KRAS G12C inhibitors and uses thereof

Abstract

The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof, methods for preparing the same and uses thereof. The compounds of the present invention are effective in inhibiting KRAS proteins having a G12C mutation and are suitable for use in methods for treating cancers mediated in whole or in part by the KRAS G12C mutation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 850,289, filed May 20, 2019, which is incorporated herein by reference in its entirety. Background Art

[0003] Mutations in KRAS are known to be oncogenic and are common in pancreatic, lung, colorectal, gallbladder, thyroid, and bile duct cancers. The glycine 12 to cysteine mutation in KRAS is a relatively common genotype in non-small cell lung cancer and colorectal cancer. This mutation provides a selective covalent inhibition strategy for mutant KRAS while sparing wild-type KRAS, thereby providing specificity for cancer cells. There is a need to develop new KRAS G12C inhibitors for the treatment of KRAS G12C-mediated cancers (i.e., cancers mediated in whole or in part by KRAS G12C mutations). The compounds and compositions of the present invention provide a means for selectively inhibiting KRAS G12C and for treating cancers, particularly those mediated by KRAS G12C mutations.

[0004] Overview

[0005] In certain embodiments, the present invention relates to a compound having the following structure:

[0006] (a) Structure of Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof,

[0009] in:

[0010] * is a quaternary carbon atom;

[0011] A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, which is surrounded by one R 8b and an R 8c replace;

[0012] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0013] C is aryl or heteroaryl optionally substituted with one or more R4;

[0014] x1 is C=O or C(R1)(R2);

[0015] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0016] y1 is y1a and y2 is y 2a ;or

[0017] y1 is *—y 1b —y 1c and y2 is y 2a ;or

[0018] y1 is y 1a and y2 is *—y 2b —y 2c ;or

[0019] y1 is *—y 1d y 1e and y2 is y 2a ;or

[0020] y1 is y 1a and y2 is *—y 2d y 2e ;or

[0021] y1 is *y 1a —y 1b —y 1c and y2 are bonds; or

[0022] y1 is the key and y2 is *y 2a —y 2b —y 2c ;

[0023] y 1a and y 2a are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0024] y 1b 、y 1c 、y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0025] y 1d 、y 1e 、y 2d and y 2e are each independently C(R3) or N;

[0026] The condition is y 1a and y 2a Neither can be a heteroatom;

[0027] The condition is y 1b and y 2a Neither can be a heteroatom, and the condition is y 1b and y 1c Neither can be a heteroatom;

[0028] The condition is y 1a and y 2b Neither can be a heteroatom, and the condition is y 2b and y 2c Neither can be a heteroatom;

[0029] The condition is y 1d and y 2a Neither can be a heteroatom;

[0030] The condition is y 1a and y 2d Neither can be a heteroatom;

[0031] The condition is y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom; and

[0032] The condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom;

[0033] R1 and R2 are each independently H or F;

[0034] R3 at each occurrence is independently H or C1-C4 alkyl;

[0035] R4 is independently at each occurrence H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3;

[0036] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0037] R 8b is H, C1-C3 alkyl-CN or C1-C3 alkyl-OCH3;

[0038] R 8c is H or C1-C4 alkyl;

[0039] R8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0040] R 8e is H, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, haloalkoxy, (CH2) m N(R3)2, N(R3)2, C(O)N(R3)2, N(H)C(O)C1-C3 alkyl, CH2N(H)C(O)C1-C3 alkyl, heteroaryl or heterocyclyl;

[0041] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0042] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0043] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3;

[0044] m is independently 1, 2, or 3 at each occurrence;

[0045] n is 0, 1, 2, or 3; and

[0046] p is 0 or 1; or

[0047] (b) Structure of Formula Ia:

[0048]

[0049] or a pharmaceutically acceptable salt thereof,

[0050] in:

[0051] * is a quaternary carbon atom;

[0052] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0053] x1 is C=O or C(R1)(R2);

[0054] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0055] y1 is y1a and y2 is y 2a ;or

[0056] y1 is *—y 1b —y 1c and y2 is y 2a ;or

[0057] y1 is y 1a and y2 is *—y 2b —y 2c ;or

[0058] y1 is *—y 1d y 1e and y2 is y 2a ,;or

[0059] y1 is y 1a and y2 is *—y 2d y 2e ;or

[0060] y1 is *y 1a —y 1b —y 1c and y2 are bonds; or

[0061] y1 is the key and y2 is *y 2a —y 2b —y 2c ;

[0062] y 1a and y 2a are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0063] y 1b 、y 1c 、y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0064] y 1d 、y 1e 、y 2d and y 2e are each independently C(R3) or N;

[0065] The condition is y 1a and y 2a Neither can be a heteroatom;

[0066] The condition is y 1b and y 2a Neither can be a heteroatom, and the condition is that y 1b and y 1c Neither can be a heteroatom;

[0067] The condition is y 1a and y 2b Neither can be a heteroatom, and the condition is that y 2b and y 2c Neither can be a heteroatom;

[0068] The condition is y 1d and y 2a Neither can be a heteroatom;

[0069] The condition is y 1a and y 2d Neither can be a heteroatom;

[0070] The condition is y 1a and y 1b Neither can be a heteroatom, and the condition is that y 1b and y 1c Neither can be a heteroatom; and

[0071] The condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom;

[0072] z1, z2, z3 and z4 are each independently C or N;

[0073] R1 and R2 are each independently H or F;

[0074] R3 at each occurrence is independently H or C1-C4 alkyl;

[0075] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0076] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0077] R 8b is H, C1-C3 alkyl-CN or C1-C3 alkyl-OCH3;

[0078] R 8c is H or C1-C4 alkyl;

[0079] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0080] R 8e is H, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, haloalkoxy, (CH2) m N(R3)2, N(R3)2, C(O)N(R3)2, N(H)C(O)C1-C3 alkyl, CH2N(H)C(O)C1-C3 alkyl, heteroaryl or heterocyclyl;

[0081] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0082] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0083] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3;

[0084] m is independently 1, 2, or 3 at each occurrence; and

[0085] n is 0, 1, 2 or 3; or

[0086] (c) Structure of Formula II:

[0087]

[0088] or a pharmaceutically acceptable salt thereof,

[0089] in:

[0090] x1 is C=O or C(R1)(R2);

[0091] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0092] y 1a and y 2a Each independently is (C(R11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 2a Neither can be a heteroatom;

[0093] z1, z2, z3 and z4 are each independently C or N;

[0094] R1 and R2 are each independently H or F;

[0095] R3 at each occurrence is independently H or C1-C4 alkyl;

[0096] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0097] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0098] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0099] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0100] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0101] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0102] m, if present, is 1; or

[0103] (d) Structure of Formula III:

[0104]

[0105] or a pharmaceutically acceptable salt thereof,

[0106] in:

[0107] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0108] x1 is C=O or C(R1)(R2);

[0109] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0110] is a single or double bond that satisfies all valences;

[0111] y 1a is a key, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0112] when When it is a single bond, y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 2b Neither can be a heteroatom, and the condition is that y 2b and y 2c Neither can be a heteroatom; or

[0113] when When it is a double bond, y 2b and y 2c are each independently C(R3) or N, provided that y 1a and y 2b Neither can be a heteroatom;

[0114] z1, z2, z3 and z4 are each independently C or N;

[0115] R1 and R2 are each independently H or F;

[0116] R3 at each occurrence is independently H or C1-C4 alkyl;

[0117] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0118] R 8ais H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0119] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0120] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0121] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0122] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0123] m is independently 1, 2 or 3 at each occurrence; or

[0124] (e) Structure of Formula IV:

[0125]

[0126] or a pharmaceutically acceptable salt thereof,

[0127] in:

[0128] x1 is C=O or C(R1)(R2);

[0129] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0130] y 1b and y 1c Each independently is (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1b and y 1c Neither can be C=CH2, and further conditions are y1b and y 1cNeither can be C=O;

[0131] z1, z2, z3 and z4 are each independently C or N;

[0132] R1 and R2 are each independently H or F;

[0133] R3 at each occurrence is independently H or C1-C4 alkyl;

[0134] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0135] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0136] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0137] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0138] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0139] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0140] m, if present, is 1; or

[0141] (f) Structure of Formula V:

[0142]

[0143] or a pharmaceutically acceptable salt thereof,

[0144] in:

[0145] x1 is C=O or C(R1)(R2);

[0146] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0147] y 1a 、y 1b and y 1c Each independently is (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1a and y 1b Neither can be C=CH2, provided that y 1b and y 1c Neither can be C=CH2, provided that y 1a and y 1b Neither can be C=O, and further condition is y 1b and y 1c Neither can be C=O;

[0148] z1, z2, z3 and z4 are each independently C or N;

[0149] R1 and R2 are each independently H or F;

[0150] R3 at each occurrence is independently H or C1-C4 alkyl;

[0151] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0152] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0153] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0154] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0155] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0156] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0157] m, when present, is 1.

[0158] In other embodiments, the present invention is directed to methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein. Detailed Description of the Invention

[0160] definition

[0161] Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature and techniques relating to the chemistry, cell and tissue culture, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0162] Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th Edition", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0163] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0164] All of the above and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0165] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cattle, porcine, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0166] "Treating" a condition or patient means taking steps to obtain a beneficial or desired result, including a clinical result. As used herein, and as is well known in the art, "treatment" is an approach used to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or symptoms, reduction in the extent of the disease, stabilization (i.e., non-worsening) of the disease state, prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to the expected survival if not receiving treatment.

[0167] The term "prevention" is art-recognized and, when used in connection with a condition such as local recurrence (e.g., pain), a disease such as cancer, a syndromic complex such as heart failure, or any other medical condition, is well known in the art and includes administering a composition that reduces the frequency of symptoms of a medical condition or delays the onset of the condition in a subject relative to a subject that has not received the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated population, e.g., by a statistically and / or clinically significant amount.

[0168] A substance, compound, or agent can be "administered" or "administered" to a subject using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracerebrally, and transdermally (by absorption, e.g., through a skin catheter). The compound or agent can also be suitably introduced via a rechargeable or biodegradable polymer device or other device (e.g., a patch and pump) or a formulation that provides for extended, slow, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods.

[0169] The appropriate method of administering a substance, compound, or medicament to a subject will also depend on, for example, the age and / or physical condition of the subject and the chemical and biological properties of the compound or medicament (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or medicament is administered orally, for example, by ingestion to a subject. In some embodiments, the orally administered compound or medicament is in an extended-release or slow-release formulation, or is administered using a device for such slow- or extended-release.

[0170] The term "alkoxy" refers to an alkyl group (preferably a lower alkyl group) connected to an oxygen. Representative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0171] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond; and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter of which refers to alkenyl groups having substituents replacing hydrogen on one or more carbon atoms of the alkenyl group. Such substituents may be present on one or more carbons that are included or not included in one or more double bonds. In addition, such substituents include all those contemplated for alkyl groups, as discussed below, except where prohibited by stability. For example, it is contemplated that alkenyl groups are substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

[0172] "Alkyl" or "alkane" is a fully saturated, straight or branched chain, non-aromatic hydrocarbon. Typically, a straight or branched chain alkyl group has 1 to about 6, preferably 1 to about 3, carbon atoms, unless otherwise defined. Examples of straight or branched chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl. C1-C6 straight or branched chain alkyl groups are also referred to as "lower alkyl groups."

[0173] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to alkyl groups having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise indicated, such substituents may include, for example, halogen (e.g., fluorine), hydroxy, oxo, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic groups. In preferred embodiments, the substituents on the substituted alkyl group are selected from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, carbonyl, cyano, or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl are selected from fluorine, carbonyl, cyano or hydroxy. It will be understood by those skilled in the art that, if appropriate, the substituted groups on the hydrocarbon chain themselves may be substituted. For example, the substituents of the substituted alkyl may include substituted and unsubstituted forms of the following groups: amino, azido, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates) and silyl, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF , -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted by alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF , -CN, etc.

[0174] The term "C x –C y ", when used in conjunction with a chemical group such as alkyl or alkoxy, is intended to include groups containing from x to y carbons in the chain. For example, the term "C x –C y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight and branched chain alkyl groups containing from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl. C0 alkyl represents hydrogen, where the group is in a terminal position, or if internal, a bond.

[0175] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0176] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0177] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl groups having substituents replacing hydrogen on one or more carbons of the alkynyl group. Thus, substituents may be present on one or more carbons that are or are not included in one or more triple bonds. Furthermore, such substituents include all substituents contemplated for alkyl groups, as discussed above, except where prohibited by stability. For example, alkynyl groups are contemplated to be substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

[0178] As used herein, the term "amide" refers to a group

[0179]

[0180] Each R A independently represent hydrogen, hydrocarbon, aryl, heteroaryl, acyl or alkoxy, or two R A Together with the nitrogen atom to which they are attached they form a heterocyclic ring having 3 to 8 atoms in the ring structure.

[0181] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, For example , can be represented by the following groups

[0182] or

[0183] Each R A independently represent hydrogen or a hydrocarbon group, or two R A Together with the nitrogen atom to which they are attached they form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0184] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0185] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0186] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom on the ring is carbon. Preferably, the ring is a 6-10 membered ring, more preferably a 6-membered ring. The term "aryl" also includes a polycyclic ring system with two or more rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Aryl includes benzene, naphthalene, phenanthrene, aniline, etc.

[0187] The term "carbocycle" refers to a saturated or unsaturated ring in which each atom in the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkyl and cycloalkenyl rings. "Carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with another ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring such as phenyl can be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0188] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, unless otherwise defined, a monocyclic cycloalkyl has 3 to about 10 carbon atoms, 3 to 8 carbon atoms, or more typically 3 to 6 carbon atoms. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules (e.g., rings) that share one, two, or three or more atoms between the two rings. For example fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds).

[0189] A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0190] The term "bridged bicyclic compound" refers to a bicyclic molecule in which two rings share three or more atoms, separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered a pair of cyclopentane rings, each sharing three of its five carbon atoms.

[0191] As used herein, the term "ether" refers to a hydrocarbyl group attached to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0192] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0193] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, eg, wherein no two heteroatoms are adjacent.

[0194] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups, but substituents such as acetyl (which has a =O substituent on the attached carbon) and ethoxy (attached through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, and combinations thereof.

[0195] The term "fused bicyclic compound" refers to a bicyclic molecule in which the two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e. the so-called bridgehead atoms are directly connected ( For example , α-thujene and decalin). For example, in a fused cycloalkyl, each ring shares two adjacent atoms with another ring, and the second ring of the fused bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring and an aromatic ring.

[0196] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0197] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more rings, wherein two or more carbon atoms are common to two adjacent rings, wherein at least one ring is heteroaromatic, For example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, quinoline, quinoxaline, naphthyridine and the like.

[0198] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0199] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3 to 10-membered rings, preferably 3 to 7-membered rings, more preferably 5 to 6-membered rings, in some cases most preferably 5-membered rings, and in other cases most preferably 6-membered rings, the ring structure including at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more rings, wherein two or more carbon atoms are common to two adjacent rings, wherein at least one ring is a heterocyclic ring, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, oxazoline, imidazoline, and the like.

[0200] The terms "polycyclic," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of the polycyclic ring can be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0201] The term "spirocyclic compound" refers to a bicyclic molecule in which the two rings have only a single common atom, the spiro atom.

[0202] The term "substituted" refers to a group having a substituent replacing a hydrogen on one or more carbons of the backbone or a substituent replacing a hydrogen on one or more nitrogens of the backbone. It should be understood that "substituted" or "substituted with" includes the implicit proviso that the substitution is consistent with the valence allowed by the replacing atom and the substituent, and that the substitution results in a stable compound. For example , which do not spontaneously undergo transformations such as through rearrangement, cyclization, elimination, etc. 。 The substitutions may be one or more and the same or different for appropriate organic compounds.

[0203] A "protecting group" is a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, protecting groups can be selectively removed as needed during the synthetic process. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, pp. 3rd edition, 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods , Volumes 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxy group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers ( For example TMS or TIPS groups), glycol ethers such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[0204] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0205] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a patient.

[0206] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of any base compound disclosed herein. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monobasic, dibasic and tribasic carboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacids or dibasic acid salts can be formed, and such salts can exist in hydrated, solvated or substantially anhydrous forms. Generally, acid addition salts of the compounds disclosed herein are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be useful, for example, in isolating the compounds of the invention for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0207] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound of the present invention, or any intermediate thereof. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts is known to those skilled in the art.

[0208] Many compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may exist in either the R or S configuration, using the R and S notations consistent with the rules described in Pure Appl. Chem. (1976), 45, 11–30. The present disclosure contemplates all stereoisomeric forms, such as enantiomeric and diastereomeric forms of the compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, WO 01 / 062726.

[0209] Additionally, certain alkenyl-containing compounds may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both the mixture and the individual isomers.

[0210] Some compounds may also exist in tautomeric forms. These forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0211] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized (e.g., hydrolyzed or oxidized) in the host after administration to form a compound of the present disclosure (e.g., a compound of the present invention). Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protecting) group on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminized, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using esters or phosphoramidates as biologically unstable or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to produce the compounds of the present invention or pharmaceutically acceptable salts thereof. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.

[0212] Example compounds

[0213] In certain embodiments, the present invention relates to compounds having the structure of Formula I:

[0214]

[0215] or a pharmaceutically acceptable salt thereof,

[0216] in:

[0217] * is a quaternary carbon atom;

[0218] A is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, which is surrounded by one R 8b and an R 8c replace;

[0219] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0220] C is aryl or heteroaryl optionally substituted with one or more R4;

[0221] x1 is C=O or C(R1)(R2);

[0222] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0223] y1 is y 1a and y2 is y 2a ;or

[0224] y1 is *—y 1b —y 1c and y2 is y 2a ;or

[0225] y1 is y 1a and y2 is *—y 2b —y 2c ;or

[0226] y1 is *—y 1d y 1e and y2 is y 2a ;or

[0227] y1 is y 1a and y2 is *—y 2d y 2e ;or

[0228] y1 is *y 1a —y 1b —y 1c and y2 are bonds; or

[0229] y1 is the key and y2 is *y 2a —y 2b —y 2c ;

[0230] y 1a and y 2a are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0231] y 1b 、y 1c 、y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0232] y 1d 、y 1e 、y 2d and y 2e are each independently C(R3) or N;

[0233] The condition is y 1a and y 2a Neither can be a heteroatom;

[0234] The condition is y 1b and y 2aNeither can be a heteroatom, and the condition is y 1b and y 1c Neither can be a heteroatom;

[0235] The condition is y 1a and y 2b Neither can be a heteroatom, and the condition is y 2b and y 2c Neither can be a heteroatom;

[0236] The condition is y 1d and y 2a Neither can be a heteroatom; the condition is that y 1a and y 2d Neither can be a heteroatom;

[0237] The condition is y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom; and

[0238] The condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom;

[0239] R1 and R2 are each independently H or F;

[0240] R3 at each occurrence is independently H or C1-C4 alkyl;

[0241] R4 is independently at each occurrence H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3;

[0242] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0243] R 8b is H, C1-C3 alkyl-CN or C1-C3 alkyl-OCH3;

[0244] R 8c is H or C1-C4 alkyl;

[0245] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0246] R 8e is H, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, haloalkoxy, (CH2) m N(R3)2, N(R3)2, C(O)N(R3)2, N(H)C(O)C1-C3 alkyl, CH2N(H)C(O)C1-C3 alkyl, heteroaryl or heterocyclyl;

[0247] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0248] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0249] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3;

[0250] m is independently 1, 2, or 3 at each occurrence;

[0251] n is 0, 1, 2, or 3; and

[0252] p is 0 or 1.

[0253] In certain such embodiments, the present invention relates to compounds having the structure of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

[0254] y1 is y 1a and y2 is y 2a , the condition is y 1a and y 2a Neither can be a heteroatom, and further provided that when y1 is y 1a and y2 is y 2a When y 1a or y 2a cannot be a key; or

[0255] y1 is *—y 1b —y 1c and y2 is y 2a , the condition is y 1b and y 2a Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a key, conditional on y 1b and y1c Neither can be a heteroatom, provided that y 1b and y 1c Neither can be C=O, and further condition is y 1b and y 1c Neither can be C=CH2; or

[0256] y1 is y 1a and y2 is *—y 2b —y 2c , the condition is y 1a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a key, conditional on y 2b and y 2c Neither can be a heteroatom, provided that y 2b and y 2c Neither can be C=O, and further condition is y 2b and y 2c Neither can be C=CH2; or

[0257] y1 is *—y 1d y 1e and y2 is y 2a , the condition is y 1d and y 2a Neither can be a heteroatom; or

[0258] y1 is y 1a and y2 is *—y 2d y 2e , the condition is y 1a and y 2d Neither can be a heteroatom; or

[0259] y1 is *y 1a —y 1b —y 1c and y2 is the key, the condition is y 1a 、y 1b and y 1c Cannot be a key, the condition is y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1a and y 1b Neither can be C=O, the condition is y 1b and y 1c Neither can be C=O, the condition is y 1a and y1b Neither can be C=CH2, and further condition is y 1b and y 1c Neither can be C=CH2; or

[0260] y1 is the key and y2 is *y 2a —y 2b —y 2c , the condition is y 2a 、y 2b and y 2c Cannot be a key, the condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom, provided that y 2a and y 2b Neither can be C=O, the condition is y 2b and y 2c Neither can be C=O, the condition is y 2a and y 2b Neither can be C=CH2, and further condition is y 2b and y 2c Neither can be C=CH2.

[0261] In certain embodiments, n is 0.

[0262] In certain embodiments, p is 1.

[0263] In certain embodiments, B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0264] In certain embodiments, n is 0, p is 1, and B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, n is 0, p is 1, and B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0265] In a preferred embodiment, A is a 6-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, which is separated by one R 8b and an R 8c In a more preferred embodiment, A is a 6-membered heterocyclyl. In an even more preferred embodiment, A is a piperazinyl.

[0266] In certain embodiments, the compound of Formula I has the structure of Formula Ia:

[0267]

[0268] or a pharmaceutically acceptable salt thereof,

[0269] in:

[0270] * is a quaternary carbon atom;

[0271] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0272] x1 is C=O or C(R1)(R2);

[0273] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0274] y1 is y 1a and y2 is y 2a ;or

[0275] y1 is *—y 1b —y 1c and y2 is y 2a ;or

[0276] y1 is y 1a and y2 is *—y 2b —y 2c ;or

[0277] y1 is *—y 1d y 1e and y2 is y 2a ;or

[0278] y1 is y 1a and y2 is *—y 2d y 2e ;or

[0279] y1 is *y 1a —y 1b —y 1c and y2 are bonds; or

[0280] y1 is the key and y2 is *y 2a —y 2b —y 2c ;

[0281] y 1a and y 2a are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0282] y 1b 、y 1c 、y 2b and y 2care each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0283] y 1d 、y 1e 、y 2d and y 2e are each independently C(R3) or N;

[0284] The condition is y 1a and y 2a Neither can be a heteroatom;

[0285] The condition is y 1b and y 2a Neither can be a heteroatom, and the condition is y 1b and y 1c Neither can be a heteroatom;

[0286] The condition is y 1a and y 2b Neither can be a heteroatom, and the condition is y 2b and y 2c Neither can be a heteroatom;

[0287] The condition is y 1d and y 2a Neither can be a heteroatom;

[0288] The condition is y 1a and y 2d Neither can be a heteroatom;

[0289] The condition is y 1a and y 1b Neither can be a heteroatom, and the condition is y 1b and y 1c Neither can be a heteroatom; and

[0290] The condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom;

[0291] z1, z2, z3 and z4 are each independently C or N;

[0292] R1 and R2 are each independently H or F;

[0293] R3 at each occurrence is independently H or C1-C4 alkyl;

[0294] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0295] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0296] R 8b is H, C1-C3 alkyl-CN or C1-C3 alkyl-OCH3;

[0297] R 8c is H or C1-C4 alkyl;

[0298] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0299] R 8e is H, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, haloalkoxy, (CH2) m N(R3)2, N(R3)2, C(O)N(R3)2, N(H)C(O)C1-C3 alkyl, CH2N(H)C(O)C1-C3 alkyl, heteroaryl or heterocyclyl;

[0300] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0301] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0302] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3;

[0303] m is independently 1, 2, or 3 at each occurrence; and

[0304] n is 0, 1, 2 or 3.

[0305] In certain such embodiments, the compound of Formula I has the structure of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein:

[0306] y1 is y 1a and y2 is y 2a , the condition is y 1a and y 2a Neither can be a heteroatom, and further provided that when y1 is y 1a and y2 is y 2a When y 1a or y 2a cannot be a key; or

[0307] y1 is *—y 1b —y 1c and y2 is y 2a , the condition is y 1b and y 2a Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a key, conditional on y 1b and y 1c Neither can be a heteroatom, provided that y 1b and y 1c Neither can be C=O, and further condition is y 1b and y 1c Neither can be C=CH2; or

[0308] y1 is y 1a and y2 is *—y 2b —y 2c , the condition is y 1a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a key, conditional on y 2b and y 2c Neither can be a heteroatom, provided that y 2b and y 2c Neither can be C=O and further condition is y 2b and y 2c Neither can be C=CH2; or

[0309] y1 is *—y 1d y 1e and y2 is y 2a , the condition is y 1d and y 2a Neither can be a heteroatom; or

[0310] y1 is y 1aand y2 is *—y 2d y 2e , the condition is y 1a and y 2d Neither can be a heteroatom; or

[0311] y1 is *y 1a —y 1b —y 1c and y2 is the key, condition is y 1a 、y 1b and y 1c Cannot be a key, the condition is y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1a and y 1b Neither can be C=O, the condition is y 1b and y 1c Neither can be C=O, the condition is y 1a and y 1b Neither can be C=CH2, and further condition is y 1b and y 1c Neither can be C=CH2; or

[0312] y1 is the key and y2 is *y 2a —y 2b —y 2c , the condition is y 2a 、y 2b and y 2c Cannot be a key, the condition is y 2a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom, provided that y 2a and y 2b Neither can be C=O, the condition is y 2b and y 2c Neither can be C=O, the condition is y 2a and y 2b Neither can be C=CH2 and further condition is y 2b and y 2c Neither can be C=CH2.

[0313] In certain embodiments, n is 0.

[0314] In certain embodiments, B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0315] In certain embodiments, n is 0, and B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In other embodiments, n is 0, and B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0316] In further embodiments, the compound of Formula Ia has the structure of Formula Ib:

[0317]

[0318] or a pharmaceutically acceptable salt thereof.

[0319] In yet other embodiments, the compound of Formula Ia has the structure of Formula Ic:

[0320]

[0321] or a pharmaceutically acceptable salt thereof.

[0322] In certain embodiments, the compound of Formula Ia has the structure of Formula Id:

[0323]

[0324] or a pharmaceutically acceptable salt thereof.

[0325] In further embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic or Id, or a pharmaceutically acceptable salt thereof, wherein:

[0326] * is a quaternary carbon atom;

[0327] x1 is C=O or C(R1)(R2);

[0328] y1 is y 1a and y2 is y 2a ;or

[0329] y1 is *—y 1b —y 1c and y2 is y 2a ;or

[0330] y1 is y 1a and y2 is *—y 2b —y 2c ;or

[0331] y1 is *—y 1d y 1e and y2 is y 2a ;or

[0332] y1 is y 1a and y2 is *—y 2d y 2e ;

[0333] y 1a and y 2a Each independently is C(R 11 )2, O, N(R3) or S;

[0334] y 1b 、y 1c 、y 2b and y 2c Each independently is C(R 11 )2, O, N(R3) or S;

[0335] y 1d 、y 1e 、y 2d and y 2e are each independently C(R3) or N;

[0336] The condition is y 1a and y 2a Neither can be a heteroatom;

[0337] The condition is y 1b and y 2a Neither can be a heteroatom, and further proviso that y 1b and y 1c Neither can be a heteroatom;

[0338] The condition is y 1a and y 2b Neither can be a heteroatom, and further proviso that y 2b and y 2c Neither can be a heteroatom;

[0339] The condition is y 1d and y 2a Neither can be a heteroatom;

[0340] The condition is y 1a and y 2d Neither can be a heteroatom;

[0341] z1, z2, z3 and z4 are each independently C or N;

[0342] R1 and R2 are each independently H or F;

[0343] R3 is independently H or CH3 at each occurrence;

[0344] R4, R5, R6 and R7 are each independently H, F, Cl, CH3 or OCH3, or each R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0345] R 8a is H, C1-C3 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C3 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0346] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0347] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl; and

[0348] R 11 is independently at each occurrence H, F, Cl, CH 3 or OCH 3 .

[0349] In certain embodiments, the compound of Formula I has the structure of Formula II:

[0350]

[0351] or a pharmaceutically acceptable salt thereof,

[0352] in:

[0353] x1 is C=O or C(R1)(R2);

[0354] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0355] y 1a and y 2a Each independently is (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 2a Neither can be a heteroatom;

[0356] z1, z2, z3 and z4 are each independently C or N;

[0357] R1 and R2 are each independently H or F;

[0358] R3 at each occurrence is independently H or C1-C4 alkyl;

[0359] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0360] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0361] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0362] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0363] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0364] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0365] m, when present, is 1.

[0366] In certain embodiments, R 8d is H or halogen (such as F). In another embodiment, R 8d It is H or F.

[0367] In certain embodiments, the compound of Formula II has the structure of Formula IIa:

[0368]

[0369] or a pharmaceutically acceptable salt thereof.

[0370] In further embodiments, the compound of Formula II has the structure of Formula IIb:

[0371]

[0372] or a pharmaceutically acceptable salt thereof.

[0373] In further embodiments, the present invention relates to compounds of Formula II, IIa or IIb, or pharmaceutically acceptable salts thereof, wherein:

[0374] x1 is C=O or C(R1)(R2);

[0375] y 1a and y 2a Each independently is C(R 11 )2, O, N(R3) or S, provided that y 1a and y 2a Neither can be a heteroatom;

[0376] z1, z2, z3 and z4 are each independently C or N;

[0377] R1 and R2 are each independently H or F;

[0378] R3 is H or CH3;

[0379] R4, R5, R6 and R7 are each independently H, F, Cl, CH3 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N; and

[0380] R 11 is independently at each occurrence H, F, Cl, CH 3 or OCH 3 .

[0381] In certain embodiments, the compound of Formula I has the structure of Formula III:

[0382]

[0383] or a pharmaceutically acceptable salt thereof,

[0384] in:

[0385] B is a 5-7 membered saturated or partially saturated cycloalkyl or heterocyclic group;

[0386] x1 is C=O or C(R1)(R2);

[0387] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0388] is a single or double bond that satisfies all valences;

[0389] y 1a is a key, (C(R 11 )2) m, C=CH2, C=O, O, N(R3), S, S(O) or S(O)2;

[0390] when When it is a single bond, y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 2b Neither can be a heteroatom, and the condition is y 2b and y 2c Neither can be a heteroatom; or

[0391] when When it is a double bond, y 2b and y 2c are each independently C(R3) or N, provided that y 1a and y 2b Neither can be a heteroatom;

[0392] z1, z2, z3 and z4 are each independently C or N;

[0393] R1 and R2 are each independently H or F;

[0394] R3 at each occurrence is independently H or C1-C4 alkyl;

[0395] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0396] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0397] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0398] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0399] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0400] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0401] m is independently 1, 2 or 3 at each occurrence.

