WO2022240971A2

WO2022240971A2 - Kras g12d inhibitors and uses thereof

Info

Publication number: WO2022240971A2
Application number: PCT/US2022/028742
Authority: WO
Inventors: Noah NATHEL; Martina S. MCDERMOTT; Neil A. O'BRIEN; Dennis Slamon; Tristin E. ROSE; Brendan M. O'boyle; Justin A. HILF; Michael D. Bartberger; Zhengao FENG; Brian M. Stoltz
Original assignee: 1200 Pharma Llc; The Regents Of The University Of California
Priority date: 2021-05-11
Filing date: 2022-05-11
Publication date: 2022-11-17
Also published as: WO2022240971A3

Abstract

The invention relates to compounds of Formula I or II, and pharmaceutically acceptable salts thereof, and methods of making and using the same. The compounds of the invention are effective in inhibiting KRAS protein with a G12D mutation and are suitable for use in methods of treating cancers mediated, in whole or in part, by KRAS G12D mutation.

Description

KRAS G12D INHIBITORS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/277455, filed November 9, 2021; U.S. Provisional Application No. 63/209638, filed June 11, 2021; and U.S. Provisional Application No. 63/187109, filed May 11, 2021, each of which is incorporated by reference herein in its entirety.

BACKGROUND

Mutations in KRAS are known to be oncogenic and are common in pancreatic, lung, colorectal, gall, thyroid and bile duct cancers. Mutation of Glycine 12 to Aspartate in KRAS is a relatively common genotype in non-small cell lung cancers, pancreatic ductal adenocarcinomas and colorectal cancers. There is a need to develop KRAS G12D inhibitors for treating KRAS G12D-mediated cancers (i.e., cancers that are mediated, entirely or partly, by KRAS G12D mutation). The compounds and compositions of the present invention provide means for selectively inhibiting KRAS G12D and for treating cancers, particularly those that are mediated by the KRAS G12D mutation.

SUMMARY

In certain embodiments, the invention relates to a compound having

(a) the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁- C₃ alkoxy, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

R_h is H or optionally substituted C₁-C₃ alkyl;

B is a 5 - 6 membered saturated or partially saturated cycloalkyl or heterocyclyl;

C is an aryl or heteroaryl optionally substituted with one or more R₄; x₁ is C(R₁)(R₂) or C=O; x2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y_1e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_2a — y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); orR₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R₃ in each occurrence is independently H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R₄ in each instance is independently hydroxy, halogen, N( R₃)₂, (W)tC₁-C₃ alkyl, (W)tC₁-C₃ haloalkyl, (W)tC₂-C₄ alkenyl, (W)tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl;

W in each occurrence is independently S or O;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO₂R₃, -SO₂R₃, -SO( R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂,

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O) R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₅ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (b) the structure of Formula la:

(Formula la) or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

R_h is H or optionally substituted C₁-C₃ alkyl;

B is a 5 - 6 membered saturated or partially saturated cycloalkyl or heterocyclyl; x₁ is C(RI)(R₂) or C=O; x₂ is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_{2a —} y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R.4) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy,

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂, optionally substituted cycloalkyl, optionally

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, O CH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (c) the structure of Formula la-1, la-2, or la-3:

(Formula la-3), or a pharmaceutically acceptable salt thereof, wherein:

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁- C₃ alkoxy, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R_h is H or optionally substituted C₁-C₃ alkyl; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y₂e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms;and with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F, such as H); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂, , optionally substituted cycloalkyl, optionally

R₆ in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (d) the structure of Formula la-4 or la- 5:

or a pharmaceutically acceptable salt thereof, wherein:

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of

R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

R_h is H or optionally substituted C₁-C₃ alkyl; x₁ is C(RI)(R₂) or C=O; x₂ is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; yia is a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b and y_1c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that, in Formula la-4, when A is diazabicyclo[3.2. ljoctanyl, y_1b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F; or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R₄ in each instance is independently hydroxy, halogen, N(R₃)₂, (W)tC₁-C₃ alkyl, (W)tC₁-C₃ haloalkyl, (W)tC₂-C₄ alkenyl, (W)tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl;

W in each occurrence is independently S or O;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂,

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano,

(CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (e) the structure of Formula IF

(Formula II) or a pharmaceutically acceptable salt thereof, wherein: * is the quaternary carbon atom;

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅;

R_h is H or optionally substituted C₁-C₃ alkyl;

C is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more

R₄;

D is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more

R₄; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or

S(O)₂; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that both y_2b and y_2c cannot be heteroatoms; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R₃ in each occurrence is independently H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R₄ in each instance is independently hydroxy, halogen, N(R₃)₂, (W)tC₁-C₃ alkyl, (W)tC₁-C₃ haloalkyl, (W)tC₂-C₄ alkenyl, (W)tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl;

W in each occurrence is independently S or O;

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂,

, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (f) the structure of Formula IIa-1, IIa-2 or IIa-3:

or a pharmaceutically acceptable salt thereof, wherein:

R_h is H or optionally substituted C₁-C₃ alkyl; C is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more Rb

D is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more Rb x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a and y_2a are each independently (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; y_1b and y_1c are each independently (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; with the proviso that both y_1a and y_2a cannot be heteroatoms; and with the proviso that both y_1b and y_1c cannot be heteroatoms; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇;

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (g) the invention relates to a compound having the structure of Formula IIa-1-1, Fla-2- 1 or IIa-3-1:

or a pharmaceutically acceptable salt thereof, wherein:

R_h is H or optionally substituted C₁-C₃ alkyl;

C is a 6-membered aryl or heteroaryl;

D is a 6-membered aryl or heteroaryl;

X₁ , X₃ , X₄ and X₅ are each independently C or N; x₁ is C(RI)(R₂) or C=O; x₂ is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is absent if x₁ is N, or R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is absent if X₃ is N, or R_4-3 is H, CH₃, C1 or F;

R_4-4 is absent if X4 is N, or R_4-4 is H, C1 or F;

R_4-5 is absent if X5 is N, or R_4-5 is H, C1 or F;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO₂R₃, -SO2R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -

SO₂N(R₃)₂, -C(O)N(R₃)₂,

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2 or 3; or (h) the structure of Formula Ia-1-1, Ia-2-1, Ia-4-1 or Ia-5-1 :

or a pharmaceutically acceptable salt thereof, wherein: x₁ is C(RI)(R₂) or C=O;

X2a is -0-R₆-1 or -OCH₂-R_6-1;

X is C or N, with the proviso that R_4-1 is absent when X is N;

R_h is H or optionally substituted C₁-C₃ alkyl; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R₄-I is H, NH₂, OH or CH₃;

R₄-2 is H, C1, F, CN, cyclopropyl, C(CH), CH₃ or CH₂CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂, optionally substituted cycloalkyl, optionally

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably wherein

/ denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl

(preferably wherein denotes the point of attachment), heterocyclyl

wherein

denotes the point of attachment), aryl, heteroaryl (preferably or

wherein denotes the point of attachment), haloalkyl, heteroalkyl,

hydroxyalkyl, heterocyclylalkyl (preferably and

wherein

denotes the point of attachment), heteroarylalkyl (preferably wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R₇; and

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4; or (i) the structure of Formula IIa-2-2 or IIa-3-2:

or a pharmaceutically acceptable salt thereof, wherein: x₁ is C(RI)(R₂) or C=O; x_2a is -O-R_6-1 or -OCH₂-R_6-1;

X is C or N, with the proviso that R_4-1 is absent when X is N;

R_h is H or optionally substituted C₁-C₃ alkyl; R₁ and R₂ are each independently H, F, methyl or hydroxy; or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R_4-5 is H, C1 or F;

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl (preferably wherein denotes the point of attachment), heterocyclyl (preferably

wherein denotes the point of attachment), aryl, heteroaryl (preferably wherein denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably wherein denotes the point of attachment), heteroarylalkyl (preferably wherein

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4.

In some embodiments, the invention relates to compounds having the structure of Formula I, la, la-1, la-2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1 or IIa-3-1, wherein A is a 6 - 12 membered saturated or partially saturated monocyclic or bridged heterocyclic ring optionally substituted with one or more R₅, R_h is H, R₅ occurs one or two times and R₅ in each instance is optionally substituted C₁-C₃ alkyl. In other embodiments,

R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃, C(O)CH₃, C(O)OCH₃ or S(O)₂CH₃), R₅ occurs one or two times and R₅ in each instance is optionally substituted C₁- C₃ alkyl. In yet other embodiments, R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃, C(O)CH₃, C(O)OCH₃ or S(O)2CH₃) and there is no instance of R₅. In yet other embodiments, R_h is H and there in no instance of R₅.

In some embodiments, the invention relates to compounds having the structure of Formula I, la, la-1, la-2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1 or IIa-3-1, wherein R_h is H, R₅ occurs one or two times and R₅ in each instance is optionally substituted C₁-C₃ alkyl. In other embodiments, R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃, C(O)CH₃, C(O)OCH₃ or S(O)2CH₃), R₅ occurs one or two times and R₅ in each instance is optionally substituted C₁-C₃ alkyl. In yet other embodiments, R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃, C(O)CH₃, C(O)OCH₃ or S(O)2CH₃) and there is no instance of R₅. In yet other embodiments, R_h is H and there in no instance of R₅.

In some embodiments, the invention relates to compounds having the structure of Formula Ia-1-1, Ia-2-1, Ia-4-1, Ia-5-1, IIa-2-2 or IIa-3-2 (and their various stereochemical specific embodiments), wherein R_h is H, R₅ in each instance is C₁-C₃ alkyl, and u is 1 or 2. In other embodiments, R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃,

C(O)CH₃, C(O)OCH₃ or S(O)2CH₃), R₅ in each instance is C₁-C₃ alkyl, and u is 1 or 2. In yet other embodiments, R_h is optionally substituted C₁-C₃ alkyl (such as CH₃, CF₃, C(O)CH₃, C(O)OCH₃ or S(O)2CH₃) and u is 0. In yet other embodiments, R_h is H and u is 0

In certain other embodiments, the invention relates to a compound having (a) the structure of Formula I':

or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom; A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁- C₃ alkoxy, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;

C is an aryl or heteroaryl optionally substituted with one or more R₄; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, SCO), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_2a — y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁- C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (b) the structure of Formula Fa:

(Formula Fa) or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

B is a 5 - 6 membered saturated or partially saturated cycloalkyl or heterocyclyl; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, SCO), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_{2a —} y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R.4) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl(such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); R₆ in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or

(c) the structure of Formula I'a -1, I'a -2, or I'a -3:

(Formula I'a -3), or a pharmaceutically acceptable salt thereof, wherein:

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁- C₃ alkoxy, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); x₁ is C(RI)(R₂) or C=O; x₂ is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y₂e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms;

; and with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; z₁, z₂, z₃ and z₄ are each independently C(H), C(R.4) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

(d) the structure of F ormula I'a -4 or I'a -5:

or a pharmaceutically acceptable salt thereof, wherein:

R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl;x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; yia is a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b and y_1c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that, in Formula I'a -4, when A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO₂N(R₃)₂, -C(O)N(R₃)₂

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (e) the structure of Formula IF :

(Formula IF)

or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

C is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more

R₄;

D is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more

R₄; x₁ is C(R₁)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R₆; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or

W in each occurrence is independently S or O;

HC(=O)-, -CO₂R₃, -SO2R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂,

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (f) the structure of F ormula II'a - 1 , II'a -2 or II'a -3 :

or a pharmaceutically acceptable salt thereof, wherein:

C is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more RF

RF x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

W in each occurrence is independently S or O;

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-,

-CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1; or (g) the invention relates to a compound having the structure of Formula II'a -1-1, II'a -2- 1 or II'a -3-1:

(Formula II'a -1-1),

or a pharmaceutically acceptable salt thereof, wherein:

C is a 6-membered aryl or heteroaryl;

D is a 6-membered aryl or heteroaryl;

X₁ , X₃ , X₄, and X₅ are each independently C or N; x₁ is C(RI)(R.2) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R.₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R₆; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F, such as

H); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is absent if X₁ is N, or R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is absent if X₃ is N, or R_4-3 is H, CH₃, C1 or F;

R_4-4 is absent if X₄ is N, or R_4-4 is H, C1 or F;

R_4-5 is absent if X₅ is N, or R_4-5 is H, C1 or F;

-CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2 or 3; or

(h) the structure of Formula I'a-1-1, I'a-2-1, I'a-4-1 or I'a-5-1:

X2a is -0-R₆-1 or -OCH₂-R_6-1;

X is C or N, with the proviso that R_4-1 is absent when X is N; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F, such as

R_4-1 is H, NH₂, OH or CH₃;

R₄-2 is H, C1, F, CN, cyclopropyl, C(CH), CH₃ or CH₂CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_6-1 is C₁-Ce alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein f denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl

wherein denotes the point of

attachment), aryl, heteroaryl (preferably

_or

wherein denotes the point of attachment), haloalkyl, heteroalkyl,

hydroxyalkyl, heterocyclylalkyl (preferably and

wherein

denotes the point of attachment), heteroarylalkyl (preferably wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R₇; and R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4 (such as 0); or (i) the structure of Formula II'a -2-2 or II'a -3-2:

H); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl; R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R_4-5 is H, C1 or F;

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -

SO₂N(R₃)₂, -C(O)N(R₃)₂,

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein denotes the point of attachment), aryl, heteroaryl (preferably wherein denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably and

wherein denotes the point of attachment), heteroarylalkyl (preferably w_herein

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4 (such as 0). In other embodiments, the invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein.

BRIEF DESCRIPTION OF THE FIGURES The Figure shows the atomic structure of one epimer of Intermediate 2-48F, specifically epimer (lri',8'ri)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H- spiro[indene- 1 ,7'-quinazoline] .

DETAILED DESCRIPTION Definitions

Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, 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.

The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See , e.g. , Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

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

A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals ( e.g ., canines, felines, etc.) and rodents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g, pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g, by a statistically and/or clinically significant amount.

“Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g, through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g, patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

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

The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. R₆presentative alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkenyl,” as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls” the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 6 carbon atoms, preferably from 1 to about 3 unless otherwise defined. Examples of straight chained and branched alkyl groups include, but are not limited to methyl, ethyl, «-propyl, iso-propyl, «-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group is also referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen (e.g, fluoro), a hydroxyl, an oxo, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF₃, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF₃, -CN, and the like.

The term “C_x-C_y,” when used in conjunction with a chemical moiety, such as, alkyl or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “C_x-C_y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.

The term “alkylamino,” as used herein, refers to an amino group substituted with at least one alkyl group.

