 131 3 - ( 4 - ( 4 - acryloylpiperazin B 468 . 10 1 - yl ) -6 - chloroquinazolin 7 - yl) - 2 - fluoro - N , N dimethylbenzamide US 10 , 111 , 874 B2 129 130 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [M + H ] * I - 132 1 -( 4 - ( 6 - chloro - 7 - ( 2, 6 - B 415 . 3 difluorophenyl) quinazolin 4 -yl ) piperazin - 1 - yl )prop 2 - en - 1 - one

I - 133 1 - 0 ( 4 - ( 6 -chloro - 7 - ( 4 B 413 .30 fluoro - 2 hydroxyphenyl) quinazolin 4 -yl )piperazin - 1 yl )prop - 2 - en - 1 -one

OH

1 - 134 1 - ( 4 - ( 6 -chloro - 7 - ( 2 B 409 . 30 hydroxyphenyl ) quinazolin 4 - yl ) - 2 methylpiperazin - 1 yl) prop - 2 -en - 1 -one

OH

I - 135 1 - ( 4 - ( 6 - chloro - 7 B 430 . 30 ( quinolin - 5 - yl ) quinazolin 4 - yl ) piperazin - 1 - yl) prop 2 - en - 1 - one US 10 , 111 , 874 B2 131 132 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ] * I - 136 1 - ( 4 - ( 6 - chloro - 7 B 430 . 35 ( isoquinolin -5 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 137 4 -( 4 - acryloylpiperazin -1 B 388 . 30 yl) - 7 -( 2 fluorophenyl) quinazoline 6 - carbonitrile

NC

A

I- 138 1 - ( 4 - ( 6 - chloro - 7 - ( 2 B 413 . 25 fluoro - 6 hydroxyphenyl) quinazolin 4 - yl) piperazin - 1 yl) prop - 2 - en - 1 -one

OH

I - 139 2- ( 1 - acryloyl- 4 -( 6 - chloro B 454 . 30 7 - ( 2 , 4 difluorophenyl) quinazolin 4 - yl) piperazin -2 CN yl )acetonitrile US 10 , 111 , 874 B2 133 134 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [ M + H ] * I - 140 1 - ( 4 - ( 6 - chloro - 7 - ( 5 433 . 15 methyl- 1H - indazol- 4 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

HN

1 - 141 1- ( 4 -( 6 -chloro -7 - ( 2 481. 10 fluoro - 5 ( trifluoromethoxy ) phenyl) quinazolin -4 yl) piperazin - 1 - yl ) prop - 2 en - 1 - one

F3CO

1 - 142 3 - ( 4 - ( 4 - acryloylpiperazin B 462 . 20 1 - yl) - 6 - chloroquinazolin cyclopropylbenzamide7 - yl) - N

N I - 143 1 - ( 3 - ( 4 - ( 4 462 . 10 acryloylpiperazin - 1- yl) - 6 chloroquinazolin -7 -yl ) - 4 fluorophenyl) cyclopropanecarbonitrile US 10 , 111 , 874 B2 135 136 TABLE 1 - continued Exemplary Compounds of Structure (I )

No. Structure Name Method [ M + H ] *

1 - 144 1 - ( 4 - ( 6 -chloro - 7 - (1H B 419 . 25 indazol- 5 - yl) quinazolin 4 - yl) piperazin - 1 -yl ) prop Z 2 - en - 1 - one

NH I - 145 1 - acryloyl -4 - (6 - chloro - 7 B 440 . 30 difluorophenyl( 2 , 4) quinazolin CN 4 -yl )piperazine - 2 carbonitrile

I - 146 1 -acryloyl - 4 - ( 6 - chloro - 7 B 420 . 25 hydroxyphenyl( 2 ) quinazolin 4 - yl ) piperazine - 2 carbonitrile

OH

1 - 147 1 - ( 4 - ( 6 -chloro - 7 -( 5 B 437 . 10 cyclopropyl- 2 fluorophenyl) quinazolin 4 -yl )piperazin - 1 - yl) prop 2 - en - 1 - one

> US 10 , 111 , 874 B2 137 138 TABLE 1 -continued Exemplary Compounds of Structure ( I)

No . Structure Name Method FM + H ] + I - 148 1 - ( 4 - (6 -chloro - 7 - ( 5 , 6 , 7 , 8 433 . 20 tetrahydronaphthalen - 1 yl) quinazolin - 4 yl) piperazin - 1 - yl )prop - 2 en - 1 - one

I - 149 1 - ( 4 - ( 7 - ( 3 B 435 . 30 aminobenzo [ d ] isoxazol 4 - yl) - 6 - chloroquinazolin 4 - yl) piperazin - 1 - yl) prop 2 - en - 1 - one

NH

ON

I - 150 1 - ( 4 - ( 7 - ( 2 - fluorophenyl) 431. 30 6 ( trifluoromethyl) quinazolin 4 -yl ) piperazin - 1 yl) prop - 2 -en - 1 -one

A

1 - 151 1 - ( 4 - acryloylpiperazin - 1 S 430. 30 yl) - 7 -chloro - 6 - ( 2 ,4 difluorophenyl )quinazolin 2 ( 1H ) - one US 10 , 111 , 874 B2 139 140 TABLE 1 -continued Exemplary Compounds of Structure ( 1) No. Structure Name Method [ M + H ] + 1 - 152 1 - ( 4 - (6 - chloro - 7 - ( 1H 419 . 30 indazol- 7 -yl ) quinazolin 4 -yl )piperazin - 1 -yl ) prop 2 - en - 1 - one

NH

1 - 153 1 - ( 4 - ( 6 - chloro - 7 - ( 2 445 . 10 hydroxynaphthalen - 1 yl) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

??