[0402] In certain such embodiments, R 8d is H or a halogen (such as F).

[0403] In other such embodiments, the compound of Formula I has the structure of Formula III, or a pharmaceutically acceptable salt thereof, wherein:

[0404] when When it is a single bond, y 2b and y 2c are each independently a bond, (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 2b Neither can be a key, conditional on y 1a and y 2b Neither can be a heteroatom, provided that y 2b and y 2c Neither can be a heteroatom, provided that y 2b and y 2c Neither can be C=O, and further condition is y 2b and y 2c Neither can be C=CH2; or

[0405] when When it is a double bond, y 2b and y 2c are each independently C(R3) or N, provided that y 1a and y 2b Neither can be a heteroatom.

[0406] In certain embodiments, the compound of Formula III has the structure of Formula IIIa:

[0407]

[0408] or a pharmaceutically acceptable salt thereof. In some such embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0409] Alternatively, the compound of Formula III has the structure of Formula IIIb:

[0410]

[0411] or a pharmaceutically acceptable salt thereof. In some such embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0412] Alternatively, the compound of Formula III has the structure of Formula IIIc:

[0413]

[0414] or a pharmaceutically acceptable salt thereof. In some such embodiments, B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

[0415] In further embodiments, the present invention relates to compounds of Formula III, IIIa, IIIb or IIIc, or pharmaceutically acceptable salts thereof, wherein:

[0416] x1 is C=O or C(R1)(R2);

[0417] y 1a It is C(R 11 )2, O, N(R3) or S;

[0418] is a single or double bond that satisfies all valences;

[0419] when When it is a single bond, y 2b and y 2c Each independently is C(R 11 )2, O, N(R3) or S, provided that y 1a and y 2b Neither can be a heteroatom, and further proviso that y 2b and y 2c Neither can be a heteroatom; or

[0420] when When it is a double bond, y 2b and y 2c are each independently C(R3) or N, provided that y 1a and y 2b Neither can be a heteroatom;

[0421] z1, z2, z3 and z4 are each independently C or N;

[0422] R1 and R2 are each independently H or F;

[0423] R3 is independently H or CH3 at each occurrence;

[0424] R4, R5, R6 and R7 are each independently H, F, Cl, CH3 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N; and

[0425] R 11 is independently at each occurrence H, F, Cl, CH 3 or OCH 3 .

[0426] In certain embodiments, the compound of Formula I has the structure of Formula IV:

[0427]

[0428] or a pharmaceutically acceptable salt thereof,

[0429] in:

[0430] x1 is C=O or C(R1)(R2);

[0431] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0432] y 1b and y 1c Each independently is (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1b and y 1c Neither can be C=CH2, and further condition is y 1b and y 1c Neither can be C=O;

[0433] z1, z2, z3 and z4 are each independently C or N;

[0434] R1 and R2 are each independently H or F;

[0435] R3 at each occurrence is independently H or C1-C4 alkyl;

[0436] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0437] R 8ais H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0438] R 8d is H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0439] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0440] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0441] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0442] m, when present, is 1.

[0443] In certain embodiments, R 8d is H or a halogen (such as F).

[0444] In certain embodiments, the compound of Formula IV has the structure of Formula IVa:

[0445]

[0446] or a pharmaceutically acceptable salt thereof.

[0447] Alternatively, the compound of Formula IV has the structure of Formula IVb:

[0448]

[0449] or a pharmaceutically acceptable salt thereof.

[0450] Alternatively, the compound of Formula IV has the structure of Formula IVc:

[0451]

[0452] or a pharmaceutically acceptable salt thereof.

[0453] In certain embodiments, the compound of Formula I has the structure of Formula V:

[0454]

[0455] or a pharmaceutically acceptable salt thereof,

[0456] in:

[0457] x1 is C=O or C(R1)(R2);

[0458] x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2;

[0459] y 1a 、y 1b and y 1c Each independently is (C(R 11 )2) m , C=CH2, C=O, O, N(R3), S, S(O) or S(O)2, provided that y 1a and y 1b Neither can be a heteroatom, provided that y 1b and y 1c Neither can be a heteroatom, provided that y 1a and y 1b Neither can be C=CH2, provided that y 1b and y 1c Neither can be C=CH2, provided that y 1a and y 1b Neither can be C=O, and further condition is y 1b and y 1c Neither can be C=O;

[0460] z1, z2, z3 and z4 are each independently C or N;

[0461] R1 and R2 are each independently H or F;

[0462] R3 at each occurrence is independently H or C1-C4 alkyl;

[0463] R4, R5, R6 and R7 are each independently H, OH, F, Cl, Br, N(R3)2, CF3, CH3, OCFH2 or OCH3, or each of R4, R5, R6 and R7 is absent when the z to which they are attached is N;

[0464] R 8a is H, C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each C1-C4 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R9;

[0465] R 8dis H, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, hydroxyalkyl or C(O)N(R3)2;

[0466] R9 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally replaced by one or more R 10 replace;

[0467] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl;

[0468] R 11 is independently at each occurrence H, F, Cl, C1-C3 alkyl, or OCH3; and

[0469] m, when present, is 1.

[0470] In certain embodiments, R 8d is H or halogen (such as F).

[0471] In certain embodiments, the compound of Formula V has the structure of Formula Va:

[0472]

[0473] or a pharmaceutically acceptable salt thereof.

[0474] Alternatively, the compound of Formula V has the structure of Formula Vb:

[0475]

[0476] or a pharmaceutically acceptable salt thereof.

[0477] Alternatively, the compound of Formula V has the structure of Formula Vc:

[0478]

[0479] or a pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the present invention relates to any compound described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0481] R 8a is a C1-C3 alkyl group substituted with one R9;

[0482] R9 is cycloalkyl, heterocyclyl, aryl or heteroaryl, and cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by one or more R10 Replacement; and

[0483] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl.

[0484] In some embodiments, the present invention relates to a compound of Formula Id, IIa, IIIa, IIIb or IIIc, or a pharmaceutically acceptable salt thereof, wherein:

[0485] R 8a is a C1-C3 alkyl group substituted with one R9;

[0486] R9 is cycloalkyl, heterocyclyl, aryl or heteroaryl, and cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally replaced by one or more R 10 Replacement; and

[0487] R 10 is independently at each occurrence halogen, hydroxy, C1-C3 alkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, or hydroxyalkyl.

[0488] In some aspects, the C1-C3 alkyl group is a methylene group. 8d 、R 8e , R9 or R 11 When they are C1-C3 alkyl groups, they may each independently be a methylene group.

[0489] In some aspects, R8 is C1-C3 alkyl, and C1-C3 alkyl is methylene.

[0490] In some aspects, R9 is replaced by an R 10 substituted heterocyclic group, and R 10 It's methyl.

[0491] In some aspects, the heterocyclyl group is pyrrolidine and the N atom of the pyrrolidine is substituted with methyl.

[0492] In some embodiments, the present invention relates to a compound of Formula IIa or IIb, or a pharmaceutically acceptable salt thereof, wherein:

[0493] x1 is C=O or C(R1)(R2);

[0494] y 1a It is CH2;

[0495] y 2a It is C(R 11 )2, O, N(R3) or S;

[0496] z1, z2, z3 and z4 are each C;

[0497] R1 and R2 are H;

[0498] R3 is H or CH3;

[0499] R4, R5, R6 and R7 are each independently H, F, Cl, CH3 or OCH3; and

[0500] R 11 is independently H, CH3 or OCH3 at each occurrence.

[0501] In some aspects, y 2a It is C(R 11 )2, and R 11 In one occurrence it is H and in another occurrence it is H, CH 3 or OCH 3 .

[0502] In another aspect, y 2a It's O.

[0503] In a further aspect, y 2a is N(R3) and R3 is H.

[0504] In a still further aspect, y 2a It’s S.

[0505] In some embodiments, the present invention relates to a compound of Formula IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt thereof, wherein:

[0506] It is a single bond;

[0507] x1 is C=O or C(R1)(R2);

[0508] y 1a It is C(R 11 )2, O, N(R3) or S;

[0509] y 2b and y 2c Each independently is C(R 11 )2, O, N(R3) or S, provided that y 1a and y 2b Neither can be a heteroatom, and further proviso that y 2b and y 2c Neither can be a heteroatom;

[0510] z1, z2, z3 and z4 are each independently C;

[0511] R1 and R2 are H;

[0512] R3 is independently H or CH3 at each occurrence;

[0513] R4, R5, R6 and R7 are each independently H, F, Cl, CH3 or OCH3; and

[0514] R 11 is independently H, CH3 or OCH3 at each occurrence.

[0515] In some aspects, y 1a It is C(R 11 )2, and R 11 In one occurrence it is H and in another occurrence it is H, CH 3 or OCH 3 .

[0516] In some aspects, y 1a It's O.

[0517] In some aspects, y 1a It is N(R3).

[0518] In some aspects, y 1a It’s S.

[0519] In another aspect, y 2b It is C(R 11 )2, and y 2c is O, N(R3) or S.

[0520] In some aspects, y 2b It is C(R 11 )2, and R 11 In one occurrence it is H and in another occurrence it is H, CH 3 or OCH 3 .

[0521] In a further aspect, y 2c It's O.

[0522] In a further aspect, y 2c It is N(R3).

[0523] In a further aspect, y 2c It’s S.

[0524] In another aspect, y 2b is O, N(R3) or S, and y 2c It is C(R 11 )2.

[0525] In some aspects, y 2c It is C(R 11 )2, and R 11 In one occurrence it is H and in another occurrence it is H, CH 3 or OCH 3 .

[0526] In a further aspect, y 2b It's O.

[0527] In a further aspect, y 2b It is N(R3).

[0528] In a further aspect, y 2b It’s S.

[0529] In further embodiments, the present invention relates to a compound of formula IIIa, IIIb or IIIc (eg, IIIa), or a pharmaceutically acceptable salt thereof, wherein:

[0530] B is a 6-membered saturated cycloalkyl or heterocyclic group;

[0531] x1 is C(R1)(R2);

[0532] It is a single bond;

[0533] y 1a Yes (C (R 11 )2) m ;

[0534] y 2b Yes (C (R 11 )2) m ;

[0535] y 2c Yes (C (R 11 )2) m or N(R3);

[0536] z1, z2, z3 and z4 are each C;

[0537] R1 and R2 are each independently H;

[0538] R3 at each occurrence is independently C1-C4 alkyl;

[0539] R4, R5, R6 and R7 are each independently H, F or CH3;

[0540] R 11 is H independently at each occurrence; and

[0541] m is independently 1 at each occurrence.

[0542] In a further aspect, the compound has about 1000 M -1 s -1 or larger KRASG12C k obs / [i].

[0543] In a further aspect, the compound has an average IC greater than 1000 nM against the drug-resistant cell lines of Table 5.50 .

[0544] In a further aspect, the compound has an average IC of about 1000 nM or less against the drug-sensitive cell lines of Table 5. 50 .

[0545] In some embodiments, the present invention relates to a compound of Formula I, II, IIa, III, IIIa or IIIb, or a pharmaceutically acceptable salt thereof, wherein x1 is C=O or C(R1)(R2), R1 and R2 are H, and z1, z2, z3 and z4 are each C.

[0546] In some embodiments, the present invention relates to a compound of Formula Id, IIa, IIb, IIIa, IIIb or IIIc, or a pharmaceutically acceptable salt thereof, wherein x1 is C=O or C(R1)(R2), R1 and R2 are H, and z1, z2, z3 and z4 are each C.

[0547] In further embodiments, the invention relates to a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, wherein x1 is C═O or C(R1)(R2), R1 and R2 are H, and z1, z2, z3 and z4 are each C.

[0548] In some embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic, III, IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered cycloalkyl.

[0549] In some embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic, III, IIIa, IIIb or IIIc, or a pharmaceutically acceptable salt thereof, wherein B is a 5- or 6-membered heterocyclyl. In some aspects, the 5- or 6-membered heterocyclyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, sulfolane, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, thiomorpholinyl, dioxythiomorpholinyl, morpholinyl, 1,4-dithianyl, thianyl, lactamyl and lactonyl.

[0550] In some embodiments, x2 is O.

[0551] In further embodiments, when R3 is C1-C4 alkyl, the C1-C4 alkyl is methyl or ethyl.

[0552] In some embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic, II, III, IV or V, or a pharmaceutically acceptable salt thereof, wherein R8d is F. In some aspects, the present invention relates to a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, wherein R 8b In a further aspect, the present invention relates to a compound of formula I or Ia, or a pharmaceutically acceptable salt thereof, wherein R 8c It is H and R 8e It’s H.

[0553] In further embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, wherein R 11 is C1-C3 alkyl. In a further aspect, C1-C3 alkyl is methyl or ethyl.

[0554] In some embodiments, the present invention relates to a compound of Formula I, Ia, Ib, Ic, Id, III, IIIa, IIIb, or IIIc, or a pharmaceutically acceptable salt thereof, wherein m is 1 at each occurrence.

[0555] In some embodiments, the present invention relates to a compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, wherein R 8d is H, F, methyl, ethyl, OCH3, CH2OH or CH2OCH3, and R 8e is H, methyl, ethyl, F, CF3, CF2H or CH2F.

[0556] In further embodiments, the present invention relates to compounds of Formula Ib, Ic, II, III, IV or V, or pharmaceutically acceptable salts thereof, wherein R 8d It is H, F, methyl, ethyl, OCH3, CH2OH or CH2OCH3.

[0557] In some aspects, the present invention relates to a compound of Formula I having a structure selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0558] In particular aspects, the compound is selected from Compound 1 to Compound 50, or a pharmaceutically acceptable salt thereof.

[0559] In a particular aspect, the compound is selected from Compound 1 to Compound 33, or a pharmaceutically acceptable salt thereof.

[0560] In another aspect, the compound is selected from compounds 7, 9, 11, 13, 14, 17, 21, 22, 25, 26, 27, 29, 30, 31, 33, 35, 36, 42, 44, 46, 47, 50, 51, 55, 58, 63, 70, 71, 73, 77, 87, 88, 91, 93, 95, 96, 98, 99 and 100, or a pharmaceutically acceptable salt thereof.

[0561] In a further aspect, the compound is selected from compounds 7, 9, 11, 13, 17, 21, 22, 25, 26, 30, 31, 33, 35, 36, 42, 44, 46, 47, 50, 51, 55, 58, 63, 70, 71, 73, 77, 87, 88, 91, 93, 95, 96, 98, 99 and 100, or a pharmaceutically acceptable salt thereof.

[0562] In some aspects, the present invention relates to a compound of Formula I having a structure selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0563] In a further aspect, the present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of:

[0564]

[0565]

[0566]

[0567]

[0568]

[0569] .

[0570] In a further aspect, the present invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof having a structure selected from the group consisting of:

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] .

[0577] In some aspects, the present invention relates to a compound having a formula IIIa selected from the following structures, or a pharmaceutically acceptable salt thereof:

[0578]

[0579] .

[0580] In certain embodiments, the present invention relates to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient.

[0581] Example Methods of Treatment / Use

[0582] The compounds described herein are inhibitors of KRAS G12C and are therefore useful in treating diseases in which the underlying pathology is mediated, at least in part, by KRAS G12C. Such diseases include cancer and other diseases in which there are disorders of transcription, cell proliferation, apoptosis, or differentiation.

[0583] In certain embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject an effective amount of any compound described herein or a pharmaceutically acceptable salt thereof. For example, the cancer can be selected from carcinoma (e.g., endometrial cancer, bladder cancer, breast cancer, colon cancer (e.g., colorectal cancer, such as colon adenocarcinoma and colon adenoma)), sarcoma (e.g., sarcoma such as Kaposi's tumor, osteosarcoma, tumors of mesenchymal origin (e.g., fibrosarcoma or rhabdomyosarcoma)), kidney, epidermis, liver, lung (e.g., ， adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), esophagus, gallbladder, ovary, pancreas (e.g. ， Examples of cancers that can be treated with the compounds of the present invention include hematopoietic tumors of the lymphoid lineage (e.g., leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma), and myeloid hematopoietic tumors, such as acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia. Other cancers include central or peripheral nervous system tumors, such as astrocytomas, neuroblastomas, gliomas, or schwannomas; seminoma; teratoma; xeroderma pigmentosum; retinoblastoma; keratoacanthoma; and follicular thyroid carcinoma.

[0584] In certain embodiments, the cancer treated is selected from pancreatic cancer, gallbladder cancer, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gallbladder cancer, and bile duct cancer.

[0585] In other specific embodiments, the cancer treated is selected from pancreatic cancer, colorectal cancer, and lung cancer (including non-small cell lung cancer).

[0586] In some aspects, the subject is a mammal, such as a human.

[0587] Further disclosed herein are methods for inhibiting KRAS G12C in a cell, comprising contacting the cell with any compound described herein or a pharmaceutically acceptable salt thereof, thereby inhibiting the KRAS G12C enzyme in the cell. For example, the cell is a cancer cell. In preferred embodiments, cell proliferation is inhibited or cell death is induced.

[0588] Further disclosed herein are methods for treating a disease treatable by KRAS G12C inhibition in a subject, comprising administering to a subject in need of such treatment an effective amount of any compound described herein and / or a pharmaceutically acceptable salt thereof. Diseases treatable by KRAS G12C inhibition include, for example, cancer. Other exemplary diseases include pancreatic cancer, gallbladder cancer, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gallbladder cancer, and bile duct cancer.

[0589] The method of treatment comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable salt thereof. Individual embodiments include methods of treating any of the aforementioned conditions or diseases by administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0590] Certain embodiments include methods of modulating KRAS G12C activity in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof. Additional embodiments provide methods of treating a condition or disease mediated by KRAS G12C in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof. Other embodiments of the present invention provide methods of treating a condition or disease mediated by KRAS G12C in a subject in need thereof, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the condition or disease is selected from cancers having genetic aberrations that activate KRAS activity. These include, but are not limited to, cancer.

[0591] The present method also provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for treating a condition or disease mediated by KRAS G12C.

[0592] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat a condition or disease mediated by KRASG12C.

[0593] Still other embodiments of the present method provide a compound according to Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0594] Still other embodiments of the present method include use of a compound of Formula I, Ia, Ib, Ic, Id, II, IIa, IIb, III, IIIa, IIIb, IIIc, IV, IVa, IVb, IVc, V, Va, Vb or Vc, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a condition or disease mediated by KRAS G12C.

[0595] Example Example of Predicted Affinity of Compounds for KRAS G12C

[0596] Covalent KRAS G12C inhibitor MRTX1257:

[0597]

[0598] MRTX1257 is known in the art to be potent and selective and has been shown to have desirable pharmacokinetic properties. MRTX1257 has also been shown to have desirable efficacy in xenograft models of cancer.

[0599] Compounds were covalently docked into a modified version of the KRAS G12C protein (PDB accession code 6N2K) using a covalent docking protocol implemented in the computer program MOE version 2019.0101 (Molecular Operating Environment, Chemical Computing Group, Montreal, CA). The receptor geometry was generated by minimizing the binding site residues of 6N2K in the presence of MRTX1257. Estimated binding affinity (in arbitrary units) was calculated for each compound covalently docked into this modified receptor, where more negative values correspond to higher estimated predicted affinity. See Table 1. The predicted binding affinity of MRTX1257 at this receptor is -10.7148.

[0600] Compounds of particular interest were covalently docked into the published KRAS G12C crystal structure (PDB accession code 6N2K) using the CovDock covalent docking module in the Schrödinger Computational Chemistry Suite (v. 2020-1, Schrödinger, LLC, New York, NY). Predicted docking scores and estimated binding affinities ("MMGBSA" and "CovDock") are provided (in arbitrary units), with more negative values corresponding to greater predicted affinity. See Table 2.

[0601] Example compounds

[0602] Specific embodiments of the invention include those compounds listed in Table 1. Disclosed for each compound is an identification number ("Compound"), a chemical structure ("Structure"), and a predicted binding affinity (in arbitrary units, AU) for KRAS G12C ("Score").

[0603] Additional specific embodiments of the invention include those compounds listed in Table 2. Disclosed for each compound is an identification number ("Compound"), a chemical structure ("Structure"), and the predicted binding affinity (in arbitrary units, AU) to KRAS G12C from two different methods ("MMGBSA" and "CovDock") ("Score").

[0604] Specific embodiments of the present invention include those compounds listed in Table 3. Disclosed for each compound is an identification number ("Compound"), a chemical structure ("Structure"), and an example method used to synthesize the compound ("Method").

[0605] Incorporated by Reference

[0606] All publications and patents mentioned herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0607] Equivalent objects

[0608] While specific embodiments of the present invention have been discussed, the foregoing description is illustrative and not restrictive. Numerous variations of the present invention will become apparent to those skilled in the art upon reading this specification and the claims that follow. The full scope of the present invention should be determined by reference to the claims and their full scope of equivalents, the specification, and such variations.

[0609] Example

[0610] Synthesis scheme

[0611] The compounds disclosed herein can be synthesized by a variety of specific methods. The examples outlining specific synthetic routes and the general schemes below are intended to provide guidance to the ordinary synthetic chemist, who will readily appreciate that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, times, temperatures, etc. can be modified as needed within the skill and judgment of those skilled in the art.

[0612] Example 1: Synthesis of Tetralin, Tetrahydroquinoline and Chromane-functionalized Compounds

[0613] Preparation of intermediate 1-1

[0614]

[0615] The starting material, 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.288 g, 6.34 mmol) was dissolved in tetrahydrofuran (25 mL) and transferred to lithium diisopropylamide (7.3 mmoles, 0.5 M solution in tetrahydrofuran / hexane, prepared by diisopropylamine / n After 120 minutes, a solution of tetrachlorodibromoethane (2.68 g, 76.30 mmol) in tetrahydrofuran (15 mL) was added rapidly via cannula.

[0616] At 40 DEG C, 8-bromo-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (412.3 mg, 23% yield) was added to the bromo-2-of 1-1-ol (5-nitro-1-oxo-2-nitro-3-oxo-4-nitro-3-oxo-5-nitro-3-oxo-2-nitro-3-oxo-3-oxo-4 ...

[0617] 1 H NMR (400 MHz, chloroform-d) δ 5.24 (td, J = 3.3, 2.6, 1.3 Hz, 1H), 3.05–2.94 (m, 1H), 2.71 (ddd, J = 18.2, 11.3, 6.7 Hz, 1H), 2.48–2.36 (m, 1H),2.32–2.20 (m, 1H), 2.17 (dtd, J = 14.6, 2.6, 1.4 Hz, 1H), 2.09–2.00 (m, 1H)ppm

[0618] LCMS: [M+H] + m / z = 280.9 amu.

[0619] Preparation of intermediate 1-2

[0620]

[0621] Under a nitrogen atmosphere, acetonitrile (2 mL) was added to a vial containing 8-bromo-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (52.3 mg, 0.186 mmol) and silver (I) nitrate (47.6 mg, 0.28 mmol). The reaction was warmed to 50°C and stirred for 8 hours, at which point TLC analysis indicated consumption of the starting material. Silica gel was added and the solvent removed in vacuo to yield a white powder. Purification by flash chromatography (0-30% EtOAc / hexanes) provided the intermediate 1-2,2,4-dichloro-5,6,7,8-tetrahydroquinazolin-8-yl nitrate as a white solid.

[0622] 1 H NMR (400 MHz, chloroform- d ) δ 6.00 (dd, J = 5.7, 4.6 Hz, 1H), 2.93 –2.81 (m, 1H), 2.72 (ddd, J = 18.1, 7.7, 6.2 Hz, 1H), 2.34 – 1.92 (m, 4H)ppm

[0623] LCMS: [M+H] + m / z = 264.0 amu.

[0624] Preparation of intermediate 1-3

[0625]

[0626] A solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazolin-8-yl nitrate in toluene (0.025 M) was treated with triethylamine (50% vol / vol). The reaction was stirred at ambient temperature for 90 minutes and concentrated onto silica gel. Flash chromatography was performed using differential refractive index detection (0-50% hexane / EtOAc). Product fractions were combined and concentrated to yield the intermediate 1-3,2,4-dichloro-6,7-dihydroquinazolin-8(5H)-one as a white solid.

[0627] 1 H NMR (400 MHz, chloroform-d) δ 1 H NMR (400 MHz, chloroform- d ) δ 3.05 (t,J = 6.2Hz, 2H), 2.91–2.76 (m, 2H), 2.38–2.16 (m, 2H) ppm

[0628] LCMS: [M+H] + m / z = 217.0 amu.

[0629] Preparation of intermediate 1-4

[0630]

[0631] Preparation of intermediate 1-5

[0632]

[0633] Preparation of tetralin-functionalized compounds

[0634]

[0635] The catalyst used in the Tsuji step can be selected in the R or S configuration to produce an enantiomerically enriched product at the quaternary stereocenter. As will be appreciated by one of ordinary skill in the art, exocyclic olefins can be transformed in a variety of ways to produce analogs of the compound.

[0636] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, OH, CH 3 or OCH 3 , R, at each occurrence and if present, is independently Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0637] Furthermore, the ketone of cyclohexanone in the compounds obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0638] Preparation of tetrahydroquinoline-functionalized compounds

[0639]

[0640] The catalyst for the Tsuji step can be selected in the R or S configuration to produce an enantiomerically enriched product at the quaternary stereocenter.The amine in the tetrahydroquinoline can be substituted with an optionally substituted alkyl group using procedures readily apparent to one of ordinary skill in the art.

[0641] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, CH 3 or OCH 3 , R is independently at each occurrence and when present, Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0642] Furthermore, the ketone of cyclohexanone in the compounds obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0643] Preparation of chromane-functionalized compounds

[0644]

[0645] The catalyst used in the Tsuji step can be selected in the R or S configuration to produce an enantiomerically enriched product at the quaternary stereocenter.

[0646] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, CH 3 or OCH 3 , R is independently at each occurrence and when present, Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0647] Furthermore, the ketone of cyclohexanone in the compounds obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0648] Preparation of thiochromane-functionalized compounds

[0649]

[0650] The catalyst used in the Tsuji step can be selected in the R or S configuration to produce an enantiomerically enriched product at the quaternary stereocenter.

[0651] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, CH 3 or OCH 3 , R is independently at each occurrence and when present, Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0652] Furthermore, the ketone in the compound obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0653] Preparation of benzomorpholine-functionalized compounds

[0654]

[0655] Compounds obtained using this synthetic route include, but are not limited to, those wherein R, at each occurrence and when present, is independently Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0656] Furthermore, the amine in the morpholine can be substituted with an optionally substituted alkyl group using procedures readily apparent to those skilled in the art. Furthermore, the ketone in the compound obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those skilled in the art.

[0657] Example 2: Synthesis of indane-functionalized compounds

[0658]

[0659] The synthesis produces a racemic mixture and separation of the enantiomers using chiral HPLC or SFC chromatography under optimized conditions can be readily achieved by one of ordinary skill in the art.

[0660] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, CH 3 or OCH 3 , R is independently at each occurrence and when present, Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0661] Furthermore, the ketone of cyclohexanone in the compounds obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0662] Example 3: Synthesis of Coumarin Functionalized Compounds

[0663]

[0664] The synthesis produces a racemic mixture and separation of the enantiomers using chiral HPLC or SFC chromatography under optimized conditions can be readily achieved by one of ordinary skill in the art.

[0665] Compounds obtained using this synthetic route include, but are not limited to, those wherein X is H, Cl, F, CH 3 or OCH 3 , R is independently at each occurrence and when present, Cl, F, CH 3 or OCH 3 , and n is 0, 1 or 2. Other substituents for X and R will be apparent to those skilled in the art, particularly those found in the commercially available molecules used in the first step of this synthesis.

[0666] Furthermore, the ketone of cyclohexanone in the compounds obtained using this synthetic route can be converted to C(H)OH, CH2, OCH3, C(H)F or CF2 using procedures known to those of ordinary skill in the art.

[0667] Example 4: Synthesis of compounds C-1 to C-8, C-15 and C-16

[0668] Synthesis of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline

[0669]

[0670] A solution of 5,6,7,8-tetrahydroquinazoline-2,4-diol (750 g, 4.51 mol) in POCl3 (3.30 kg, 21.5 mol) was stirred at 110°C for 4 hours. TLC (dichloromethane / methanol = 10 / 1) indicated that 5,6,7,8-tetrahydroquinazoline-2,4-diol had been completely consumed. TLC (petroleum ether / ethyl acetate = 3 / 1, R f = 0.66), indicating the formation of a new spot. The reaction mixture was cooled to 15°C and then diluted with ethyl acetate (2000 mL). The organic phase was quenched with ice water (6000 mL) and adjusted to pH = 8 with solid NaHCO₃, then extracted with ethyl acetate (2000 mL*2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to obtain the crude product. The residue was purified by flash silica gel chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (230 g, 1.11 mol, 25% yield) as a white solid.

[0671] 1 H NMR (400 MHz, chloroform- d ) δ 2.95 - 2.80 (m, 2H), 2.75 - 2.65 (m, 2H), 1.90 - 1.84 (m, 4H) ppm

[0672] LC / MS: [M+H] + m / z = 203.4 amu.

[0673] Alternative synthesis of intermediate 1-1

[0674]

[0675] To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (150 g, 664 mmol) in THF (600 mL) at -70°C was added LDA (2 M, 499 mL). The mixture was stirred at -70°C for 30 minutes. The mixture was added to a solution of tetrachlorodibromoethane (325 g, 997 mmol, 120 mL) in THF (2.80 L) at -70 to -40°C and stirred at -40°C for 1 hour. LCMS indicated the reaction was complete. The mixture was poured into saturated NH4Cl solution (8.00 L) with stirring at 0°C, then stirred at 0°C for 30 minutes. The mixture was extracted with ethyl acetate (5.00 L x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 500 / 1 to 20 / 1) to give intermediate 1-1,8-bromo-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (182 g, 512 mmol, 26% yield) as an off-white solid.

[0676] LC / MS: [M+H] + m / z = 282.9 amu.

[0677] Synthetic intermediate 4-1

[0678]

[0679] To a solution of 8-bromo-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (90.0 g, 253 mmol) in dioxane (1200 mL) and H2O (1000 mL) was added CaCO3 (76.1 g, 760 mmol) at 25°C, and the reaction was stirred at 130°C for 48 hours. LCMS showed 35% of intermediate 1-1 remaining and 47% of the desired mass was detected. Ethyl acetate (3000 mL) was added to the reaction and stirred for 10 minutes. The reaction was filtered, and the filtrate was washed with brine (2000 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give intermediate 4-1,2,4-dichloro-5,6,7,8-tetrahydroquinazolin-8-ol (60.0 g, 268 mmol, 53% yield) as a yellow oil.