The term “alkylthio,” as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term “alkynyl,” as used herein, 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 moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term “amide,” as used herein, refers to a group

wherein each R^A independently represent a hydrogen, hydrocarbyl group, aryl, heteroaryl, acyl, or alkoxy, or two R^A are taken together with the N atom to which they are attached complete a heterocycle having from 3 to 8 atoms in the ring structure.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g ., a moiety that can be represented by

wherein each R^A independently represents a hydrogen or a hydrocarbyl group, or two R^A are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “aminoalkyl,” as used herein, refers to an alkyl group substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 6- to 10- membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g. , the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, aniline, and the like.

The term “carbocycle” refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and nonaromatic carbocycles. Non-aromatic carbocycles include both cycloalkyl and cycloalkenyl rings. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes 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 of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. ljheptane, 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. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3- to about 10-carbon atoms, from 3- to 8-carbon atoms, or more typically from 3- to 6-carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings (e.g., fused bicyclic compounds, bridged bicyclic compounds, and spirocyclic compounds).

A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.

The term “bridged bicyclic compound” or “bridged ring” refers to a bicyclic molecule in which the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2. ljheptane, can be thought of as a pair of cyclopentane rings each sharing three of their five carbon atoms. A “bridged bicyclic compound” or “bridged ring” compound can include one or more heteroatoms (such as nitrogen atoms) in the ring system, for example, diazabicyclo[3.2.1]octanes such as 3,8-diazabicyclo[3.2.1]octane.

The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. 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.

The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The term “heteroalkyl”, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, for example, wherein no two heteroatoms are adjacent.

The term “hydrocarbyl”, as used herein, 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, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, and combinations thereof.

The term “fused bicyclic compound” refers to a bicyclic molecule in which 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 ( e.g ., a-thujene and decalin). For example, in a fused cycloalkyl each of the rings shares two adjacent atoms with the other ring, and the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single 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 cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, quinoline, quinoxaline, naphthyridine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

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 instances, most preferably a 5-membered ring, in other instances, most preferably a 6-membered ring, which ring structures include 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 cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g ., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. The terms “heterocyclyl” and “heterocyclic” also include spirocyclic ring systems having two or more cyclic rings in which one carbon is common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g. , the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactones, lactams, oxazolines, imidazolines, 1- azaspiro[4.4]nonane and the like.

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, one of the rings is a bridged ring. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term “spirocyclic compound”, “spirocycle”, and “spirocyclic” refers to a bicyclic molecule in which the two rings have only one single atom, the spiro atom, in common.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone, or substituents replacing a hydrogen on one or more nitrogens of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g. , which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substitutions can be one or more and the same or different for appropriate organic compounds.

“Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3^rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. R₆presentative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethyl silyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. R₆presentative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g, TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt that is suitable for or compatible with the treatment of patients.

The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds disclosed herein. Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono- , di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds disclosed herein are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g ., oxalates, may be used, for example, in the isolation of compounds of the invention for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds of the invention, or any of their intermediates. Illustrative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See , e.g. , WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixtures and separate individual isomers.

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

“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g, compounds of the invention). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile 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 this disclosure are metabolized to produce a compound of the invention, or a pharmaceutically acceptable salt 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.

As used herein, the terms “quaternary carbon atom” or “quaternary carbon center” refer to a carbon atom having four non-hydrogen substituents. The terms “quaternary carbon atom” or “quaternary carbon center” include tetrasubstituted carbon atoms and tetrasubstituted carbon centers as they are commonly used in the art.

Example Compounds

In certain embodiments, the invention relates to a compound having the structure of Formula I:

(Formula I) or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

R_h is H or optionally substituted C₁-C₃ alkyl;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y₂d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, SCO), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_2a — y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F, such as H); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); R₆ in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F (such as H); R₅ in each instance is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); and

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; or two occurrences of R₅ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl. In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, - OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)₂.

In other embodiments, R₅ in each instance is independently F, Cl, optionally substituted C1-C₃ alkyl, optionally substituted C2-C₃ alkenyl, optionally substituted C2-C3 alkynyl, cyano, C1-C₃ cyanoalkyl, C1-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH2_F, -SCF₃, -SCHF₂ or -SCH₂F.ln some embodiments, the invention relates to a compound of Formula I wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other such embodiments, both R₁ and R₂ are F.

In some embodiments, the invention relates to a compound of Formula I wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I is a compound having the structure of Formula la:

(Formula la) or a pharmaceutically acceptable salt thereof, wherein: * is the quaternary carbon atom;

R_h is H or optionally substituted C₁-C₃ alkyl;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y₂d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_{2a —} y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R.4) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-,

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F (such as H); R₅ in each instance is such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); and R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; or two occurrences of R₅ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl.

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, - OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)₂.

In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F.

In some embodiments, the invention relates to a compound of Formula la wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; z₁ is C(H) or C(R₄) and R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; z₁ is C(R₄) and R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃.

In some embodiments, the invention relates to a compound of Formula la wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula la wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula la wherein R₁ and R₂, together with the carbon atom to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound of Formula la wherein zi, z₂, z₃, and z₄ are each independently C(H) or C(R₄). In certain embodiments, the invention relates to a compound having the structure of

Formula I':

or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y₂d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, SCO), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bond; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_{2a —} y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

HC(=O)-, -CO₂R₃, -SO2R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂, optionally substituted cycloalkyl, optionally

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, - CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F (such as H); R₅ in each instance is hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; or two occurrences of R₅ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl.

In some embodiments, the invention relates to a compound of Formula F wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other embodiments, both R₁ and R₂ are F.

In some embodiments, the invention relates to a compound of Formula F wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula F wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula F wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula F wherein R₁ is CH₃ and R₂ is F. In some embodiments, the invention relates to a compound of Formula F wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula Fa:

(Formula Fa) or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R₆; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_2b — y_2c; or y₁ is * — y_1d=y₁e and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y₂d=y_2e; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a — y_2b — y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1d, y₁e, y_2b and y_2e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bond; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that when y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_2a — y_2b — y_2c and A is diazabicyclo[3.2.1]octanyl, y_2b cannot be O; z₁, Z2, Z3 and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

HC(=O)-, -CO₂R₃, -SO2R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂ optionally substituted cycloalkyl, optionally

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each instance is hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

In some embodiments, the invention relates to a compound of Formula Fa wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; z₁ is C(H) or C(R₄) and R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; z₁ is C(R₄) and R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃.In certain embodiments, the invention relates to a compound of Formula Fa wherein z₁, z₂, z₃, and z₄ are each independently C(H) or C(R₄). In some embodiments, the invention relates to a compound of Formula Fa wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Fa wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Fa wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Fa wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Fa wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I has the structure of Formula F. In certain embodiments, the compound of Formula F has the structure of Formula Fa. In certain embodiments, the compound of Formula la has the structure of Formula Fa.

In certain embodiments, the invention relates to a compound having the structure of Formula I, la, F, I'a, or a pharmaceutically acceptable salt thereof, wherein: y₁ is y_1a and y₂ is y_2a, with the proviso that both y_1a and y_2a cannot be heteroatoms, and the further proviso that neither y_1a or y_2a can be a bond when y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a, with the proviso that both y_1b and y_2a cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be bonds, the proviso that both y_1b and y_1c cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be C=O, and the further proviso that both y_1b and y_1c cannot be C=CH₂; or y₁ is y_1a and y₂ is * — y_2b — y₂c, with the proviso that both y_1a and y_2b cannot be heteroatoms, the proviso that both y_2b and y_2c cannot be bonds, the proviso that both y_2b and y_2c cannot be heteroatoms, the proviso that both y_2b and y_2c cannot be C=O, and the further proviso that both y_2b and y_2c cannot be C=CH₂; or y₁ is * — y_1d=y_1e and y₂ is y_2a, with the proviso that both y_1d and y_2a cannot be heteroatoms; or y₁ is y_1a and y₂ is * — y₂d=y_2e, with the proviso that both y_1a and y_2b cannot be heteroatoms; or y₁ is *y_{1a —} y_1b — y_1c and y₂ is a bond, with the proviso that none of y_1a, y_1b and y_1c can be a bond, the proviso that both y_1a and y_1b cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be heteroatoms, the proviso that both y_1a and y_1b cannot be C=O, the proviso that both y_1b and y_1c cannot be C=O, the proviso that both y_1a and y_1b cannot be C=CH₂, and the further proviso that both y_1b and y_1c cannot be C=CH₂; or y₁ is a bond and y₂ is *y_2a — y_2b — y₂c, with the proviso that none of y_2a, y_2b and y_2c can be a bond, the proviso that both y_2a and y_2b cannot be heteroatoms, the proviso that both y_2b and y_2c cannot be heteroatoms, the proviso that both y_2a and y_2b cannot be C=O, the proviso that both y_2b and y_2c cannot be C=O, the proviso that both y_2a and y_2b cannot be C=CH₂, and the further proviso that both y_2b and y_2c cannot be C=CH₂.

In some embodiments, A is a 6 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅, wherein no instance of R₅ is C₁-C₃ cyanoalkyl. In specific embodiments, A is

each optionally substituted with one or more R₅,

wherein denotes the point of attachment to the pyrimidine ring.

In some embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅ In preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅ In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In other preferred embodiments,

i nach optionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring. In even more preferred embodiments, A is each optionally

substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring.

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.

In other embodiments, x₁ is C(RI)(R.2), R₁ is H and R₂ is H.

In other embodiments, X2 is O.

In other embodiments, x₃ is C₁-C₆ alkyl substituted with R6, R6 is cycloalkyl, heterocyclyl, aryl, or heteroaryl each of which is optionally substituted with one or more R₇. In preferred embodiments x₃ is C₁-C₃ alkyl and R6 is heterocyclyl.

In yet other embodiments, zi, z₂, z₃ and z₄ are each independently C(H) or C(R₄).

In certain embodiments, p is 1. In other embodiments, p is 2.

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

In certain embodiments, p is 2, and B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, p is 2, and B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

In perferred embodiments, R₄ in each instance is independently OH, F, C1, Br, N(R )2, CFH2, CHF₂, CF₃, OCFH2, OCHF₂, OCF₃, SCFH2, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl.

In certain embodiments, the invention relates to a compound having the structure of Formula I, la, F, I'a, or a pharmaceutically acceptable salt thereof, wherein R₅ is hydroxy, halogen, C₁-C₃ alkyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(= )-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In certain embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, or la-3:

or a pharmaceutically acceptable salt thereof, wherein:

R_h is H or optionally substituted C₁-C₃ alkyl; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y_2c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_2b and y₂e are each independently C(R₃) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be bonds; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms;

; and with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃,

-C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and

In some embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3 wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; and z₁ is C(H) or C(R₄) and R₄ in this instance is F. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; and z₁ is C(R₄) and R₄ in this instance is F.

In some embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula la-1, la-2 or la-3, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of Formula I'a - 1, I'a -2, or I'a -3:

or a pharmaceutically acceptable salt thereof, wherein:

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁- C₃ alkoxy, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

W in each occurrence is independently S or O; R₅ in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy,

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each instance is hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH_3. In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and

In some embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3 wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; and z₁ is C(H) or C(R₄) and R₄ in this instance is F. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; and z₁ is C(R₄) and R₄ in this instance is F.

In some embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -1, I'a -2 or I'a -3, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

each optionally substituted with one or more R₅,

wherein denotes the point of attachment to the pyrimidine ring.

In preferred embodiments, A is a 7 or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅ In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In other preferred embodiments, each optionally substituted

with one or more denotes the point of attachment to the pyrimidine ring. In even more preferred embodiments, A is each optionally substituted with one or more R₅, wherein

denotes the point of attachment to the pyrimidine ring. In certain embodiments, the invention relates to a compound having the structure of

Formula la-4 or la- 5:

or a pharmaceutically acceptable salt thereof, wherein:

R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_h is H or optionally substituted C₁-C₃ alkyl; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a is a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b and y_1c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that, in Formula la-4, when A is diazabicyclo[3.2. ljoctanyl, y_1b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and

In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F. In some embodiments, the invention relates to a compound of Formula la-4 or la-5 wherein x₁ is C(RI)(R.2); one of R₁ and R₂ is F and the other is H; z₁ is C(H) or C(R₄) and

R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; z₁ is C(R₄) and R₄ in this instance is F; and z₄ is C(R₄) and R₄ in this instance is F, C1, Br or CH₃.

In some embodiments, the invention relates to a compound of Formula la-4 or la-5, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la-4 or la-5, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula la-4 or la-5, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula la-4 or la-5, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula la-4 or la-5, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula I'a -4 or I'a -5:

(Formula I'a -4),

(Formula I'a -5), or a pharmaceutically acceptable salt thereof, wherein:

A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C₁-C₃ cyanoalkyl, then a second and independent instance of R₅ must occur (i.e., there must be a second instance of R₅ that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -CO₂N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl), or if A is piperazinyl and one instance of

R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R₅ must occur that is hydroxy, halogen, substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C02N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a is a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y_1b and y_1c are each independently a bond, (C(R₅)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that, in Formula I'a -4, when A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each instance is hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃.

In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F.In some embodiments, the invention relates to a compound of Formula I'a -4 or I'a -5 wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; z₁ is C(H) or C(R₄) and R₄ in this instance is F; and Z4 is C(R₄) and R₄ in this instance is F, C1, Br or CH₃. In other embodiments, both R₁ and R₂ are F. In yet other embodiments, R₁ and R₂ are both H; z₁ is C(R₄) and R₄ in this instance is F; and Z4 is C(R₄) and R₄ in this instance is F, C1, Br or CH₃. In some embodiments, the invention relates to a compound of Formula I'a -4 or I'a - 5, wherein R₁ is CH₃ and R₂ is H. In other embodiments, the invention relates to a compound of Formula I'a -4 or I'a -5, wherein R₁ is H and R₂ is CH₃.

In some embodiments, the invention relates to a compound of Formula I'a -4 or I'a - 5, wherein R₁ is CH₃ and R₂ is F. In other embodiments, the invention relates to a compound of Formula I'a -4 or I'a -5, wherein R₁ is F and R₂ is CH₃.

In some embodiments, the invention relates to a compound of Formula I'a -4 or I'a - 5, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, or a pharmaceutically acceptable salt thereof.

In some embodiments, the invention relates to a compound having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅, wherein no instance of R₅ is C₁-C₃ cyanoalkyl.

In preferred embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅.

In more preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅.

In other embodiments, the compound has the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein A is a 6 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅.

each optionally substituted with one or more R₅,

wherein denotes the point of attachment to the pyrimidine ring.

In preferred embodiments, the invention relates to a compound having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R.5. In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In other preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring that is not substituted with R₅ (i.e., there is not instance of R₅).

In preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅, In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is

optionally substituted with one or more R₅, wherein ^ denotes the point of attachment to the pyrimidine ring. In other preferred embodiments, A is an 8-membered bridged

0 heterocyclyl. In even more preferred embodiments, A is

each optionally substituted with one or more R₅, wherein ^ denotes the point of attachment to the pyrimidine ring. In some preferred embodiments, A is not substituted (i.e., there is no instance of R₅).

In other embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein x₁ is C(RI)(R₂), RI is H and R₂ is H.

In other embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein x₂ is O.

In other embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein X₃ is C₁-C₆ alkyl substituted with R6, R₆ is cycloalkyl, heterocyclyl, aryl, or heteroaryl each of which is optionally substituted with one or more R₇. In preferred embodiments X₃ is C₁-C₃ alkyl and R6 is heterocyclyl.

In perferred embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein R₄ in each instance is independently OH, F, C1, Br, N(R₃)₂, CFH₂, CHF₂, CF₃, OCFH₂, OCHF₂, OCF₃, SCFH₂, SCHF₂, SCF₃, CHS, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl.

In more preferred embodiments, R₄ in each instance is independently OH, F, C1, Br, CFH₂, CHF₂, CF₃, CH₃, cyclopropyl or cyclobutyl. In more preferred embodiments, R₄ in each instance is independently, F, C1, Br, OH or CH₃.

In yet other embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein z₁, z₂, z₃ and z₄ are each independently C(H) or C(R₄).

In certain embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein p is 1. In other embodiments, the invention relates to a compound having the structure of Formula la-1, la- 2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein p is 2.

In more specific embodiments, the invention relates to a compound having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein: y_1a, y_2a, y_1b, y_1c, y_2b and y_2c are (C( R₈)₂)_n; y_1d, y₁e, y_2d and y_2e are C(R₃);

R₈ in each instance is H; R₃ in each instance is H; and n in each instance is 1.

In some embodiments, the invention relates to compounds having the structure of Formula la-2, la-3, I'a -2 or I'a -3, wherein z₁ is C(H), z₂ is C(H), z₃ is C(H) and z₄ is C(R.4).

In some embodiments, the invention relates to compounds having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein z₁ is C(H), z₂ is C(H), z₃ is C(H), z₄ is C(R.4), and

R₄ is OH, F, C1, Br, CFH2, CHF₂, CF₃, CH₃, cyclopropyl or cyclobutyl. In preferred embodiments, R.4 is F, C1, Br or CH₃. In some embodiments, z₁ is C(H), z₂ is C(R₄), z₃ is C(H) and z₄ is C(R.4).

In some embodiments, the invention relates to compounds having the structure of Formula la-1, la-2, la-3, la-4, la-5, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein z₁ is C(H), z₂ is C(H), z₃ is C(H), z₄ is C(R₄), and R₄ is OH, F, C1, Br, CFH2, CHF₂, CF₃, CH₃, cyclopropyl or cyclobutyl. In preferred embodiments, R₄ is OH, F, C1, Br or CH₃. In other embodiments, z₁ is C(H), z₂ is C(H), z₃ is C(R₄) and z₄ is C(H). In other embodiments, z₁ is C(H), z₂ is C(R₄), z₃ is C(H) and z₄ is C(H). In other embodiments, z₁ is C(R₄), z₂ is C(H), z₃ is C(H) and z₄ is C(H). In some embodiments, z₁ is C(F).

In some embodiments, the invention relates to compounds having the structure of Formula la-2 or I'a -2, wherein: y_1a is (C(R₈)₂)_n; y_2c is C=CH₂, (C(R₈)₂)_n or N(R₅); z₁ is C(H), z₂ is C(H), z₃ is C(H) and z₄ is C(R₄);

R₃ is C₁-C₄ alkyl;

R₄ is OH, F, C1, Br, N(R₃)₂, CFH2, CHF₂, CF₃, OCFH2, OCHF₂, OCF₃, SCFH2, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl R₈ in each instance is independently H or C₁-C₃ alkyl; and n in each instance is 1.

In further embodiments, when y_2c is (C(R₈)₂)_n, n is 1 and one instance of R₈ is H and the other is selected from H or C₁-C₃ alkyl.

In other embodiments, the invention relates to compounds having the structure of Formula la-2, la-3, I'a -2 or I'a -3, wherein: y_1a and y_2b are (C(R₈)₂)_n, wherein R₈ in each instance is H and n in each instance is i; y_2c is (C(R.8)₂)_n, wherein R₅ in one instance is H or C₁-C₃ alkyl, R₅ in the other instance is H and n is 1; y_2b and y_2e are C(R₃); z₁ is C(H), z₂ is C(H), z₃ is C(H) and z₄ is C(R₄);

R₄ is OH, F, C1, Br, N(R₃)₂, CFH2, CHF₂, CF₃, OCFH2, OCHF₂, OCF₃, SCFH2, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl; and

R₃ in each instance is H.

In preferred embodiments, R₄ is F, C1 or CH₃.

In other embodiments, the invention relates to compounds having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein: y_1a, y_2a, y_1b, y_1c, y_2b and y_2c are (C(R₈)₂)_n; z₁ is C(H), z₂ is C(R₄), z₃ is C(H) and z₄ is C(R₄);

R₈ in each instance is H;

R₄ in each instance is independently OH, F, C1, Br, N(R₃)₂, CFH2, CHF₂, CF₃, OCFH2, OCHF₂, OCF₃, SCFH2, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl; and n in each instance is 1.

In preferred embodiments, the invention relates to compounds having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein: z₁ is C(H); z₂ is C(R₄), wherein R₄ is OH, N(R₃)₂, CH₃, OCH₃, SCH₃ or CN, and R₃ in each instance is independently H or C₁-C₄ alkyl; z₃ is C(H); and z₄ is C(R₄), wherein R₄ is F, C1, CFH2, CHF₂, CF₃, CH₃, OCH₃, SCH₃, CN or propargyl.

In other embodiments, the invention relates to compounds having the structure of Formula la-4, Ia-4a, Ia-4b, Ia-4a-1, Ia-4b-1, la-5, Ia-5a, Ia-5b, Ia-5a-1, Ia-5b-1, I'a -4, I'a - 4a, I'a -4b, I'a -4a-1, I'a -4b-1, I'a -5, I'a -5a, I'a -5b, I'a -5a-1 or I'a -5b-1, wherein: x₁ is C(RI)(R₂); y_1a, y_2a, y_1b, y_1c, y_2b and y_2c are (C(R₈)₂)_n; z₁ is C(R₄) or C(H), z₂ is C(H), z₃ is C(H) and z₄ is C(R₄); R₁ is F and R₂ is H; R₁ is H and R₂ is F; or both R₁ and R₂ are F; or both R₁ and R₂ are H; R₈ in each instance is H; when z₁ is C(R₄), z₁ is C(F); z₄ is C(OH), C(F), C(C1), C(Br), C(N(R₃)₂), C(CFH₂), C(CHF₂), C(CF₃),

C(OCFH₂), C(OCHF₂), C(OCF₃), C(SCFH₂), C(SCHF₂), C(SCF₃), C(CH₃), C(OCH₃), C(SCH₃), C((W)tCF₂H), C(CN), C(propargyl), C(cyclopropyl) or C(cyclobutyl) (preferably is C(F), C(C1), C(Br) or C(CH₃)); and n in each instance is 1.

In some embodiments, the invention relates to compounds having the structure of Formula la-4, la-5, I'a -4 or I'a -5, wherein: z₁ is C(H), z₂ is C(R₄), z₃ is N and z₄ is C(R₄); the instance of R₄ through z₂ is N(R₃)₂; and

R₃ in each occurrence through z₂ is H. In other embodiments, z₁ isN, z₂ is C(R₄), z₃ is C(H) and z₄ is C(R₄).

In some embodiments, the invention relates to compounds having the structure of Formula I, la, la-1, la-2, la-3, la-4, la-5, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein: each optionally substituted

with one or two R₅, wherein

denotes the point of attachment to the pyrimidine ring;

R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ hydroxalkyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -OH, -CN, -CH₂CN, -C(O)OR₃, -C(O)N(R₃)₂, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -

OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂,

and

R₃ in each occurrence is independently H, C₁-C₄ alkyl or C₁-C₄ haloalkyl.

In more preferred embodiments, R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -CN, -CH₂CN, -C(O)OR₃, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, - OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

In some embodiments, the invention relates to compounds having the structure of Formula I, la, la-1, la-2, la-3, la-4, la-5, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, wherein:

A is

each optionally substituted with one or two R₅, wherein ^ denotes the point of attachment to the pyrimidine ring;

OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂,

and

In more preferred embodiments, R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -CN, -CH₂CN, -C(O)OR₃, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -

OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

In certain embodiments, the compound of Formula la-1 has the structure of Formula la- la or la- 1b:

In certain embodiments, the compound of Formula I'a -1 has the structure of

Formula I'a -1a or I'a -1b:

(Formula I'a - la) or

(Formula I'a -1b).

In certain embodiments, the compound of Formula la-2 has the structure of Formula Ia-2a or Ia-2b:

In certain embodiments, the compound of Formula la-2 has the structure of Formula Ia-2a-1 or Ia-2b-1:

(Formula Ia-2a-1), or

(Formula Ia-2b-1).

In certain embodiments, the compound of Formula I'a-2 has the structure of

Formula I'a-2a or I'a-2b:

In certain embodiments, the compound of Formula I'a-2 has the structure of Formula I'a-2a-1 orI'a-2b-1:

(Formula I'a-2a-1) or

(Formula I'a -2b-1).

In certain embodiments, the compound of Formula la-3 has the structure of Formula

Ia-3a or Ia-3b:

(Formula Ia-3a), or

(Formula Ia-3b).

In certain embodiments, the compound of Formula I'a -3 has the structure of

Formula I'a -3 a or I'a -3b: (F ormul a F a-3 a) or

(Formula I'a -3b).

In certain embodiments, the compound of Formula la-4 has the structure of Formula

Ia-4a or Ia-4b:

In certain embodiments, the compound of Formula la-4 has the structure of Formula Ia-4a-1 orIa-4b-1:

In certain embodiments, the compound of Formula I'a-4 has the structure of Formula I'a-4a or I'a-4b:

(Formula I'a-4a) or

(Formula I'a-4b).

In certain embodiments, the compound of Formula I'a-4 has the structure of

Formula I'a-4a-1 orI'a-4b-1:

In certain embodiments, the compound of Formula la-5 has the structure of Formula

Ia-5a or Ia-5b:

Ia-5a-1 or Ia-5b-1:

(Formula Ia-5a-1), or

In certain embodiments, the compound of Formula I'a-5 has the structure of

Formula I'a-5a or I'a-5b:

In certain embodiments, the compound of Formula I'a -5 has the structure of Formula I'a -5a-1 or I'a -5b-1:

In perferred embodiments, the invention relates to compounds having the structure of Formula la-4 (preferably Ia-4a or Ia-4a-1), Formula la-5 (preferably Ia-5a or Ia-5a-1), Formula I'a -4 (preferably I'a -4a or I'a -4a-1) or I'a -5 (preferably, I'a -5a or I'a -5a-1), or pharmaceutically acceptable salts thereof, wherein:

x₁ is C(RI)(R₂); x₂ is O; x₃ is C₁-C₃ alkyl substituted with one R₆; y_1a, when present, is C(R₈)₂; y_1b and y_1c is each C(R₅)₂; z₁ is C(H) or C(F); z₂ and Z3 are each C(H); z₄ is C(R₄); R₁ and R₂ are each H; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F; or R₁ and R₂ are each F; R₄ is F, C1, Br or CH₃ (i.e., z₄ is C(F), C(C1), C(Br), or C(CH₃)); R₆ is cycloalkyl, heterocyclyl (preferably wherein denotes the point of attachment), aryl, heteroaryl (preferably

wherein denotes the point of attachment), heterocyclylalkyl (preferably,

wherein denotes the point of

attachment), (wherein denotes the point of attachment) or heteroaryl alkyl

(preferably

wherein denotes the point of attachment), each of which is optionally substituted with one or more R₇; R₈ in each instance is H; and p is 1. In some embodiments, R₁ and R₂ are each H; z₁ is C(H); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In some embodiments, R₁ and R₂ are each H; z₁ is C(F); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In some embodiments, R₁ is F and R₂ is H; z₁ is C(H); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In some embodiments, R₁ is H and R₂ is F; z₁ is C(H); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is F and R₂ is H; z₁ is C(F); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is H and R₂1S F; z₁ is C(F); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl. In yet other embodiments, R₁ and R₂ are each F; z₁ is C(H); z₄ is C(C1); and R6 is cycloalkyl, heterocyclyl or heteroaryl.

In some embodiments, R6 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl

(preferably wherein denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl (preferably wherein denotes the point of

denotes the point of attachment), aryl, heteroaryl (preferably wherein denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably wherein denotes the point of attachment), or heteroarylalkyl (preferably wherein denotes the point of attachment).

each optionally substituted with one, two or three R₅, wherein

denotes the point of attachment; x₁ is C(RI)(R₂);

X2 is O; x₃ is C₁-C₃ alkyl substituted with one R6; y_1a, when present, is C(R₈)₂; y_1b and y_1c is each C(R₅)₂; z₁ is C(H) or C(F); z₂ is C(H), C(NH₂) or C(OH); z₃ is C(H); z₄ is C(R₄); R₁ and R₂ are each H; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F;

R₄ is F, C1, Br or CH₃ (i.e., z₄ is C(F), C(C1), C(Br), or C(CH₃));

OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -

R₆ is cycloalkyl (preferably

wherein

denotes the point of attachment), heterocyclyl (preferably

denotes the point of attachment), or heterocyclylalkyl (preferably,

wherein denotes the point of attachment); R₈ in each instance is H; and p is 1. In some embodiments, R₁ and R₂ are each H; z₁ is C(H); z₂ is C(H); z₄ is C(C1); and R6 is cycloalkyl or heterocyclyl. In some embodiments, R₁ is F and R₂ is H; z₁ is C(H); z₂ is C(H); z₄ is C(C1); and R6 is cycloalkyl or heterocyclyl. In some embodiments, R₁ is H and R₂ is F; z₁ is C(H); z₂ is C(H); z₄ is C(C1); and R6 is cycloalkyl or heterocyclyl.

In specific embodiments, R₆ is cycloalkyl (preferably wherein denotes the point of attachment), heterocyclyl (preferably

heterocyclylalkyl (preferably, wherein

denotes the point of attachment).