1 - 154 1 - ( 4 - ( 6 - chloro - 7 - ( 2 403 . 25 ethynylphenyl) quinazolin 4 -yl ) piperazin - 1 - yl) prop 2 - en - 1 - one

1 - 155 3 - ( 4 - ( 4 -acryloylpiperazin ? 440 . 25 1 - yl) - 6 -chloroquinazolin 7 -yl ) - 4 - fluorobenzamide

HUN US 10 , 111 , 874 B2 141 142 TABLE 1- continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ] * 1 - 156 1 - (4 - ( 6 - chloro - 7 - ( 2 - B 433. 35 ( cyclopropylmethyl) phenyl ) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

I - 157 1 - ( 4 - ( 7 - ( 2 B 413 . 10 ( trifluoromethyl) phenyl ) quinazolin - 4 -yl ) piperazin 1 -yl ) prop - 2 -en - 1 - one

CF3

I - 158 1 - ( 4 - ( 6 - chloro - 8 - fluoro - 7 O 415 . 25 fluorophenyl( 2 ) quinazolin 4 -yl ) piperazin - 1 - yl ) prop 2 - en - 1 - one

I - 159 1 - ( 4 - ( 6 -chloro - 7 - ( 2 397 . 25 fluorophenyl) cinnolin - 4 yl) piperazin -1 -yl ) prop - 2 en - 1 - one US 10 , 111 , 874 B2 143 144 TABLE 1 -continued ExemplaryExemplary Compounds of of Structure ( I) No . Structure Name Method [ M + H ] *

I- 160 4 - ( 4 - ( 4 - acryloylpiperazin 434 . 25 1 - yl) - 6 -chloroquinazolin 7 - yl) indolin - 2 -one

HN

1 - 161 2 - ( 2 - ( 4 - ( 4 B 436 . 1 acryloylpiperazin - 1 - yl ) -6 chloroquinazolin - 7 yl) phenyl ) acetamide

H?N

1 - 162 1 - ( 4 - ( 6 - chloro - 7 - ( 1H B 419 . 3 indazol- 6 - yl) quinazolin 4 -yl ) piperazin - 1 - yl) prop 2 - en - 1 - one

1 - 163 1 - ( 4 - ( 7 - ( 2 - fluorophenyl) A 379 . 25 6 -hydroxyquinazolin - 4 yl )piperazin - 1 - yl) prop - 2 en - 1 - one US 10 , 111 , 874 B2 145 146 TABLE 1 -continued Exemplary Compounds of Structure (I )

No . Structure Name Method [M + H ]*

I - 164 1 - (4 - ( 7 - ( 2 B 435 .25 aminobenzo [d ]oxazol - 5 yl) - 6 - chloroquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

H2N

I - 165 1 - ( 4 - ( 7 - 1H ? 419 . 30 benzo [ d ] imidazol- 4 -yl ) - 6 chloroquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

CM AN

HN .

I - 166 1 - ( 4 - ( 6 - ( 2 H 419 . 10 ( trifluoromethyl )phenyl ) thieno [ 3 , 2 - d ]pyrimidin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

1 - 167 1 - ( 4 - (6 - chloro - 7 - ( 1H B 419 . 30 indazol- 4 - yl) quinazolin 4 -yl )piperazin - 1 - yl) prop 2 - en - 1 - one

HN US 10 , 111 , 874 B2 147 148 TABLE 1 - continued Exemplary Compounds of Structure (I )

No. Structure Name Method [ M + H ] * I - 168 2 - ( 2 - ( 4 - ( 4 B 418. 1 acryloylpiperazin - 1 - yl ) - 6 chloroquinazolin - 7 yl) phenyl ) acetonitrile

IN

CM

1 - 169 1 - ( 4 -( 6 -chloro - 7 -( 4 463 . 30 hydroxy - 2 ( trifluoromethyl) phenyl ) quinazolin - 4 -yl ) piperazin 1 - yl) prop - 2 - en - 1- one

HO

1 - 170 3 - ( 4 - ( 4 - acryloylpiperazin B 396 . 25 1 - yl) - 6 -chloroquinazolin 7 - yl) pyridin - 2 ( 1H ) -one

NH 1 - 171 4 - ( 4 - acryloylpiperazin - 1 P 453. 30 yl ) - 6 - chloro - 7 (naphthalen - 1 yl) quinolin - 3 carbonitrile

CN US 10 , 111 , 874 B2 149 150 TABLE 1 -continued Exemplary Compounds of Structure (I ) No. Structure Name Method [M + H ] + 1 - 172 4 - ( 4 -acryloylpiperazin - 1 439 . 25 yl ) -6 -chloro - 7 - ( 2 , 4 difluorophenyl) quinolin 3 - carbonitrile

1 - 173 4 - ( 4 - acryloylpiperazin - 1 P 471. 35 yl )- 6 -chloro - 7 - ( 2 ( trifluoromethyl) phenyl) quinoline - 3 -carbonitrile

CN

CF3

I - 174 N - ( 3 - ( 4 - ( 4 B 454 . 10 acryloylpiperazin -1 - yl )- 6 chloroquinazolin - 7 -yl ) - 4 fluorophenyl )acetamide

HN .