[0680] 1 H NMR (400 MHz, chloroform- d ) δ 4.67 - 4.61 (m, 1H), 3.87 (d, J = 2.4 Hz,1H), 2.80 - 2.65 (m, 2H), 2.24 - 2.16 (m, 1H), 2.11 - 2.02 (m, 1H), 1.87 -1.72 (m, 2H) ppm

[0681] LCMS: [M+H] + m / z = 218.8 amu.

[0682] Alternative synthesis of intermediates 1-3

[0683]

[0684] To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline-8-ol (50.0 g, 223 mmol) in DCM (1000 mL) was added DMP (142 g, 335 mmol) at 25 ° C, and the reaction was stirred at 25 ° C for 1 hour. LCMS showed that the reaction was complete. Water (500 mL) was added to the mixture, adjusted to about pH = 9 by gradually adding NaHCO3 solution, and extracted with DCM (300 mL * 2). The combined organic phases were washed with Na2SO3 solution (1000mL * 2), brine (1000mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give intermediate 1-3, 2,4-dichloro-6,7-dihydroquinazoline-8 (5 H )-ketone (26.0 g, 119 mmol, 53% yield) as a yellow solid.

[0685] 1 H NMR (400 MHz, chloroform- d ) δ 3.05 (t, J = 6.0 Hz, 2H), 2.84 (t, J = 6.4Hz, 2H), 2.31 - 2.24 (m, 2H) ppm

[0686] LCMS: [M+H] + m / z = 217.0 amu.

[0687] Synthetic intermediate 4-2

[0688]

[0689] To 2,4-dichloro-6,7-dihydroquinazoline-8(5 H To a cooled (0 °C) solution of )-ketone (2.00 g, 9.21 mmol) in DCM (37 mL) was added triethylamine (6.4 mL, 46.01 mmol), followed by ( S)-2-(piperazin-2-yl)acetonitrile·2HCl (1.49 g, 9.21 mmol). The resulting solution was stirred at 0°C for 2 hours. After the starting material was consumed, di-tert-butyl dicarbonate (4.02 g, 18.43 mmol) was added and the reaction was heated to 40°C and stirred for 1.5 hours. The reaction mixture was cooled to room temperature and diluted with H2O (50 mL) and extracted with DCM (40 mL * 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0→10% MeOH in DCM) to give intermediate 4-2, ( S )-tert-butyl 4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (3.01 g, 7.41 mmol, 80% yield) as a yellow solid.

[0690] 1 H NMR (400 MHz, chloroform- d ) δ 4.59 (td, J = 7.2, 6.8, 3.3 Hz, 1H), 4.13(dt, J = 14.0, 2.3 Hz, 1H), 4.05 (s, 1H), 4.03 – 3.94 (m, 1H), 3.42 (dd, J =13.9, 4.0 Hz, 1H), 3.26 (s, 1H), 3.17 (td, J = 12.1, 3.4 Hz, 1H), 2.89 – 2.80(m, 2H), 2.80 – 2.71 (m, 3H), 2.71 – 2.60 (m, 1H), 2.21 – 2.02 (m, 2H), 1.49(s, 9H) ppm

[0691] LCMS: [M+H] + m / z = 406.1 / 408.1 amu.

[0692] Synthesis of compound C-1

[0693]

[0694] To contain ( STo a vial of tert-butyl 4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (300 mg, 0.74 mmol) and 1,2-bis(bromomethyl)benzene (195 mg, 0.74 mmol) in THF (7.2 mL) was added potassium tert-butoxide (183 mg, 1.63 mmol). The reaction was stirred at room temperature overnight. Upon completion, saturated NH4Cl (15 mL, aq.) was added and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel using flash column chromatography (20→100% EtOAc in hexane) to give ( S )-4-(2'-chloro-8'-oxo-1,3,5',8'-tetrahydro-6' H -butyl spiro[indene-2,7'-quinazoline]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate (151 mg, 0.30 mmol, 40% yield) as an orange oil.

[0695] 1 H NMR (400 MHz, chloroform- d ) δ 7.38 (dd, J = 7.4, 1.4 Hz, 1H), 7.28 (td, J = 7.5, 1.3 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 4.05 (s, 1H), 3.56 (dddd, J = 15.7, 9.6, 6.4, 2.6 Hz, 4H), 3.50 – 3.40 (m,2H), 3.35 (ddd, J = 12.5, 7.2, 2.9 Hz, 2H), 3.22 (dd, J = 15.9, 7.2 Hz, 1H),2.85 (ddd, J = 16.9, 11.8, 5.5 Hz, 1H), 2.76 (dd, J = 12.8, 7.5 Hz, 1H), 2.57(dd, J= 16.3, 1.8 Hz, 2H), 2.02 – 1.93 (m, 1H), 1.64 – 1.49 (m, 2H), 1.47(s, 9H) ppm

[0696] LCMS: [M+H] + m / z = 508.2 / 510.2 amu.

[0697] To a cooled (0°C) vial containing NaH (14 mg, 0.35 mmol, 60% dispersion in mineral oil) was added THF (0.5 mL) followed by ( S )-(1-methylpyrrolidin-2-yl)methanol (90 µL, 0.74 mmol). The mixture was stirred for 45 minutes, at which time ( S )-4-(2'-chloro-8'-oxo-1,3,5',8'-tetrahydro-6' H -spiro[indene-2,7'-quinazoline]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.15 mmol). The mixture was warmed to room temperature and stirred for 3 hours. After completion, the reaction was quenched with saturated NH4Cl (5 mL, aq.) and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product ( S )-2-(cyanomethyl)-4-(2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6' H -tert-Butyl spiro[indene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.

[0698] LCMS: [M+H] + m / z = 587.3 amu.

[0699] To a solution containing the crude product ( S )-2-(cyanomethyl)-4-(2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6' HTo a vial of tert-butyl 2-spiro[indene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (30 mg, 0.05 mmol, est.) was added H3PO4 (20 µL, 0.33 mmol) dropwise. The reaction was stirred at room temperature for 3 hours, at which time H2O (1 mL) was added and the solution was made basic by the slow addition of 2 M NaOH solution (aq.). Once basic, the mixture was extracted with DCM (2 mL x 3), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product 2-(( S )-4-(2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6' H -spiro[indene-2,7'-quinazoline]-4'-yl)piperazin-2-yl) was used in the next step without further purification.

[0700] LCMS: [M+H] + m / z = 487.3 amu.

[0701] To the crude product 2-(( S )-4-(2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6' H To a cooled (0°C) solution of 2-(1-spiro[indene-2,7'-quinazoline]-4'-yl)piperazin-2-yl) (25 mg, 0.05 mmol, est.) in DCM (0.6 mL) was added triethylamine (70 µL, 0.51 mmol) followed by a 0.2 M solution of prop-2-enoyl chloride (1.02 mL, 0.20 mmol) in DCM. The mixture was warmed to room temperature and stirred for 1.5 hours, at which time the solution was concentrated, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→50% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to yield compound C-1, 2-(( S )-1-acryloyl-4-(2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6' H -spiro[indene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (4.4 mg, 1.12 mmol, 20% yield over 3 steps) as a light brown solid.

[0702] 1H NMR (400 MHz, DMSO- d 6, TFA salt) δ 10.39 (bs, 1H), 7.28 – 7.11 (m,4H), 6.87 (s, 1H), 6.61 (bs, 3H), 6.20 (dd, J = 16.7, 2.3 Hz, 1H), 5.79 (dd, J = 10.4, 2.3 Hz, 1H), 4.66 (ddd, J = 12.8, 9.1, 2.7 Hz, 1H), 4.49 (ddd, J =13.0, 6.4, 2.6 Hz, 1H), 4.17 – 3.97 (m, 2H), 3.76 (bs, 2H), 3.45 – 3.06 (m,8H), 3.06 – 2.86 (m, 5H), 2.30 – 1.92 (m, 4H), 1.92 – 1.75 (m, 2H) ppm

[0703] LCMS: [M+H] + m / z = 541.3 amu.

[0704] Synthesis of compound C-2

[0705]

[0706]

[0707] 1-Bromo-2,3-bis(bromomethyl)benzene (127 mg, 0.37 mmol) and intermediate 4-2 (150 mg, 0.37 mmol) were dissolved in anhydrous THF (7.4 mL) and treated with KOtBu (124 mg, 1.11 mmol). The mixture was stirred for 9 hours and then partitioned between EtOAc and H2O. The organic phase was collected and washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (10→30% EtOAc in hexanes) to give (2 S )-tert-Butyl 4-(4-bromo-2'-chloro-8'-oxo-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate (39.2 mg, 18% yield) was obtained as a light yellow film.

[0708] LCMS: [M+H] +m / z = 586.1 / 588.1 amu (1:1).

[0709] 1-Methyl-L-prolinol (21.78 mg, 0.19 mmol) was dissolved in anhydrous THF (400 µL) and treated with NaH (4.5 mg, 0.11 mmol). The mixture was aged for 30 minutes and then added to (2 S The mixture was stirred for 24 hours and then partitioned between EtOAc and 1:1 brine:1M NaOH. The organic phase was collected and washed with brine, dried over K2CO3, concentrated, and purified by flash column chromatography on silica gel (2→3% MeOH in DCM + 1% Et3N) to give (2 S )-4-(4-bromo-2'-((( S tert-Butyl 2-(cyanomethyl)piperazine-1-carboxylate (20.2 mg, 80% yield) was obtained as a light yellow film.

[0710] 1 H NMR (400 MHz, acetonitrile- d 3, major diastereomer) δ 7.60 – 7.57 (m, 1H),7.46 (dt, J = 7.6, 1.2 Hz, 1H), 7.20 – 7.10 (m, 1H), 4.58 (d, J = 4.4 Hz,1H), 4.35 (ddd, J = 21.3, 10.9, 5.0 Hz, 1H), 4.16 (dt, J = 11.0, 6.1 Hz, 1H),4.07 – 3.84 (m, 2H), 3.24 (dd, J = 13.6, 3.9 Hz, 1H), 3.09 – 2.96 (m, 4H),2.96 – 2.74 (m, 7H), 2.69 – 2.51 (m, 2H), 2.41 (s, 3H), 2.31 – 2.22 (m, 1H), 2.05 – 1.90 (m, 3H), 1.79 – 1.64 (m, 3H), 1.46 (d, J = 2.8 Hz, 9H) ppm

[0711] LCMS: [M+H] + m / z = 619.2 / 621.2 amu (1:1).

[0712] (2 S )-4-(4-bromo-2'-((( S tert-Butyl)-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl)-2-(cyanomethyl)piperazine-1-carboxylate was treated with HCl (4N in dioxane, 500 µL) and the mixture was aged at room temperature (RT) for 20 minutes and then concentrated. The residue was washed with anhydrous DCM (300 µL) and i The mixture was treated with Pr2EtN (53 µL, 0.30 mmol) and stirred at room temperature for 24 hours, then cooled to 0°C and treated with acrylic anhydride (4.2 µL, 0.04 mmol). After 15 minutes, the mixture was concentrated and purified by preparative HPLC (C18, 10→70% ACN in H2O + 0.25% TFA) to give compound C-2, 2-((2 S )-1-acryloyl-4-(4-bromo-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-1,3,5',8'-tetrahydro-6'H-spiro[indene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (2.8 mg, 15% yield) as a colorless film.

[0713] 1 H NMR (500 MHz, CDCl3) δ 7.57 (dt, J = 8.1, 1.4 Hz, 1H), 7.35 (dt, J = 7.4, 1.4 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.44 (dt, J = 17.3, 1.5 Hz,1H), 6.16 (ddd, J = 17.3, 10.4, 1.5 Hz, 1H), 5.86 (dt, J = 10.4, 1.5 Hz, 1H),4.34 (td, J = 4.8, 1.5 Hz, 2H), 4.24 (s, 1H), 3.78 (td, J= 4.9, 1.5 Hz, 4H),3.64 (td, J = 5.9, 1.5 Hz, 2H), 3.33 – 2.47 (m, 10H), 2.17 – 2.00 (m, 2H), 2.00 – 1.52 (m, 9H) ppm

[0714] LCMS: [M+H] + m / z = 619.2 / 621.2 amu (1:1).

[0715] Synthesis of compound C-3

[0716]

[0717] 2,4-Dichloro-6,7-dihydro-5H-quinazolin-8-one (1085 mg, 5 mmol) was dissolved in anhydrous DCM (20 mL) and the mixture was cooled to 0°C and then treated with tert-butyl piperazine-1-carboxylate (931 mg, 5 mmol) and Et3N (1.39 mL, 10 mmol). After 70 minutes, the mixture was diluted with DCM and washed with half-saturated NaHCO3, brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (2→4% MeOH in DCM) to give tert-butyl 4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxylate (1.811 g, 4.94 mmol, 99% yield) as a light yellow foam (Rf = 0.34 (96:4 CHCl3:MeOH)).

[0718] 1 H NMR (500 MHz, chloroform- d ) δ 3.60 – 3.52 (m, 8H), 2.81 – 2.73 (m, 4H), 2.15 – 2.07 (m, 2H), 1.49 (s, 9H) ppm

[0719] LCMS: [M+H] + m / z = 367.1 / 369.1 amu (3:1).

[0720] Tert-butyl 4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)piperazine-1-carboxylate (500 mg, 1.36 mmol) was dissolved in anhydrous THF (6.8 mL), then cooled to -78°C and treated with LiHMDS, 1.0 M in THF (1.77 mL, 1.77 mmol), followed by allyl cyanoformate (269 µL, 2.04 mmol). The mixture was stirred for 1 hour, then quenched with saturated NH4Cl and partitioned between saturated NH4Cl and EtOAc. The organic phase was collected and washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (0→50% EtOAc in hexanes) to afford allyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (436.8 mg, 0.969 mmol, 71% yield) as a light yellow foam (Rf = 0.29 (7:3 hexanes:EtOAc + 1% AcOH)).

[0721] 1 H NMR (400 MHz, chloroform- d ) δ 11.91 (s, 1H), 5.96 (ddt, J = 17.3, 10.4,5.7 Hz, 1H), 5.36 (dq, J = 17.2, 1.5 Hz, 1H), 5.28 (dq, J = 10.5, 1.3 Hz,1H), 4.73 (dt, J = 5.7, 1.4 Hz, 2H), 3.59 – 3.49 (m, 4H), 3.45 – 3.37 (m,4H), 2.70 – 2.60 (m, 2H), 2.55 (td, J = 7.7, 2.1 Hz, 2H), 1.46 (s, 9H) ppm

[0722] 13 C NMR (101 MHz, CDCl3) δ 171.02, 165.69, 161.53, 158.62, 156.49,154.74, 131.65, 118.97, 116.99, 102.24, 80.42, 65.87, 47.97, 43.14 (br),28.47, 23.54, 20.11 ppm

[0723] LCMS: [M+H] + m / z = 451.1 amu.

[0724] Allyl 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (50 mg, 0.110 mmol) and 1-(bromomethyl)-2-nitro-benzene (29 mg, 0.13 mmol) were dissolved in anhydrous toluene (550 µL) and treated with potassium tert-amylate, 1.7 M in toluene (78 uL, 0.13 mmol). The mixture was warmed to 65°C and stirred for 24 hours, then potassium tert-amylate, 1.7 M in toluene (65 µL, 0.11 mmol) and 1-(bromomethyl)-2-nitro-benzene (24 mg, 0.11 mmol) were added and the reaction was stirred for an additional 24 hours. The mixture was partitioned between EtOAc and H2O, and the organic phase was collected and washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (0→40% Me2CO in hexanes) to afford allyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-chloro-7-(2-nitrobenzyl)-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (33.7 mg, 0.0575 mmol, 52% yield) as a yellow film.

[0725] 1 H NMR (400 MHz, chloroform- d ) δ 7.85 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 (ddd, J = 8.7, 7.2, 1.5 Hz, 1H), 7.42 (dd, J = 7.8, 1.7 Hz, 1H), 7.37 (ddd, J =8.2, 7.1, 1.7 Hz, 1H), 5.77 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.21 (dq, J =12.5, 1.4 Hz, 1H), 5.17 (dq, J = 5.8, 1.2 Hz, 1H), 4.60 (ddt, J = 13.2, 5.9,1.3 Hz, 1H), 4.53 (ddt, J= 13.1, 5.7, 1.4 Hz, 1H), 4.00 (d, J = 14.1 Hz,1H), 3.68 (d, J = 14.2 Hz, 1H), 3.62 – 3.51 (m, 4H), 3.51 – 3.32 (m, 4H), 2.81 (ddd, J = 17.1, 11.1, 4.4 Hz, 1H), 2.61 (dt, J = 17.0, 4.3 Hz, 1H), 2.48(dt, J = 13.7, 4.2 Hz, 1H), 1.84 (ddd, J = 13.7, 11.1, 4.4 Hz, 1H), 1.46 (s,9H) ppm

[0726] 13 C NMR (101 MHz, CDCl3) δ 190.91, 169.86, 167.09, 159.38, 154.63, 150.62, 133.96, 133.00, 130.95, 130.72, 128.40, 124.99, 122.28, 119.58,80.59, 66.72, 59.23, 48.02, 43.45, 34.82, 30.24, 28.45, 23.38 ppm

[0727] LCMS: [M+H] + m / z = 586.2 amu.

[0728] Allyl 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-chloro-7-(2-nitrobenzyl)-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (8.4 mg, 0.014 mmol) was dissolved in MeOH (500 µL) and cooled to 0°C. NaBH4 (50 µL, 20 mg / mL, 0.029 mmol) was added as a stock solution in MeOH. The mixture was stirred for 5 minutes, quenched with AcOH (150 µL), concentrated, and then co-evaporated from CHCl3 to give crude allyl 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-chloro-8-hydroxy-7-(2-nitrobenzyl)-5,6,7,8-tetrahydroquinazoline-7-carboxylate, which was used without purification.

[0729] 1H NMR (400 MHz, CDCl3, major diastereomer) δ 7.83 (dd, J = 8.1, 1.5 Hz,1H), 7.56 – 7.45 (m, 2H), 7.45 – 7.30 (m, 1H), 5.81 (ddt, J = 17.4, 10.4, 5.9Hz, 1H), 5.32 – 5.19 (m, 2H), 4.68 – 4.48 (m, 2H), 4.45 – 4.37 (m, 1H), 3.77(d, J = 14.4 Hz, 1H), 3.68 – 3.30 (m, 10H), 2.55 – 2.41 (m, 2H), 2.29 – 2.14(m, 1H), 1.75 – 1.60 (m, 1H), 1.46 (d, J = 2.3 Hz, 9H) ppm

[0730] 13 C NMR (101 MHz, CDCl3) δ 176.76, 173.07, 166.23, 165.61, 157.89,154.82, 151.05, 133.37, 132.68, 131.52, 128.25, 124.89, 119.21, 113.75,80.48, 71.77, 65.98, 51.10, 47.89, 34.34, 28.51, 25.61, 22.86, 21.04 ppm

[0731] LCMS: [M+H] + m / z = 588.2 / 590.2 amu (3:1).

[0732] Crude allyl 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-chloro-8-hydroxy-7-(2-nitrobenzyl)-5,6,7,8-tetrahydroquinazoline-7-carboxylate (14.1 mg, 0.020 mmol, est.) was dissolved in EtOH (335 µL) and H2O (84 µL) and treated with iron powder (13.4 mg, 0.240 mmol) and AcOH (6.8 µL, 0.120 mmol). The mixture was warmed to 65 °C for 30 min, then cooled, diluted with EtOAc, filtered through a thin pad of silica gel and concentrated to afford tert-butyl 4-(2-chloro-8-hydroxy-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazolin-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (11.1 mg, 22.2 µmol, 93% yield) as a light yellow film (Rf = 0.37 (major), 0.53 (minor) (7:3 EtOAc:hexanes)).

[0733] LCMS: [M+H] + m / z = 500.2 / 502.2 amu.

[0734] 1-Methyl-L-prolinol (12 mg, 0.10 mmol) was dissolved in anhydrous THF (470 μL) and KO t Bu, 1.7 M in THF (47 µL, 0.08 mmol), was treated and the mixture was stirred for 5 minutes. This solution was added to the dry residue of tert-butyl 4-(2-chloro-8-hydroxy-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazolin-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (10 mg, 0.020 mmol). After 1 hour, the reaction was diluted with 1 M NaOH and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give crude tert-butyl 4-(8-hydroxy-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazine-1-carboxylate (13.2 mg, >100% yield) as a brown film which was used in the next step without purification.

[0735] LCMS: [M+H] + m / z = 579.3 amu.

[0736] Crude tert-butyl 4-(8-hydroxy-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazolin-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (13.2 mg, 0.020 mmol, est.) was dissolved in DCM (460 µL) and treated with Dess-Martin periodinane (19.2 mg, 0.050 mmol). After 30 minutes, the reaction was quenched with iPrOH (2 drops), stirred for 10 minutes, and concentrated. The residue was dissolved in 94:6 CHCl3:MeOH + 1% Et3N and filtered through a short column of silica gel eluting with 94:6 CHCl3:MeOH + 1% Et3N to give crude tert-butyl 4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2',8-dioxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazine-1-carboxylate (13.2 mg, 100% yield) as a light brown oily residue which was used in the next step without purification.

[0737] LCMS: [M+H] + m / z = 577.3 / 579.3 amu (3:1)

[0738] The crude product tert-butyl 4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2',8-dioxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (13.2 mg, 0.020 mmol, est.) was treated with TFA (50 µL) for 20 minutes, then concentrated and co-evaporated once from DCM and further dried under vacuum. The residue was dissolved in anhydrous MeCN (200 µL) and i The mixture was treated with Pr2EtN (12 µL, 0.070 mmol) and acrylic anhydride (1.3 µL, 0.010 mmol). After 1 h, the mixture was concentrated, redissolved in ACN:H2O (1:1), and purified by preparative HPLC (C18, 5→70% ACN in H2O + 0.25% TFA) to afford compound C-3, 4-(4-acryloylpiperazin-1-yl)-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,6-tetrahydro-2'H,8H-spiro[quinazoline-7,3'-quinoline]-2',8-dione (2.04 mg, 3.8 µmol, 17% yield) as a light yellow film.

[0739] 1 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J J = 3.9 Hz, 1H), 7.25 – 7.19 (m,1H), 7.12 – 7.03 (m, 1H), 6.85 – 6.77 (m, 1H), 6.58 (ddd, J J = 16.8, 10.5, 1.1Hz, 1H), 6.34 (dt, J J = 16.8, 1.9 Hz, 1H), 5.77 (dt, J J = 10.5, 1.9 Hz, 1H),4.82 – 4.68 (m, 1H), 3.99 – 3.54 (m, 7H), 3.10 (s, 3H), 2.93 (d, J J = 29.4 Hz,1H), 2.73 (dd, J J = 26.6, 16.0 Hz, 2H), 2.44 – 2.25 (m, 2H), 2.25 – 2.02 (m,2H), 1.90 (t, J J = 11.6 Hz, 1H), 1.71 – 1.51 (m, 1H), 1.50 – 1.37 (m, 1H),0.96 – 0.78 (m, 6H) ppm

[0740] LCTOF: [M+H] + m / z = 531.2715 amu (C 29 H 25 N6O4 + calculated value = 531.2714).

[0741] Synthesis of compound C-4

[0742]

[0743]

[0744] Tert-butyl (S)-4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (2.11 g, 5.2 mmol) and anhydrous THF (52 mL) were cooled to -78°C and treated with 1.0 M LHMDS in THF (6.8 mL, 6.8 mmol). After 5 minutes, allyl cyanoformate (1025 µL, 7.8 mmol) was added. HPLC analysis of an aliquot diluted with MeOH / AcOH (t = 19:50) indicated high conversion to the major product. The reaction was quenched by the addition of saturated NaHCO₃ and then partitioned between EtOAc and saturated NaHCO₃. The organic phase was collected and washed with saturated NaHCO, brine, dried over NaSO, concentrated, and purified by flash column chromatography on silica gel (10→70% EtOAc in hexanes) to give (S)-allyl 4-(4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-hydroxy-5,6-dihydroquinazoline-7-carboxylate (1.477 g, 3.02 mmol, 58% yield) as a light pink solid.

[0745] 1 H NMR (400 MHz, chloroform- d ) δ 11.95 (s, 1H), 5.98 (ddt, J = 17.2, 10.5,5.7 Hz, 1H), 5.38 (dq, J = 17.2, 1.5 Hz, 1H), 5.31 (dq, J = 10.4, 1.2 Hz,1H), 4.75 (dt, J = 5.7, 1.5 Hz, 2H), 4.58 (d, J = 7.8 Hz, 1H), 4.15 – 4.02(m, 1H), 3.98 (dt, J = 13.8, 2.1 Hz, 1H), 3.83 – 3.76 (m, 1H), 3.31 (dd, J =13.8, 4.0 Hz, 1H), 3.06 (td, J = 12.3, 3.5 Hz, 1H), 2.81 – 2.49 (m, 7H), 1.50(s, 9H) ppm

[0746] LCMS: [M+H] +m / z = 490.2 / 492.2 amu (3:1).

[0747] (S)-Allyl 4-(4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-hydroxy-5,6-dihydroquinazoline-7-carboxylate (200 mg, 0.41 mmol), 1-(bromomethyl)-2-nitro-benzene (176 mg, 0.82 mmol), NaI (122 mg, 0.82 mmol) and Na2CO3 (173 mg, 1.6 mmol) were suspended in anhydrous MeCN (1.4 mL) and warmed to 80°C. After 5 h, the mixture was poured into H2O and extracted with EtOAc (2 times), and the combined extracts were washed with brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (0→60% EtOAc in hexanes) to give allyl 4-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-7-(2-nitrobenzyl)-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (199 mg, 0.319 mmol, 78% yield, Rf = 0.34 (1:1 hexanes:EtOAc)).

[0748] 1 H NMR (400 MHz, CDCl3, major diastereomer) δ 7.86 (dd, J = 8.1, 1.6 Hz,1H), 7.55 – 7.33 (m, 3H), 5.76 (ddq, J = 17.4, 10.4, 5.9 Hz, 1H), 5.26 – 5.13(m, 2H), 4.55 (dt, J = 5.5, 1.4 Hz, 3H), 4.23 – 3.76 (m, 4H), 3.67 (d, J =1.1 Hz, 1H), 3.25 (ddd, J = 12.7, 7.0, 3.8 Hz, 1H), 3.15 (s, 1H), 3.05 (ddd, J = 12.8, 11.2, 3.8 Hz, 1H), 2.96 – 2.79 (m, 2H), 2.76 – 2.57 (m, 2H), 2.54 –2.44 (m, 1H), 1.96 – 1.79 (m, 1H), 1.48 (s, 9H) ppm.

[0749] Allyl 4-((S)-4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-7-(2-nitrobenzyl)-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (40 mg, 0.064 mmol) was dissolved in MeOH (640 uL), cooled to 0°C, and treated with NaBH4 (4.8 mg, 0.13 mmol). After 15 minutes, the reaction was quenched with AcOH (1 drop) and concentrated to give crude allyl 4-((S)-4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-hydroxy-7-(2-nitrobenzyl)-5,6,7,8-tetrahydroquinazoline-7-carboxylate, which was used without purification.

[0750] LCMS: [M+H] + m / z = 627.2 / 629.2 amu (3:1).

[0751] Crude 4-((S)-4-(tert-Butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-hydroxy-7-(2-nitrobenzyl)-5,6,7,8-tetrahydroquinazoline-7-carboxylic acid allyl ester (40.13 mg, 0.064 mmol) was dissolved in EtOH (600 µL) and H2O (200 µL), then treated with iron powder (35.7 mg, 0.64 mmol) and AcOH (18.3 µL, 0.32 mmol) and warmed to 65°C. After 40 min, the mixture was cooled, diluted with EtOAc, filtered through a short plug of silica gel, and concentrated to give crude tert-butyl (2S)-4-(2-chloro-8-hydroxy-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (37.8 mg, >100% yield) as a light yellow film, which was used further without purification.

[0752] LCMS: [M+H] + m / z = 539.2 amu.

[0753] 1-Methyl-L-prolinol (37 mg, 0.32 mmol) was dissolved in THF (1.2 mL) and KO tBu, 1.7 M in THF (150 µL, 0.256 mmol) was treated. The mixture was stirred for 5 minutes and then added to the dry residue of crude (2S)-tert-butyl 4-(2-chloro-8-hydroxy-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (34.5 mg, 0.064 mmol) and the mixture was stirred at 0°C for 20 minutes and then at room temperature for 40 minutes. The mixture was partitioned between 1M NaOH and DCM and the aqueous phase was extracted twice more with DCM. The combined extracts were washed with brine, dried over K2CO3, filtered and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-(8-hydroxy-2-((( S

[0147] The product was prepared by mixing tert-butyl 4-[(2 ...

[0754] LCMS: [M+H] + m / z = 618.3 amu.

[0755] The crude product (2 S )-2-(cyanomethyl)-4-(8-hydroxy-2-((( S Tert-butyl 2-(1-methylpyrrolidin-2-yl)methoxy)-2'-oxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazine-1-carboxylate (38.9 mg, 0.0600 mmol, est.) was dissolved in DCM (700 µL) and treated with Dess-Martin periodinane (39.8 mg, 0.090 mmol) at room temperature. After 1.5 h, the mixture was dissolved in aqueous H3PO4 and washed with Et2O (2 times), then basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-(2-((( S

[0147] The product was stirred at 4°C for 24 h at 4°C and then stirred for 24 h to 30 min. The product was stirred at 4°C ...

[0756] LCMS: [M+H] + m / z = 616.3 amu.

[0757] The crude product (2 S )-2-(cyanomethyl)-4-(2-((( S tert-Butyl)-1-methylpyrrolidin-2-yl)methoxy)-2',8-dioxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (27.4 mg, 0.040 mmol, est.) was treated with 4N HCl in dioxane (200 µL). After 35 minutes, the mixture was concentrated and co-evaporated from MeOH, then resuspended in anhydrous MeCN (445 µL) and washed with water. i The reaction mixture was treated with Pr2EtN (39 µL, 0.22 mmol) and acrylic anhydride (6.2 µL, 0.050 mmol). After 35 min, the reaction was concentrated, reconstituted in ACN / H2O, and purified by preparative HPLC (C18, 5→70% ACN in H2O + 0.25% TFA) to afford compound C-4, 2-(2 S )-1-acryloyl-4-(2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-2',8-dioxo-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazin-2-yl)acetonitrile (2.4 mg, 10% yield) as a white film.