In specific embodiments, R₆ is

wherein denotes the point of attachment.

wherein denotes the point of attachment. In other specific embodiments, R₆ is

, wherein denotes the point of attachment.

In specific embodiments, R₆ is wherein denotes the point of attachment. In other specific embodiments, R₆ is

wherein

denotes the point of attachment.

In specific embodiments, R₆ is

In specific embodiments, R₆ is

wherein ^ denotes the point of attachment; R₇a in each occurrence is independently F, C1, C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁- C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as -CH=CHF) or C₂-C₃ alkynyl; R_7b is C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, - CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), optionally substituted C₃-C5 cycloalkyl or optionally substituted C4-C₆ heterocyclyl; q is 1, 2 or 3; and with the proviso that R₆ is not

In some embodiments, R₆ is in other embodiments, R₆ is

In yet other embodiments, R₆ is

.

In specific embodiments, R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -CN, -CH₂CN, -C(O)OR₃, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -

OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

In other specific embodiments, R6 is

wherein

denotes the point of attachment.

In certain embodiments, R6 is

wherein denotes the point of attachment).

In certain embodiments, the invention relates to a compound having the structure of

Formula P:

(Formula II) or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

R_h is H or optionally substituted C₁-C₃ alkyl;

R₄ (such as 6-membered aryl or heteroaryl optionally substituted with one or more R₄);

R₄ (such as 6-membered aryl or heteroaryl optionally substituted with one or more R₄); x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

W in each occurrence is independently S or O;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each instance is hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; C is 6- membered aryl or heteroaryl optionally substituted with one or more R₄; and D is 6- membered aryl or heteroaryl optionally substituted with one or more R₄.

In some embodiments, the invention relates to a compound of Formula II wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other such embodiments, both R₁ and R₂ are F.

In some embodiments, the invention relates to a compound of Formula II, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of

Formula IF:

or a pharmaceutically acceptable salt thereof, wherein:

* is the quaternary carbon atom;

C is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more RF

D is a 5- to 6-membered aryl or heteroaryl optionally substituted with one or more RF x₁ is C(RI)(R₂) or C=O; x₂ is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)₂;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y₁ is * — y_1b — y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is * — y_{2b —} y_2c; y_1a and y_2a are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y¾ and y_2c are each independently a bond, (C(R₅)₂)_n, O, N(R₃), S, S(O), or

S(O)₂; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be a bond; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; with the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that both y_2b and y_2c cannot be heteroatoms; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-,

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some embodiments, R₁ and R₂ are each independently H or F; R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -C02R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; C is 6-membered aryl or heteroaryl optionally substituted with one or more R₄; and D is 6-membered aryl or heteroaryl optionally substituted with one or more R₄.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -C02R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -C02R₃, -SO2R₃, -SO(R₃)₂, - OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)_2.

In some embodiments, the invention relates to a compound of Formula IF wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other such embodiments, both R₁ and R₂ are F. In some embodiments, the invention relates to a compound of Formula IF, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IF, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IF, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IF, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IF, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1, IIa-3-1, IF, II'a -1, II'a -2, II'a -3, II'a -1-1, II'a -2-1 or II'a -3-1 or a pharmaceutically acceptable salt thereof, wherein R₅ is hydroxy, halogen, unsubstituted C₁-C₃ alkyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, - CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In certain such embodiments, the invention relates to a compound having the structure of Formula II or IF, or a pharmaceutically acceptable salt thereof, wherein: y₁ is y_1a and y₂ is y_2a, with the proviso that both y_1a and y_2a cannot be heteroatoms, and the further proviso that both y_1a and y_2a cannot be bond; y₁ is * — y_1b — y_1c and y₂ is y_2a, with the proviso that both y_1b and y_2a cannot be heteroatoms, the further proviso that both y_1b and y_1c cannot be heteroatoms, the further proviso that both y_1b and y_2a cannot be bond, and the further proviso that both y_1b and y_1c cannot be bond; or y₁ is y_1a and y₂ is * — y_2b — y₂c, with the proviso that both y_1a and y_2b cannot be heteroatoms, the further proviso that both y_2b and y_2c cannot be heteroatoms, the further proviso that both y_1a and y_2b cannot be bond, and the further proviso that both y_2b and y_2c cannot be bond.

In some embodiments, the invention relates to a compound having the structure of Formula II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1, IIa-3-1, IF, II'a -1, II'a -2, II'a -3, II'a -1-1, II'a -2-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, A is a 6 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅, In specific embodiments, A is

each optionally substituted with one or more R₅,

wherein denotes the point of attachment to the pyrimidine ring. In preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅, In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring that is not substituted with R₅ (i.e., there is not instance of R₅). In other preferred embodiments, A is

optionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring. In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In even more preferred embodiments, A is each optionally substituted with one or more R₅, wherein

denotes the point of attachment to the pyrimidine ring. In some preferred embodiments, A is not substituted (i.e., there is no instance of R₅).

In certain embodiments, the invention relates to a compound having the structure of Formula II or IF, or a pharmaceutically acceptable salt thereof, wherein 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.

In other embodiments, the invention relates to a compound having the structure of Formula II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1, IIa-3-1, IIa-2-2, IIa-3-2, IF, II'a -1, II'a -2, II'a -3, IFal-1, II'a -2-1, II'a -3-1, II'a -2-2 or II'a -3-2, or a pharmaceutically acceptable salt thereof, wherein x₁ is C(RI)(R₂), R₁ is H and R₂ is H.

In other embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein X2 is O.

In other embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, x₃ is C₁-C₆ alkyl substituted with R6, R₆ is cycloalkyl, heterocyclyl, aryl, or heteroaryl each of which is optionally substituted with one or more R₇. In preferred embodiments x₃ is C₁-C₃ alkyl and R6 is heterocyclyl.

In preferred embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein R₄ in each instance is independently OH, F, C1, Br, N(R₃)₂, CFH₂, CHF₂, CF₃, OCFH2, OCHF₂, OCF₃, SCFH2, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl. In preferred embodiments, R₄ is F, C1, Br, OH or CH₃.

In certain embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein p is 1. In other embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein p is 2.

In certain embodiments, the invention relates to a compound having the structure of Formula II or IF, or a pharmaceutically acceptable salt thereof, wherein p is 1, and B is a 5- membered saturated or partially saturated cycloalkyl or heterocyclyl. In certain embodiments, the invention relates to a compound having the structure of Formula II or IF, or a pharmaceutically acceptable salt thereof, wherein p is 1, and B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

In certain specific embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein: y_1a, y_2a, y_1b, y_1c, y_2b and y_2c are (C(R₈)₂)_n;

R.8 in each instance is H; R₃ in each instance is H; and n in each instance is 1.

In certain embodiments, the invention relates to a compound having the structure of Formula IIa-1, IIa-2 or IIa-3:

or a pharmaceutically acceptable salt thereof, wherein:

R_h is H or optionally substituted C₁-C₃ alkyl;

R₄;

R₄; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

W in each occurrence is independently S or O;

R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH₃, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1. In some such embodiments, R₁ and R₂ are each independently H or F; R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R₅ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; C is 6-membered aryl or heteroaryl optionally substituted with one or more R₄; and D is 6-membered aryl or heteroaryl optionally substituted with one or more R₄.

In some embodiments, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other embodiments, both R₁ and R₂ are F.

In some embodiments, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein R₁ is H and R₂ is CH₃. In other embodiemnts, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein R₁ is F and R₂ is CH₃. In other embodiemnts, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-1, IIa-2 or IIa-3, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred emodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of Formula II'a -1, II'a -2 or II'a -3:

or a pharmaceutically acceptable salt thereof, wherein:

R₄; D is a 5- or 6-membered aryl or heteroaryl optionally substituted with one or more Rb x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y_1a and y_2a are each independently (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; y_1b and y_1c are each independently (C(R₅)₂)_n, O, N(R₃), S, S(O), or S(O)2; with the proviso that both y_1a and y_2a cannot be heteroatoms; and with the proviso that both y_1b and y_1c cannot be heteroatoms; R₁ and R₂ are each independently CH₃, OH, H or F (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

W in each occurrence is independently S or O;

In some embodiments, the invention relates to a compound of Formula II'a -1, II'a -2 or II'a -3, wherein x₁ is C(RI)(R₂); and one of R₁ and R₂ is F and the other is H. In other embodiments, both R₁ and R₂ are F.

In some embodiments, the invention relates to a compound of Formula II'a -1, II'a -2 or II'a -3, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -1, II'a -2 or II'a -3, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -1, II'a -2 or II'a -3, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -1, II'a -2 or II'a -3, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -1, II'a -2 or II'a -3, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula IIa-1, IIa-2, IIa-3, II'a -1, II'a -2 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein: both y_1a and y_2a cannot be heteroatoms, and the further proviso that both y_1a and y_2a cannot be bond; or both y_1b and y_2a cannot be heteroatoms, the further proviso that both y_1b and y_1c cannot be heteroatoms, the further proviso that both y_1b and y_1c cannot be heteroatoms, and the further proviso that both y_1b and y_1c cannot be bond.

In some embodiments, A is a 6 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅. In

the pyrimidine ring. In some embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅,

In some embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅, In preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅, In more preferred embodiments, A is a 7- or 8-membered bridged heterocyclyl. In other o

ptionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring. In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In even more preferred embodiments, A is each optionally substituted with one or more R₅, wherein denotes the point of attachment to the

pyrimidine ring. In some embodiments, the invention relates to compounds having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, wherein: each optionally substituted

with one or two R₅, wherein denotes the point of attachment to the pyrimidine ring;

R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ hydroxalkyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -OH, -CN, -CH₂CN, -C(O)OR₃, -C(O)N(R₃)₂, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, - OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂, -S(O)NR₃N(R₃)₂; and

-S(O)NR₃N(R₃)₂

In some embodiments, the invention relates to compounds having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, wherein:

A is

each optionally substituted with one or two R₅, wherein denotes the point of attachment to the pyrimidine ring; R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ hydroxalkyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -OH, -CN, -CH₂CN, -C(O)OR₃, -C(O)N(R₃)₂, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, - OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂, -S(O)NR₃N(R₃)₂; and

In more preferred embodiments, R₅ in each occurrence is independently optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, C₁-C₃ haloxalkyl, C₁-C₃ alkoxy, F, C1, -CN, -CH₂CN, -C(O)OR₃, -N(O)OR₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, - OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)₂

In some embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein ring C is heteroaryl and one or two of the non-bridgehead atoms is N. In specific embodiments, one member is N. In other embodiments, ring D is heteroaryl and one or two of the nonbridgehead atoms is N. In specific embodiments, one member is N. In other specific embodiments, ring C and D is heteroaryl and one or two of the non-bridgehead atoms in each is N. In preferred embodiments, ring C is heteroaryl, one or two of the non-bridgehead atoms of ring C is N, and ring D is aryl. In other preferred embodiments, ring C is aryl, ring D is heteroaryl and one or two of the non-bridgehead atoms of ring D is N.

In other embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1, II'a -3-1, IIa-2-2, II'a -2-2, IIa-3 -2 or II'a -3 -2, or a pharmaceutically acceptable salt thereof, wherein x₁ is C(RI)(R₂), R₁ is H and R₂ is H.

In other embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3, II'a -3, IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein X₃ is C₁-C₆ alkyl substituted with R6, R₆ is cycloalkyl, heterocyclyl, aryl, or heteroaryl each of which is optionally substituted with one or more R₇. In preferred embodiments X₃ is C₁-C₃ alkyl and R6 is heterocyclyl. In preferred embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein R.4 in each instance is independently OH, F, C1, Br, N(R₃)₂,

CFH₂, CHF₂, CF₃, OCFH₂, OCHF₂, OCF₃, SCFH₂, SCHF₂, SCF₃, CH₃, OCH₃, SCH₃, (W)tCF₂H, CN, propargyl, cyclopropyl or cyclobutyl.

In other preferred embodiments, R.4 is absent in both ring C and D.

In certain specific embodiments, the invention relates to a compound having the structure of Formula II, IF, IIa-1, II'a -1, IIa-2, II'a -2, IIa-3 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein: y_1a, y_2a, y ib and y_1c are (C(R₅)₂)_n; R₈ in each instance is H; R₃ in each instance is H; and n in each instance is 1.

In certain embodiments, the compound of Formula IIa-1 has the structure of Formula Ila- la or Ila- 1b:

(Formula Ila- la), or

In some embodiments, the invention relates to a compound of Formula Ila-1a or Ila- 1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Ila-1a or Ila-1b, wherein R₁ is CH₃ and R₂ is H. In some embodiments, the invention relates to a compound of Formula Ila-1a or Ila- 1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Ila-1a or Ila-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a - la or II'a - 1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -1a or II'a -1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -1a or II'a -1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula II'a -1 has the structure of

Formula II'a -1a or II'a -1b:

(Formula II'a -1a) or

(Formula II'a -1b).

In some embodiments, the invention relates to a compound of Formula II'a - la or II'a -1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -1a or II'a -1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -1a or

II'a -1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -1a or II'a -1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -1a or II'a -1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-2 has the structure of Formula IIa-2a or IIa-2b:

(Formula IIa-2a), or

(Formula IIa-2b).

In some embodiments, the invention relates to a compound of Formula IIa-2a or Ila- 2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2a or IIa-2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-2a or Ila-

2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2a or Iia-2b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Iia-2a or Iia- 2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-2 has the structure of Formula IIa-2a-1 or IIa-2b-1 :

(Formula IIa-2a-1), or

In some embodiments, the invention relates to a compound of Formula IIa-2a-1 or IIa-2b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2a-1 or IIa-2b-1, wherein R₁ is CH₃ and R₂ is H. In some embodiments, the invention relates to a compound of Formula IIa-2a-1 or

IIa-2b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2a-1 or IIa-2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-2a- or IIa-2b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -2 has the structure of Formula II'a -2a or II'a -2b:

(Formula II'a -2a) or

(Formula II'a -2b).

In some embodiments, the invention relates to a compound of Formula II'a -2a or II'a -2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2a or II'a -2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2a or

II'a -2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2a or II'a -2b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2a or II'a -2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -2 has the structure of Formula II'a -2a-1 or II'a -2b-1:

(Formula II'a -2a-1) or

In some embodiments, the invention relates to a compound of Formula II'a -2a-1 or II'a -2b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2a-1 or II'a -2b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2a-1 or II'a -2b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2a-1 or II'a -2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2a-1 or II'a -2b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-3 has the structure of Formula IIa-3a or IIa-3b:

(Formula IIa-3b).