F

I - 175 1 - ( 2 - ( 4 - ( 4 B 444 . 1 acryloylpiperazin - 1 - yl) - 6 chloroquinazolin - 7 yl) phenyl ) cyclopropanecarbonitrile

N US 10 , 111 , 874 B2 151 152 TABLE 1 -continued Exemplary Compounds of Structure ( I) No. Structure Name Method [M + H ] * 1 - 176 1 - ( 2 - ( 4 - ( 4 462 . 2 acryloylpiperazin - 1 - yl ) - 6 chloroquinazolin - 7 yl) phenyl ) cyclopropanecarboxamide

OCNH2 1 - 177 1 - (4 - (4 - acryloylpiperazin - T 430 . 20 1 - yl) - 6 -chloroquinazolin 7 - yl) - 5 - chloropyridin 2 ( 1H ) - one

1 - 178 N - ( 4 - ( 4 - ( 4 464 . 10 acryloylpiperazin - 1 - yl ) - 6 chloroquinazolin - 7 - yl ) - 5 methylpyrimidin - 2 yl) acrylamide

N

1 - 179 1 - ( 4 - ( 7 - ( 2 - amino - 5 B 410 . 10 methylpyrimidin - 4 -yl ) - 6 chloroquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

H N US 10 , 111 , 874 B2 153 154 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ]* I - 180 1 - ( 4 - ( 6 - chloro - 7 , 8 ' 431. 10 biquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one

N

I - 181 1 -( 4 -( 4 -acryloylpiperazin T 430 . 10 1 - yl) - 6 - chloroquinazolin 7- yl ) - 4 - chloropyridin 2 ( 1H ) -one

I - 182 4 - ( 4 - acryloylpiperazin - 1 P 419 . 15 yl) - 6 - chloro - 7 - ( 2 hydroxyphenyl) quinoline 3 - carbonitrile

CN

OH 1 - 183 1 - ( 4 - ( 7 - ( 2 - ( 1H -pyrazol - 4 B 445 . 20 yl) phenyl ) - 6 chloroquinazolin - 4 yl) piperazin - 1 - yl) prop - 2 Beton en - 1 - one

NH US 10 , 111 , 874 B2 155 156 TABLE 1 -continued Exemplary Compounds of Structure (I ) No . Structure Name Method [M + H ]*

I - 184 4 - ( 4 -acryloylpiperazin - 1 453 . 15 yl) - 6 -chloro - 7 - ( 2 -chloro hydroxyphenyl) quinoline 3 - carbonitrile

CN

I - 185 1 - ( 4 - ( 6 - chloro - 7 B 385 . 10 (thiophen - 2 yl ) quinazolin - 4 yl) piperazin - 1 -yl ) prop - 2 en - 1 - one

SN

1 - 186 1- ( 4 -( 6 -chloro -7 -( 2 462 . 25 ( thiazol- 2 yl) phenyl ) quinazolin - 4 yl )piperazin - 1 - yl) prop - 2 en - 1 - one

1

1 - 187 1 - ( 4 - ( 6 - chloro - 7 - ( 2 U 462 . 25 ( thiazol- 5 yl) phenyl ) quinazolin - 4 yl) piperazin - 1 - yl) prop - 2 en - 1 - one US 10 , 111 , 874 B2 157 158 TABLE 1 -continued Exemplary Compounds of Structure (1 ) No . Structure Name Method [M + H ] * 1 - 188 1 - ( 4 - ( 6 -chloro - 7 - ( 2 B 463 . 20 fluoro - 5 - ( 1H -pyrazol - 4 yl) phenyl) quinazolin - 4 yl) piperazin - 1- yl) prop - 2 en - 1 - one

I - 189 4 - ( 4 - acryloylpiperazin - 1 P 439 .60 yl) -6 - chloro - 7 - ( 2 fluorophenyl ) quinazolin - 3 carboxamide

NH2

F

I - 190 1 - ( 4 - ( 7 - ( 2 -amino - 4 B 410 . 10 methylpyrimidin - 5 -yl ) - 6 chloroquinazolin - 4 yl) piperazin - 1 -yl ) prop - 2 en - 1 - one

H?N

I - 191 1 - ( 4 - (6 - chloro - 7 - ( 2 B 422 .20 methyl- 5 (methylamino ) phenyl ) quinazolin - 4 - yl) piperazin - 1 yl) prop - 2 - en - 1 -one

HN