[0758] 1 H NMR (400 MHz, CDCl3, mixture of diastereomers) δ 7.86 (d, J = 5.3 Hz,1H), 7.18 – 7.07 (m, 2H), 7.02 – 6.90 (m, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.50(dd, J = 16.7, 11.2 Hz, 1H), 6.31 (dd, J = 16.8, 2.0 Hz, 1H), 5.76 (dd, J =10.5, 1.9 Hz, 1H), 4.45 (d, J = 11.0 Hz, 1H), 4.27 (dd, J = 10.7, 5.8 Hz,1H), 3.97 (dd,J = 13.9, 2.4 Hz, 1H), 3.92 – 3.77 (m, 2H), 3.27 – 3.08 (m,2H), 2.93 – 2.56 (m, 6H), 2.48 (s, 3H), 2.35 – 2.18 (m, 2H), 2.09 – 1.94 (m,1H), 1.87 – 1.71 (m, 4H), 0.87 – 0.74 (m, 4H) ppm

[0759] LCTOF: [M+H] + m / z = 570.2814 amu (C 31 H 36 The calculated value of N7O4 is 570.2823 amu).

[0760] Synthesis of compound C-5

[0761]

[0762]

[0763] To a cooled (-78°C) solution of (S)-tert-butyl 4-(2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (1.0 g, 2.5 mmol) in THF (25 mL) was added LiHMDS (3.2 mL, 3.2 mmol, 1 M in THF) dropwise. The reaction was stirred for 5 minutes before allyl cyanoformate (0.39 mL, 3.7 mmol) was added. The mixture was stirred for 2 hours before being quenched with saturated NH4Cl (50 mL, aq.) and allowed to warm to room temperature. The mixture was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to afford 4-(( S )-allyl 4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (547 mg, 1.12 mmol, 45% yield) as a light yellow solid.

[0764] LCMS: [M+H] + m / z = 490.2 amu.

[0765] To a vial containing allyl 4-((S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (233 mg, 0.48 mmol) and 1-bromo-2-(bromomethyl)benzene (0.16 mL, 1.2 mmol) in MeCN (4.8 mL) was added Na2CO3 (141 mg, 1.9 mmol) and NaI (143 mg, 0.96 mmol). The mixture was heated to 60 °C and stirred overnight. Upon completion, the mixture was cooled to room temperature, filtered through a cotton plug, rinsed with DCM, concentrated in vacuo, and purified using flash column chromatography on silica gel (0→70% EtOAc in hexanes) to afford 7-(2-bromobenzyl)-4-(( S )-allyl 4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (217 mg, 0.33 mmol, 69% yield) as a white solid.

[0766] 1 H NMR (400 MHz, chloroform- d ) δ 7.51 (dd, J = 7.9, 1.2 Hz, 1H), 7.24 (ddd, J = 7.8, 4.0, 1.8 Hz, 1H), 7.16 (td, J = 7.5, 1.3 Hz, 1H), 7.05 (td, J = 7.7,1.8 Hz, 1H), 5.82 (dddt, J = 17.2, 10.4, 6.8, 5.7 Hz, 1H), 5.31 – 5.15 (m,2H), 4.69 – 4.47 (m, 3H), 4.22 – 3.88 (m, 2H), 3.81 – 3.45 (m, 3H), 3.30 –3.14 (m, 1H), 3.10 – 2.54 (m, 6H), 1.97 – 1.80 (m, 1H), 1.76 – 1.54 (m, 1H), 1.48 (d, J = 4.2 Hz, 10H) ppm

[0767] LCMS: [M+H] + m / z = 658.1 / 660.1 amu.

[0768] To contain 7-(2-bromobenzyl)-4-(( S To a dried vial containing allyl 4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (219 mg, 0.33 mmol) were added Pd2(dba)3 (15 mg, 0.02 mmol) and ( R )- p -(CF3)3-t-BuPHOX (39 mg, 0.07 mmol) was added, followed by toluene (11 mL). The headspace was purged with argon and the vial was capped. The mixture was stirred at room temperature for 30 minutes, then warmed to 40°C and stirred overnight. After completion, the mixture was cooled, diluted with DCM (5 mL), and filtered through a celite plug, which was washed with more DCM (20 mL). The solvent was removed in vacuo and the crude product was purified on silica gel using flash column chromatography (0→50% EtOAc in hexane) to give ( S )-4-(( R In the presence of tert-butyl 7-allyl-7-(2-bromobenzyl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (183 mg, 0.30 mmol, 92% yield) was added as an off-white solid.

[0769] LCMS: [M+H] + m / z = 614.2 / 616.2 amu.

[0770] To a cooled (0°C) vial containing NaH (24 mg, 0.60 mmol, 60% dispersion in mineral oil) was added THF (1 mL) followed by ( S )-(1-methylpyrrolidin-2-yl)methanol (142 µL, 1.20 mmol). The mixture was stirred for 45 minutes, at which time ( S )-4-(( R )-7-allyl-7-(2-bromobenzyl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester (147 mg, 0.24 mmol). The mixture was warmed to room temperature and stirred for 3 hours. After completion, the reaction was quenched with saturated NH4Cl (10 mL, aq.) and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product ( S )-4-((R )-7-allyl-7-(2-bromobenzyl)-2-((( S tert-Butyl 2-(methylpyrrolidin-2-yl)methoxy)-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate was used in the next step without further purification.

[0771] LCMS: [M+H] + m / z = 693.2 amu.

[0772] To contain crude ( S )-4-(( R )-7-allyl-7-(2-bromobenzyl)-2-((( S To a dried vial of tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate (99 mg, 0.14 mmol, est.) was added K2CO3 (40 mg, 0.29 mmol), followed by PPh3 (8 mg, 0.03 mmol) and finally Pd(OAc)2 (3 mg, 0.01 mmol). The headspace was purged with argon, MeCN (4 mL) was added and the vial was capped. The mixture was warmed to 80 ° C and stirred overnight. Upon completion, the mixture was cooled, diluted with DCM (5 mL) and filtered through a plug of celite, which was washed with more DCM (20 mL). The solvent was removed in vacuo and the crude product ( S )-2-(cyanomethyl)-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -tert-Butyl spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.

[0773] LCMS: [M+H] + m / z = 613.3 amu.

[0774] To a solution containing the crude product ( S )-2-(cyanomethyl)-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' HTo a vial of tert-butyl 2-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (4.2 mg, 0.007 mmol, est.) was added H3PO4 (5µL, 0.07 mmol) dropwise. The reaction was stirred at room temperature for 3 hours, at which time H2O (1 mL) was added and the solution was made basic by the slow addition of 2 M NaOH solution (aq.). Once basic, the mixture was extracted with DCM (2 mL*3), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product 2-(( S )-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile was used in the next step without further purification.

[0775] LCMS: [M+H] + m / z = 513.3 amu.

[0776] To 2-(( S )-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 2-(2-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (3 mg, 0.006 mmol, est.) in DCM (0.3 mL) was added N,N-diisopropylethylamine (10 µL, 0.09 mmol) followed by acrylic anhydride (6 µL, 0.05 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→60% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to afford compound C-5, 2-(( S )-1-acryloyl-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (0.8 mg, 0.001 mmol, 4% yield over 4 steps) as a light brown solid and a mixture of exo- and endo-olefin isomers.

[0777] Product 1 H NMR is consistent with the reported diastereoisomer diagnostic peaks

[0778] LCMS: [M+H] + m / z = 567.3 amu.

[0779] Synthesis of compound C-6

[0780]

[0781] To a solution containing ( S )-2-(cyanomethyl)-4-(( R )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a vial of tert-butyl 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (20 mg, 0.03 mmol, crude est.) was added 10% palladium on carbon (7 mg, 0.007 mmol). The vial was sealed and placed under a hydrogen atmosphere using a balloon. The reaction was stirred vigorously overnight. Upon completion, the reaction mixture was diluted with DCM (2 mL) and filtered through a plug of celite, washed with more DCM (10 mL). The solvent was removed in vacuo, and the crude product (2 S )-2-(cyanomethyl)-4-((2 R )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H tert-Butyl-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.

[0782] LCMS: [M+H] + m / z = 615.3 amu.

[0783] To a solution containing the crude product (2 S )-2-(cyanomethyl)-4-((2 R )-4-methyl-2'-(((S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a vial of tert-butyl 2-((2-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (20 mg, 0.03 mmol, est.) was added H3PO4 (20 µL, 0.33 mmol) dropwise. The reaction was stirred at room temperature for 2 hours, at which time H2O (2 mL) was added and the solution was made basic by slowly adding 2 M NaOH solution (aq.). Once basic, the mixture was extracted with DCM (2 mL * 3), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product 2-((2 S )-4-((2 R )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile was used in the next step without further purification.

[0784] LCMS: [M+H] + m / z = 515.3 amu.

[0785] To the crude product 2-((2 S )-4-((2 R )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (17 mg, 0.03 mmol, est.) in DCM (0.4 mL) was added N , N -Diisopropylethylamine (57 µL, 0.33 mmol) was added, followed by acrylic anhydride (20 µL, 0.17 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→60% MeCN in H2O+.25% TFA). The combined fractions containing the desired product were lyophilized to afford compound C-6, 2-((2 S )-1-acryloyl-4-((2 R)-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (2.6 mg, 0.005 mmol, 14% yield over 5 steps) as a fluffy white solid and a mixture of epimers at the benzylmethyl center.

[0786] Product mixture 1 H NMR is consistent with the diagnostic peaks reported for the epimers

[0787] LCMS: [M+H] + m / z = 569.3 amu.

[0788] Synthesis of compound C-7

[0789]

[0790] To contain 7-(2-bromobenzyl)-4-(( S To a dried vial containing allyl 4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazoline-7-carboxylate (297 mg, 0.44 mmol) were added Pd2(dba)3 (20 mg, 0.02 mmol) and ( S )- p -(CF3)3-t-BuPHOX (52 mg, 0.09 mmol) was then added toluene (15 mL). The headspace was purged with argon and the vial was capped. The mixture was stirred at room temperature for 30 minutes, then warmed to 40°C and stirred overnight. Upon completion, the mixture was cooled, diluted with DCM (15 mL), and filtered through a plug of celite, which was washed with more DCM (30 mL). The solvent was removed in vacuo, and the crude product was purified on silica gel using flash column chromatography (0→50% EtOAc in hexane) to give ( S ) -4-(( S In the presence of tert-butyl 7-allyl-7-(2-bromobenzyl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (233 mg, 0.38 mmol, 86% yield) was added as an off-white solid.

[0791] LCMS: [M+H] + m / z = 614.1 / 616.1 amu.

[0792] ( S )-4-(( S )-7-allyl-7-(2-bromobenzyl)-2-chloro-8-oxo-5,6,7,8-tetrahydroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester and the crude product from subsequent steps 2 to 4 were used further using the procedures and reagents detailed for the synthesis of compound C-5. For the final step, the combined fractions containing the desired product were lyophilized to give compound C-7, 2-(( S )-1-acryloyl-4-(( S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (7 mg, 0.013 mmol, 19% yield over 4 steps) as a fluffy light yellow solid and a mixture of exo- and endo-olefin isomers.

[0793] 1 H NMR, reporting the diagnostic peak of the major isomer of the complex mixture (21H in 41H) (400 MHz, DMSO- d 6, TFA salt) δ 10.31 (s, 1H), 7.37 – 7.17 (m, 4H), 6.96 – 6.76 (m, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H), 5.88 (d, J = 1.7 Hz, 1H), 5.79 (dd, J =10.3, 2.3 Hz, 1H), 4.95 (s, 1H), 4.78 (s, 1H), 4.66 (dd, J = 13.0, 2.8 Hz,1H), 4.51 (dd, J = 12.9, 6.4 Hz, 1H), 3.84 – 3.73 (m, 1H), 3.57 (dd, J =11.7, 5.9 Hz, 1H), 2.96 (d, J = 4.5 Hz, 3H), 2.06 (d, J = 1.5 Hz, 3H) ppm

[0794] LCMS: [M+H] + m / z = 567.3 amu.

[0795] Synthesis of compound C-15

[0796] To the crude product 2-(( S )-4-(( S )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (35 mg, 0.07 mmol, est.) in DCM (1.4 mL) was added N , N -diisopropylethylamine (120 µL, 0.68 mmol) was added, followed by 2-fluoroacrylic anhydride (55 mg, 0.34 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 25→65% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to afford compound C-15, 2-(( S )-1-(2-fluoroacryloyl)-4-(( S )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (13.6 mg, 0.023 mmol, 34% yield over 4 steps) as a fluffy white solid and a mixture of exo- and endo-olefin isomers.

[0797] 1 H NMR; reported internal olefins: (400 MHz, acetonitrile- d 3, TFA salt) δ 12.18 (bs, 1H), 7.41– 7.19 (m, 4H), 5.85 (t, J = 1.5 Hz, 1H), 5.37 – 5.14 (m, 2H), 4.84 (bs, 1H), 4.68 (dd, J = 14.3, 1.2Hz, 1H), 4.53 (dd,J = 14.3, 5.9 Hz, 1H), 4.24 (dt, J = 14.1, 2.3 Hz, 1H), 4.19 – 4.03 (m, 2H), 3.72 – 3.50 (m, 2H), 3.43 (dd, J =14.0, 3.7 Hz, 1H), 3.35 (d, J = 15.8 Hz, 1H), 3.32 – 3.18 (m, 1H), 3.18 –3.06 (m, 1H), 3.03 – 2.70 (m, 8H), 2.34 – 2.21 (m, 1H), 2.15 – 1.98 (m, 5H),1.91 – 1.75 (m, 2H)ppm

[0798] LCMS: [M+H] + m / z = 585.3 amu.

[0799] Synthesis of compound C-8

[0800]

[0801] To a solution of crude product ( S )-2-(cyanomethyl)-4-(( S )-4-methylene-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a vial of tert-butyl 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (84 mg, 0.14 mmol, est.) was added 10% palladium on carbon (29 mg, 0.03 mmol). The vial was sealed and placed under a hydrogen atmosphere using a balloon. The reaction was stirred vigorously overnight. Upon completion, the reaction mixture was diluted with DCM (5 mL) and filtered through a plug of celite, washing with more DCM (20 mL). The solvent was removed in vacuo and the crude product ( S )-2-(cyanomethyl)-4-(( S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' Htert-Butyl-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.

[0802] LCMS: [M+H] + m / z = 615.3 amu.

[0803] The crude product from the previous step ( S )-2-(cyanomethyl)-4-(( S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H tert-Butyl-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate and the crude product from the subsequent step 2 were used further using the procedures and reagents detailed for the synthesis of compound C-6. For the final step, the combined fractions containing the desired product were lyophilized to give compound C-8, 2-(( S )-1-acryloyl-4-(( S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (4.7 mg, 0.008 mmol, 12% yield over 5 steps) as a fluffy off-white solid and a mixture of epimers at the benzylmethyl center.

[0804] 1 H NMR, reporting diagnostic peaks for the complex mixture (18H in 41H): (400 MHz, DMSO- d 6, TFA salt) δ10.37 (broad d, J = 68.4 Hz, 1H), 7.47 – 6.99 (m, 4H), 6.97 – 6.76 (m, 1H), 6.20 (d, J = 16.6 Hz, 1H), 5.79 (d, J = 10.5 Hz, 1H), 4.94 (bs, 1H), 4.78 (bs, 1H), 4.65 (ddd, J = 21.7, 13.0, 2.7 Hz, 1H), 4.49 (td, J= 13.1, 6.3 Hz,1H), 2.95 (dd, J = 21.2, 4.6 Hz, 3H), 1.31 (dd, J = 10.8, 6.7 Hz, 3H) ppm

[0805] LCMS: [M+H] + m / z = 569.3 amu.

[0806] Synthesis of compound C-16

[0807] To the crude product 2-(( S )-4-(( S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (35 mg, 0.07 mmol, est.) in DCM (1.4 mL) was added N , N -diisopropylethylamine (120 µL, 0.68 mmol) was added, followed by 2-fluoroacrylic anhydride (55 mg, 0.34 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 25→65% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to afford compound C-16, 2-((2 S )-1-(2-fluoroacryloyl)-4-((2 S )-4-methyl-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-8'-oxo-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (6.3 mg, 0.010 mmol, 16% yield over 5 steps) as a fluffy white solid and a mixture of epimers at the benzylmethyl center.

[0808] 1 H NMR reports as a mixture of diastereomers at the methyl center (400 MHz, acetonitrile- d3, TFA salt) δ 12.26 (bs, 1H), 7.45 – 6.97 (m, 4H), 5.42 – 5.06 (m, 2H), 4.83 (bs, 1H),4.66 (ddd, J = 16.1, 14.3, 1.2 Hz, 1H), 4.51 (dt, J = 14.2, 6.2 Hz, 1H), 4.41– 3.79 (m, 6H), 3.79 – 3.30 (m, 5H), 3.30 – 2.56 (m, 11H), 2.44 – 2.15 (m,2H), 2.15 – 1.98 (m, 2H), 1.88 – 1.76 (m, 1H), 1.35 (dd, J = 11.1, 6.8 Hz,3H) ppm

[0809] LCMS: [M+H] + m / z= 587.3 amu.

[0810] Example 5: Synthesis of Compounds C-9 to C-14

[0811] Synthetic intermediate 5-1

[0812]

[0813] NaH (2.74 g, 68 mmol) was suspended in anhydrous THF (45 mL) and cooled to 0°C. Tetralin-1-one (3.64 mL, 27 mmol) was added and the mixture was warmed to room temperature and treated with diallyl carbonate (5.89 mL, 41 mmol). The mixture was stirred for 12 hours, then carefully quenched by adding saturated NH4Cl and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel and concentrated. The residue was purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to give allyl 1-hydroxy-3,4-dihydronaphthalene-2-carboxylate (6.211 g, 26.97 mmol, 99% yield) as a colorless oil.

[0814] LCTOF: [M+H] + m / z = 231.1019 amu.

[0815] Allyl 1-hydroxy-3,4-dihydronaphthalene-2-carboxylate (2.98 g, 13 mmol) and ethyl 4-bromobutyrate (2.78 mL, 19 mmol) were dissolved in anhydrous DMF (39.8 mL) and treated with KCO (3.58 g, 26 mmol). The mixture was stirred at 50°C for 4 hours. The mixture was poured into H2O and extracted with EtOAc (3 times). The combined extracts were washed sequentially with dilute Na2S2O3, brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→25% EtOAc in hexanes) to provide allyl 2-(4-ethoxy-4-oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3.27 g, 9.49 mmol, 73% yield).

[0816] 1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.9, 1.5 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.77 (ddt, J = 17.2, 10.8, 5.5 Hz, 1H), 5.16 – 5.07 (m, 2H), 4.55 (ddt, J = 5.6, 3.2,1.5 Hz, 2H), 4.07 (qd, J = 7.1, 1.8 Hz, 2H), 3.04 (ddd, J = 17.5, 9.5, 4.8Hz, 1H), 2.92 (dt, J = 17.5, 5.3 Hz, 1H), 2.56 (ddd, J = 13.7, 5.7, 4.6 Hz,1H), 2.34 – 2.27 (m, 2H), 2.16 (ddd, J = 13.9, 9.6, 4.9 Hz, 1H), 2.03 – 1.84(m, 2H), 1.79 – 1.59 (m, 2H), 1.25 – 1.16 (m, 3H) ppm

[0817] LCMS: [M+H] +m / z = 345.1 amu.

[0818] Anhydrous toluene was bubbled with N2 for 20 minutes before use. R )- p -(CF3)3-t-BuPHOX (449 mg, 0.76 mmol) and Pd2(dba)3 (261 mg, 0.28 mmol) were placed in a flame-dried 250 mL round-bottom flask, then evacuated and backfilled with N2 (three times). Toluene (80 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Separately, allyl 2-(4-ethoxy-4-oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3.27 g, 9.5 mmol) was dissolved in toluene (40 mL) and bubbled through for 20 minutes before being added to the catalyst mixture and stirring continued for 15 hours. The reaction was exposed to air and amended with a small amount of silica gel. Stirring was continued for 5 minutes, followed by filtration through a thin pad of silica gel, rinsing with 8:2 hexane:EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to afford (R)-ethyl 4-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.91 g, 9.69 mmol, >100% yield) as a yellow oil.

[0819] 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 7.8, 1.6 Hz, 1H), 7.31 (td, J = 7.5, 1.5 Hz, 1H), 7.18 – 7.11 (m, 1H), 7.07 (dd, J = 7.7, 0.9 Hz, 1H), 5.69– 5.57 (m, 1H), 4.96 – 4.89 (m, 2H), 3.95 (q, J = 7.1 Hz, 2H), 2.84 (t, J =6.4 Hz, 2H), 2.35 (ddt, J = 13.9, 7.1, 1.3 Hz, 1H), 2.22 – 2.16 (m, 1H), 2.13(t, J = 7.1 Hz, 2H), 1.91 (t, J = 6.4 Hz, 2H), 1.64 – 1.36 (m, 4H), 1.07 (t,J = 7.2 Hz, 3H) ppm

[0820] 13 C NMR (101 MHz, CDCl3) δ 201.12, 173.41, 143.17, 134.00, 133.17,131.84, 128.75, 128.06, 126.70, 118.25, 60.31, 47.66, 39.10, 34.70, 33.76,30.79, 25.10, 19.44, 14.28 ppm

[0821] LCMS: [M+H] + m / z = 301.2 amu.

[0822] Ethyl (R)-4-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.85 g, 9.5 mmol) was dissolved in MeCN (14 mL) and EtOAc (14 mL), then treated with H₂O (21 mL), NaIO₄ (10.15 g, 48 mmol), and RuCl₃·xH₂O (43 mg, 0.21 mmol) and stirred vigorously at room temperature. After 90 minutes, a second portion of NaIO₄ (2 g) was added. After an additional 30 minutes, the mixture was poured into 0.5 M NaHSO₄ and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na₂SO₄, filtered through Celite, and concentrated. The residue was reconstituted in MeOH (48 mL) and treated dropwise with SOCl₂ (8.3 mL, 114 mmol) at 0°C. The mixture was warmed to room temperature and stirred for 7 hours, then quenched with H2O, stirred for 15 minutes, then poured into H2O and extracted with EtOAc (3 times). The combined extracts were washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% EtOAc in hexane) to obtain (R)-4-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-yl)butanoic acid methyl ester (2.34 g, 7.36 mmol, 78% yield).

[0823] 1 H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (td, J= 7.5, 1.5 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.23 – 7.16 (m, 1H), 3.62 (s, 3H), 3.60 (s, 3H), 3.13 – 3.02 (m, 1H), 3.01 – 2.83 (m, 2H), 2.51 (d, J = 15.9 Hz,1H), 2.42 (ddd, J = 13.7, 11.6, 5.1 Hz, 1H), 2.31 – 2.22 (m, 2H), 2.09 – 2.02(m, 1H), 1.78 – 1.65 (m, 2H), 1.61 – 1.51 (m, 2H) ppm

[0824] 13 C NMR (101 MHz, CDCl3) δ 200.15, 173.59, 172.07, 142.92, 133.37,131.36, 128.79, 128.23, 126.81, 51.60, 46.83, 39.46, 34.13, 33.34, 30.60,25.04, 19.46ppm

[0825] LCMS: [M+H] + m / z = 319.1 amu.

[0826] Methyl (R)-4-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.34 g, 7.4 mmol) was dissolved in EtOAc (35 mL) and treated with HClO4, 60% (120 uL, 1.1 mmol). Pd / C, 10 wt% (wet) (460 mg) was added under N2 atmosphere, and the vessel was then charged with H2 (4 times) and stirred vigorously at room temperature for 12 hours. The mixture was filtered through celite, concentrated, and further dried under vacuum, then added to MeOH (30 mL) and treated with SOCl2 (5 mL, 68.92 mmol) at 0°C, warmed to room temperature, and stirred for 1 hour. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (5→35% EtOAc in hexanes) to afford (S)-methyl 4-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.96 g, 6.44 mmol, 88% yield) as a colorless oil.

[0827] LC / MS, ESI [M+H] + = 305.1 m / z.

[0828] A mixture of NaOMe (7.73 mL, 7.7 mmol) in anhydrous toluene (40 mL) was warmed to 100° C., and a solution of (S)-methyl 4-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.96 g, 6.4 mmol) in toluene (25 mL) was added dropwise over a period of approximately 60 minutes. Heating was continued for 4.5 hours after the mixture was cooled to room temperature and poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give crude (S)-methyl 3-hydroxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-3-ene-4-carboxylate (1.78 g, >100% yield) as a light yellow oil, which was used in the next step without further purification.

[0829] 1 H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 7.22 – 6.99 (m, 4H), 3.80 –3.75 (m, 3H), 2.83 (t, J = 6.8 Hz, 2H), 2.72 – 2.62 (m, 1H), 2.56 (d, J =16.3 Hz, 1H), 2.44 – 2.23 (m, 3H), 2.22 – 2.08 (m, 1H), 1.79 – 1.36 (m, 4H)ppm

[0830] 13 C NMR (101 MHz, CDCl3) δ 172.98, 171.00, 135.75, 135.08, 129.79,128.87, 125.88, 125.86, 96.77, 51.56, 40.09, 39.84, 33.12, 32.09, 31.73,25.73, 19.41ppm

[0831] LCMS: [M+Na] + m / z = 295.1 amu.

[0832] Crude (S)-methyl 3-hydroxy-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-3-ene-4-carboxylate (485.7 mg, 1.8 mmol, est.) was dissolved in anhydrous MeCN (8.9 mL) and treated with thiourea (163 mg, 2.1 mmol) and DBU (399 µL, 2.7 mmol). The mixture was warmed to 80°C for 18 hours, then cooled and concentrated to approximately 1 mL before diluting into H 2 O. The resulting solid was collected by filtration, then redissolved in EtOH (3.6 mL) and treated with 1M NaOH (1.96 mL, 2.0 mmol) followed by MeI (122.1 uL, 2.0 mmol). The mixture was stirred vigorously at room temperature for 45 minutes, then additional 1M NaOH (500 μL) and MeI (40 μL) were added. After 12 hours, the mixture was poured into aqueous NaH2PO4 and extracted with CHCl3 (3 times). The combined extracts were washed with brine, dried over Na2SO4, corrected with 0.05 volumes of MeOH, filtered through a thin pad of silica gel, rinsed with 95:5 CHCl3:MeOH and concentrated to give the crude product ( R )-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (495 mg, 1.58 mmol, 89% yield) as a white solid which was used in the next step without further purification.

[0833] LCMS: [M+H] + m / z = 313.1 amu.

[0834] The crude product ( R )-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (495 mg, 1.6 mmol, est.) was suspended in anhydrous DCM (3.2 mL) and i The mixture was treated with Pr2EtN (552 µL, 3.2 mmol), cooled to 0°C, and then trifluoromethanesulfonic anhydride, 1M in DCM (2.38 mL, 2.4 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 2 volumes of hexanes and filtered through a thin pad of silica gel, rinsing with 9:1 hexanes:EtOAc. The residue was dissolved in DCM:hexanes and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to provide intermediate 5-1, ( R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (480 mg, 1.08 mmol, 68.1% yield) as pale yellow vitreous glass.

[0835] LCMS: [M+H] + m / z = 445.1 amu.

[0836] Synthetic intermediate 5-2

[0837]

[0838] Intermediate 5-1, ( R )-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (160 mg, 0.36 mmol) was dissolved in anhydrous DMF (1 mL) and i Pr2EtN (0.19 mL, 1.1 mmol) and tert-butyl piperazine-1-carboxylate (74 mg, 0.40 mmol) were treated, and the mixture was stirred at room temperature overnight. The mixture was poured into saturated NaHCO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified on silica gel by flash column chromatography (5→40% EtOAc in hexane) to obtain (R)-4-(2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (162.8 mg, 0.339 mmol, 94% yield) as a white foam.

[0839] LCMS: [M+H] + m / z = 481.3 amu.

[0840] (R)-tert-Butyl 4-(2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (162.8 mg, 0.34 mmol) was dissolved in DCM, cooled to 0°C, and treated with mCPBA (101 mg, 0.44 mmol). The mixture was stirred for 30 minutes and then diluted with Et2O (Rf = 0.47 (Et2O)), washed with half-saturated NaHCO3 (3 times), brine, then dried over Na2SO4 and concentrated to give crude tert-butyl 4-((2R)-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (169.6 mg, 0.342 mmol, 100% yield) as a white foam which was used in the next step without further purification.

[0841] LCMS: [M+H] + m / z = 497.3 amu.

[0842] 1-Methyl-L-prolinol (79 mg, 0.68 mmol) was dissolved in anhydrous THF (2 mL) and treated with KOtBu, 1.7 M in THF (400 µL, 0.68 mmol). The mixture was aged for 5 minutes and then added to a solution of crude tert-butyl 4-((2R)-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (169.6 mg, 0.34 mmol, est.) in anhydrous THF (1 mL) at 0°C. The mixture was stirred for 30 minutes, then poured into aqueous K2CO3 and extracted with Et2O (3 times). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give crude tert-butyl 4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (187.3 mg, 0.342 mmol, 100% yield) as a white foam which was used in the next step without further purification.

[0843] LCMS: [M+H] + m / z = 548.4 amu.

[0844] Crude tert-butyl 4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (187 mg, 0.34 mmol, est.) was treated with 4N HCl in dioxane (2.5 mL, 10 mmol) at room temperature for 1 hour. The mixture was concentrated and then dissolved in 1N HCl and washed with Et2O (2 times). The ether washes were extracted once with 1N HCl, and the combined aqueous solutions were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over K2CO3, filtered and concentrated to give intermediate 5-2, ( R )-2'-((( S

[0266] The product of 4'-(4'-piperazin-1-yl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (155.4 mg, 0.347 mmol, >100% yield) was obtained as a clear glass and used in the next step without further purification.

[0845] LCMS: [M+H] + m / z = 448.3 amu.

[0846] Synthesis of compound C-9

[0847] Intermediate 5-2, ( R )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (77.7 mg, 0.17 mmol) was dissolved in anhydrous MeCN (1.5 mL), treated with acrylic anhydride (30 µL, 0.26 mmol) and stirred at room temperature for 30 minutes. The mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→70% ACN in H2O + 0.25% TFA) to give compound C-9, 1-(4-(( R )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-1-yl)prop-2-en-1-one (62.4 mg, 0.124 mmol, 72% yield) as a white foam.

[0848] 1H NMR (400 MHz, acetonitrile- d 3) δ 12.48 (s, 1H), 7.17 – 7.01 (m, 4H), 6.75 –6.65 (m, 1H), 6.21 (dt, J = 16.9, 1.9 Hz, 1H), 5.73 (dt, J = 10.5, 1.8 Hz,1H), 4.77 (dd, J = 12.5, 4.6 Hz, 1H), 4.69 (dd, J = 12.5, 3.2 Hz, 1H), 4.06 –3.90 (m, 4H), 3.82 – 3.61 (m, 6H), 3.18 – 3.05 (m, 1H), 2.91 (s, 3H), 2.85(q, J = 6.6 Hz, 2H), 2.81 – 2.59 (m, 6H), 2.36 – 2.23 (m, 1H), 2.21 – 1.91(m, 3H), 1.86 – 1.75 (m, 1H), 1.75 – 1.53 (m, 3H) ppm

[0849] LCMS: [M+H] + m / z = 502.3 amu.