In some embodiments, the invention relates to a compound of Formula IIa-3a or Ila- 3b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3a or IIa-3b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3a or Ila-

3b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3a or IIa-3b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-3a or Ila- 3b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5- membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-3 has the structure of Formula IIa-3 a- 1 or IIa-3b-1:

(Formula IIa-3a-1), or

In some embodiments, the invention relates to a compound of Formula IIa-3a-1 or IIa-3b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3a-1 or IIa-3b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3a-1 or IIa-3b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3a-1 or IIa-3b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-3a-1 or IIa-3b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -3 has the structure of Formula II'a -3 a or II'a -3b:

(Formula II'a -3b).

In some embodiments, the invention relates to a compound of Formula II'a -3a or II'a -3b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3a or II'a -3b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3a or

II'a -3b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -3 has the structure of Formula II'a -3 a- 1 or II'a -3b-1:

(Formula II'a -3a-1) or

(Formula II'a -3b-1).

In some embodiments, the invention relates to a compound of Formula II'a -3a-1 or II'a -3b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3a-1 or II'a -3b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3a-1 or II'a -3b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3a-1 or II'a -3b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -3a-1 or II'a -3b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-memebred. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula IIa-1-1, IIa-2-1 or IIa-3-1:

(Formula IIa-1-1),

or a pharmaceutically acceptable salt thereof, wherein:

R_h is H or optionally substituted C₁-C₃ alkyl;

C is a 6-membered aryl or heteroaryl;

D is a 6-membered aryl or heteroaryl;

X₁ , X₃ , X4, and X₅ are each independently C or N; x₁ is C(RI)(R₂) or C=O;

X2 is a bond, C(R₃)₂, C=O, O, N(R₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is absent if x₁ is N, or R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is absent if x₃ is N, or R_4-3 is H, CH₃, C1 or F;

R_4-4 is absent if X4 is N, or R_4-4 is H, C1 or F;

R_4-5 is absent if X5 is N, or R_4-5 is H, C1 or F;

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl(such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl);

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2 or 3. In some such embodiments, R₁ and R₂ are each independently H or F; and R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In some embodiments, the invention relates to a compound of Formula IIa-1-1, Ila- 2-1 or IIa-3-1 wherein x₁ is C(R₁)(R₂); one of R₁ and R₂ is F and the other is H; x₁ , x₃ , X4 and X5 are each C; R_4-1, R_4-4 and R_4-5 are each H; and R_4-3 is H or F. In other embodiments, both R₁ and R₂ are F. In some embodiments, R_4-3 is F. In some embodiments, R_4-3 is H. In yet other embodiments, R₁ and R₂ are both H; X₁ , X₃ , X₄ and X₅ are each C; R_4-1, R_4-4 and

R_4-5 are each H; and R_4-3 is F.

In some embodiments, the invention relates to a compound of Formula IIa-1-1, Ila- 2-1 or IIa-3-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-1-1, IIa-2-1 or IIa-3-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-1-1, Ila- 2-1 or IIa-3-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-1-1, IIa-2-1 or IIa-3-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-1-1, IIa- 2-1 or IIa-3-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of Formula II'a - 1-1, II'a -2-1 or II'a -3-1:

or a pharmaceutically acceptable salt thereof, wherein: A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅;

C is a 6-membered aryl or heteroaryl;

D is a 6-membered aryl or heteroaryl;

X₁ , X₃ , X₄ and X₅ are each independently C or N; x₁ is C(RI)(R.2) or C=O;

X2 is a bond, C(R₃)2, C=O, O, N(R.₃), S, S(O), or S(O)2;

X₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R₆; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is absent if X₁ is N, or R_4-1 is H, NH₂, OH or CH₃;

R_4-3 is absent if X₃ is N, or R_4-3 is H, CH₃, C1 or F;

R_4-4 is absent if X₄ is N, or R_4-4 is H, C1 or F;

R_4-5 is absent if X₅ is N, or R_4-5 is H, C1 or F;

- SO2N(R₃)₂, -C(O)N(R₃)₂,

R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2 or 3. In some such embodiments, R₁ and R₂ are each independenctly H or F; and R₅ in each occurrence is independently such as hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -C02R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO2R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -C02R₃, -SO2R₃, -SO(R₃)₂, - OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)₂.

In some embodiments, the invention relates to a compound of Formula II'a -1-1, II'a -2-1 or II'a -3-1 wherein x₁ is C(RI)(R₂); one of R₁ and R₂ is F and the other is H; x₁ ,

X₃, X4 and X5 are each C; R_4-1, R_4-4 and R_4-5 are each H; and R_4-3 is H or F. In other embodiments, both R₁ and R₂ are F. In some embodiments, R_4-3 is F. In some embodiments,

R_4-3 is H. In yet other embodiments, R₁ and R₂ are both H; X₁ , X₃ , X₄ and X₅ are each C;

R_4-1, R_4-4 and R_4-5 are each H; and R_4-3 is F.

In some embodiments, the invention relates to a compound of Formula II'a -1-1, II'a -2-1 or II'a -3-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -1-1, II'a -2-1 or II'a -3-1, wherein R₁ is CH₃ and R₂ is H. In some embodiments, the invention relates to a compound of Formula II'a -1-1, II'a -2-1 or II'a -3-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -1-1, II'a -2-1 or II'a -3-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -1-1,

II'a -2-1 or II'a -3-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compounds of Formula IIa-2-1 have the structure of Formula IIa-2-1a or IIa-2-1b:

(Formula IIa-2- la), or

(Formula IIa-2-1b).

In some embodiments, the invention relates to a compound of Formula IIa-2-1a or IIa-2-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-1a or IIa-2-1b, wherein R₁ is CH₃ and R₂ is H. In some embodiments, the invention relates to a compound of Formula IIa-2-1a or IIa-2-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-1a or IIa-2-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-2-1a or IIa-2-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compounds of Formula IIa-2-1 have the structure of Formula IIa-2- la- 1 or IIa-2-1b-1:

(Formula IIa-2-1a-1), or

(Formula IIa-2-1b-1).

In some embodiments, the invention relates to a compound of Formula IIa-2-1a-1 or IIa-2-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-2-1a-1 or IIa-2-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-2-1a-1 or

IIa-2-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-2-1a-1 or IIa-2-1b-1, wherein R₁ is CH₃ and R₂ is F. In some embodiments, the invention relates to a compound of Formula IIa-2-1a-1 or IIa-2-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compounds of Formula II'a -2-1 have the structure of

Formula II'a -2-1a or Formula II'a -2-1b:

(Formula II'a -2-1 a), or

In some embodiments, the invention relates to a compound of Formula II'a -2-1 a or II'a -2-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-1a or II'a -2-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2-1 a or II'a -2-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-1a or II'a -2-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2-1 a or II'a -2-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compounds of Formula II'a -2-1 have the structure of Formula II'a -2-1a-1 or Formula II'a -2-1b-1:

(Formula II'a -2-1a-1), or

(Formula II'a -2-1b-1).

In some embodiments, the invention relates to a compound of Formula II'a -2-1a-1 or II'a -2-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-1a-1 or II'a -2-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2-1a-1 or II'a -2-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-1a-1 or II'a -2-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2-1a-1 or II'a -2-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compounds of Formula IIa-3-1 have the structure of

Formula IIa-3-1a or IIa-3-1b:

In some embodiments, the invention relates to a compound of Formula IIa-3-1a or IIa-3-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-1a or IIa-3-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3-1a or IIa-3-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-1a or IIa-3-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-3-1a or IIa-3-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compounds of Formula IIa-3-1 have the structure of Formula IIa-3- la- 1 or IIa-3-1b-1:

In some embodiments, the invention relates to a compound of Formula IIa-3-1a-1 or IIa-3-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-1a-1 or IIa-3-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3-1a-1 or IIa-3-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-1a-1 or IIa-3-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-3-1a-1 or IIa-3-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compounds of Formula II'a -3-1 have the structure of Formula II'a -3-1a or II'a -3-1b:

In some embodiments, the invention relates to a compound of Formula II'a -3-1a or II'a -3-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -3-1a or II'a -3-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3-1a or II'a -3-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -3-1a or II'a -3-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -3-1a or II'a -3-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compounds of Formula II'a -3-1 have the structure of Formula II'a -3-1a-1 or II'a -3-1b-1:

In some embodiments, the invention relates to a compound of Formula II'a -3-1a-1 or II'a -3-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3-1a-1 or II'a -3-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3-1a-1 or II'a -3-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In some embodiments, A is a 6 - 12 membered saturated or partially saturated monocyclic, polycyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅. In specific embodiments,

each optionally substituted with one or more R₅, wherein denotes the

point of attachment to the pyrimidine ring. In some embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅

In some embodiments, A is a 7 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅

In preferred embodiments, A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅ In more preferred embodiments, A is a 7-membered bridged heterocyclyl. In other preferred each

optionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring.

In other preferred embodiments, A is an 8-membered bridged heterocyclyl. In even more preferred embodiments,

each optionally substituted with one or more R₅, wherein

denotes the point of attachment to the pyrimidine ring. In other preferred embodiments,

more preferred embodiments, A is . In more preferred embodiments, A is In more preferred embodiments, A is

. In more preferred embodiments, A is

In some embodiments, the invention relates to a compound having the structure of Formula IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1, II'a -3-1, IIa-2-2, II'a -2-2, IIa-3-2 or II'a -3-2, or a pharmaceutically acceptable salt thereof, wherein ring C is heteroaryl and one or two of the non-bridgehead atoms is N, wherein the R_4-1, R_4-3 and/or R_4-4 group is present only if bound to a non-bridgehead carbon. In specific embodiments, one member is N, wherein the R_4-1, R_4-3 or R_4-4 group is present only if bound to a non-bridgehead carbon. In other embodiments, ring D is heteroaryl and one or two of the non-bridgehead atoms is N, wherein the R_4-5 group is present only if bound to a non-bridgehead carbon. In specific embodiments, one member is N, wherein the R_4-5 group is present only if bound to a nonbridgehead carbon. In preferred embodiments, ring C is heteroaryl, one or two of the nonbridgehead atoms of ring C is N, wherein the R_4-1, R_4-3 and/or R_4-4 group is present only if bound to a non-bridgehead carbon, and ring D is aryl. In other preferred embodiments, ring C is aryl, ring D is heteroaryl and one or two of the non-bridgehead atoms of ring D is N, wherein the R_4-5 group present only if bound to a non-bridgehead carbon.

In some embodiments, the invention relates to a compound having the structure of Formula IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein X₁ , X₃ , X₄ and X₅ are each C; and R_4-1, R_4-3, R_4-4 and R_4-5 are each H. In certain such embodiments, x₁ is CH₂. In certain embodiments, x₁ is C(RI)(R₂); and R₁ and R₂ are each F; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F. In other embodiments, R_4-3 is F.

In other embodiments, the invention relates to a compound having the structure of Formula IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1, or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein X2 is O. In certain such embodiments, x₁ is CH₂. In certain embodiments, x₁ is C(RI)(R₂); and R₁ and R₂ are each F; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F. In other embodiments, the invention relates to a compound having the structure of Formula IIa-1-1, II'a - 1-1, IIa-2-1, II'a -2-1, IIa-3-1 or II'a -3-1, or a pharmaceutically acceptable salt thereof, wherein X₃ is C₁-C₆ alkyl substituted with one R6. In certain such embodiments, R6 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R₇. In preferred embodiments X₃ is C₁-C₃ alkyl and R6 is heterocyclyl. In other embodiments, R_4-1, R_4-3, R_4-4 and R_4-5 are each H. In certain embodiments, x₁ is CH₂. In other embodiments, x₁ is C(RI)(R₂); and R₁ and R₂ are each F; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F. In other embodiments, R_4-3 is F.

In specific embodiments, the invention relates to compounds of Formula IIa-2-1 (preferably IIa-2-1 a or IIa-2-1a-1), II'a -2-1 (preferably II'a -2-1 a or II'a -2-1a-1), IIa-3-1 (preferably IIa-3-1 a or IIa-3-1a-1) or II'a -3-1 (preferably II'a -3-1 a or II'a -3-1a-1), or pharmaceutically acceptable salts thereof, wherein:

A is

X₁ , X₃ , X₄ and X₅ are each C; x₁ is C(RI)(R₂); x₂ is O; x₃ is C₁-C₃ alkyl substituted with one R₆; R₁ and R₂ are each H; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F; or R₁ and R₂ are each F;

R6 is cycloalkyl, heterocyclyl (preferably

wherein denotes the point of attachment), aryl, heteroaryl (preferably

wherein denotes the point of attachment), heterocyclylalkyl (preferably

wherein

denotes the point of attachment), heteroarylalkyl (preferably

wherein

denotes the point of attachment), or

(wherein denotes the point of attachment), each of which is optionally substituted with one or more R₇;

R_4-3 is H or F; and

R_4-1, R_4-4 and R_4-5 are each H. In certain such embodiments, R₁ and R₂ are each H. In other embodiments, R₁ and R₂ are each H; R_4-3 is H; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ and R₂ are each H; R_4-3 is F; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is F and R₂ is H; R_4-3 is H; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is F and R₂1S H; R_4-3 is F; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is H and R₂ is F;

R_4-3 is H; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ is H and R₂ is F; R_4-3 is F; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ and R₂ are each F; R_4-3 is H; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, R₁ and R₂ are each F; R_4-3 is F; and R6 is cycloalkyl, heterocyclyl or heteroaryl. In specific embodiments, R₆ is

In specific embodiments, the invention relates to compounds of Formula IIa-2-1 (preferably IIa-2-1a or IIa-2-1a-1), II'a -2-1 (preferably II'a -2-1a or II'a -2-1a-1), IIa-3-1 (preferably IIa-3-1a or IIa-3-1a-1) or II'a -3-1 (preferably II'a -3-1a or II'a -3-1a-1), or pharmaceutically acceptable salts thereof, wherein:

A is each optionally substituted with one, two or three R₅, wh

erein denotes the point of attachment;

X₁ , X₃ , X₄ and X₅ are each C; x₁ is C(RI)(R₂);

X2 is O; x₃ is C₁-C₃ alkyl substituted with one R₆; R₁ and R₂ are each H; or R₁ is F and R₂ is H; or R₁ is H and R₂ is F;

-

OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or and R₆ is cycloalkyl (preferably wherein denotes the point of attachment), heterocyclyl (preferably

denotes the point of attachment), or heterocyclylalkyl (preferably, , wherein denotes the point of

attachment).

In certain such embodiments, R₁ and R₂ are each H. In certain such embodiments, R₁ is F and R₂ is H. In certain such embodiments, R₁ is H and R₂ is F. In other embodiments, R₁ and R₂ are each H; R_4-3 is H; and R6 is cycloalkyl or heterocyclyl. In other embodiments, R₁ is F and R₂ is H; R_4-3 is H; and R6 is cycloalkyl or heterocyclyl. In other embodiments, R₁ is H and R₂ is F; R_4-3 is H; and R6 is cycloalkyl or heterocyclyl.