[0850] Synthesis of compound C-10

[0851] 2-Fluoroacrylic acid (164.6 mg, 1.83 mmol) was suspended in anhydrous DCM (2.7 mL) and cooled to 0° C., then treated with DCC (189 mg, 0.910 mmol). The mixture was stirred for 3 hours, then filtered through celite and concentrated to give 2-fluoroacrylic anhydride (139 mg, 0.860 mmol, 47% yield) as a brown solid, which was used without purification.

[0852] Intermediate 5-2, ( R )-2'-((( S)-1-methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1-yl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (77.7 mg, 0.17 mmol) was dissolved in anhydrous MeCN (1.5 mL), treated with 2-fluoroacrylic anhydride (48 mg, 0.30 mmol) and stirred at room temperature for 1 hour, then diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→50% ACN in H2O + 0.25% TFA) to give compound C-10, 2-fluoro-1-(4-(( R )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-1-yl)prop-2-en-1-one (63 mg, 0.12 mmol, 70% yield) as a white foam.

[0853] 1 H NMR (400 MHz, acetonitrile- d 3) δ 12.44 (s, 1H), 7.21 – 6.87 (m, 4H), 5.27(q, J = 3.8 Hz, 1H), 5.19 (dd, J = 25.4, 3.8 Hz, 1H), 4.77 (dd, J = 12.5, 4.4Hz, 1H), 4.68 (dd, J = 12.5, 3.2 Hz, 1H), 4.13 – 3.85 (m, 4H), 3.81 – 3.49(m, 6H), 3.11 (d, J = 5.1 Hz, 1H), 2.94 – 2.59 (m, 10H), 2.37 – 2.26 (m, 1H), 1.96 (s, 4H), 1.87 – 1.54 (m, 4H) ppm

[0854] LCMS: [M+H] + m / z = 520.2 amu.

[0855] Synthetic intermediate 5-3

[0856]

[0857]

[0858] Intermediate 5-1, ( R )-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (160 mg, 0.36 mmol) was dissolved in anhydrous DMF (1 mL) and stirred with i Pr2EtN (0.19 mL, 1.1 mmol) was added followed by tert-butyl (3S)-3-methylpiperazine-1-carboxylate (79.3 mg, 0.40 mmol) and the mixture was warmed to 60°C. After 13 hours, the mixture was cooled and poured into saturated NaHCO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel and concentrated. The residue was purified by flash column chromatography on silica gel (5→40% EtOAc in hexanes) to afford tert-butyl (S)-3-methyl-4-((R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (158.9 mg, 0.321 mmol, 89% yield) as a white foam.

[0859] LCMS: [M+H] + m / z = 495.3 amu.

[0860] (S)-tert-Butyl 3-methyl-4-((R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (158.9 mg, 0.32 mmol) was dissolved in DCM, cooled to 0°C, and treated with mCPBA (96.1 mg, 0.42 mmol). After 20 minutes, the mixture was diluted with Et2O, washed with half-saturated NaHCO3 (3 times), brine, then dried over Na2SO4 and concentrated to give crude tert-butyl (3S)-3-methyl-4-((2R)-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (167 mg, >100% yield) as a white foam, which was used further without purification.

[0861] LCMS: [M+H] + m / z = 511.3 amu.

[0862] 1-Methyl-L-prolinol (75.3 mg, 0.65 mmol) was dissolved in anhydrous THF (2 mL) and KO t The mixture was treated with 1.7M Bu in THF (385 μL, 0.66 mmol). The mixture was aged for 5 minutes and then added to crude tert-butyl (3S)-3-methyl-4-((2R)-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (167 mg, 0.33 mmol, est.) in anhydrous THF (1 mL) at 0°C. After 30 minutes, the mixture was poured into aqueous K2CO3 and extracted with Et2O (3 times). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give crude (S)-tert-butyl 3-methyl-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (178.4 mg, 0.3176 mmol, 97% yield) which was used further without purification.

[0863] LCMS: [M+H] + m / z = 562.4 amu.

[0864] Crude (S)-tert-butyl 3-methyl-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (178.4 mg, 0.318 mmol, est.) was treated with 4N HCl in dioxane (2.5 mL) and aged at room temperature. After 50 minutes, the mixture was dissolved in 1N HCl and washed with Et2O (2 times). The ether washes were back-extracted once with 1N HCl, and the combined aqueous solutions were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over K2CO3, filtered, and concentrated to afford intermediate 5-3, ( R )-4'-((S)-2-methylpiperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (136.2 mg, 0.295 mmol, 93% yield) was obtained as a clear glass and was used further without purification.

[0865] LCMS: [M+H] +m / z = 462.3 amu.

[0866] Synthesis of compound C-11

[0867] Intermediate 5-3, ( R )-4'-((S)-2-methylpiperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (68.1 mg, 0.15 mmol est.) was dissolved in anhydrous MeCN (750 µL) and treated with acrylic anhydride (25.5 µL, 0.22 mmol). After 10 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→55% in H 2 O + 0.25% ACN in TFA) to give compound C-11, 1-(( S )-3-methyl-4-((R)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-1-yl)prop-2-en-1-one (61.1 mg, 0.119 mmol, 80% yield) as a white foam.

[0868] 1 H NMR (400 MHz, acetonitrile- d3 ) δ 11.56 – 10.71 (m, 1H), 6.34 – 6.00 (m,4H), 5.85 – 5.68 (m, 1H), 5.27 (d, J = 16.8 Hz, 1H), 4.78 (d, J = 10.1 Hz,1H), 4.04 – 3.64 (m, 3H), 3.54 – 3.25 (m, 2H), 3.21 – 2.38 (m, 5H), 2.30 –1.60 (m, 13H), 1.47 – 0.52 (m, 8H), 0.37 (d, J = 4.3 Hz, 3H) ppm

[0869] LCMS: [M+H] + m / z = 516.3 amu.

[0870] Synthesis of compound C-12

[0871] Intermediate 5-3, ( R )-4'-((S)-2-methylpiperazin-1-yl)-2'-((( S )-1-Methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (68.1 mg, 0.148 mmol, est.) was dissolved in anhydrous MeCN (750 µL) and treated with 2-fluoroacrylic anhydride (35.9 mg, 0.22 mmol). After 10 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC to give compound C-12, 2-fluoro-1-((S)-3-methyl-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-1-yl)prop-2-en-1-one (52.4 mg, 0.0982 mmol, 67% yield) as a white foam.

[0872] 1 H NMR (400 MHz, acetonitrile- d 3) δ 12.63 (s, 1H), 7.16 – 7.03 (m, 4H), 5.32 –5.25 (m, 1H), 5.19 (dd, J = 22.7, 3.9 Hz, 1H), 4.78 (dd, J = 12.4, 4.8 Hz,1H), 4.68 (dd, J = 12.3, 3.2 Hz, 1H), 4.37 (dt, J = 13.8, 3.2 Hz, 1H), 4.29 –4.00 (m, 2H), 3.78 – 3.63 (m, 2H), 3.55 (ddd, J = 14.2, 11.7, 3.4 Hz, 1H),3.10 (d, J = 9.4 Hz, 1H), 2.91 (s, 3H), 2.90 – 2.67 (m, 5H), 2.67 – 2.56 (m,4H), 2.35 – 2.23 (m, 1H), 2.18 – 1.92 (m, 5H), 1.89 – 1.78 (m, 1H), 1.78 –1.60 (m, 2H), 1.52 (ddd,J = 13.7, 8.4, 5.4 Hz, 1H), 1.34 (d, J = 6.7 Hz, 3H)ppm

[0873] LCMS: [M+H] + m / z = 534.3 amu.

[0874] Synthetic intermediate 5-4

[0875]

[0876] Intermediate 5-1, ( R )-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (160 mg, 0.36 mmol) was dissolved in anhydrous DMF (1 mL) and i Pr2EtN (188 μL, 1.1 mmol) and 2-[(2 S The mixture was treated with 2-[(S)-((R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (223 mg, 0.429 mmol, >100% yield) and stirred at room temperature for 20 minutes. The mixture was then poured into saturated NaHCO and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over NaSO, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (5→40% EtOAc in hexanes) to afford tert-butyl (S)-2-(cyanomethyl)-4-((R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (223 mg, 0.429 mmol, >100% yield) as a white foam.

[0877] LCMS: [M+H] + m / z = 520.3 amu.

[0878] (S)-tert-Butyl 2-(cyanomethyl)-4-((R)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (223 mg, 0.43 mmol) was dissolved in DCM, cooled to 0°C, and treated with mCPBA (128 mg, 0.56 mmol). The mixture was stirred for 20 minutes, then diluted with Et2O and washed with half-saturated NaHCO3 (3 times), brine, then dried over Na2SO4 and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-((2 R )-tert-butyl 2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazine-1-carboxylate (225.9 mg, 0.4217 mmol, 98% yield) as a white foam which was carried forward without purification.

[0879] LCMS: [M+H] + m / z = 536.3 amu.

[0880] 1-Methyl-L-prolinol (97 mg, 0.84 mmol) was dissolved in anhydrous THF (2.5 mL) and KO t Bu, 1.7M in THF (496 µL, 0.84 mmol) was treated. The mixture was aged for 5 minutes and then added to the crude (2 S )-2-(cyanomethyl)-4-((2 R To a solution of tert-butyl 2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (226 mg, 0.42 mmol, est.) in anhydrous THF (1.5 mL) was added the resulting mixture, which was stirred for 30 minutes, then poured into aqueous K2CO3 and extracted with Et2O (3 times). The combined extracts were washed with brine, dried over Na2SO4, and concentrated to give the crude product ( S )-2-(cyanomethyl)-4-(( R )-tert-butyl 2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (230 mg, 0.392 mmol, 93.0% yield) was added as an oily residue which was used further without further purification.

[0881] LCMS: [M+H]+ m / z = 587.4 amu.

[0882] The crude product ( S )-2-(cyanomethyl)-4-(( R )-tert-Butyl 2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (230 mg, 0.39 mmol) was treated with 4N HCl in dioxane (3 mL, 12 mmol) and aged at room temperature for 1 hour. The mixture was concentrated and then partitioned between 1N HCl and Et2O, and the aqueous phase was collected and washed once more with Et2O. The ethereal washes were back-extracted once with 1N HCl, and the combined aqueous phases were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over K2CO3, filtered, and concentrated to afford Intermediate 5-4, 2-(( S )-4-(( R )-2'-((( S To the product was added 4-[[(4- ...

[0883] LCMS: [M+H] + m / z = 487.3 amu.

[0884] Synthesis of compound C-13

[0885] The intermediate 5-4, 2-(( S )-4-(( R )-2'-((( S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (85.4 mg, 0.18 mmol) was dissolved in anhydrous MeCN (1.5 mL) and treated with acrylic anhydride (30 µL, 0.26 mmol). The mixture was stirred for 20 minutes, then diluted with 0.25% TFA in H2O, filtered, and purified by preparative HPLC (C18, 5→55% ACN in H2O+0.25% TFA) to afford compound C-13, 2-((S)-1-acryloyl-4-((R)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (26.9 mg, 0.0498 mmol, 28% yield).

[0886] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.44 (d, J = 126.7 Hz, 1H), 7.15 – 7.02(m, 4H), 6.71 (s, 1H), 6.31 – 6.20 (m, 1H), 5.78 (dd, J = 10.5, 2.1 Hz, 1H),4.84 – 4.64 (m, 2H), 4.64 – 4.50 (m, 1H), 4.39 (s, 1H), 4.11 – 3.90 (m, 1H),3.78 – 3.65 (m, 2H), 3.63 – 3.46 (m, 2H), 3.15 – 3.04 (m, 1H), 2.91 (s, 3H), 2.89 – 2.62 (m, 11H), 2.37 – 2.23 (m, 1H), 2.14 – 1.94 (m, 4H), 1.87 – 1.76(m, 1H), 1.76 – 1.54 (m, 3H) ppm

[0887] LCMS: [M+H] + m / z = 541.3 amu.

[0888] Synthesis of compound C-14

[0889] The intermediate 5-4, 2-(( S )-4-(( R)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (85.4 mg, 0.18 mmol) was dissolved in anhydrous MeCN (1.5 mL) and treated with 2-fluoroacrylic anhydride (42.7 mg, 0.26 mmol). After 9 hours, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC in three injections (C18, 10→55% ACN in H2O+0.25% TFA) to give compound C-14, 2-(( S )-1-(3-fluorobut-1,3-dien-2-yl)-4-(( R )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (55.6 mg, 0.0995 mmol, 57% yield) as a light yellow glassy solid.

[0890] 1 H NMR (400 MHz, acetonitrile- d 3) δ 12.43 (s, 1H), 7.21 – 7.03 (m, 4H), 5.38 –5.19 (m, 2H), 4.94 – 4.67 (m, 3H), 4.65 – 4.53 (m, 1H), 4.40 (d, J = 8.7 Hz,1H), 3.72 (ddd, J = 11.7, 7.5, 4.7 Hz, 2H), 3.62 – 3.38 (m, 3H), 3.14 – 3.02(m, 1H), 2.92 (s, 3H), 2.90 – 2.60 (m, 11H), 2.36 – 2.23 (m, 1H), 2.17 – 1.93(m, 5H), 1.85 – 1.76 (m, 1H), 1.74 – 1.55 (m, 3H) ppm

[0891] LCMS: [M+H] + m / z = 559.3 amu.

[0892] Example 6: Synthesis of Compounds C-17 to C-21

[0893] Synthetic intermediate 6-1

[0894]

[0895] 2-Fluoroacetophenone (6.91 g, 50 mmol) was dissolved in glacial AcOH (150 mL) and treated with glyoxylic acid, 50% in H2O (8.3 mL, 75 mmol), followed by concentrated HCl (7.9 mL, 100 mmol), and the mixture was heated to reflux under N2 for 24 hours, then cooled to room temperature and concentrated. The crude isolate was purified by flash column chromatography on silica gel (8:2 hexanes:EtOAc) to give ( E )-4-(2-fluorophenyl)-4-oxobut-2-enoic acid (6.97 g, 35.9 mmol, 72% yield) as a yellow solid.

[0896] 1 H NMR (400 MHz, CDCl3) δ 7.89 – 7.81 (m, 2H), 7.60 (dddd, J = 8.4,7.1, 5.1, 1.9 Hz, 1H), 7.29 (td, J = 7.5, 1.1 Hz, 1H), 7.19 (ddd, J = 10.9,8.3, 1.1 Hz, 1H), 6.84 (dd, J = 15.6, 1.3 Hz, 1H) ppm.

[0897] Will( E )-4-(2-fluorophenyl)-4-oxobut-2-enoic acid (6.97 g, 36 mmol) was dissolved in acetic acid (105 mL) and treated with Pd / C, 10 wt% (wet) (1.2 g, 3.6 mmol). The vessel was evacuated and backfilled with H2, then heated to 90°C for 2 hours. The mixture was cooled, filtered through celite, concentrated, and co-evaporated once from toluene, then further dried under vacuum to give crude 4-(2-fluorophenyl)butanoic acid (6.40 g, 35.1 mmol, 98% yield). Rf = 0.39 (7:3 hexanes:EtOAc + 2% AcOH), which was used in the next step without further purification.

[0898] 1 H NMR (500 MHz, chloroform- d ) δ 11.59 (s, 1H), 7.18 (q, J= 6.3, 5.2 Hz,2H), 7.10 – 6.98 (m, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H),1.99 (q, J = 7.5 Hz, 2H) ppm.

[0899] Crude 4-(2-fluorophenyl)butanoic acid (6.2 g, 34 mmol) was treated with Eaton's reagent (34 mL) and the mixture was warmed to 50°C for 1 hour. The mixture was cooled to room temperature and poured into ice water and extracted with DCM (3 times). The combined extracts were washed with saturated NaHCO3, brine, then dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to provide 5-fluoro-3,4-dihydronaphthalen-1(2H)-one (4.403 g, 26.8 mmol, 79% yield).

[0900] 1 H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 7.7, 1.2 Hz, 1H), 7.32 – 7.23(m, 2H), 7.21 (dd, J = 8.1, 1.3 Hz, 1H), 2.96 (t, J = 6.2 Hz, 2H), 2.67 (dd, J = 7.4, 5.7 Hz, 2H), 2.16 (p, J = 6.4 Hz, 2H) ppm.

[0901] 5-Fluoro-3,4-dihydronaphthalen-1(2H)-one (4.40 g, 27 mmol) was dissolved in anhydrous THF (45 mL) and cooled to 0°C, then treated with NaH (2.68 g, 67 mmol). The mixture was allowed to warm to room temperature, diallyl carbonate (5.77 mL, 40 mmol) was added, and stirring continued for 21 hours. The reaction was cooled in an ice bath and quenched by dropwise addition of saturated NH4Cl, then diluted with H2O and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to afford allyl 5-fluoro-1-hydroxy-3,4-dihydronaphthalene-2-carboxylate (6.04 g, 24.3 mmol, 91% yield) as a light yellow oil.

[0902] 1 H NMR (400 MHz, CDCl3, major tautomer) δ 12.38 (s, 1H), 7.61 (dd, J =7.8, 1.4 Hz, 1H), 7.30 – 7.20 (m, 1H), 7.09 (ddd, J = 9.3, 8.3, 1.2 Hz, 1H),5.99 (ddq, J = 17.1, 10.5, 5.7 Hz, 1H), 5.43 – 5.33 (m, 1H), 5.29 (dt, J =10.4, 1.3 Hz, 1H), 4.74 (dt, J = 5.5, 1.4 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H),2.61 (t, J = 7.6 Hz, 2H) ppm

[0903] LCMS: [M+H] + m / z = 249.1 amu.

[0904] Allyl 5-fluoro-1-hydroxy-3,4-dihydronaphthalene-2-carboxylate (3.97 g, 16 mmol) was dissolved in anhydrous DMF (48 mL) and treated with ethyl 4-bromobutyrate (3.4 mL, 24 mmol), KI (2.65 g, 16 mmol) and K2CO3 (4.42 g, 32 mmol), and the mixture was heated to 50°C for 3 hours. The mixture was poured into H2O and extracted with EtOAc (3 times). The combined extracts were washed with diluted Na2S2O3, brine, then dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (5→30% EtOAc in hexanes) to afford intermediate 6-allyl 1,2-(4-ethoxy-4-oxobutyl)-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.601 g, 12.7 mmol, 79.4% yield) as a colorless oil.

[0905] LCMS: [M+H] + m / z = 363.1 amu.

[0906] Synthetic intermediate 6-2

[0907]

[0908]

[0909] Under N2 atmosphere, Pd2(dba)3 (174 mg, 0.19 mmol) and ( S )- p -(CF3)3- t -BuPHOX (300 mg, 0.51 mmol) was suspended in anhydrous, degassed MTBE (40 mL). The mixture was warmed to 25°C and stirred for 45 minutes. Separately, the intermediate 6-1, 2-(4-ethoxy-4-oxobutyl)-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid allyl ester (2.3 g, 6.4 mmol) was dissolved in MTBE (40 mL) and bubbled for 20 minutes before being added to the catalyst mixture. After 16 hours, the reaction was exposed to air and corrected with 0.3 volumes of hexanes and a small amount of silica gel. The mixture was stirred for 10 minutes then filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to give ( S)-ethyl 4-(2-allyl-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.954 g, 6.14 mmol, 97% yield) as a light yellow viscous oil.

[0910] LCMS: [M+H] + m / z = 319.1 amu.

[0911] Will( S Ethyl 4-(2-allyl-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.95 g, 6.1 mmol) was dissolved in EtOAc (12 mL) and MeCN (12 mL), treated with H2O (19 mL), NaIO4 (6.56 g, 31 mmol), and RuCl3·xH2O (28.0 mg, 0.14 mmol), and the mixture was vigorously stirred at room temperature for 2 hours. The mixture was then diluted with 0.5M NaHSO4 and EtOAc, stirred for 5 minutes, and then filtered through Celite. The organic phase was collected and the aqueous phase was extracted with EtOAc two more times. The combined extracts were washed with brine, dried over Na2SO4, filtered through Celite, concentrated, and further dried in vacuo. The oily residue was dissolved in MeOH (35 mL), cooled to 0°C, and treated dropwise with SOCl2 (4.3 mL, 59 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours, then concentrated. The residue was taken up in Et2O and washed with NaHCO3 (2 times), brine, then dried over Na2SO4 and concentrated to give the crude product ( S )-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.05 g, 99% yield) was a viscous oil that was used in the next step without further purification.

[0912] LCMS: [M+H] + m / z = 337.1 amu.

[0913] The crude product ( S)-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.05 g, 6.1 mmol, est.) was dissolved in EtOAc (31 mL) and treated with Pd / C, 10 wt% (410 mg, 6.1 mmol) and HClO4, 60% (100 μL, 0.91 mmol), and the vessel was charged with H2. The mixture was stirred vigorously for 12 hours, then filtered through celite, concentrated, and purified by flash column chromatography on silica gel (5→40% EtOAc in hexanes) to give ( R )-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.349 g, 69% yield) as a colorless oil.

[0914] 1 H NMR (400 MHz, chloroform- d ) δ 7.11 – 7.01 (m, 1H), 6.87 – 6.78 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 2.85 – 2.71 (m, 3H), 2.70 – 2.63 (m, 1H), 2.37(d, J = 14.2 Hz, 1H), 2.32 – 2.26 (m, 3H), 1.82 – 1.64 (m, 4H), 1.54 – 1.32(m, 2H) ppm

[0915] LCMS: [M+H] + m / z = 323.2 amu.

[0916] NaH (39.5 mg, 1.0 mmol) was suspended in anhydrous toluene (1.5 mL) and treated with MeOH (8.3 uL, 0.21 mmol), and the mixture was stirred until gas evolution ceased. RTo the mixture was added methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (265 mg, 0.82 mmol) in anhydrous toluene (2 mL) and the mixture was warmed to 70°C. After 50 minutes, a second batch of NaH (20 mg) and MeOH (8.3 µL, 0.206 mmol) was added and stirring was maintained for another 6 hours. The mixture was cooled to room temperature and poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to give (1 R )-methyl 5'-fluoro-3-oxo-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate (188 mg, 0.648 mmol, 79% yield) as a colorless, glassy oil.

[0917] LCMS: [M+H] + m / z = 291.1 amu.

[0918] (1 R )-5'-fluoro-3-oxo-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-4-carboxylic acid methyl ester (188 mg, 0.65 mmol) was dissolved in anhydrous MeCN (3.2 mL) and treated with thiourea (59.2 mg, 0.78 mmol) and DBU (145 µL, 0.97 mmol), and the mixture was heated to 80°C for 11.5 hours. The mixture was cooled and concentrated to a total volume of approximately 500 µL, then diluted with aqueous NaH2PO4, and the resulting solid was collected by centrifugation.

[0919] LCMS: [M+H] + m / z = 317.1 amu.

[0920] The still wet material was suspended in EtOH (2 mL), treated with 1M NaOH (712 µL, 0.71 mmol), treated with MeI (48 µL, 0.78 mmol), and stirred vigorously at room temperature for 7 hours. The mixture was poured into aqueous NaH2PO4 and extracted with CHCl3 (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel (0→10% MeOH in C2Cl2) to give ( R)-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (131.9 mg, 0.399 mmol, 62% yield) as a white solid.

[0921] LCMS: [M+H] + m / z = 331.1 amu.

[0922] Will( R )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (132 mg, 0.40 mmol) was suspended in anhydrous DCM (1 mL) and washed with freshly distilled i The mixture was treated with Pr2EtN (139 μL, 0.80 mmol), then cooled to 0°C and trifluoromethanesulfonic anhydride, 1M in DCM (599 μL, 0.60 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 2.5 hours. The mixture was then diluted with 2 volumes of hexanes and filtered through a short column of silica gel, rinsed with 9:1 hexanes:EtOAc and concentrated. The residue was purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to give intermediate 6-2, ( R )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (132.7 mg, 0.287 mmol, 71.9% yield) as a colorless residue.

[0923] LCMS: [M+H] + m / z = 463.1 amu.

[0924] Synthetic intermediate 6-3

[0925]

[0926] Intermediate 6-2 , ( R )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinoline [oxazoline]-4'-yl trifluoromethanesulfonate (66.4 mg, 0.14 mmol) was dissolved in anhydrous DMF (410 µL) and iPr2EtN (75 µL, 0.43 mmol) and 2-[(2S)-piperazin-2-yl]acetonitrile dihydrochloride (31.3 mg, 0.16 mmol) were treated and the mixture was stirred at room temperature. After 15 minutes, Boc2O (50 µL, 0.22 mmol) was added and stirring continued for 16 hours. The mixture was diluted with EtOAc and washed with saturated NH4Cl, brine, then dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( S )-2-(cyanomethyl)-4-(( R )-tert-butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazine-1-carboxylate (154.8 mg, >100% yield) as a white foam which was carried on without further purification.

[0927] LCMS: [M+H] + = 538.3 m / z.

[0928] The crude product ( S )-2-(cyanomethyl)-4-(( R )-tert-Butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (impure, 0.14 mmol) was dissolved in DCM (480 µL), cooled to 0°C, and treated with mCPBA (43 mg, 0.19 mmol). After 30 minutes, the mixture was diluted with Et2O and washed with half-saturated NaHCO3 (3 times), brine, then dried over Na2SO4 and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-((2 R )-tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazine-1-carboxylate (140 mg, >100% yield) as a white foam which was carried forward without purification.

[0929] LCMS: [M+H] + m / z = 554.3 amu.

[0930] 1-Methyl-L-prolinol (33 mg, 0.287 mmol) was dissolved in anhydrous THF (1 mL) and treated with KOtBu, 1.7 M in THF (169 μL, 0.287 mmol). The mixture was stirred for 5 minutes and then added to the crude (2 S )-2-(cyanomethyl)-4-((2 R To this was added tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (impure, 0.14 mmol) in anhydrous THF (500 µL). After 1 hour, the mixture was poured into aqueous K2CO3 and extracted with Et2O (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on basic alumina (0→100% CHCl in hexanes, then 100% EtOAc) to afford ( S )-2-(cyanomethyl)-4-(( R )-5-fluoro-2'-((( S tert-Butyl)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (86.1 mg, 0.142 mmol, 99% yield).

[0931] LCMS: [M+H] + m / z = 605.4 amu.

[0932] At room temperature, ( S )-2-(cyanomethyl)-4-(( R )-5-fluoro-2'-((( Stert-Butyl 3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (86.1 mg, 0.14 mmol) was treated with 4N HCl in dioxane (1 mL) for 30 minutes. The mixture was then concentrated, dissolved in 1N HCl, and washed with EtO (2 times), then basified with KCO and back-extracted with EtOAc (3 times). The combined extracts were dried over K2CO3, filtered and concentrated to afford intermediate 6-3,2-((S)-4-((R)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (54.8 mg, 0.109 mmol, 76% yield) as a colorless film.

[0933] LCMS: [M+H] + m / z = 505.3 amu.

[0934] Synthesis of compound C-17

[0935] Intermediate 6-3, 2-((S)-4-((R)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (27.4 mg, 0.054 mmol) was dissolved in MeCN (360 µL) and treated with acrylic anhydride (9.4 µL, 0.081 mmol). After 30 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 5→65% ACN in H2O+0.25% TFA) to give compound C-17, 2-(( S )-1-acryloyl-4-(( R )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (11.7 mg, 39% yield) as a colorless film.

[0936] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.45 (s, 1H), 7.14 (td, J= 8.1, 5.9 Hz,1H), 6.95 – 6.85 (m, 2H), 6.72 (s, 1H), 6.30 – 6.20 (m, 1H), 5.78 (dd, J =10.5, 2.1 Hz, 1H), 4.81 – 4.66 (m, 2H), 4.58 (dt, J = 14.2, 2.5 Hz, 1H), 3.76– 3.66 (m, 2H), 3.55 (d, J = 7.5 Hz, 3H), 3.16 – 3.06 (m, 1H), 2.91 (s, 3H), 2.85 – 2.61 (m, 11H), 2.35 – 2.23 (m, 1H), 2.14 – 1.92 (m, 4H), 1.88 – 1.78(m, 1H), 1.78 – 1.54 (m, 4H) ppm

[0937] 19 F NMR (376 MHz, acetonitrile- d 3) δ -119.81 (dd, J = 10.1, 5.9 Hz) ppm

[0938] LCMS: [M+H] + m / z = 559.3 amu.

[0939] Synthesis of compound C-18

[0940] Intermediate 6-3, 2-((S)-4-((R)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (27.4 mg, 0.054 mmol) was dissolved in MeCN (400 µL) and treated with 2-fluoroacrylic anhydride (13 mg, 0.081 mmol). After 30 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18 10→60% ACN in H2O+0.25% TFA) to give compound C-18, 2-(( S )-4-(( R )-5-fluoro-2'-((( S)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (25.3 mg, 0.0439 mmol, 81% yield) as a colorless film.

[0941] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.69 (s, 1H), 7.21 – 7.11 (m, 1H), 6.92(td, J = 8.6, 1.5 Hz, 2H), 5.38 – 5.22 (m, 2H), 4.80 (dd, J = 12.3, 5.1 Hz,1H), 4.73 (dd, J = 12.3, 3.2 Hz, 1H), 4.62 (dt, J = 14.3, 2.3 Hz, 1H), 4.44(d, J = 8.8 Hz, 1H), 3.79 – 3.67 (m, 2H), 3.59 (d, J = 13.1 Hz, 1H), 3.44 (d, J = 24.8 Hz, 2H), 3.18 – 3.05 (m, 1H), 2.95 (s, 3H), 2.92 – 2.64 (m, 11H), 2.38 – 2.26 (m, 1H), 2.19 – 1.92 (m, 4H), 1.92 – 1.81 (m, 1H), 1.80 – 1.65(m, 2H), 1.65 – 1.54 (m, 1H) ppm

[0942] 19 F NMR (376 MHz, acetonitrile- d 3) δ -107.54, -119.80 (dd, J = 10.1, 5.9 Hz)ppm

[0943] LCMS: [M+H] + m / z= 577.3 amu.

[0944] Synthetic intermediate 6-4

[0945]

[0946] Tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (2.16 g, 10 mmol) was dissolved in DCM (32 mL), cooled to 0°C, and treated with EtN (1.67 mL, 12 mmol) and BocO (2.52 mL, 11 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2.5 hours. The product was then washed with 0.5M NaHSO, brine, dried over NaSO, concentrated, and purified by flash column chromatography on silica gel (15→60% EtOAc in hexanes) to afford di-tert-butyl (R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (2.828 g, 8.94 mmol, 90% yield) as a white solid.

[0947] LCMS: [M+Na] + m / z = 339.2 amu.

[0948] (R)-di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (297 mg, 0.94 mmol) was dissolved in anhydrous THF (1.9 mL) and treated with MeI (234 µL, 3.8 mmol). The mixture was cooled to 0°C, NaH (45.06 mg, 1.1 mmol) was added, and the mixture was allowed to warm to room temperature. After 90 minutes, the mixture was poured into saturated NH4Cl and extracted with EtOAc (2 times). The combined extracts were washed with diluted Na2S2O3, brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (5→60% EtOAc in hexanes) to give (R)-di-tert-butyl 2-(methoxymethyl)piperazine-1,4-dicarboxylate (203.1 mg, 0.615 mmol, 66% yield) as a colorless oil that crystallized upon standing.

[0949] 1 H NMR (400 MHz, CDCl3) δ 4.12 (d, J = 19.8 Hz, 1H), 3.99 (dt, J =13.6, 2.0 Hz, 1H), 3.95 – 3.81 (m, 1H), 3.73 (d, J = 12.3 Hz, 1H), 3.26 (d, J= 7.5 Hz, 2H), 3.23 (s, 3H), 2.82 (dt, J = 13.2, 4.6 Hz, 2H), 2.77 – 2.60 (m,1H), 1.35 (s, 18H) ppm

[0950] 13 C NMR (101 MHz, CDCl3) δ 154.77 (2), 79.95, 79.73, 69.02, 58.87,50.04, 43.44, 42.46, 39.27, 28.25, 28.23 ppm

[0951] LCMS: [M+Na] + m / z = 353.2 amu.

[0952] (R)-di-tert-butyl 2-(methoxymethyl)piperazine-1,4-dicarboxylate (203.1 mg, 0.62 mmol) was treated with 4N HCl in dioxane (2 mL) at room temperature for 90 minutes. A gelatinous solid was obtained, which was suspended in Et2O, filtered, and dried under vacuum to afford Intermediate 6-4, ( R )-2-(Methoxymethyl)piperazine dihydrochloride (105.3 mg, 0.519 mmol, 84% yield) as a white, hygroscopic solid.

[0953] 1 H NMR (600 MHz, D2O) δ 3.91 – 3.86 (m, 1H), 3.81 – 3.72 (m, 5H), 3.72 – 3.68 (m, 1H), 3.56 – 3.47 (m, 1H), 3.45 – 3.43 (m, 3H), 3.43 – 3.37 (m, 1H)pp,

[0954] Synthetic intermediate 6-5

[0955]

[0956]

[0957] Intermediate 6-2, ( R )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (66.4 mg, 0.14 mmol) was dissolved in anhydrous DMF (410 µL) and reacted with iPr2EtN (75 µL, 0.43 mmol) and intermediate 6-4, ( R)-2-(methoxymethyl)piperazine dihydrochloride (35 mg, 0.17 mmol) was treated and the mixture was stirred at room temperature. After 90 minutes, Boc2O (49 µL, 0.21 mmol) was added and stirring continued for 2 hours. The mixture was then diluted with EtOAc and washed with saturated NH4Cl, brine, dried over Na2SO4, concentrated, and purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( R )-tert-butyl 4-((R)-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (84.3 mg, >100% yield) as a white foam.

[0958] LCMS: [M+H] + m / z = 543.3 amu.

[0959] Will( R )-tert-Butyl 4-((R)-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (84.3 mg, 0.16 mmol) was dissolved in DCM (520 µL), cooled to 0°C, and treated with mCPBA (46.5 mg, 0.20 mmol). After 40 minutes, the mixture was diluted with Et2O and washed with half-saturated NaHCO3 (2 times), brine, dried over Na2SO4, and concentrated to give the crude product (2 R )-4-((2 R )-tert-Butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (87.8 mg, >100% yield) as a white foam. The crude product was used further without further purification.

[0960] LCMS: [M+H] + m / z = 559.3 amu.

[0961] 1-Methyl-L-prolinol (36 mg, 0.31 mmol) was dissolved in THF (1 mL) and treated with KOtBu, 1.7M in THF (183 µL, 0.31 mmol). The mixture was stirred for 5 minutes and then added to the crude (2 R )-4-((2 RTo a solution of tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (86.8 mg, 0.16 mmol, est.) in anhydrous THF (500 µL). After 50 minutes, the mixture was poured into aqueous K2CO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product ( R )-4-(( R )-5-fluoro-2'-((( S

[0147] To the solution of tert-butyl 4-(2-((2-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (110.6 mg, >100% yield) was obtained as a light yellow glassy oil which was used without further purification.

[0962] LCMS: [M+H] + m / z = 610.4 amu.

[0963] At room temperature, the crude product ( R )-4-(( R )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylic acid tert-butyl ester (94.7 mg, 0.16 mmol) was treated with 4N HCl in dioxane (2 mL). After 60 minutes, the mixture was concentrated and the residue was dissolved in 1N HCl and washed with Et2O (2 times), then basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were dried over anhydrous K2CO3, filtered and concentrated to give intermediate 6-5, ( R )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (78.2 mg, 99% yield) as a light yellow oily residue.

[0964] LCMS: [M+H] + m / z = 510.3 amu.

[0965] Synthesis of compound C-19

[0966] At 0°C, intermediate 6-5, ( R )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (26.1 mg, 0.051 mmol) was dissolved in anhydrous MeCN (340 µL) and treated with acrylic anhydride (8.9 µL, 0.077 mmol) and then allowed to warm to room temperature. After 10 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18 10→60% ACN in H2O+0.25% TFA) to give compound C-19, 1-(( R )-4-(( R )-5-fluoro-2'-((( S)

[0147] The mixture was stirred at 40°C for 2 h. The mixture was stirred at 40°C for 2 h. To obtain 4-(2-((2-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazin-1-yl)prop-2-en-1-one (14.4 mg, 0.0255 mmol, 50% yield) as a colorless film.

[0967] 1 H NMR (400 MHz, acetonitrile- d3) δ 10.48 (s, 1H), 7.05 (td, J = 7.9, 5.8 Hz, 1H), 6.86 – 6.76 (m, 2H), 6.62 (t, J = 13.0 Hz, 1H), 6.12 (dd, J = 16.8, 2.2Hz, 1H), 5.62 (dd, J = 10.5, 2.2 Hz, 1H), 4.74 – 4.64 (m, 1H), 4.61 – 4.48(m, 2H), 4.35 (d, J = 35.1 Hz, 2H), 3.69 – 3.53 (m, 3H), 3.51 – 3.42 (m, 1H), 3.21 (s, 3H), 3.05 – 2.96 (m, 1H), 2.82 (s, 3H), 2.80 – 2.51 (m, 11H), 2.28 –2.14 (m, 1H), 2.07 – 1.83 (m, 4H), 1.77 – 1.60 (m, 2H), 1.55 (t, J = 6.5 Hz,2H) ppm

[0968] 19 F NMR (376 MHz, acetonitrile- d3 ) δ -119.75 (t, J = 9.8, 5.8 Hz) ppm

[0969] LCMS: [M+H] + m / z = 564.3 amu.

[0970] Synthesis of compound C-20

[0971] Intermediate 6-5, ( R )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S(31.0 mg, 0.061 mmol) was dissolved in MeCN (610 µL) and treated with 2-fluoroacrylic anhydride (14.8 mg, 0.091 mmol). After 1 hour, HPLC analysis indicated complete conversion to the major product. The mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→55% ACN in H2O+0.25% TFA) to afford compound C-20, 2-fluoro-1-((R)-4-((R)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazin-1-yl)prop-2-en-1-one (29.2 mg, 0.0502 mmol, 83% yield) as a colorless film.

[0972] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.49 (s, 1H), 7.17 (td, J = 8.0, 5.9 Hz,1H), 6.93 (td, J = 8.6, 1.7 Hz, 2H), 5.29 (q, J = 3.9 Hz, 1H), 5.20 (dd, J =24.2, 3.9 Hz, 1H), 4.81 (dd, J = 12.3, 4.5 Hz, 1H), 4.73 – 4.64 (m, 2H), 4.57(d, J = 9.8 Hz, 2H), 3.82 – 3.66 (m, 2H), 3.63 – 3.35 (m, 5H), 3.33 (s, 3H), 3.20 – 3.08 (m, 1H), 2.94 (s, 3H), 2.90 – 2.62 (m, 8H), 2.40 – 2.26 (m, 1H), 2.20 – 1.94 (m, 4H), 1.91 – 1.72 (m, 2H), 1.72 – 1.63 (m, 2H) ppm

[0973] LCMS: [M+H] + m / z = 582.3 amu.

[0974] Synthesis of compound C-21

[0975] Intermediate 6-5, ( R )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S )-1-Methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (6.53 mg, 0.013 mmol) was dissolved in anhydrous MeCN (85 µL) and trans- 4-Dimethylaminocroton hydrochloride (4.2 mg, 0.026 mmol), EDC•HCl (4.9 mg, 0.026 mmol) and i The mixture was treated with Pr2EtN (4.5 µL, 0.026 mmol). After 15 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→55% ACN in H2O + 0.25% TFA) to afford compound C-21, (E)-4-(dimethylamino)-1-((R)-4-((R)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)-2-(methoxymethyl)piperazin-1-yl)but-2-en-1-one (7.3 mg, 0.0118 mmol, 92% yield) as a light yellow film.

[0976] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.38 (s, 1H), 7.05 (td, J = 8.0, 5.9 Hz,1H), 6.86 – 6.77 (m, 2H), 6.71 (d, J = 14.7 Hz, 1H), 6.60 (dt, J = 15.3, 6.8Hz, 1H), 4.69 (dd, J = 12.5, 4.5 Hz, 1H), 4.62 – 4.22 (m, 4H), 3.70 (d, J =6.5 Hz, 2H), 3.67 – 3.57 (m, 2H), 3.47 (d, J= 13.3 Hz, 1H), 3.33 (d, J =30.6 Hz, 3H), 3.23 – 3.18 (m, 3H), 3.07 – 2.98 (m, 1H), 2.82 (s, 3H), 2.79 –2.47 (m, 15H), 2.25 – 2.14 (m, 1H), 2.07 – 1.81 (m, 4H), 1.76 – 1.61 (m, 2H), 1.59 – 1.51 (m, 2H) ppm

[0977] LCMS: [M+H] + m / z = 582.3 amu.

[0978] Example 7: Synthesis of Compounds C-22 and C-23

[0979] Synthetic intermediate 7-1

[0980]

[0981] 3,4-Dihydroquinolin-2(1H)-one (5.0 g, 34 mmol) was dissolved in anhydrous MeCN (68 mL) and treated with di-tert-butyl dicarbonate (8.15 g, 37 mmol) and DMAP (830 mg, 6.8 mmol), and the mixture was stirred at room temperature. After 13 hours, TLC analysis showed complete conversion to a single major product. The mixture was concentrated and purified by flash column chromatography on silica gel (15→20% EtOAc in hexanes) to afford tert-butyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (8.26 g, 33.4 mmol, 98% yield) as a colorless oil that crystallized upon standing.

[0982] 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.14 (m, 2H), 7.05 (td, J = 7.4, 1.3Hz, 1H), 6.94 (dd, J = 8.1, 1.3 Hz, 1H), 2.98 – 2.90 (m, 2H), 2.69 – 2.61 (m,2H), 1.60 (s, 9H) ppm

[0983] 13C NMR (101 MHz, CDCl3) δ 169.37, 151.85, 137.16, 128.06, 127.40, 125.94, 124.19, 117.02, 85.05, 32.37, 27.76, 25.55 ppm.

[0984] Freshly prepared LDA, 1M in THF (4.85 mmol) was cooled to -78°C and tert-butyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.00 g, 4.04 mmol) was added dropwise as a solution in THF (10 mL). The mixture was stirred for 40 minutes before allyl imidazole-1-carboxylate (738 mg, 4.85 mmol) was added as a solution in THF (10 mL). After 30 minutes, the cooling bath was removed and the mixture was allowed to warm to room temperature and stirred for 30 minutes before being quenched with saturated NH4Cl. The mixture was partitioned between saturated NH4Cl and EtOAc, and the organic phase was collected and washed with saturated NH4Cl, brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→50% EtOAc in hexanes) to give 3-allyl 1-(tert-butyl) 2-oxo-3,4-dihydroquinoline-1,3(2H)-dicarboxylate (649.6 mg, 1.96 mmol, 49% yield) as a colorless oil.

[0985] 1 H NMR (500 MHz, CDCl3) δ 7.23 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1Hz, 1H), 7.08 (td, J = 7.5, 1.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.84 (ddt, J = 17.3, 10.7, 5.6 Hz, 1H), 5.28 (dq, J = 17.1, 1.6 Hz, 1H), 5.20 (dq, J =10.5, 1.3 Hz, 1H), 4.71 – 4.58 (m, 2H), 3.67 (dd, J = 10.0, 5.5 Hz, 1H), 3.40(dd, J= 15.7, 10.1 Hz, 1H), 3.11 (dd, J = 15.7, 5.6 Hz, 1H), 1.61 (s, 9H)ppm

[0986] 13 C NMR (126 MHz, CDCl3) δ 168.20, 165.33, 151.31, 136.47, 131.49,128.43, 127.90, 124.67, 123.86, 118.61, 117.15, 85.64, 66.27, 48.62, 28.89, 27.74 ppm.

[0987] 3-allyl 1-(tert-butyl) 2-oxo-3,4-dihydroquinoline-1,3(2H)-dicarboxylate (3.45 g, 10 mmol) was dissolved in anhydrous DMF (20 mL) and treated with ethyl 4-bromobutyrate (2.23 mL, 16 mmol), KI (1.73 g, 10.4 mmol), and KCO (4.3 g, 31 mmol), and the mixture was stirred at room temperature. After 23 hours, the mixture was diluted with H O and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na SO, filtered through a thin pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (0→40% EtOAc in hexanes) to afford intermediate 7-3-allyl 1-(tert-butyl) 1,3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1,3(2H)-dicarboxylate (4.36 g, 9.79 mmol, 94% yield) as a colorless oil.

[0988] LCMS: [M+2H-Boc] + m / z = 346.1 amu.

[0989] Synthetic intermediate 7-2

[0990]

[0991] To an oven-dried flask containing the intermediate 7-1,3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1,3(2H)-dicarboxylic acid 3-allyl 1-(tert-butyl) ester (2.22 mg, 5.0 mmol) was added Pd2(dba)3 (228 mg, 0.25 mmol) and ( R )- p-(CF3)3-t-BuPHOX (590 mg, 1.0 mmol) was then added THF (50 mL). The headspace was purged with argon and the flask was equipped with a condenser. The mixture was stirred at room temperature for 30 minutes, then warmed to 50°C and stirred overnight. Upon completion, the mixture was cooled, diluted with DCM (50 mL), and filtered through a plug of celite, which was washed with more DCM (100 mL). The solvent was removed in vacuo, and the mixture was purified on silica gel using flash column chromatography (0→60% EtOAc in hexane) to give ( S )-3-allyl-3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1(2 H )-tert-Butyl formate (1.78 mg, 4.43 mmol, 89% yield) as an off-white solid.

[0992] LCMS: [M+H] + m / z = 402.2 amu.

[0993] Towards( S )-3-allyl-3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1(2 H To a solution of tert-butyl 4-(2-(2-methyl-1-oxo-4-yl)-formate (1.78 g, 4.4 mmol) in MeCN (7.2 mL) and EtOAc (7.2 mL) was added H₂O (9.5 mL), followed by NaIO₄ (3.8 g, 17 mmol), and finally RuCl₃·xH₂O (28 mg, 0.13 mmol). The mixture was stirred vigorously at room temperature for 20 minutes, at which point an additional 2 equivalents of NaIO₄ were added. After an additional 20 minutes, an additional 1 equivalent of NaIO₄ was added, and the reaction was stirred for a final hour. Upon completion, the reaction mixture was cooled to room temperature and poured into a half-saturated solution of Na₂S₂O₃ (30 mL). The mixture was extracted with EtOAc (30 mL * 3), and the combined organics were dried over Na₂SO₄, filtered, and concentrated to provide the crude acid, which was used without further purification.

[0994] LCMS: [M+H] + m / z= 420.2 amu.

[0995] The crude acid was added to MeOH (45 mL) and cooled to 0°C. SOCl2 (3.9 mL, 53 mmol) was added dropwise to the cooled solution, and the reaction was warmed to room temperature and stirred overnight. After completion, H2O (100 mL) was slowly added and then extracted with EtOAc (60 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated to obtain the crude product ( R )-methyl 4-(3-(2-methoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)butanoate, which was used in the next step without further purification.

[0996] LCMS: [M+H] + m / z = 320.1 amu.

[0997] To crude product ( R To a solution of methyl 4-(3-(2-methoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)butanoate (1.42 g, 4.43 mmol, est.) in THF (45 mL) was added BH3·THF (13.3 mL, 13 mmol, 1 M in THF). The reaction was heated to 50°C and stirred overnight. Upon completion, 1 M HCl was slowly added dropwise to quench the reaction until no more bubbles were observed. After stirring for another 20 minutes, the aqueous solution was made basic using 2 M NaOH. The mixture was extracted with DCM (100 mL * 3), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product ( R )-methyl 4-(3-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydroquinolin-3-yl)butanoate, which was used without further purification.

[0998] LCMS: [M+H] + m / z = 306.1 amu.

[0999] To crude product ( RTo a cooled (0°C) solution of methyl 4-(3-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydroquinolin-3-yl)butanoate (1.35 g, 4.4 mmol, est.) in CHCl3 / MeOH (2:1, 45 mL) was added AcOH (2.5 mL, 44 mmol), followed by formaldehyde solution (1.8 mL, 22 mmol, 37% in H2O). The mixture was stirred for 1 hour, then NaBH(OAc)3 (1.88 g, 8.9 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for an additional 4 hours, the reaction was quenched with half-saturated NaHCO3 (100 mL) and extracted with DCM (60 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified using flash column chromatography on silica gel (10→80% EtOAc in hexanes) to give ( R )-methyl 4-(3-(2-methoxy-2-oxoethyl)-1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)butanoate (270 mg, 0.94 mmol, 75% yield) as a light yellow foam.

[1000] 1 H NMR (400 MHz, chloroform- d ) δ 7.09 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 6.95(dd, J = 7.3, 1.1 Hz, 1H), 6.68 – 6.52 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.14 (dd, J = 11.5, 1.7 Hz, 1H), 3.00 (d, J = 11.5, 1H), 2.90 (s, 3H), 2.78 –2.58 (m, 2H), 2.41 (d, J = 14.7 Hz, 1H), 2.37 – 2.23 (m, 3H), 1.78 – 1.64 (m,2H), 1.55 – 1.33 (m, 2H) ppm

[1001] LCMS: [M+H] + m / z = 320.1 amu.

[1002] Towards( RTo a cooled (-78°C) solution of methyl 4-(3-(2-methoxy-2-oxoethyl)-1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)butanoate (398 mg, 1.3 mmol) in THF (12.5 mL) was added LDA (1.38 mL, 2.5 mmol, 1.8 M in hexanes). The mixture was warmed to room temperature and stirred for 2 hours. The reaction was then quenched with saturated NH4Cl (30 mL) and extracted with DCM (20 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The mixture was purified on silica gel using flash column chromatography (0→40% EtOAc in hexanes) to give (1 R )-1'-methyl-3-oxo-1',4'-dihydro-2' H -Methyl spiro[cyclohexane-1,3'-quinoline]-4-carboxylate (270 mg, 0.94 mmol, 75% yield) as a light yellow-foam.

[1003] LCMS: [M+H] + m / z = 288.1 amu.

[1004] To contain (1 R )-1'-methyl-3-oxo-1',4'-dihydro-2' H To a vial of a solution of methyl-spiro[cyclohexane-1,3'-quinoline]-4-carboxylate (135 mg, 0.47 mmol) in MeCN (2.4 mL) was added thiourea (43 mg, 0.56 mmol) followed by DBU (105 µL, 0.70 mmol). The vial was sealed and the reaction was stirred overnight. Upon completion, the mixture was cooled to room temperature, poured into saturated NaHCO3 (10 mL), and extracted with DCM (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product ( R )-2-mercapto-1'-methyl-1',4',5,8-tetrahydro-2' H ,6 H -Spiro[quinazoline-7,3'-quinoline]-4-ol was used in the next step without further purification.

[1005] LCMS: [M+H] + m / z = 314.1 amu.

[1006] To contain crude ( R )-2-mercapto-1'-methyl-1',4',5,8-tetrahydro-2' H ,6 HTo a vial of 7-spiro[quinazoline-7,3'-quinoline]-4-ol (147 mg, 0.47 mmol, est.) was added EtOH (1.7 mL) followed by 1M NaOH (0.52 mL, 0.52 mmol, aq.). Once the substrate was completely dissolved, MeI (33 µL, 0.52 mmol) was added. The reaction was stirred for 1 hour, then saturated NaHCO3 (10 mL) was added and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product ( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H -Spiro[quinazoline-7,3'-quinoline]-4-ol was used in the next step without further purification.

[1007] LCMS: [M+H] + m / z = 328.1 amu.

[1008] To crude product ( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H -spiro[quinazoline-7,3'-quinoline]-4-ol (83 mg, 0.25 mmol) in DCM (1 mL) was added N , N -Diisopropylethylamine (88 µL, 0.51 mmol). After stirring for 5 minutes, the mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (380 µL, 0.38 mmol, 1M in DCM) was added. The reaction was stirred for 2 hours, then hexanes (2 mL) were added and the mixture was passed through a silica gel plug, rinsing with 30% EtOAc in hexanes (20 mL). The combined organics were concentrated in vacuo to give Intermediate 7-2, ( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H -Spiro[quinazoline-7,3′-quinolin]-4-yl trifluoromethanesulfonate was used in subsequent reactions without further purification.

[1009] LCMS: [M+H] + m / z = 460.1 amu.

[1010] Synthetic intermediate 7-3

[1011]

[1012] To intermediate 7-2, ( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H To a cooled (0°C) solution of spiro[quinazoline-7,3'-quinolin]-4-yl trifluoromethanesulfonate (126 g, 0.27 mmol) in DCM (3 mL) was added triethylamine (191 µL, 1.4 mmol) followed by ( S )-2-(piperazin-2-yl)acetonitrile·2HCl (79 mg, 0.49 mmol). The resulting solution was warmed to room temperature and stirred for 6 hours. After the starting material was consumed, di-tert-butyl dicarbonate (240 mg, 1.1 mmol) was added, the reaction was heated to 40°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, poured into saturated NaHCO3 (15 mL, aq.) and extracted with DCM (10 mL * 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography (10→80% EtOAc in hexane) to give ( S )-2-(cyanomethyl)-4-(( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H -butyl spiro[quinazoline-7,3'-quinoline]-4-yl)piperazine-1-carboxylate (119 mg, 0.22 mmol, 81% yield) as a white foam.

[1013] LCMS: [M+H] + m / z = 535.2 amu.

[1014] Towards( S )-2-(cyanomethyl)-4-(( R )-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2' H ,6 H To a cooled (0°C) solution of tert-butyl-spiro[quinazoline-7,3'-quinolin]-4-yl)piperazine-1-carboxylate (119 mg, 0.22 mmol) in DCM (2.2 mL) was added m CPBA (154 mg, 0.66 mmol). The mixture was stirred for 30 minutes, then half-saturated NaHCO3 (5 mL, aq.) was added and the mixture was extracted with DCM (5 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (7R )-4-(( S )-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-1'-methyl-2-(methylsulfonyl)-1',4',5,8-tetrahydro-2' H ,6 H -Spiro[quinazoline-7,3'-quinoline]1'-oxide was used in the next step without further purification.

[1015] LCMS: [M+H] + m / z = 583.2 amu.

[1016] To a cooled (0 °C) vial containing NaH (26 mg, 0.68 mmol, 60% dispersion in mineral oil) was added THF (1 mL) followed by ( S )-(1-methylpyrrolidin-2-yl)methanol (132 µL, 1.11 mmol). The mixture was stirred for 45 minutes, at which time the crude product (7 R )-4-(( S )-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-1'-methyl-2-(methylsulfonyl)-1',4',5,8-tetrahydro-2' H ,6 H -spiro[quinazoline-7,3'-quinoline]1'-oxide (126 mg, 0.22 mmol, est.). The mixture was warmed to room temperature and stirred for 3 hours. After completion, the reaction was quenched with saturated NH4Cl (5 mL, aq.) and the mixture was extracted with DCM (5 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (7 R )-4-(( S )-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H -Spiro[quinazoline-7,3'-quinoline]1'-oxide was used in the next step without further purification.

[1017] LCMS: [M+H] + m / z = 618.3 amu.

[1018] To a solution containing the crude product (7 R )-4-(( S)-4-(tert-butoxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H To a vial containing 1'-spiro[quinazoline-7,3'-quinoline]1'-oxide (138 mg, 0.22 mmol, est.) was added B2Pin2 (28 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 hour, at which time saturated NaHCO3 (5 mL, aq.) was added and the mixture was extracted with DCM (5 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Intermediate 7-3, ( S )-2-(cyanomethyl)-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H -tert-Butyl spiro[quinazoline-7,3'-quinolin]-4-yl)piperazine-1-carboxylate was used in the subsequent reaction without further purification.

[1019] LCMS: [M+H] + m / z = 602.3 amu.

[1020] Synthesis of compound C-22

[1021] To a solution containing intermediate 7-3, ( S )-2-(cyanomethyl)-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H To a vial of tert-butyl 2-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazine-1-carboxylate (134 mg, 0.22 mmol, est.) was added H3PO4 (137 µL, 2.2 mmol) dropwise. The reaction was stirred at room temperature for 2 hours, at which time H2O (5 mL) was added and the solution was made basic by slowly adding 2 M NaOH solution (aq.). Once basic, the mixture was extracted with DCM (5 mL * 3), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product 2-(( S )-4-(( R )-1'-methyl-2-(((S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H -spiro[quinazoline-7,3'-quinoline]-4-yl)piperazin-2-yl)acetonitrile was used in the next step without further purification.

[1022] LCMS: [M+H] + m / z = 502.3 amu.

[1023] To the crude product 2-(( S )-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H To a cooled (0°C) solution of 1-spiro[quinazoline-7,3'-quinolinyl]-4-yl)piperazin-2-yl)acetonitrile (57 mg, 0.11 mmol, est.) in DCM (2.3 mL) was added N , N 1-Diisopropylethylamine (200 µL, 1.1 mmol) was added, followed by acrylic anhydride (40 µL, 0.34 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→60% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to yield compound C-22, 2-(( S )-1-acryloyl-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H -spiro[quinazoline-7,3'-quinoline]-4-yl)piperazin-2-yl)acetonitrile (7.9 mg, 0.014 mmol, 13% yield over 5 steps) as a fluffy off-white solid.

[1024] 1 H NMR (400 MHz, acetonitrile- d 3, TFA salt) δ 10.48 (s, 1H), 7.14 – 7.00 (m, 1H), 6.94 (dd, J= 7.4, 1.6 Hz, 1H), 6.82 – 6.64 (m, 2H), 6.61 (td, J = 7.3, 1.1Hz, 1H), 6.25 (dd, J = 16.7, 2.1 Hz, 1H), 5.77 (dd, J = 10.6, 2.1 Hz, 1H), 5.00 (bs, 1H), 4.81 – 4.61 (m, 2H), 4.49 (d, J = 14.1 Hz, 1H), 4.33 (bs, 1H), 4.12 – 3.88 (m, 1H), 3.78 – 3.63 (m, 2H), 3.62 – 3.38 (m 2H), 3.15 – 3.00 (m,3H), 2.97 – 2.85 (m, 5H), 2.80 (bs, 2H), 2.75 – 2.51 (m, 6H), 2.50 (s, 14H), 2.34 – 2.23 (m, 1H), 2.15 – 1.96 (m, 3H), 1.69 – 1.54 (m, 2H) ppm

[1025] LCMS: [M+H] + m / z = 556.3 amu.

[1026] Synthesis of compound C-23

[1027] To the crude product 2-(( S )-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H To a cooled (0 °C) solution of 1-spiro[quinazoline-7,3'-quinoline]-4-yl)piperazin-2-yl)acetonitrile (57 mg, 0.11 mmol, crude est.) in DCM (2.3 mL) was added N , N-diisopropylethylamine (200 µL, 1.1 mmol) was added, followed by 2-fluoroacrylic anhydride (55 mg, 0.34 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→60% MeCN in H2O + 25% TFA). The combined fractions containing the desired product were lyophilized to yield compound C-23, 2-(( S )-1-(2-fluoroacryloyl)-4-(( R )-1'-methyl-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2' H ,6 H -spiro[quinazoline-7,3'-quinoline]-4-yl)piperazin-2-yl)acetonitrile (10.5 mg, 0.018 mmol, 16% yield over 5 steps) as a fluffy off-white solid.

[1028] 1 H NMR (400 MHz, acetonitrile- d 3, TFA salt) δ 10.65 (s, 1H), 7.07 (ddd, J = 8.2,7.3, 1.6 Hz, 1H), 6.93 (dd, J = 7.4, 1.6 Hz, 1H), 6.67 (dd, J = 8.3, 1.1 Hz,1H), 6.60 (td, J = 7.3, 1.1 Hz, 1H), 5.42 – 5.09 (m, 2H), 4.84 (bs, 1H), 4.70(qd, J = 12.4, 4.2 Hz, 2H), 4.47 (d, J = 14.1 Hz, 1H), 4.32 (d, J = 12.1 Hz,1H), 3.87 (bs, 4H), 3.76 – 3.61 (m, 2H), 3.52 (d, J= 14.1 Hz, 1H), 3.43 –3.30 (m, 1H), 3.16 – 2.98 (m, 3H), 2.98 – 2.80 (m, 7H), 2.80 – 2.50 (m, 6H),2.37 – 2.22 (m, 1H), 2.18 – 1.96 (m, 2H), 1.70 – 1.55 (m, 2H) ppm

[1029] LCMS: [M+H] + m / z = 574.3 amu.

[1030] Example 8: Synthesis of Compounds C-24 to C-30

[1031] Synthetic intermediate 8-1

[1032]

[1033] Under N2 atmosphere, Pd2(dba)3 (174 mg, 0.19 mmol) and ( R )- p -(CF3)3- t -BuPHOX (300 mg, 0.51 mmol) was suspended in degassed anhydrous MTBE (40 mL), and the mixture was warmed to 25°C and stirred for 45 minutes. Separately, intermediate 6-1,2-(4-ethoxy-4-oxo-butyl)-5-fluoro-1-oxo-tetrahydronaphthalene-2-carboxylic acid allyl ester (2.3 g, 6.4 mmol) was dissolved in MTBE (40 mL) and bubbled with N2 for 20 minutes before being added to the catalyst mixture. After 13 hours, the reaction was exposed to air and amended with 0.3 volumes of hexane and a small amount of silica gel. The mixture was stirred for 10 minutes before being filtered through a thin pad of silica gel and concentrated. The residue was purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to afford (R)-ethyl 4-(2-allyl-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.89 g, 5.94 mmol, 94% yield) as a light yellow viscous oil.

[1034] LCMS: [M+H] + m / z = 319.2 amu.