In specific embodiments, R₆ is

In specific embodiments, R₆ is cycloalkyl (preferably wherein

wherein denotes the point of attachment), or heterocyclylalkyl (preferably, or wherein denotes the point of attachment).

In specific embodiments, R6 is

In specific embodiments, R₆ is the point of attachment. In other specific embodiments, R₆ is

wherein denotes the point of attachment.

In specific embodiments, R₆ is

, wherein denotes the point of attachment.

In specific embodiments, R₆ is wherein

/ denotes the point of attachment. In other specific embodiments, R₆ is

wherein denotes the point of

attachment.

In specific embodiments, R6 is or

wherein denotes the point of attachment.

In specific embodiments, R_.6 is

wherein denotes the point of attachment; R_7a in each occurrence is independently F, C1, C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁- C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as -CH=CHF) or C₂-C₃ alkynyl; R_7b is C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, - CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), optionally substituted C₃-C5 cycloalkyl or optionally substituted C4-C₆ heterocyclyl; q is 1, 2 or 3; and with the proviso that R₆ is not

In some embodiments, R6 is

In other embodiments, R.₆ is In yet other embodiments, R6 is .In other specific embodiments, R6 is

denotes the point of attachment.

In certain embodiments, R6 is

In other embodiments, the invention relates to compounds of Formula I, la, la-1, la-

2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, I', I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, II', II'a -1, II'a - 2 or II'a -3, or pharmaceutically acceptable salts thereof, wherein: x₁ is C(RI)(R₂); x₃ is C₁-C₃ alkyl substituted with one R6; R₁ and R₂ are each H;

R₃ in each occurrence is independently H or CH₃;

R6 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more R₇; and R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃ or CH₂OC(O)N(R₃)₂. In other embodiments, R₁ and R₂ are each F. In other embodiments, R₁ is F and R₂ is H. In yet other embodiments, R₁ is H and R₂ is F. In some aspects, the invention relates to compounds of Formula I, la, la-1, la-2, la-

3, la-4, la- 5, II, Ila, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, IF a, II'a -1, II'a -2 or II'a -3, or a pharmaceutically acceptable salts thereof, wherein X₃ is methylene. In other aspects, X₃ is methylene. When R6 or R₅ is C₁-C₃ alkyl, each independently may be CH₃. In some aspects, the invention relates to compounds of Formula I, la, la-1, la-2, la- 3, la-4, la- 5, II, IIa-1, IIa-2, IIa-3, I', I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, II'a -3, or pharmaceutically acceptable salts thereof, wherein R₆ is heterocyclyl optionally substituted with one or two R₇; R₇ in each instance is independently F, methyl, ethyl, isopropyl, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃,

CH₂N(H)C(O)R₃ or CH₂OC(O)N(R₃)₂; and n in each instance is independently 1 or 2.

In some aspects heterocyclyl is pyrrolidinyl and the N atom of pyrrolidinyl is methyl substituted. In some aspects heterocyclyl is 7a-methylhexahydro- 1H-pyrrolizinyl, In some aspects heterocyclyl is 2-fluoro-7a-methylhexahydro- 1H-pyrrolizinyl, In some aspects heterocyclyl is (7a-methylhexahydro- 1H-pyrrolizin-3-yl)methyl dimethylcarbamatyl. In other aspects heterocyclyl is l-azabicyclo[2.2.1]heptanyl. In other aspects heterocyclyl is azetidinyl optionally substituted with one or two R₇, and preferred embodiments include 3-methylazetidin-3-aminyl and 3-ethylazetidin-3-aminyl.

In some embodiments, the invention relates to compounds of Formula I, la, F or I'a, or pharmaceutically acceptable salts thereof, wherein B is a 5- or 6-membered heterocyclyl. In some aspects, the 5- or 6-membered heterocyclyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, sulfolanyl, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, thiomorpholinyl, thiomorpholinyl dioxide, morpholinyl, 1,4- dithianyl, thianyl, lactamyl and lactonyl.

In other embodiments, the invention relates to compounds of Formula I, la, la-1, la- 2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a - 2 or II'a -3, or pharmaceutically acceptable salts thereof, wherein R₃ is C₁-C₄ alkyl. In preferred embodiments, C₁-C₄ alkyl is methyl or ethyl.

In some aspects, the invention relates to a compound of Formula Formula I, la, la-1, la-2, la-3, la-4, la-5, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4 or I'a -5, or a pharmaceutically acceptable salt thereof, wherein A is a 6 - 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅, wherein when A is a 6 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring, then no instance of R₅ is C₁-C₃ cyanoalkyl.

In preferred embodiments, the inventions relates to a compound of Formula I, la, la- 1, la-2, la-3, la-4, la-5, Ia-1-1, Ia-2-1, Ia-4-1, Ia-5-1, II, IIa-1, IIa-2, IIa-3, IIa-1-1, IIa-2-1, IIa-3- 1, IIa-2-2, IIa-3-2, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, I'a -1-1, I'a -2-1, I'a -4-1, I'a - 5-1, IF, II'a -1, II'a -2, II'a -3, II'a -1-1, II'a -2-1, II'a -3-1, II'a -2-2 or II'a -3-2, or a pharmaceutically acceptable salt thereof, wherein R_h, when present, is H and there is no instance of R₅ (i.e., ring A is not substituted with R₅ and u, when present, is 0).

In some aspects, the invention relates to a compound of Formula I, la, la-1, la-2, la- 3, la-4, la- 5, II, IIa-1, IIa-2, IIa-3, I', I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein one instance of R₅ is C₁-C₃ cyanoalkyl. In other aspects, the one instance of R₅ is hydroxy. In other aspects, the one instance of R₅ is halogen. In yet other aspects, the one instance of R₅ is C₁-C₃ hydroxyalkyl. In yet other aspects, the one instance of R₅ is -C02N(R₃)₂. In yet other aspects, the one instance of R₅ is C₁-C₃ alkyl optionally substituted with C₁-C₃ alkoxy.

In some aspects, the invention relates to a compound of Formula la-4, la-5, II, IIa-1, IIa-2, IIa-3, I'a -4, I'a -5, IF, II'a -1, II'a -2 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein one instance of R₅ is C₁-C₃ cyanoalkyl. In yet other aspects, the one instance of R₅ is C₁-C₃ alkyl optionally substituted with C₁-C₃ alkoxy.

In other embodiments, the invention relates to a compound of Formula I, la, la-1, la- 2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a - 2 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein one instance of R₅ is C₁- C₃ alkyl and the other is H. In preferred embodiments, C₁-C₃ alkyl is methyl or ethyl.

In other embodiments, the invention relates to compounds of Formula la-4, Ia-4a, Ia-4b, Ia-4a-1, Ia-4b-1, la-5, Ia-5a, Ia-5b, Ia-5a-1, Ia-5b-1, I'a -4, 1 a-4a, I'a -4b, I'a -4a-1, I'a -4b-1, I'a -5, I'a -5a, I'a -5b, I'a -5a-1 or I'a -5b-1, or pharmaceutically acceptable salts thereof, wherein z₄ is C(R₄) and R₄ in this instance is Br, C1, F or methyl. In preferred embodiments, R₄ is C1.

In certain embodiments, the invention relates to a compound having the structure of Formula la-4, Ia-4a, Ia-4b, Ia-4a-1, Ia-4b-1, la-5, Ia-5a, Ia-5b, Ia-5a-1, Ia-5b-1, I'a -4, I'a - 4a, I'a -4b, I'a -4a-1, I'a -4b-1, I'a -5, I'a -5a, I'a -5b, I'a -5a-1 or I'a -5b-1, or pharmaceutically acceptable salts thereof, wherein z₂ is C(R₄) and R₄ in this instance is H or OH. In preferred embodiments, R₄ is OH. In other preferred embodiments, R₄ is H.

In other embodiments, the invention relates to a compound of Formula I, la, la-1, la- 2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a - 2 or II'a -3, or a pharmaceutically acceptable salt thereof, wherein:

X2 is O; X₃ is C₁-C₃ alkyl; one instance of R₆ is wherein denotes the point of attachment to X₃.

In further embodiments, R6 is wherein

denotes the point of attachment to X₃.

In certain embodiments, the invention relates to a compound having the structure of Formula Ia-1-1, Ia-2-1, Ia-4-1 or Ia-5-1:

X2a is -O-R₆-1 or -OCH₂-R_6-1;

X is C or N, with the proviso that R_4-1 is absent when X is N;

R₄-I is H, NH₂, OH or CH₃;

R₄-2 is H, C1, F, CN, cyclopropyl, C(CH), CH₃ or CH₂CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - SO2N(R₃)₂,

-C(O)N(R₃)₂, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl

(preferably wherein

denotes the point of attachment), heterocyclyl

wherein denotes the point of attachment), aryl, heteroaryl (preferably _or wherein denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably and

wherein denotes the point of attachment), or heteroarylalkyl (preferably wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R₇; and R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4 (such as 0). In some such embodiments, R₁ and R₂ are each independently H or F (such as H); R₅ in each instance is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO2R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and u is 0.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -C02R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -C02R₃, -SO2R₃, -SO(R₃)₂, -

OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F. In preferred embodiments, x₂a is -OCH₂-R.₆-1. In other preferred embodiments, x₂a is -O-R₆-1. In yet other preferred embodiments, R.₆-1 is heterocyclyl.

In other embodiments, X is C; R₁ and R₂ are each H; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each H; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R₄-2 is F, C1, Br or CH₃; R₄- 3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In specific embodiments, R_4-1 is H. In specific embodiments, R₄-2 is C1. In specific embodiments, R₄-2 is Br. In specific embodiments, R₄-2 is CH₃. In other specific embodiments, x₂a is -O-R₆-1. In other specific embodiments, x₂a is -OCH₂-R₆-1. In yet other specific embodiments, u is 1. In yet other specific embodiments, u is 0. In yet other specific

or wherein denotes the point of attachment; or

or wherein denotes the point of attachment; or

wherein

denotes the point of attachment; or

point of attachment; or wherein

denotes the point of

wherein

denotes the point of attachment; R₇a in each occurrence is independently F, C1, C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as - CH=CHF) or C₂-C₃ alkynyl; R_7b is C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), optionally substituted C₃-C5 cycloalkyl or optionally substituted C4-C₆heterocyclyl; q is 1,

2 or 3; and with the proviso that R.₆ is not some embodiments, R_6-1 is in other embodiments, R_6-1 is In yet

attachment). In some embodiments, the invention relates to a compound of Formula Ia-1-1, Ia-2-1, Ia-4-1 or Ia-5-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-1-1, Ia-2-1, Ia-4-1 or Ia-5-1, wherein R₁ is CH₃ and R₂ is

H. In some embodiments, the invention relates to a compound of Formula Ia-1-1, la-2-

I, Ia-4-1 or Ia-5-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-1-1, Ia-2-1, Ia-4-1 or Ia-5-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Ia-1-1, Ia-2- 1, Ia-4-1 or Ia-5-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of

Formula I’a- 1-1, I'a -2-1, I'a -4-1 or I'a -5-1:

X2a is -0-R₆-1 or -OCH₂-R_6-1;

X is C or N; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F); or R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl;

R_4-1 is absent if Xis N, or R_4-1 is H, NH₂, OH or CH₃;

R_4-2 is H, C1, F, CN, cyclopropyl, C(CH), CH₃ or CH₂CH₃;

R_4-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R₆-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably wherein

denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl

(preferably wherein denotes the point of attachment), heterocyclyl

(preferably

wherein denotes the point of attachment), aryl, heteroaryl (preferably or

wherein

denotes the point of attachment), haloalkyl, heteroalkyl,

hydroxyalkyl, heterocyclylalkyl (preferably and

wherein

denotes the point of attachment), or heteroarylalkyl (preferably wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R₇;

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2 or 3; and u is 0, 1, 2, 3 or 4 (such as 0). In some such embodiments, R₁ and R₂ are each independently H or F (such as H); R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and u is 0.

In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl.

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -

OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

. In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F. In preferred embodiments, x₂a is -OCH₂-R₆-1. In other preferred embodiments, x₂a is -O-R₆-1.

In yet other preferred embodiments, R_6-1 is heterocyclyl.

In other embodiments, X is C; R₁ and R₂ are each H; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each H; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R₄-2 is F, C1, Br or CH₃; R₄- ₃ is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R₄-2 is F, C1, Br or CH₃; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R₄-2 is F, C1, Br or CH₃; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In specific embodiments, R_4-1 is H. In specific embodiments, R₄-2 is C1. In specific embodiments, R₄-2 is Br. In specific embodiments, R₄-2 is CH₃. In other specific embodiments, x₂a is -O-R₆-1. In other specific embodiments, x₂a is -OCH₂-R₆-1. In yet other specific embodiments, u is 1. In yet other specific embodiments, u is 0. In yet other specific

or wherein denotes the point of attachment; or or wherein denotes the point of attachment; or

wherein

denotes the point of attachment; or

wherein

denotes the point of attachment; R₇a in each occurrence is independently F, C1, C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as - CH=CHF) or C₂-C₃ alkynyl; R_7b is C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), optionally substituted C₃-C₅ cycloalkyl or optionally substituted C4-C₆heterocyclyl; q is 1,

2 or 3; and with the proviso that R.₆ is not some embodiments, R_6-1 is In other embodiments, R_6-1 is In yet other embodiments, R_6-1 is

In certain embodiments,

In some embodiments, the invention relates to a compound of Formula I'a -1-1, I'a - 2-1, I'a -4-1 or I'a -5-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula I'a -1-1, I'a -2-1, I'a -4-1 or I'a -5-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -1-1, I'a - 2-1, I'a -4-1 or I'a -5-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula I'a -1-1, I'a -2-1, I'a -4-1 or I'a -5-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -1-1, I'a -

2-1, I'a -4-1 or I'a -5-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is

3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula Ia-2-1 has the structure of

Formula Ia-2-1a or Ia-2-1b:

In some embodiments, the invention relates to a compound of Formula Ia-2-1a or Ia-2-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-2-1a or Ia-2-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Ia-2-1a or Ia-2-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-2-1a or Ia-2-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Ia-2-1a or Ia-2-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I'a -2-1 has the structure of Formula I'a -2-1a or I'a -2-1b:

(Formula I'a -2-1b).