[1035] Ethyl (R)-4-(2-allyl-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.89 g, 5.9 mmol) was dissolved in EtOAc (11.6 mL) and MeCN (11.6 mL) and treated with H2O (18.2 mL), NaIO4 (6.35 g, 30 mmol) and RuCl3·xH2O (27.1 mg, 0.13 mmol). The mixture was stirred vigorously at room temperature. After 2 h, the mixture was diluted with 0.5 M NaHSO4 and EtOAc, stirred for 5 min, and then filtered through celite. The organic phase was collected and the aqueous phase was extracted two more times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered through celite, concentrated, and further dried in vacuo. The residue was taken up in MeOH (35 mL), cooled to 0°C, and treated with SOCl2 (4.3 mL, 59 mmol). The mixture was treated dropwise. The cooling bath was removed and the mixture was stirred at room temperature. After 2 hours, the mixture was concentrated and reconstituted in 7:3 Et2O:hexane, filtered through a thin pad of silica gel, and concentrated to give ( R )-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.89 g, 95% yield) as a light yellow oil. Rf = 0.39 (1:1 hexanes:Et2O).

[1036] LCMS: [M+H] + m / z = 337.1 amu.

[1037] Will( R )-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.64 g, 4.9 mmol) was dissolved in EtOAc (25 mL) and treated with Pd / C, 10 wt% (320 mg) and HClO4, 60% (80 µL, 0.52 mmol), and the vessel was charged with H2. After 11 hours, the mixture was filtered through celite and concentrated. The residue was added to MeOH (28 mL) and treated dropwise with SOCl2 (2.0 mL, 28 mmol) at 0°C. The cooling bath was removed and the mixture was stirred for 2 hours, then concentrated, diluted with H2O, and extracted with Et2O (3 times). The combined extracts were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated to give ( S)-methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.69 g, 5.24 mmol, 93% yield). Rf = 0.43 (8:2 hexanes:EtOAc).

[1038] LCMS: [M+H] + m / z = 322.2 amu.

[1039] NaH (251.64 mg, 6.3 mmol) was suspended in anhydrous toluene (20 mL) and treated with MeOH (53 µL, 1.3 mmol). The mixture was stirred until gas evolution ceased, then ( S A solution of methyl 4-(5-fluoro-2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.69 g, 5.2 mmol) in toluene (10 mL) was added and the mixture was heated to 70°C. After 4 hours, the mixture was poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product (1 S )-methyl 5'-fluoro-3-oxo-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate (1.16 g, 76% yield) as a light yellow oil which was used in the next step without further purification.

[1040] 1 H NMR (600 MHz, chloroform- d ) δ 12.12 (d, J = 1.2 Hz, 1H), 7.09 – 7.04 (m,1H), 6.86 – 6.81 (m, 2H), 3.79 – 3.75 (m, 3H), 2.77 (t, J = 6.9 Hz, 2H), 2.67(dd, J = 16.4, 0.9 Hz, 1H), 2.56 (d, J = 16.2 Hz, 1H), 2.36 – 2.26 (m, 2H), 2.19 (dq, J = 18.2, 1.5 Hz, 1H), 2.12 (dq, J = 18.2, 1.4 Hz, 1H), 1.72 (dtt, J= 13.5, 6.7, 1.2 Hz, 1H), 1.63 (dtd, J = 13.5, 6.7, 1.2 Hz, 1H), 1.59 –1.52 (m, 1H), 1.51 – 1.43 (m, 1H) ppm

[1041] LCMS: [M+H] + m / z = 291.1 amu.

[1042] The crude product (1 S )-methyl 5'-fluoro-3-oxo-3',4'-dihydro-1'H-spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate (488 mg, 1.7 mmol) was dissolved in anhydrous MeCN (8.4 mL) and treated with thiourea (154 mg, 2.0 mmol) and DBU (376 µL, 2.5 mmol), and the mixture was heated to 80°C. After 3 hours, the mixture was cooled to room temperature, concentrated to approximately 1 mL, and diluted with aqueous NaH2PO4. The resulting precipitate was collected by filtration, and the still wet material was suspended in EtOH (8.4 mL), treated with 1M NaOH (1.85 mL, 1.9 mmol) and MeI (126 µL, 2.0 mmol), and the mixture was stirred vigorously at room temperature for 19 hours. The mixture was poured into aqueous NaH2PO4 and extracted with CHCl3 (3 times). The combined extracts were washed with brine, dried over Na2SO4, and purified by flash column chromatography on silica gel (0→10% MeOH in CH2Cl2) (Rf = 0.37 (95:5 CHCl3:MeOH)) to give ( S )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (403.8 mg, 1.22 mmol, 72.7% yield) as a white solid.

[1043] LCMS: [M+H] + m / z = 331.1 amu.

[1044] Will( S )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-ol (229 mg, 0.69 mmol) was suspended in anhydrous DCM (1.7 mL) and washed with freshly distilled iThe mixture was treated with Pr2EtN (241 µL, 1.4 mmol), then cooled to 0°C and trifluoromethanesulfonic anhydride, 1M in DCM (1040 µL, 1.0 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour, then diluted with 2 volumes of hexanes and filtered through a silica pipette column, rinsing with 9:1 hexanes:EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) (Rf = 0.39 (9:1 hexanes:EtOAc)) to provide intermediate 8-1, ( S )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (256.8 mg, 0.555 mmol, 80% yield) as a colorless glassy oil.

[1045] LCMS: [M+H] + = 463.1 amu.

[1046] Synthetic intermediate 8-2

[1047]

[1048]

[1049] Intermediate 8-1, ( S )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (114.5 mg, 0.25 mmol) was dissolved in anhydrous DMF (707 µL) and i Pr2EtN (129 µL, 0.74 mmol) and 2-[(2S)-piperazin-2-yl]acetonitrile dihydrochloride (58.9 mg, 0.30 mmol) were treated and the mixture was stirred at room temperature for 30 minutes. Boc2O (85.3 µL, 0.37 mmol) was added and the mixture was stirred for 15 hours, then diluted with EtOAc and washed with saturated NH4Cl, brine, dried over Na2SO4, filtered through a thin pad of silica gel and concentrated. The crude isolate was purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( S )-2-(cyanomethyl)-4-(( S)-tert-butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazine-1-carboxylate (167.8 mg, >100% yield) as a white foam.

[1050] LCMS: [M+H] + m / z = 538.3 amu.

[1051] Will( S )-2-(cyanomethyl)-4-(( S )-tert-Butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (133.1 mg, 0.25 mmol) was dissolved in DCM (825 µL), cooled to 0°C, and treated with mCPBA (62.7 mg, 0.27 mmol). After 20 minutes, the mixture was diluted with Et2O and washed with half-saturated NaHCO3 (2 times), brine, dried over Na2SO4, filtered, and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-((2 S )-tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazine-1-carboxylate was used without further purification.

[1052] LCMS: [M+H] + m / z = 554.3 amu

[1053] 1-Methyl-L-prolinol (57 mg, 0.50 mmol) was dissolved in anhydrous THF (1.5 mL) and KO t Bu, 1.7M in THF (291 µL, 0.50 mmol) was treated and the mixture was stirred for 5 min and then added to the crude (2 S )-2-(cyanomethyl)-4-((2 STo a solution of tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (137.1 mg, 0.25 mmol) in anhydrous THF (1 mL). After 30 minutes, the mixture was poured into aqueous K2CO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on basic alumina (0→100% Et2O in hexanes, then 100% EtOAc) to afford ( S )-2-(cyanomethyl)-4-(( S )-5-fluoro-2'-((( S To the solution was added tert-butyl 4-[(2 ...

[1054] LCMS: [M+H] + m / z = 605.4 amu.

[1055] At room temperature, ( S )-2-(cyanomethyl)-4-(( S )-5-fluoro-2'-((( S tert-Butyl 3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (113.5 mg, 0.19 mmol) was treated with 4N HCl in dioxane (2 mL) for 30 minutes. The mixture was then concentrated, dissolved in 1N HCl, and washed with Et2O (2 times). The combined ether washes were extracted once with 1N HCl. The combined aqueous phases were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were dried over K2CO3, filtered, and concentrated to give intermediate 8-2, 2-(( S )-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (86.5 mg, 0.171 mmol, 91% yield).

[1056] LCMS: [M+H] +m / z = 504.4 amu.

[1057] Synthesis of compound C-24

[1058] At 0°C, the intermediate 8-2, 2-(( S )-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (21.6 mg, 0.043 mmol) was dissolved in anhydrous MeCN (400 µL) and treated with acrylic anhydride (7.4 µL, 0.064 mmol) and then warmed to room temperature. After 10 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18 10→60% ACN in H2O+0.25% TFA) to give compound C-24, 2-(( S )-1-acryloyl-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (7.6 mg, 32% yield) as a colorless film.

[1059] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.74 (s, 1H), 7.14 (td, J = 8.1, 5.9 Hz,1H), 6.90 (dd, J = 9.7, 7.4 Hz, 2H), 6.72 (s, 1H), 6.25 (dd, J = 16.7, 2.1Hz, 1H), 5.77 (dd, J = 10.6, 2.1 Hz, 1H), 4.80 – 4.64 (m, 2H), 4.51 (dt, J =14.1, 2.4 Hz, 1H), 4.42 – 4.25 (m, 1H), 3.96 (d, J= 24.6 Hz, 1H), 3.77 –3.62 (m, 2H), 3.63 – 3.40 (m, 2H), 3.14 – 3.02 (m, 1H), 2.91 (s, 3H), 2.88 –2.60 (m, 11H), 2.35 – 2.23 (m, 1H), 2.16 – 1.91 (m, 4H), 1.88 – 1.78 (m, 1H), 1.76 – 1.63 (m, 2H), 1.57 (dt, J = 12.7, 6.2 Hz, 1H) ppm

[1060] LCMS: [M+H] + m / z = 559.3 amu.

[1061] Synthesis of compound C-25

[1062] At room temperature, the intermediate 8-2, 2-(( S )-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)piperazin-2-yl)acetonitrile (21.6 mg, 0.043 mmol) was dissolved in anhydrous MeCN (400 µL) and treated with 2-fluoroacrylic anhydride (10.4 mg, 0.0643 mmol). After 25 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18 10→60% ACN in HO+0.25% TFA) to afford compound C-25, 2-((S)-4-((S)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (20.1 mg, 0.0349 mmol, 81% yield).

[1063] 1 H NMR (400 MHz, acetonitrile- d 3) δ 9.90 (s, 1H), 6.15 (td, J= 8.1, 5.9 Hz,1H), 5.97 – 5.87 (m, 2H), 4.38 – 4.18 (m, 2H), 3.86 (s, 1H), 3.77 (dd, J =12.3, 5.7 Hz, 1H), 3.70 (dd, J = 12.3, 3.4 Hz, 1H), 3.56 (dt, J = 14.2, 2.3Hz, 1H), 3.38 (d, J = 9.8 Hz, 1H), 3.11 (s, 1H), 2.79 – 2.65 (m, 2H), 2.60 –2.50 (m, 1H), 2.48 – 2.31 (m, 1H), 2.17 – 2.04 (m, 1H), 1.94 (s, 3H), 1.92 –1.85 (m, 2H), 1.85 – 1.75 (m, 3H), 1.74 – 1.61 (m, 5H), 1.38 – 1.25 (m, 1H), 1.18 – 0.90 (m, 4H), 0.90 – 0.79 (m, 1H), 0.71 (dq, J = 20.4, 6.6 Hz, 2H),0.60 (dt, J = 13.1, 6.1 Hz, 1H) ppm

[1064] LCMS: [M+H] + m / z = 577.3 amu.

[1065] Synthesis of compound C-26

[1066] The intermediate 8-2, 2-(( S )-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (21.6 mg, 0.043 mmol) was dissolved in anhydrous MeCN (400 µL) and i Pr2EtN (14.9 µL, 0.086 mmol), trans-The mixture was treated with 4-dimethylaminocroton hydrochloride (14.2 mg, 0.086 mmol) and EDC•HCl (16.4 mg, 0.086 mmol), and the mixture was stirred at room temperature. After 16 h, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18 10→60% ACN in HO+0.25% TFA) to afford compound C-26, 2-((S)-1-((E)-4-(dimethylamino)but-2-enoyl)-4-((S)-5-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (20.5 mg, 0.0333 mmol, 78% yield) as a light brown stained film.

[1067] 1 H NMR (400 MHz, acetonitrile- d 3) δ 12.13 (s, 1H), 10.63 (s, 1H), 7.14 (td, J = 8.2, 5.9 Hz, 1H), 6.94 – 6.85 (m, 2H), 6.79 – 6.69 (m, 1H), 4.82 – 4.64 (m,2H), 4.60 – 4.28 (m, 2H), 4.12 – 3.94 (m, 1H), 3.81 (d, J = 6.2 Hz, 2H), 3.77– 3.31 (m, 5H), 3.20 – 3.01 (m, 2H), 2.92 (s, 3H), 2.87 – 2.60 (m, 16H), 2.35– 2.23 (m, 1H), 2.16 – 1.90 (m, 4H), 1.88 – 1.77 (m, 1H), 1.71 (dt, J = 13.4,7.0 Hz, 2H), 1.59 (s, 1H) ppm

[1068] LCMS: [M+H] + m / z = 616.4 amu.

[1069] Synthetic intermediate 8-3

[1070]

[1071]

[1072] Intermediate 8-1, ( S )-5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate (114.5 mg, 0.25 mmol) was dissolved in anhydrous DMF (710 µL) and i Pr2EtN (129 μL, 0.74 mmol) and the dihydrochloride salt of intermediate 6-4: (2 R )-2-(methoxymethyl)piperazine dihydrochloride (60.3 mg, 0.30 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Boc2O (85 μL, 0.37 mmol) was then added and stirring continued for 16 hours. The mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (2 times), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( R )-4-(( S )-tert-butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (148.1 mg, >100% yield) as a white foam.

[1073] LCMS: [M+H] + m / z = 543.3 amu.

[1074] Will ( R )-4-(( S )-tert-Butyl 5-fluoro-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (134.4 mg, 0.25 mmol) was dissolved in DCM (825µL), cooled to 0°C, and treated with mCPBA (62.7 mg, 0.27 mmol). After 20 minutes, the mixture was diluted with Et2O and washed with half-saturated NaHCO3 (2 times), brine, dried over Na2SO4, and concentrated to give the crude product (2 R )-4-((2 STo the solution was added tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (150.1 mg, >100% yield) as a white foam which was used in the next step without purification.

[1075] LCMS: [M+H] + m / z = 559.3 amu.

[1076] 1-Methyl-L-prolinol (57.0 mg, 0.50 mmol) was dissolved in anhydrous THF (1.5 mL) and quenched with Ko t Bu, 1.7M in THF (291.29 μL, 0.50 mmol) was treated. The mixture was stirred for 5 minutes and then added to the crude product (2 R )-4-((2 S To a solution of tert-butyl 5-fluoro-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (138.3 mg, 0.25 mmol, est.) in anhydrous THF (1 mL). After 1 hour, the mixture was poured into aqueous K2CO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product ( R )-4-(( S )-5-fluoro-2'-((( S tert-Butyl (1-methylpyrrolidin-2-yl)methoxy-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazine-1-carboxylate (165.9 mg, >100% yield) as a pale yellow foam, which was used in the subsequent step without purification. Rf = 0.45 (95:5 CHCl:MeOH + 2% EtN).

[1077] LCMS: [M+H] + m / z = 605.4 amu.

[1078] At room temperature, the crude product ( R )-4-(( S )-5-fluoro-2'-((( Stert-Butyl 2-(methoxymethyl)piperazine-1-carboxylate (165.9 mg, 0.27 mmol) was treated with 4N HCl in dioxane (2 mL) for 30 minutes. The mixture was dissolved in 1N HCl and washed with Et2O (2 times), and the combined ether layers were extracted once with 1N HCl. The combined aqueous phases were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were dried over K2CO3, filtered, and concentrated to give intermediate 8-3, ( S )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (123.9 mg, 0.243 mmol, 89% yield).

[1079] LCMS: [M+H] + m / z = 510.3 amu.

[1080] Synthesis of compound C-27

[1081] Intermediate 8-3, ( S )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (31.0 mg, 0.061 mmol) was dissolved in MeCN (610 µL) and treated with acrylic anhydride (10.5 µL, 0.091 mmol). After 1 hour, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→55% ACN in H2O+0.25% TFA) to give compound C-27, 1-(( R )-4-((S)-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazin-1-yl)prop-2-en-1-one (29.2 mg, 0.0502 mmol, 83% yield) as a colorless film.

[1082] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.59 (s, 1H), 7.05 (td, J = 8.0, 5.9 Hz,1H), 6.86 – 6.76 (m, 2H), 6.62 (t, J = 13.2 Hz, 1H), 6.12 (dd, J = 16.8, 2.2Hz, 1H), 5.62 (dd, J = 10.6, 2.2 Hz, 1H), 4.74 – 4.61 (m, 1H), 4.62 – 4.46(m, 2H), 4.37 (s, 2H), 3.70 – 3.53 (m, 2H), 3.46 (dd, J = 13.9, 4.0 Hz, 2H),3.32 (d, J = 28.1 Hz, 3H), 3.18 (s, 3H), 3.01 (dt, J = 12.1, 8.3 Hz, 1H), 2.82 (s, 3H), 2.76 – 2.49 (m, 8H), 2.20 (ddd, J = 12.6, 8.3, 5.4 Hz, 1H), 2.11 – 1.81 (m, 4H), 1.76 (dt, J = 12.5, 6.5 Hz, 1H), 1.70 – 1.55 (m, 2H), 1.49 – 1.40 (m, 1H) ppm

[1083] LCMS: [M+H] + m / z = 582.3 amu.

[1084] Synthesis of compound C-28

[1085] Intermediate 8-3, ( S )-5-fluoro-4'-(( R )-3-(methoxymethyl)piperazin-1-yl)-2'-((( S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline] (31.0 mg, 0.061 mmol) was dissolved in MeCN (610 µL) and treated with 2-fluoroacrylic anhydride (14.8 mg, 0.091 mmol). After 90 minutes, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 10→55% ACN in H2O+0.25% TFA) to give compound C-28, 2-fluoro-1-(( R )-4-(( S )-5-fluoro-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]-4'-yl)-2-(methoxymethyl)piperazin-1-yl)prop-2-en-1-one (29.2 mg, 0.0502 mmol, 83% yield) as a colorless film.

[1086] 1 H NMR (400 MHz, acetonitrile- d 3) δ 10.72 (s, 1H), 7.05 (td, J = 8.0, 5.9 Hz,1H), 6.85 – 6.76 (m, 2H), 5.20 – 5.03 (m, 2H), 4.69 (dd, J = 12.3, 5.3 Hz,1H), 4.61 – 4.35 (m, 4H), 3.70 – 3.54 (m, 2H), 3.47 – 3.31 (m, 3H), 3.30 –3.20 (m, 2H), 3.18 (s, 3H), 3.00 (dt, J = 11.7, 8.4 Hz, 1H), 2.83 (s, 3H), 2.75 – 2.48 (m, 8H), 2.27 – 2.17 (m, 1H), 2.07 – 1.81 (m, 4H), 1.80 – 1.68(m, 1H), 1.68 – 1.51 (m, 2H), 1.45 (ddd, J = 13.2, 7.9, 5.1 Hz, 1H) ppm

[1087] LCMS: [M+H] + m / z = 582.3 amu.

[1088] Example 9: Synthesis of Compounds C-29 and C-30

[1089] Synthetic intermediate 9-1

[1090]

[1091] Under N2 atmosphere, ( S )- p -(CF3)3- t -BuPHOX (368 mg, 0.62 mmol) and Pd2(dba)3 (214 mg, 0.23 mmol) were dissolved in degassed anhydrous toluene (68 mL), and the mixture was stirred at room temperature for 30 minutes. Separately, 2-(4-ethoxy-4-oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid allyl ester (2.68 g, 7.8 mmol) was dissolved in toluene (30 mL) and bubbled with N2 for 20 minutes before being added to the catalyst mixture. After 13 hours, the reaction was warmed to 40°C. After an additional 24 hours, the mixture was cooled, exposed to air, amended with a small amount of silica gel and stirred for 10 minutes before being filtered through a thin pad of silica gel. The filtrate was concentrated and purified by flash column chromatography on silica gel (0→10% EtOAc in hexanes) to give ( S )-ethyl 4-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.39 g, >100% yield) as a yellow oil.

[1092] 1 H NMR matched that of the R enantiomer.

[1093] LCMS: [M+H] + m / z = 301.2 amu.

[1094] Will( SEthyl 4-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.76 g, 5.9 mmol) was dissolved in EtOAc (12 mL) and MeCN (12 mL), then treated with H₂O (18 mL), RuCl₃·xH₂O (27 mg, 0.13 mmol), and NaIO₄ (5 g, 23 mmol), and the mixture was stirred vigorously at room temperature. After 1 hour, NaIO₄ (1.25 g, 5.9 mmol) was added. After 90 minutes, the mixture was poured into 0.5 M NaHSO₄ and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na₂SO₄, filtered through Celite, and concentrated. The residue was dissolved in methanol (35 mL), cooled to 0°C, and SOCl₂ (5.3 mL, 73 mmol) was added dropwise. The mixture was stirred at room temperature for 90 minutes, amended with H2O (10 mL) and stirred for 15 minutes, then poured into H2O and extracted with Et2O (3 times). The combined extracts were washed with NaHCO3 (3 times), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( S )-methyl 4-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.22 g, 3.84 mmol, 66% yield) as a light yellow oil.

[1095] 1 H NMR matched that of the R enantiomer.

[1096] LCMS: [M+H] + m / z = 319.1 amu.

[1097] Will( SMethyl 4-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.22 g, 3.8 mmol) was dissolved in EtOAc (10 mL) and treated with Pd / C, 10 wt% (wet) (240 mg) and HClO₄ (62 µL, 0.57 mmol), and the vessel was sparged with H₂. After 17 hours, the reaction mixture was filtered through celite and concentrated. The residue was added to MeOH (10 mL), cooled to 0°C, treated with SOCl₂ (1.5 mL, 19 mmol), and then warmed to room temperature. After 1.5 hours, the mixture was concentrated, diluted with H₂O, and extracted with Et₂O (3 times). The combined extracts were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered through a pad of silica gel, and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to afford ( R )-methyl 4-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (1.02 g, 3.36 mmol, 88% yield).

[1098] 1 H NMR matched that of the S enantiomer.

[1099] LCMS: [M+H] + m / z = 305.2 amu.

[1100] Towards( R To a cooled (-78°C) solution of methyl 4-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (287 mg, 0.94 mmol) in THF (9.5 mL) was added LDA (0.79 mL, 1.42 mmol, 1.8 M in hexanes). The mixture was warmed to room temperature and stirred for 2 hours. The reaction was then quenched with saturated NH4Cl (20 mL) and extracted with DCM (15 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (1 R )-3-oxo-3',4'-dihydro-1' H -Methyl spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate was used in the next step without further purification.

[1101] LCMS: [M+H] + m / z = 273.1 amu.

[1102] To contain crude product (1 R)-3-oxo-3',4'-dihydro-1' H To a vial of a solution of methyl-spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate (257 mg, 0.94 mmol, est.) in MeCN (4.7 mL) was added thiourea (86 mg, 1.13 mmol) followed by DBU (211 µL, 1.41 mmol). The vial was sealed and the reaction was stirred overnight. Upon completion, the mixture was cooled to room temperature, poured into saturated NaHCO3 (15 mL), and extracted with DCM (15 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product ( S )-2'-mercapto-3,4,5',8'-tetrahydro-1 H ,6' H -Spiro[naphthalene-2,7'-quinazoline]-4'-ol was used in the next step without further purification.

[1103] LCMS: [M+H] + m / z = 299.1 amu.

[1104] To contain crude ( S )-2'-mercapto-3,4,5',8'-tetrahydro-1 H ,6' H To a vial of 2-spiro[naphthalene-2,7'-quinazoline]-4'-ol (281 mg, 0.94 mmol, est.) was added EtOH (4 mL) followed by 1M NaOH (1.05 mL, 1.05 mmol, aq.). Once the substrate was completely dissolved, MeI (65 µL, 1.04 mmol) was added. The reaction was stirred for 1 h, then saturated NaHCO3 (15 mL) was added and the mixture was extracted with DCM (15 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product ( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' H -Spiro[naphthalene-2,7'-quinazoline]-4'-ol was used in the next step without further purification.

[1105] LCMS: [M+H] + m / z = 313.1 amu.

[1106] To crude product ( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' HA solution of spiro[naphthalene-2,7'-quinazoline]-4'-ol (90 mg, 0.29 mmol, est.) in DCM (1.2 mL) was added N , N -Diisopropylethylamine (100 µL, 0.58 mmol). After stirring for 5 minutes, the mixture was cooled to 0°C and trifluoromethanesulfonic anhydride (432 µL, 0.43 mmol, 1M in DCM) was added. The reaction was stirred for 2 hours, then hexanes (2.4 mL) were added and the mixture was passed through a silica gel plug, rinsing with 30% EtOAc in hexanes (20 mL). The combined organics were concentrated in vacuo to give intermediate 9-1, ( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7′-quinazoline]-4′-yl trifluoromethanesulfonate, which was used in the subsequent reaction without further purification.

[1107] LCMS: [M+H] + m / z = 445.1 amu.

[1108] Synthetic intermediate 9-2

[1109]

[1110]

[1111] To intermediate 9-1, ( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 2-spiro[naphthalene-2,7'-quinazoline]-4'-yl trifluoromethanesulfonate (128 g, 0.29 mmol) in DCM (3.2 mL) was added triethylamine (201 µL, 1.44 mmol) followed by ( S )-2-(piperazin-2-yl)acetonitrile·2HCl (84 mg, 0.52 mmol). The resulting solution was warmed to room temperature and stirred for 5 hours. After the starting material was observed to be consumed, di-tert-butyl dicarbonate (252 mg, 1.16 mmol) was added, the reaction was heated to 40°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into saturated NaHCO3 (15 mL, aq.) and extracted with DCM (10 mL * 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography (0→50% EtOAc in hexane) to give ( S)-2-(cyanomethyl)-4-(( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' H -butyl spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (150 mg, 0.29 mmol, quantitative) as a white foam.

[1112] LCMS: [M+H] + m / z = 520.2 amu.

[1113] Towards( S )-2-(cyanomethyl)-4-(( S )-2'-(methylthio)-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of tert-butyl-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (150 mg, 0.29 mmol) in DCM (2.9 mL) was added m CPBA (73 mg, 0.32 mmol). The mixture was stirred for 30 minutes, then half-saturated NaHCO3 (10 mL, aq.) was added and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (2 S )-2-(cyanomethyl)-4-((2 S )-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1 H ,6' H -tert-Butyl spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate was used in the next step without further purification.

[1114] LCMS: [M+H] + m / z = 536.2 amu.

[1115] To a cooled (0 °C) vial containing NaH (35 mg, 0.86 mmol, 60% dispersion in mineral oil) was added THF (1 mL) followed by ( S )-(1-methylpyrrolidin-2-yl)methanol (171 µL, 1.44 mmol). The mixture was stirred for 45 minutes, at which time the crude product (2 S )-2-(cyanomethyl)-4-((2 S )-2'-(methylsulfinyl)-3,4,5',8'-tetrahydro-1H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (159 mg, 0.29 mmol, est.). The mixture was warmed to room temperature and stirred for 3 hours. After completion, the reaction was quenched with saturated NH4Cl (10 mL, aq.) and the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product ( S )-2-(cyanomethyl)-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H -tert-butyl spiro[naphthalene-2,7′-quinazoline]-4′-yl)piperazine-1-carboxylate, which was used in the subsequent step without further purification.

[1116] LCMS: [M+H] + m / z = 587.3 amu.

[1117] To a solution containing the crude product ( S )-2-(cyanomethyl)-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H To a vial of tert-butyl spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazine-1-carboxylate (141 mg, 0.24 mmol, est.) was added H3PO4 (147 µL, 2.4 mmol) dropwise. The reaction was stirred at room temperature for 2 hours, at which time H2O (10 mL) was added and the solution was made basic by slowly adding 2 M NaOH solution (aq.). Once basic, the mixture was extracted with DCM (10 mL * 3). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford Intermediate 9-2, 2-(( S )-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7′-quinazoline]-4′-yl)piperazin-2-yl)acetonitrile, which was used in the subsequent reaction without further purification.

[1118] LCMS: [M+H]+ m / z = 487.3 amu.

[1119] Synthesis of compound C-29

[1120] To intermediate 9-2, 2-(( S )-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (61 mg, 0.13 mmol, est.) in DCM (2.5 mL) was added N , N -diisopropylethylamine (220 µL, 1.25 mmol) was added, followed by acrylic anhydride (47 µL, 0.38 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 20→60% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to afford compound C-29, 2-(( S )-1-acryloyl-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (11.7 mg, 0.022 mmol, 17% yield over 5 steps) as a fluffy off-white solid.

[1121] 1 H NMR (400 MHz, acetonitrile- d 3, TFA salt) δ 10.64 (s, 1H), 7.24 – 6.91 (m, 4H), 6.87 – 6.59 (m, 1H), 6.25 (d, J = 16.9 Hz, 1H), 5.77 (d, J= 10.6 Hz, 1H),5.39 – 4.17 (m, 10H), 4.17 – 3.84 (m, 1H), 3.78 – 3.63 (m, 2H), 3.63 – 3.39(m, 2H), 3.18 – 3.03 (m, 1H), 3.03 – 2.43 (m, 10H), 2.43 – 2.22 (m, 1H), 2.22 – 1.98 (m, 2H), 1.85 – 1.50 (m, 4H) ppm

[1122] LCMS: [M+H] + m / z = 541.3 amu.

[1123] Synthesis of C-30

[1124] To intermediate 9-2, 2-(( S )-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H To a cooled (0°C) solution of 1-spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (61 mg, 0.13 mmol, est.) in DCM (2.5 mL) was added N , N 1-Diisopropylethylamine (220 µL, 1.26 mmol) was added, followed by 2-fluoroacrylic anhydride (31 mg, 0.19 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours, at which time the solution was concentrated in vacuo, added to DMSO, filtered, and purified using preparative HPLC (C18, 10→55% MeCN in H2O + 0.25% TFA). The combined fractions containing the desired product were lyophilized to provide compound C-30, 2-(( S )-1-(2-fluoroacryloyl)-4-(( S )-2'-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1 H ,6' H -spiro[naphthalene-2,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (16.2 mg, 0.029 mmol, 23% yield over 5 steps) as a fluffy off-white solid.

[1125] 1H NMR (400 MHz, acetonitrile- d 3, TFA salt) δ 10.88 (s, 1H), 7.21 – 6.94 (m, 4H), 6.13 – 5.11 (m, 5H), 4.97 – 4.61 (m, 3H), 4.50 (d, J = 14.2 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 4.08 (s, 1H), 3.78 – 3.61 (m, 2H), 3.59 – 3.25 (m, 3H), 3.14 – 2.98 (m, 1H), 2.92 (s, 3H), 2.90 – 2.81 (m, 3H), 2.77 (d, J = 16.4 Hz,1H), 2.72 – 2.57 (m, 4H), 2.37 – 2.18 (m, 1H), 2.16 – 1.96 (m, 2H), 1.87 –1.49 (m, 4H) ppm

[1126] LCMS: [M+H] + m / z = 559.3 amu.

[1127] Example 10: Synthesis of Compounds C-31 and C-32

[1128] Synthetic intermediate 10-1

[1129]

[1130]

[1131] A mixture of allyl 1-hydroxy-3,4-dihydronaphthalene-2-carboxylate (207 mg, 0.90 mmol) and ethyl acrylate (115 µL, 1.1 mmol) was treated with TfOH (24 µL, 0.27 mmol) and stirred at room temperature. After 2 hours, the mixture was poured into saturated NaHCO₃ and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→15% EtOAc in hexanes) to afford allyl 2-(3-ethoxy-3-oxopropyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (255.1 mg, 86% yield) as a colorless oil.

[1132] 11H NMR (400 MHz, CDCl3) δ 8.03 (dd, J J = 7.9, 1.8 Hz, 1H), 7.47 (td, J J = 7.4, 1.5 Hz, 1H), 7.30 (t, J J = 7.6 Hz, 1H), 7.21 (d, J J = 7.7 Hz, 1H), 5.78(ddt, J J = 17.1, 10.5, 5.5 Hz, 1H), 5.16 (dq, J J = 8.6, 1.4 Hz, 1H), 5.14 –5.12 (m, 1H), 4.63 – 4.52 (m, 2H), 4.11 (q, J J = 7.1 Hz, 2H), 3.05 (ddd, J J =17.5, 9.7, 5.0 Hz, 1H), 2.95 (dt, J J = 17.6, 5.3 Hz, 1H), 2.63 – 2.50 (m, 2H),2.46 – 2.28 (m, 2H), 2.23 (ddd, J J = 13.9, 10.9, 5.1 Hz, 1H), 2.12 (ddd, J J =13.7, 9.7, 5.0 Hz, 1H), 1.23 (t, J J = 7.2 Hz, 3H) ppm

[1133] 13 13C NMR (101 MHz, CDCl3) δ 195.11, 173.15, 171.40, 142.89, 133.71,132.04, 131.50, 128.84, 128.16, 126.98, 118.52, 65.88, 60.62, 56.86, 31.26,30.01, 28.97, 25.93, 14.31 ppm。

[1134] The ([[]] S )- p -(CF3)3- t-BuPHOX (36.5 mg, 0.062 mmol) and Pd2(dba)3 (21.2 mg, 0.023 mmol) were suspended in degassed anhydrous MTBE (5 mL) and stirred for 30 minutes. Separately, 2-(3-ethoxy-3-oxopropyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid allyl ester (255.1 mg, 0.77 mmol) was dissolved in MTBE (5 mL) and bubbled for 20 minutes before being added to the catalyst mixture and the reaction stirred at 25°C. After 14 hours, the reaction was exposed to air and amended with a small amount of silica gel and stirred for 10 minutes before being filtered through a thin pad of silica gel, rinsing with 1:1 hexanes:EtOAc. The filtrate was concentrated and purified by flash column chromatography on silica gel (0→20% EtOAc in hexanes) to give ( R )-ethyl 3-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (216.8 mg, 98% yield) as a light yellow oil.

[1135] 1 H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 7.8, 1.7 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 5.83– 5.69 (m, 1H), 5.14 – 5.10 (m, 1H), 5.09 – 5.05 (m, 1H), 4.08 (q, J = 7.2Hz, 2H), 3.00 (t, J = 6.5 Hz, 2H), 2.47 (ddt, J = 14.1, 7.2, 1.2 Hz, 1H),2.42 – 2.22 (m, 3H), 2.10 – 1.89 (m, 4H), 1.21 (t, J = 7.2 Hz, 3H) ppm

[1136] 13C NMR (101 MHz, CDCl3) δ 200.73, 173.69, 143.12, 133.53, 133.38,131.77, 129.09, 128.84, 128.52, 128.16, 126.84, 118.75, 60.53, 47.14, 38.97,31.09, 29.20 (2), 25.07, 14.29 ppm

[1137] LCMS: [M+H] + m / z = 287.2 amu.

[1138] Will( R Ethyl 3-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (216.8 mg, 0.76 mmol) was dissolved in EtOAc (1.5 mL) and MeCN (1.5 mL) and treated with H₂O (2.3 mL), NaIO₄ (831 mg, 3.9 mmol), and RuCl₃·xH₂O (3.45 mg, 0.020 mmol), and the mixture was stirred vigorously at room temperature. After 4 hours, the mixture was poured into 0.5M NaHSO₄ and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na₂SO₄, filtered through Celite, and concentrated. The residue was added to MeOH (4.5 mL), cooled to 0°C, and SOCl₂ (550 µL, 7.6 mmol) was added dropwise. The mixture was then stirred at room temperature. After 90 minutes, the reaction was quenched with H2O (1 mL) and stirred for 15 minutes, then poured into H2O and extracted with Et2O (3 times). The combined extracts were washed with NaHCO3 (3 times), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→25% EtOAc in hexanes) to give ( R )-methyl 3-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (176 mg, 76% yield) as a colorless oil.

[1139] 1 H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 (td, J = 7.5, 1.5 Hz, 1H), 7.30 (t, J= 7.8, 7.3 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 3.12 (ddd, J = 17.4, 11.5, 4.9 Hz, 1H), 2.92 (dt, J = 17.5, 4.5 Hz, 1H), 2.86 (d, J = 15.7 Hz, 1H), 2.51 (d, J = 15.7 Hz, 1H),2.48 – 2.38 (m, 2H), 2.28 (ddd, J = 16.1, 10.6, 5.7 Hz, 1H), 2.12 – 1.95 (m,3H) ppm

[1140] 13 C NMR (101 MHz, CDCl3) δ 199.52, 173.61, 171.83, 142.82, 133.60,131.26, 128.88, 128.31, 126.94, 51.83, 51.75, 46.18, 39.23, 31.46, 28.92,28.74, 24.98ppm

[1141] LCMS: [M+H] + m / z = 305.1 amu.

[1142] Will( R )-methyl 3-(2-(2-methoxy-2-oxoethyl)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (176 mg, 0.58 mmol) was dissolved in EtOAc (2.9 mL) and treated with Pd / C 10% (wet) (40 mg). The vessel was charged with H2 and stirred for 15 hours, then filtered through celite and concentrated. The residue was dissolved in methanol (5 mL), cooled to 0°C, and treated with SOCl2 (340 µL, 4.6 mmol), then warmed to room temperature. After 70 minutes, the mixture was poured into H2O and extracted with EtOAc (2 times). The combined extracts were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→30% EtOAc in hexanes) to give ( S)-methyl 3-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (134.7 mg, 80% yield) as a colorless oil.

[1143] 1 H NMR (400 MHz, CDCl3) δ 7.14 – 6.99 (m, 4H), 3.66 (s, 3H), 3.65 (s,3H), 2.83 (q, J = 7.3, 6.7 Hz, 2H), 2.74 (d, J = 16.4 Hz, 1H), 2.65 (d, J =16.4 Hz, 1H), 2.45 – 2.38 (m, 2H), 2.35 (d, J = 14.1 Hz, 1H), 2.26 (d, J =14.2 Hz, 1H), 1.89 – 1.74 (m, 3H), 1.74 – 1.63 (m, 1H) ppm

[1144] 13 C NMR (101 MHz, CDCl3) δ 174.00, 171.99, 135.09, 134.52, 129.54,128.74, 125.83, 125.79, 51.56, 51.29, 40.59, 40.09, 34.60, 32.36, 31.79,28.59, 25.49 ppm

[1145] LCMS: [M+H] + m / z = 291.1 amu.

[1146] A mixture of NaOMe, 1M in MeOH (560 µL, 0.56 mmol) in anhydrous toluene (3 mL) was heated to 100 °C. S )-methyl 3-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate (134.7 mg, 0.46 mmol) was added dropwise as a solution in toluene (2 mL) over a period of approximately 15 minutes. After 2.5 hours, the mixture was cooled to room temperature and poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (0→20% EtOAc in hexanes) to give (1 R)-methyl 4-oxo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-3-carboxylate (93.1 mg, 78% yield).

[1147] 1 H NMR (400 MHz, CDl3, mixture of diastereomers) δ 7.18 – 6.99 (m, 4H), 3.75 (d, J = 1.0 Hz, 3H), 3.54 – 3.40 (m, 1H), 3.02 – 2.76 (m, 3H), 2.76 –2.62 (m, 1H), 2.42 – 2.17 (m, 4H), 1.96 – 1.80 (m, 1H), 1.74 (t, J = 6.8 Hz,1H) ppm

[1148] 13 C NMR (101 MHz, CDCl3, mixture of diastereomers) δ 210.82, 210.77,169.75, 169.74, 135.26, 134.79, 134.78, 134.04, 129.61, 129.37, 128.94,128.82, 126.21, 126.09, 125.92, 125.90, 53.48, 53.33, 52.55, 52.53, 50.14,49.85, 41.89, 40.41, 37.67, 37.59, 37.16, 36.97, 34.52, 32.25, 26.59, 26.13ppm

[1149] LCMS: [M+H] + m / z = 259.1 amu.

[1150] (1 R)-methyl 4-oxo-3',4'-dihydro-1'H-spiro[cyclopentane-1,2'-naphthalene]-3-carboxylate (88.3 mg, 0.34 mmol) was dissolved in anhydrous MeCN (1.7 mL) and treated with thiourea (31.2 mg, 0.41 mmol) and DBU (76.5 µL, 0.51 mmol), and the mixture was warmed to 70°C. After 48 hours, the mixture was cooled to room temperature and concentrated. The residue was treated with 0.2M NaH2PO4, and the resulting solid was collected by centrifugation. The still wet crude isolate was suspended in EtOH (690 µL) and 1M NaOH (375 µL, 0.38 mmol) and treated with MeI (24 µL, 0.39 mmol). The mixture was sonicated and then aged at room temperature. After 30 minutes, the mixture was diluted with 0.1 M NaH2PO4 and extracted with CHCl3 (3 times). The combined extracts were dried over Na2SO4, amended with 0.05 volumes of MeOH, and filtered through a thin pad of silica gel, rinsed with 95:5 CHCl3:MeOH, and concentrated to give ( R )-2-(methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidine-6,2'-naphthyl]-4-ol (95.2 mg, 93.3% yield) as a white solid.

[1151] LCMS: [M+H] + m / z = 299.1 amu.

[1152] Will( R )-2-(Methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthyl]-4-ol (95.2 mg, 0.32 mmol) was suspended in anhydrous DCM (640 µL) and i The mixture was treated with Pr2EtN (111 µL, 0.64 mmol). The mixture was cooled to 0°C and trifluoromethanesulfonic anhydride, 1M in DCM (479 µL, 0.48 mmol) was added dropwise, and the cooling bath was removed. After 45 minutes, the mixture was diluted with hexanes and filtered through a silica gel pipette column, rinsed with 9:1 hexanes:EtOAc, and concentrated to give ( R )-2-(methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl trifluoromethanesulfonate (90.7 mg, 66% yield).

[1153] LCMS: [M+H] + m / z = 431.1 amu.

[1154] Will( R )-2-(Methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl trifluoromethanesulfonate (90.7 mg, 0.21 mmol) was dissolved in anhydrous DMF (420 µL) and reacted with 2-[(2S)-piperazin-2-yl]acetonitrile dihydrochloride (45.9 mg, 0.23 mmol) and i The mixture was treated with Pr2EtN (110 μL, 0.63 mmol). After 30 minutes, Boc2O (77.2 mg, 0.35 mmol) was added and the mixture was stirred overnight. The mixture was poured into saturated NaHCO3 and extracted with EtOAc (3 times). The combined extracts were washed with brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (5→40% EtOAc in hexanes). The fractions with the desired product were combined to give ( S )-2-(cyanomethyl)-4-(( R )-tert-butyl 2-(methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate (92.3 mg, 87% yield) as a white foam.

[1155] LCMS: [M+H] + m / z = 506.2 amu.

[1156] Will( S )-2-(cyanomethyl)-4-(( R )-tert-Butyl 2-(methylthio)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate (92.3 mg, 0.18 mmol) was dissolved in DCM (910 µL), cooled to 0°C, and treated with mCPBA (54.6 mg, 0.24 mmol). The mixture was stirred for 30 minutes, then diluted with Et2O and washed with half-saturated NaHCO3 (3 times), brine, dried over Na2SO4, and concentrated to give the crude product (2 S )-2-(cyanomethyl)-4-((6 R tert-Butyl 2-(methylsulfinyl)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate (169.6 mg, 0.342 mmol, 100% yield) was added as a white foam. The crude product was used without further purification.

[1157] LCMS: [M+H] + m / z = 522.2 amu.

[1158] 1-Methyl-L-prolinol (39.25 mg, 0.34 mmol) was dissolved in anhydrous THF (500 μL) and KO t Bu, 1.7M in THF (200 µL, 0.34 mmol). The mixture was aged for 5 minutes and then added to the crude (2 S )-2-(cyanomethyl)-4-((6 R )-tert-butyl 2-(methylsulfinyl)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate (88.9 mg, 0.17 mmol) in anhydrous THF (500µL). After 30 minutes, the mixture was poured into aqueous K2CO3 and extracted with Et2O (3 times). The combined extracts were washed with brine, dried over Na2SO4 and concentrated to give the crude product ( S )-2-(cyanomethyl)-4-(( R )-2-((( S

[00145] To tert-butyl 3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidine-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate (85.8 mg, 0.150 mmol, 88% yield) was added as a light brown foam.

[1159] LCMS: [M+H] + m / z = 573.4 amu.

[1160] At room temperature, the crude product ( S )-2-(cyanomethyl)-4-(( R )-2-((( S tert-Butyl 1-(2-((4-((4-((4-piperidin-1-yl)-1-methylpyrrolidin-2-yl)methoxy)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidine-6,2'-naphthalene]-4-yl)piperazine-1-carboxylate) (85.8 mg, 0.15 mmol) was treated with 4N HCl in dioxane (1.5 mL). After 1 hour, the mixture was concentrated and the residue was dissolved in 1N HCl and washed with Et2O (2 times). The washings were back-extracted once with 1N HCl and the combined aqueous phases were basified with K2CO3 and back-extracted with EtOAc (3 times). The combined extracts were dried over anhydrous K2CO3, filtered, and concentrated to afford Intermediate 10-1, 2-(( S)-4-(( R )-2-((( S

[0147] In the presence of 1-[[(4-((4-(((((((((((((((((((((((((((((((((((((((((- ...-((-((-(-((-(-((-(-((-(-((-(-((-(-((-(-((-(-((-(-((-(-((-(-((-(-(-((-(-(-((-(-(-

[1161] LCMS: [M+H] + m / z = 473.3 amu.

[1162] Synthesis of compound C-31

[1163] The intermediate 10-1, 2-(( S )-4-(( R )-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazin-2-yl)acetonitrile (39.6 mg, 0.084 mmol) was dissolved in anhydrous MeCN (500 µL) and heated to 400 °C. i Pr2EtN (14.5 µL, 0.0832 mmol) and acrylic anhydride (14.5 µL, 0.13 mmol) were treated. After 15 minutes, the mixture was diluted with 0.25% TFA in H2O, filtered, and purified by preparative HPLC (C18, 5→60% ACN in H2O + 0.25% TFA) to give compound C-31, 2-(( S )-1-acryloyl-4-(( R )-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazin-2-yl)acetonitrile (7.8 mg, 0.0148 mmol, 18% yield) as a colorless film.

[1164] 1H NMR (400 MHz, methanol-d4) δ 7.15 – 7.02 (m, 4H), 7.01 – 6.95 (m, 1H), 6.27 (d, J = 16.9 Hz, 1H), 5.89 – 5.75 (m, 1H), 4.55 – 4.31 (m, 4H), 3.31 (p,J = 1.7 Hz, 2H), 3.06 – 2.83 (m, 7H), 2.82 – 2.55 (m, 10H), 2.24 – 2.11 (m,1H), 1.98 – 1.85 (m, 6H), 1.85 – 1.74 (m, 1H) ppm

[1165] LCMS: [M+H] + m / z = 527.3 amu.

[1166] Synthesis of compound C-32

[1167] The intermediate 10-1, 2-(( S )-4-(( R )-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazin-2-yl)acetonitrile (39.6 mg, 0.084 mmol) was dissolved in anhydrous MeCN (500 µL) and treated with iPr2EtN (14.5 µL, 0.0832 mmol) and 2-fluoroacrylic anhydride (19.8 mg, 0.13 mmol). After 2 h, the mixture was diluted with 0.25% aqueous TFA and purified by preparative HPLC (C18, 5→55% ACN in H2O + 0.25% TFA) to afford compound C-32, 2-(( S )-1-(2-fluoroacryloyl)-4-(( R )-2-((( S

[0147] The mixture was stirred at 40°C for 24 h at 4°C for 1 hour. The mixture was stirred at 40°C for 24 h. In the presence of 1-[(2-methylpyrrolidin-2-yl)methoxy)-3',4',5,7-tetrahydro-1'H-spiro[cyclopenta[d]pyrimidin-6,2'-naphthalene]-4-yl)piperazin-2-yl)acetonitrile (28.4 mg, 62% yield).

[1168] 1H NMR (400 MHz, CD3CN) δ 10.74 (s, 1H), 7.18 – 7.06 (m, 3H), 7.06 – 6.98 (m, 1H), 5.36 – 5.15 (m, 2H), 4.86 – 4.65 (m, 4H), 4.36 (d, J = 10.5 Hz,1H), 4.08 (d, J = 16.0 Hz, 1H), 3.72 (tdd, J = 10.3, 7.8, 4.3 Hz, 2H), 3.54 –3.31 (m, 3H), 3.16 – 2.69 (m, 15H), 2.37 – 2.24 (m, 1H), 2.15 – 1.86 (m, 4H)ppm

[1169] 19 F NMR (376 MHz, CD3CN) δ -107.56 ppm

[1170] LCMS: [M+H] + m / z = 545.3 amu.

[1171] Example 11: Synthesis of spiro-tetralin and spiro-indane compounds

[1172] Preparation of functionalized spiro-tetralin compounds

[1173]

[1174] Individual stereoisomers of spirocyclic centers can be prepared by catalytic and / or stereoselective variations of the reaction sequences described above, or can be resolved from racemic forms by chiral chromatography or other conventional techniques.

[1175] Compounds obtained by this synthetic route include, but are not limited to, those wherein X is H, F, CH3, or OCH3; R, at each occurrence and when present, is independently OH, F, Cl, Br, N(R)2, CF3, CH3, OCF3, OCF2H, OCFH2, or OCH3; and n is 0, 1, or 2. Other substituents for X and R will be readily apparent to those skilled in the art, especially those found in the commercially available molecules used in the first step of this synthesis.

[1176] Additionally, heterocyclic and / or heteroaryl analogs can be prepared by variations on the general synthetic sequences detailed above, such as those detailed for synthetic intermediates 5-1, 6-2, and 7-2, particularly synthetic intermediate 6-1.

[1177] Preparation of functionalized spiro-indane compounds

[1178]

[1179]

[1180] Individual stereoisomers of spirocyclic centers can be prepared by catalytic and / or stereoselective variations of the reaction sequences described above, or can be resolved from racemic forms by chiral chromatography or other conventional techniques.

[1181] Compounds obtained by this synthetic route include, but are not limited to, those wherein X is H, F, CH3, or OCH3; R, at each occurrence and when present, is independently OH, F, Cl, Br, N(R)2, CF3, CH3, OCF3, OCF2H, OCFH2, or OCH3; and n is 0, 1, or 2. Other substituents for X and R will be readily apparent to those skilled in the art, especially those found in the commercially available molecules used in the first step of this synthesis.

[1182] Additionally, heterocyclic and / or heteroaryl analogs can be prepared by variations on the general synthetic sequences detailed above, such as those detailed for synthetic intermediates 5-1, 6-2, and 7-2, particularly synthetic intermediate 6-1.

[1183] Biological experiments

[1184] KRAS G12C kinetic modification assay

[1185] As Patricelli et al. ( Cancer Discov. 2016, 6 The reactivity of test compounds toward His6-tagged KRASG12C (2-185) protein (hereinafter in this section, “KRASG12C”) was determined using HPLC-MS assays as described (3), 316). KRASG12C (1 µM) was incubated at 22°C with test compounds at a final concentration of 10 µM in a buffer containing 20 mM HEPES, 150 mM NaCl, 1 mM MgCl2, 1 mM DTT, pH 7.5, and a final DMSO concentration of 2% by volume. Aliquots were removed at 0, 1, 3, 5, and 30 minutes, quenched by dilution into 0.1 volume of 6.2% formic acid, and analyzed by HPLC-MS using a Water Acquity equipped with a Waters LCT Premier XE. Mass spectra were deconvoluted using MaxEnt, and the extent of inhibitor incorporation was measured by ratiometric measurements. Pseudo-first-order rate constant kobs / [I] (M -1 •s -1 ) was calculated from the rates determined by nonlinear least squares fit to the first-order rate equation:

[1186] .

[1187] Cell line growth retardation assay

[1188] Cells were seeded at a density of 1,000-5,000 cells per well in 48-well tissue culture plates. After a 24-hour rest period, cells were treated with 10 µM, 1 μM, 0.4 μM, 0.08 μM, 0.016 μM, and 0.0032 μM of compound. One group of cells was treated with vehicle in which the compound was prepared and used as a control. Prior to treatment, cells were counted, and this count was used as a baseline for calculating growth inhibition. Cells were cultured in the presence of compound for 6 days and counted on day 6. All cell counts were performed using a Synentec Cellavista plate imager. Growth inhibition was calculated as the ratio of cell population doublings in the presence of compound to that in the absence of compound. If treatment resulted in a net loss of cells from baseline, the percent mortality was defined as the decrease in the number of cells in the treated wells compared to the count in the untreated wells on day 1 after seeding. The IC of each compound was calculated by fitting a curve to the data points from each dose-response assay using the Proc NLIN function in SAS for Windows, version 9.2 (SAS Institute, Inc.). 50 value.

[1189] Assigned and mean ICs of sensitive and resistant groups 50 Calculation of values

[1190] Human cancer cell lines were characterized based on whether their growth was stimulated by AMG-510 (i.e., 4-(( S )-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3- d ]pyrimidine-2(1 H )-ketone) or MRTX-849 (ie, 2-(( S )-4-(7-(8-chloronaphthalen-1-yl)-2-((( S )-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile) (data not shown; see Table 5) and were grouped as "sensitive" or "resistant" to KRAS G12C inhibition. These sensitive and resistant groups were interrogated for their responses to each compound, and the IC was calculated for each cell line using the same technique described above. 50 The average IC values of the sensitive and tolerant groups were 50 Calculated as the arithmetic mean of the group. See Table 4. "A" represents an IC of 1 µM or less. 50 "B" indicates an IC greater than 1 µM 50 "C" represents an IC greater than 5 µM 50 .

[1191] Caco-2 assay (P app A to B)

[1192] The bidirectional human intestinal permeability of compounds was estimated using a Caco-2 cell permeability assay. Caco-2 cells were seeded onto polyethylene membranes in 96-well plates. Growth medium was refreshed every 4 to 5 days until the cells formed a confluent monolayer. HBSS with 10 mM HEPES, pH 7.4, was used as the transport buffer. Compounds were tested in duplicate at 2 μM in both directions. Digoxin, nadolol, and metoprolol were included as standards. Digoxin was tested in duplicate at 10 μM in both directions, while nadolol and metoprolol were tested in duplicate in the A to B direction at 2 μM. For all experiments, the final DMSO concentration was adjusted to less than 1%. The plates were incubated in a humidified CO2 incubator at 37°C with 5% CO2 for 2 hours. After incubation, all wells were mixed with acetonitrile containing an internal standard, and the plates were centrifuged at 4,000 rpm for 10 minutes. 100 µL of supernatant was collected from each well and diluted with 100 µL of distilled water for LC / MS / MS analysis. The concentrations of test and control compounds in the starting, donor, and acceptor solutions were quantified by LC / MS / MS using the peak area ratio of the analyte to the internal standard.

[1193] Apparent permeability coefficient P app (cm / s) is calculated using the following equation:

[1194]

[1195] where dC r / dt is the cumulative concentration of the compound in the receiving chamber as a function of time (µM / s); V ris the volume of solution in the receiving chamber (0.075 mL on the apical side and 0.25 mL on the basolateral side); A is the transmission surface area, which is 0.0804 cm for the monolayer area. 2 ; and C0 is the initial concentration in the donor compartment (µM).

[1196] The outflow ratio is calculated using the following equation:

[1197] Outflow ratio = P app (BA) / P app (AB).

[1198] The recovery percentage was calculated using the following equation:

[1199] % Recovery = 100 x [(V r x C r ) + (V d x C d )] / (V d x C0),

[1200] where Vd is the volume in the donor chamber, which is 0.075 mL on the apical side and 0.25 mL on the basolateral side; and C d and C r are the final concentrations of the delivered compound in the donor and receptor compartments, respectively.

[1201] Measurement of compound metabolic stability

[1202] The metabolic stability of the compounds was determined in human, mouse, and rat hepatocytes. Compounds were diluted from 10 mM stock solutions to 5 µM in Williams Medium E. 10 µL of each compound was aliquoted into a 96-well plate, and the reaction was initiated by aliquoting 40 µL of a 625,000 cell / mL suspension into each well. The plates were incubated at 37°C with 5% CO2. At each appropriate time point, the reaction was stopped by quenching with ACN containing an internal standard (IS) at a 1:3 ratio. The plates were shaken at 500 rpm for 10 minutes and then centrifuged at 3,220 x g for 20 minutes. The supernatant was transferred to another 96-well plate containing the diluted solution. The supernatant was analyzed by LC / MS / MS.

[1203] The percentage of compound remaining after incubation was calculated using the following equation:

[1204]

[1205] Compound half-life and CL were calculated using the following equations: int :

[1206]

[1207] Activity-guided selectivity of inhibitors

[1208] A combination of in vitro data was used to identify a subclass of KRAS G12C inhibitors with desirable properties.

[1209] In particular, data from the assays described above (e.g., cell line growth delay assay, KRAS kinetic modification assay, Caco-2 assay (P app A to B), measurement of compound metabolic stability and assigned and averaged IC for sensitive and resistant groups 50 The results of the calculation of the values of (Ilia) are used to select compounds having the structural and functional characteristics defined in the subclass of formula (IIIa).

[1210] In particular, as described above, a desired property of the compounds examined in sensitive and resistant cell lines is to have an average IC of about 1 μM or less for the drug-sensitive cell lines of Table 5. 50 and had an average IC greater than 1 µM against the drug-resistant cell lines in Table 5 50 .

[1211] Those skilled in the art will readily recognize that the results of additional in vitro assays (e.g., CYP enzyme inhibition, hERG inhibition, compound solubility, target specificity analysis) and in vivo assays (e.g., rodent xenograft studies, rodent pharmacokinetic and single-dose saturation studies, rodent maximum tolerated dose studies, and oral bioavailability) can be used to identify additional subclasses of KRAS G12C inhibitors, or to narrow subclasses identified using other results, e.g., subclasses of Formula (IIIa).

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Claims

1. A compound having structural formula IV: or a pharmaceutically acceptable salt thereof, in: x1 is C=O or C(R1)(R2); x2 is O; y 1b and y 1c Each is C(R 11 )2; z1, z2, z3 and z4 are each C; R1 and R2 are each independently H or F; R4, R5 and R6 are each H; R7 is F or Cl; R 8a is C1-C3 alkyl, wherein the C1-C3 alkyl is substituted with one or more R9; R 8d is H or F; R9 is independently at each occurrence a 4- to 8-membered heterocyclyl, wherein said 4- to 8-membered heterocyclyl includes one or two nitrogen atoms and may be optionally replaced by one or more R 10 replace; R 10 is independently at each occurrence halogen, C1-C3 alkyl or haloC1-C3 alkyl; and R 11 It is H at every occurrence.

2. The compound of claim 1, wherein the compound of formula IV has the following structure: Formula IVa: Formula IVb: or Formula IVc: or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein: R 8a It is a C1-C3 alkyl group substituted with one R9.

4. The compound of claim 3, wherein R 8a It is a methylene group substituted by one R9.

5. The compound of claim 1, wherein R 8d It's F.

6. The compound of claim 1, wherein R 8d It’s H.

7. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent or excipient.

8. Use of a compound of claim 1 in the preparation of a medicament for treating cancer mediated by the KRAS G12C mutation in a subject in need thereof.

9. The compound of claim 1, wherein R7 is Cl.

10. The compound of claim 1, wherein R7 is F.

11. The compound of claim 1, wherein R9 is optionally replaced by one R 10 replace.

12. The compound of claim 1, wherein R 8a is a C1 alkyl group substituted with one R9.

13. The compound of claim 1, wherein R9 is a 4- to 8-membered heterocyclic ring structure, wherein the ring structure includes a nitrogen atom, wherein the heterocyclic group may be optionally replaced by one or more R 10 replace.

14. The compound of claim 12, wherein R9 is a 5- to 6-membered heterocyclic ring structure comprising one or two nitrogen atoms; and R9 is optionally replaced by one or more R 10 replace.

15. The compound of claim 12, wherein R9 comprises a five-membered heterocyclic ring structure comprising one or two nitrogen atoms; and R9 is optionally replaced by one or more R 10 replace.

16. The compound of claim 15, wherein R9 is a five-membered heterocyclic ring structure comprising one or two nitrogen atoms; and R9 is optionally replaced by one or more R 10 replace.

17. The compound of claim 16, wherein R9 is pyrrolidine; and R9 is optionally replaced by one or more R 10 replace.

18. The compound of claim 17, wherein R9 is pyrrolidine; and R9 is replaced by one or more R 10 replace.

19. The compound of claim 17, wherein R9 is pyrrolidine; R9 is replaced by one R 10 Replace; and R 10 It is a C1-C3 alkyl group.

20. The compound of claim 1, wherein R 8a is a C1 alkyl group substituted with one R9; R9 is a R 10 substituted heterocyclyl; and R 10 It is a C1 alkyl group.

21. Use of a compound according to claim 1 in the preparation of a medicament for treating cancer mediated by KRASG12C mutation, wherein the compound has a M of about 1000 -1 s -1 or larger KRASG12C k obs / [i].

22. The compound of claim 1, wherein the compound has the following structure:

23. The compound of claim 1, wherein the compound has the following structure:

24. The compound of claim 1, wherein the compound is a single enantiomer.

25. The compound of claim 22 or 23, wherein the compound is a single enantiomer.

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