In some embodiments, the invention relates to a compound of Formula I'a -2- la or I'a -2-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -2-1a or I'a -2-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -2- la or I'a -2-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -2-1a or I'a -2-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -2- la or I'a -2-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula Ia-4-1 has the structure of Formula Ia-4-1a or Ia-4-1b:

(Formula Ia-4-1b).

In some embodiments, the invention relates to a compound of Formula Ia-4-1a or Ia-4-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-4-1a or Ia-4-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Ia-4-1 a or

Ia-4-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-4-1a or Ia-4-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Ia-4-1a or Ia-4-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula Ia-4-1 has the structure of Formula la-4- la- 1 or Ia-4-1b-1: (Formula Ia-4-1 a- 1), or (Formula Ia-4-1b-1).

In some embodiments, the invention relates to a compound of Formula Ia-4-1a-1 or Ia-4-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-4-1a-1 or Ia-4-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Ia-4-1a-1 or Ia-4-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula Ia-4-1a-1 or Ia-4-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Ia-4-1a-1 or Ia-4-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I'a -4-1 has the structure of Formula I'a -4-1a or I'a -4-1b:

In some embodiments, the invention relates to a compound of Formula I'a -4- la or I'a -4-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -4-1a or I'a -4-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -4- la or I'a -4-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -4-1a or I'a -4-1b, wherein R₁ is CH₃ and R₂ is F. In some embodiments, the invention relates to a compound of Formula I'a -4- la or I'a -4-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula I'a -4-1 has the structure of

Formula I'a -4- la- 1 or I'a -4-1b-1:

In some embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is CH₃ and R₂ is F. In some embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula Ia-5-1 has the structure of Formula Ia-5-1a or Formula Ia-5-1b:

In some embodiments, the invention relates to a compound of Formula Ia-5-1a or Ia-5-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Ia-5-1a or Ia-5-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -4-1a-1 or I'a -4-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula Ia-5-1 has the structure of Formula Ia-5-1a-1 or Formula Ia-5-1b-1:

In some embodiments, the invention relates to a compound of Formula Ia-5-1a-1 or Ia-5-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Ia-5-1a-1 or Ia-5-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula Ia-5-1a-1 or Ia-5-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula Ia-5-1a-1 or Ia-5-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Ia-5-1a-1 or Ia-5-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I'a -5-1 has the structure of Formula I'a -5-1a or Formula I'a -5-1b:

In some embodiments, the invention relates to a compound of Formula I'a -5-1a or I'a -5-1b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -5-1a or I'a -5-1b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -5-1a or I'a -5-1b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -5-1a or I'a -5-1b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -5-1a or I'a -5-1b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula I'a -5-1 has the structure of Formula I'a -5-1a-1 or Formula I'a -5-1b-1:

In some embodiments, the invention relates to a compound of Formula I'a -5-1a-1 or I'a -5-1b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -5-1a-1 or I'a -5-1b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula I'a -5-1a-1 or I'a -5-1b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula I'a -5-1a-1 or I'a -5-1b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula I'a -5-1a-1 or I'a -5-1b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the invention relates to a compound having the structure of Formula Ia-4-1 (such as Ia-4-1a, Ia-4-1b, Ia-4-1a-1 or Ia-4-1b-1), Ia-5-1 (such as Ia-5-1a, Ia-5-1b, Ia-5-1a-1 or Ia-5-1b-1), I'a -4-1 (such as I'a -4-1a, I'a -4-1b, I'a -4-1a-1 or I'a -4-1b- 1) or I'a -5-1 (such as I'a -5-1a, I'a -5-1b, I'a -5-1a-1 or I'a -5-1b-1), or pharmaceutically acceptable salts thereof, wherein R₄-2 is Br, C1, F or methyl. In preferred embodiments, R₄-2 is C1. In other embodiments, R_4-3 is H. In other embodiments, R_4-3 is F. In yet other embodiments, x₁, when present, is C(RI)(R₂). In yet other embodiments, R₁ and R₂ are each H. In yet other embodiments, R₁ and R₂ are each F. In yet other embodiments, R₁ is F and R₂ is H. In yet other embodiments, R₁ is H and R₂ is F.

In certain embodiments, the invention relates to a compound having the structure of Formula Ia-4-1 (such as Ia-4-1a, Ia-4-1b, Ia-4-1a-1 or Ia-4-1b-1), Ia-5-1 (such as Ia-5-1a, Ia-5-1b, Ia-5-1a-1 or Ia-5-1b-1), I'a -4-1 (such as I'a -4-1a, I'a -4-1b, I'a -4-1a-1 or I'a -4-1b- 1) or I'a -5-1 (such as I'a -5-1a, I'a -5-1b, I'a -5-1a-1 or I'a -5-1b-1), or pharmaceutically acceptable salts thereof, wherein X is C; and R_4-1 is H or OH. In preferred embodiments,

R_4-1 is OH. In other preferred embodiments, R_4-1 is H. In other embodiments, R_4-3 is H. In other embodiments, R_4-3 is F. In yet other embodiments, x₁, when present, is C(RI)(R₂). In yet other embodiments, R₁ and R₂ are each H. In yet other embodiments, R₁ and R₂ are each F. In yet other embodiments, R₁ is F and R₂ is H. In yet other embodiments, R₁ is H and R₂ is F.

In certain embodiments, the invention relates to a compound having the structure of Formula IIa-2-2 or IIa-3-2:

or a pharmaceutically acceptable salt thereof, wherein: x₁ is C(RI)(R₂) or C=O (such as C(RI)(R₂)); X2a is -0-R₆-1 or -OCH₂-R_6-1;

X is C or N, with the proviso that R_4-1 is absent when X is N;

R_h is H or optionally substituted C₁-C₃ alkyl; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F, such as

R_4-1 is H, NH₂, OH or CH₃;

R₄-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R_4-5 is H, C1 or F;

HC(=O)-, -CO₂R₃, -SO₂R₃, -SO(R₃)₂, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, - o

SO₂N(R₃)₂, -C(O)N(R₃)₂

optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(0)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl (preferably

, wherein

denotes the point of attachment), heterocyclyl (preferably

wherein denotes the

point of attachment), aryl, heteroaryl (preferably

wherein

denotes the point of attachment), haloalkyl, heteroalkyl,

hydroxyalkyl, heterocyclylalkyl (preferably and

wherein

denotes the point of attachment), or heteroarylalkyl (preferably wherein

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4 (such as 0). In some such embodiments, x₁ is C(RI)(R₂); R₁ and R₂ are each independently H or F, such as H; R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and u is 0.

OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or In other

embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F. In preferred embodiments, x₂a is -OCH₂-R₆-1. In other preferred embodiments, x₂a is -O-R₆-1.

In yet other preferred embodiments, R_6-1 is heterocyclyl. In other embodiments, X is C; R₁ and R₂ are each H; R_4-4 and R_4-5 are each H; R_4-3 is

H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each H; R_4-4 and R_4-5 are each H; R_4-3 is F; and R₆-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R_4-4 and R_4-5 are each H;

R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R_4-4 and R_4-5 are each H; R_4-3 is F; and R₆-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R_4-4 and R_4-5 are each H;

R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R_4-4 and R_4-5 are each H; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R_4-4 and R_4-5 are each H;

R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R_4-4 and R_4-5 are each H; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In specific embodiments, R_4-1 is H. In other specific embodiments, x₂a is -O- R₆-1. In other specific embodiments, x₂a is -OCH₂-R₆-1. In yet other specific embodiments, u is 1. In yet other specific embodiments, u is 0. In yet other specific embodiments, R_6-1 is

the point of attachment; or or , wherein denotes the point of attachment; or

, wherein denotes the point of attachment; or

point of attachment; or wherein denotes the point of

wherein

2 or 3; and with the proviso that R.₆ is not

In some embodiments, R_6-1 is In other embodiments, R_6-1 is

In yet other embodiments, R_6-1 is

In certain embodiments, R_6-1 is

In some embodiments, the invention relates to a compound of Formula IIa-2-2 or IIa-3-2, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-2-2 or IIa-3-2, wherein R₁ is CH₃ and R₂ is H. In some embodiments, the invention relates to a compound of Formula IIa-2-2 or

IIa-3-2, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-2-2 or IIa-3-2, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-2-2 or IIa-3-2, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the invention relates to a compound having the structure of

Formula II'a -2-2 or II'a -3-2:

or a pharmaceutically acceptable salt thereof, wherein: x₁ is C(RI)(R₂) or C=O (such as C(RI)(R₂)); x_2a is -O-R₆-1 or -OCH₂-R_6-1;

X is C or N; R₁ and R₂ are each independently H, F, methyl or hydroxyl (such as H or F, such as

R_4-1 is absent if Xis N, or R_4-1 is H, NH₂, OH or CH₃;

R₄-3 is H, CH₃, C1 or F;

R_4-4 is H, C1 or F;

R_4-5 is H, C1 or F;

, optionally substituted cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl (such as hydroxy, halogen, optionally substituted C₁- C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, - C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl); R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

point of attachment), aryl, heteroaryl (preferably

wherein

denotes the point of attachment), haloalkyl, heteroalkyl,

hydroxyalkyl, heterocyclylalkyl (preferably

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; n in each occurrence is independently 1, 2, or 3; and u is 0, 1, 2, 3 or 4 (such as 0). In some such embodiments, x₁ is C(RI)(R₂); R₁ and R₂ are each independently H or F (such as H); R₅ in each occurrence is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁- C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and u is 0. In some embodiments, R₅ in each instance is independently oxo, hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R₃)₂, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and

In other embodiments, R₅ in each instance is independently F, C1, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -CO₂R₃, -SO2R₃, -SO(R₃)₂, - OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or -S(O)NR₃N(R₃)₂.

OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂, -SCH₂F, -SO₂N(R₃)₂ or

In other embodiments, R₅ in each instance is independently F, C1, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ alkoxy, -OCF₃, -OCHF₂, -OCH₂F, -SCF₃, -SCHF₂ or -SCH₂F. In preferred embodiments, x₂a is -OCH₂-R₆-1. In other preferred embodiments, x₂a is -O-R₆-1.

In yet other preferred embodiments, R_6-1 is heterocyclyl.

In other embodiments, X is C; R₁ and R₂ are each H; R_4-4 and R_4-5 are each H; R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each H; R_4-4 and R_4-5 are each H; R_4-3 is F; and R₆-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R_4-4 and R_4-5 are each H;

R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ and R₂ are each F; R_4-4 and R_4-5 are each H; R_4-3 is F; and R₆-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R_4-4 and R_4-5 are each H; R_4-3 is H; and R.₆-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is H and R₂ is F; R_4-4 and R_4-5 are each H; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R_4-4 and R_4-5 are each H;

R_4-3 is H; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In other embodiments, X is C; R₁ is F and R₂ is H; R_4-4 and R_4-5 are each H; R_4-3 is F; and R_6-1 is cycloalkyl, heterocyclyl or heteroaryl. In specific embodiments, R_4-1 is H. In other specific embodiments, x₂a is -O-

R₆-1. In other specific embodiments, x₂a is -OCH₂-R₆-1. In yet other specific embodiments, u is 1. In yet other specific embodiments, u is 0. In yet other specific embodiments, R_6-1 is

In some embodiments, the invention relates to a compound of Formula II'a -2-2 or II'a -3-2, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-2 or II'a -3-2, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2-2 or II'a -3-2, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula II'a -2-2 or II'a -3-2, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2-2 or II'a -3-2, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-3-2 has the structure of Formula IIa-3-2a or IIa-3-2b:

In some embodiments, the invention relates to a compound of Formula IIa-3-2a or

IIa-3-2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-2a or IIa-3-2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3-2a or IIa-3-2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a copound of Formula IIa-3-2a or IIa-3-2b, wherein R₁ is CH₃ and R₂ is F. In some embodiments, the invention relates to a compound of Formula IIa-3-2a or IIa-3-2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-3-2 has the structure of Formula IIa-3-2a-1 or IIa-3-2b-1 :

In some embodiments, the invention relates to a compound of Formula IIa-3-2a-1 or IIa-3-2b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3-2a-1 or IIa-3-2b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-3-2a-1 or IIa-3-2b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-3-2a-1 or IIa-3-2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-3-2a-1 or IIa-3-2b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -3-2 has the structure of Formula II'a -3-2a or II'a -3-2b:

In some embodiments, the invention relates to a compound of Formula II'a -3-2a or II'a -3-2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3-2a or II'a -3-2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3-2a or II'a -3-2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3-2a or II'a -3-2b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -3-2a or II'a -3-2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula II'a -3-2 has the structure of Formula II'a -3-2a-1 or II'a -3-2b-1:

In some embodiments, the invention relates to a compound of Formula II'a -3 -2a- 1 or II'a -3 -2b- 1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3-2a-1 or II'a -3-2b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -3 -2a- 1 or II'a -3 -2b- 1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -3-2a-1 or II'a -3-2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -3 -2a- 1 or II'a -3 -2b- 1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula IIa-2-2 has the structure of Formula IIa-2-2a or IIa-2-2b:

In some embodiments, the invention relates to a compound of Formula IIa-2-2a or

IIa-2-2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-2a or IIa-2-2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-2-2a or IIa-2-2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-2a or Iia-2-2b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula Iia-2-2a or Iia-2-2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula IIa-2-2 has the structure of Formula IIa-2-2a-1 or IIa-2-2b-1 :

In some embodiments, the invention relates to a compound of Formula IIa-2-2a-1 or IIa-2-2b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-2a-1 or IIa-2-2b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula IIa-2-2a-1 or IIa-2-2b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula IIa-2-2a-1 or IIa-2-2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula IIa-2-2a-1 or IIa-2-2b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula II'a -2-2 has the structure of

Formula II'a -2-2a or II'a -2-2b:

(Formula II'a -2-2b).

In some embodiments, the invention relates to a compound of Formula II'a -2-2a or

II'a -2-2b, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2-2a or II'a -2-2b, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a -2-2a or II'a -2-2b, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a -2-2a or II'a -2-2b, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a -2-2a or II'a -2-2b, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4-membered. In more preferred embodiments, the cycloalkyl is 3-membered. In certain embodiments, the compound of Formula II'a -2-2 has the structure of

Formula II'a -2-2a-1 or II'a -2-2b-1:

(Formula II'a -2-2a-1) or

(Formula II'a-2-2b-1).

In some embodiments, the invention relates to a compound of Formula II'a-2-2a-1 or II'a-2-2b-1, wherein R₁ is H and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a-2-2a-1 or II'a-2-2b-1, wherein R₁ is CH₃ and R₂ is H.

In some embodiments, the invention relates to a compound of Formula II'a-2-2a-1 or II'a-2-2b-1, wherein R₁ is F and R₂ is CH₃. In other embodiments, the invention relates to a compound of Formula II'a-2-2a-1 or II'a-2-2b-1, wherein R₁ is CH₃ and R₂ is F.

In some embodiments, the invention relates to a compound of Formula II'a-2-2a-1 or II'a-2-2b-1, wherein R₁ and R₂, together with the carbon to which they are bonded, form a 3- to 5-membered cycloalkyl. In preferred embodiments, the cycloalkyl is 3- to 4- membered. In more preferred embodiments, the cycloalkyl is 3-membered.

In certain embodiments, the compound of Formula Ia-2-1a, Ia-2-1b, Ia-2-1a-1, Ia-2- 1b-1, Ia-4-1a, Ia-4-1b, Ia-4-1a-1, Ia-4-1b-1, Ia-5-1a, Ia-5-1b, Ia-5-1a-1, Ia-5-1b-1, IIa-2-2a, IIa-2-2b, IIa-2-2a-1, IIa-2-2b-1, IIa-3-2a, IIa-3-2b, IIa-3-2a-1, IIa-3-2b-1, I'a-2-1a, I'a-2-1b, I'a-2-1a-1, I'a-2-1b-1, I'a-4-1a, I'a-4-1b, I'a-4-1a-1, I'a-4-1b-1, I'a-5-1a, I'a-5-1b, I'a-5-1a- 1, I'a-5-1b-1, II'a-2-2a, II'a-2-2b, II'a-2-2a-1, II'a-2-2b-1, II'a-3-2a, II'a-3-2b, II'a-3-2a-1 or II'a-3-2b-1 has an R_6-1 selected from

wherein denotes the point of attachment; and each is optionally substituted with one or more R₇; and

R.7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl. In specific embodiments, R_6-1 is

In certain embodiments, the compound of Formula Ia-2-1a, Ia-2-1b, Ia-2-1a-1, Ia-2- 1b-1, Ia-4-1a, Ia-4-1b, Ia-4-1a-1, Ia-4-1b-1, Ia-5-1a, Ia-5-1b, Ia-5-1a-1, Ia-5-1b-1, IIa-2-2a,

IIa-2-2b, IIa-2-2a-1, IIa-2-2b-1, IIa-3-2a, Da-3 -2b, IIa-3-2a-1, IIa-3-2b-1, I'a -2- la, I'a -2-1b, I'a -2-1a-1, I'a -2-1b-1, I'a -4-1a, I'a -4-1b, I'a -4-1a-1, I'a -4-1b-1, I'a -5-1a, I'a -5-1b, I'a -5-1a- 1, I'a -5-1b-1, II'a -2-2a, II'a -2-2b, II'a -2-2a-1, II'a -2-2b-1, II'a -3-2a, II'a -3-2b, II'a -3-2a-1 or II'a -3-2b-1 has an R_6-1 selected from:

wherein each is optionally substituted with one or more R₇; and R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂,

N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂,N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl.

In some embodiments, the invention relates to a compound of a Formula disclosed herein (e.g., Formula I, F, la, I'a, la-1, la-2, la-3, la-4, la-5, I'a-1, I'a-2, I'a-3, I'a-4, I'a-5, Ia-1-1, Ia-2-1, Ia-4-1, Ia-5-1, I'a-1-1, I'a-2-1, I'a-4-1, I'a-5-1, II, IF, IIa-1, IIa-2, IIa-3, II'a- 1, II'a-2, II'a-3, IIa-1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, la-1a, Ia-1b, Ia-2a, Ia- 2b, I'a-1a, I'a-1b, I'a-2a, I'a-2b, Ia-3a, Ia-3b, I'a-3a, I'a-3b, Ia-4a, Ia-4b, I'a-4a, I'a-4b, Ia-

5a, Ia-5b, I'a-5a, I'a-5b, Ila-1a, Ila-1b, II'a-1a, II'a-1b, IIa-2a, IIa-2b, II'a-2a, II'a-2b, Ila- 3 a, IIa-3b, II'a-3 a, II'a-3b, Da- 1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, IIa-2-2, Ila- 3-2, II'a-2-2, II'a-3-2), wherein -X2-X₃, if present, or -X2a, if present, is:

In certain embodiments, the invention relates to a compound of a Formula disclosed herein (e.g., Formula I, F, la, I'a, la-1, la-2, la-3, la-4, la-5, I'a-1, I'a-2, I'a-3, I'a-4, I'a-5, Ia-1-1, Ia-2-1, Ia-4-1, Ia-5-1, I'a-1-1, I'a-2-1, I'a-4-1, I'a-5-1, II, IF, IIa-1, IIa-2, IIa-3, II'a- 1, II'a-2, II'a-3, IIa-1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, la-1a, Ia-1b, Ia-2a, Ia- 2b, I'a-1a, I'a-1b, I'a-2a, I'a-2b, Ia-3a, Ia-3b, I'a-3a, I'a-3b, Ia-4a, Ia-4b, I'a-4a, I'a-4b, Ia- 5a, Ia-5b, I'a-5a, I'a-5b, Ila-1a, Ila-1b, II'a-1a, II'a-1b, IIa-2a, IIa-2b, II'a-2a, II'a-2b, Ila-

3 a, IIa-3b, II'a-3 a, II'a-3b, Da- 1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, IIa-2-2, Ila-

denotes the point of attachment.

In certain embodiments, the invention relates to a compound of a Formula disclosed herein (e.g., Formula I, F, la, I'a, la-1, la-2, la-3, la-4, la-5, I'a-1, I'a-2, I'a-3, I'a-4, I'a-5, Ia-1-1, Ia-2-1, Ia-4-1, Ia-5-1, I'a-1-1, I'a-2-1, I'a-4-1, I'a-5-1, II, IF, IIa-1, IIa-2, IIa-3, II'a-

1, II'a-2, II'a-3, IIa-1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, la-1a, Ia-1b, Ia-2a, Ia- 2b, I'a-1a, I'a-1b, I'a-2a, I'a-2b, Ia-3a, Ia-3b, I'a-3a, I'a-3b, Ia-4a, Ia-4b, I'a-4a, I'a-4b, Ia- 5a, Ia-5b, I'a-5a, I'a-5b, Ila-1a, Ila-1b, II'a-1a, II'a-1b, IIa-2a, IIa-2b, II'a-2a, II'a-2b, Ila- 3 a, IIa-3b, II'a-3 a, II'a-3b, Da- 1-1, IIa-2-1, IIa-3-1, II'a-1-1, II'a-2-1, II'a-3-1, IIa-2-2, Ila- 3-2, II'a-2-2, II'a-3-2), wherein R_6-1, if present, or R6, if present, is

wherein denotes the point of attachment; or is or

wherein

denotes the point of attachment; R₇a in each occurrence is independently F, C1, C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₃CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as -CH=CHF) or C₂-C₃ alkynyl; R_7b is C₁-C₃ alkyl (preferably CH₃ or CH₂CH₃), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), optionally substituted C₃-C₅ cycloalkyl or optionally substituted C4-C₆ heterocyclyl; q is 1, 2 or 3; and with the proviso that R.₆ is not

denotes the point of attachment.

wherein denotes the point of attachment).

In certain embodiments, the invention relates to a compound of Formula I'a -4 selected from:

acceptable salt thereof. In certain embodiments, the invention relates to a compound selected from:

acceptable salt thereof.

In certain embodiments, the invention relates to a compound selected from:

In certain embodiments, the invention relates to a compound of Formula I'a -2 selected from:

pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to a compound of Formula I'a -5 selected from:

In certain embodiments, the invention relates to a compound of Formula IF selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to a compound of Formula I' selected from:

pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to a compound of Formula I' selected from:

pharmaceutically acceptable salt thereof. In certain embodiments, the invention relates to a compound of Formula I'a -5 selected from:

pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to a compound of Formula II'a -3-2 selected from:

pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to a compound of Formula II'a -2-2 selected from:

pharamaceutically acceptable salt thereof. Specific embodiments of the invention include those compounds listed in Table 1.

The identifying number (“Cmpd”), the chemical structure (“Structure”), and the example method used to synthesize the compound (“Example”) are disclosed in Table 1 for each compound.

Other specific embodiments of the invention include those compounds listed in Table 2. The identifying number (“Cmpd”) and the chemical structure (“Structure”) for each compound is recited in columns 1 and 2, respectively, of Table 2. Each compound is synthesized using the method recited in column 3 of Table 2.

In certain embodiments, the invention relates to a pharmaceutical composition comprising any of the compounds described herein and a pharmaceutically acceptable diluent or excipient. Table 1.

Table 2.

Pharmaceutical Agents and Compositions

Also provided herein are methods of synthesizing a pharmaceutical agent and/or composition, comprising preparing a compound of a formula disclosed herein (such as a compound of Formula I, la, la-1, la-2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, I', I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2 or II'a -3, or a subgenus thereof), according to a method as described herein and synthesizing the pharmaceutical agent and/or composition from the compound of the formula disclosed herein (such as a compound of Formula I, la, la-1, la-2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2 or II'a -3, or a subgenus thereof), e.g ., by carrying out one or more chemical reactions on the compound of the formula disclosed herein (such as a compound of Formula I, la, la-1, la-2, la-3, la-4, la-5, II, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, or II'a -3, or a subgenus thereof) and/or combining the pharmaceutical agent with one or more pharmaceutically acceptable carriers and/or excipients.

The pharmaceutical agent and/or composition prepared from the compound of the formula disclosed herein (such as a compound of Formula I, la, la-1, la-2, la-3, la-4, la-5, IF, IIa-1, IIa-2, IIa-3, F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, or II'a -3, or a subgenus thereof) may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal.

When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g. , a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Example Methods of Treatment/Use

The compounds described herein are inhibitors of KRAS G12D and therefore may be useful for treating diseases wherein the underlying pathology is (at least in part) mediated by KRAS G12D. Such diseases include cancer and other diseases in which there is a disorder of transcription, cell proliferation, apoptosis, or differentiation.

Accordingly, in certain embodiments, the invention is directed to a method of treating a disease or disorder mediated by KRAS G12D in a subject afflicted therewith, comrpsing adminietering to the subect a compound as described herein (or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising the same (i.e., and a pharmaceutically acceptable diluent or excipient). In some such embodiments, the disease mediated by KRAS G12D is a cancer selected from pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, gall bladder cancer, and bile duct cancer. In specific embodiments, the cancer is selected from pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma, and small cell lung carcinoma.

In certain embodiments, the method of treating cancer in a subject in need thereof comprises administering to the subject any of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same (e.g., administering an effective amount of the compound or salt thereof or pharmaceutical composition comprising the same). For example, the cancer may be selected from carcinoma (e.g., a carcinoma of the endometrium, bladder, breast, colon (e.g, colorectal carcinomas such as colon adenocarcinoma and colon adenoma)), sarcoma (e.g, a sarcoma such as Kaposi’s, osteosarcoma, tumor of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma), kidney, epidermis, liver, lung (e.g, adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g, exocrine pancreatic carcinoma), stomach, cervix, thyroid, nose, head and neck, prostate, and skin (e.g, squamous cell carcinoma), human breast cancers (e.g, primary breast tumors, node-negative breast cancer, invasive duct adenocarcinomas of the breast, non- endometrioid breast cancers), familial melanoma, and melanoma. Other examples of cancers that may be treated with a compound of the invention include hematopoietic tumors of lymphoid lineage (e.g. leukemia, acute lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukaemia, B-cell lymphoma (such as 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 hematopoietic tumors of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia. Other cancers include a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; seminoma; teratocarcinoma; xeroderma pigmentosum; retinoblastoma; keratoctanthoma; and thyroid follicular cancer.

In particular embodiments, the treated cancer is selected from pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, and bile duct cancer.

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

In other particular embodiments, the treated cancer is selected from pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma and small cell lung carcinoma.

In some aspects, the subject is a mammal, for example, a human.

Further disclosed herein are methods of inhibiting KRAS G12D in a cell comprising contacting said cell with any of the compounds described herein, or a pharmaceutically acceptable salt thereof, such that KRAS G12D enzyme is inhibited in said cell. For example, the cell is a cancer cell. In preferred embodiments, proliferation of the cell is inhibited or cell death is induced.

Further disclosed herein is a method of treating a disease treatable by inhibition of KRAS G12D in a subject, comprising administering to the subject in recognized need of such treatment, an effective amount of any of the compounds described herein and/or a pharmaceutically acceptable salt thereof. Diseases treatable by inhibition of KRAS G12D include, for example, cancers. Further exemplary diseases include pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (including non-small cell lung cancer), gall bladder cancer, and bile duct cancer.

The methods of treatment comprise administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Individual embodiments include methods of treating any one of the above-mentioned disorders or diseases by administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Certain embodiments include a method of modulating KRAS G12D activity in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof. Additional embodiments provide a method for the treatment of a disorder or a disease mediated by KRAS G12D in a subject in need thereof, comprising administering to the subject an effective amount of the compound (such as a compound of Formula F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, or II'a -3, or a subgenus thereof), or a pharmaceutically acceptable salt thereof. Other embodiments of the invention provide a method of treating a disorder or a disease mediated by KRAS G12D, in a subject in need of treatment thereof comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the disorder or the disease is selected from carcinomas with genetic aberrations that activate KRAS activity. These include, but are not limited to, cancers.

The present method also provides the use of a compound of invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease mediated by KRAS G12D.

In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is used for the treatment of a disorder or a disease mediated by KRAS G12D. Yet other embodiments of the present method provide a compound of the invention (such as a compound of Formula I', I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, or II'a -3, or a subgenus thereof), or a pharmaceutically acceptable salt thereof, for use as a medicament.

Still other embodiments of the present method encompass the use of a compound of the invention (such as a compound of Formula F, I'a, I'a -1, I'a -2, I'a -3, I'a -4, I'a -5, IF, II'a -1, II'a -2, or II'a -3, or a subgenus thereof), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by KRAS G12D.

Example of Predicted Affinity for KRAS G12D of Example Compounds

Models of example compounds of the invention were generated using a relaxed KRAS G12D protein receptor model based on the published crystal structure of MRTX849 bound to KRAS G12C (www.rcsb.org; accession code 6UT0) with residue 12 mutated from cysteine to aspartate. Models of each example compound were composed based on the lowest-energy conformer of the core and a relatively low-energy conformation of the bicyclic amino “head” group, as determined by density functional theory using the coB97X- D functional, 6-311+G** basis set, and CPCM implicit aqueous solvation model as implemented in the Gaussian 16 program system (Gaussian, Inc., Wallingford, CT). A reasonable low-energy amino head group conformation was chosen based on its ability to best engage D 12 in a salt bridging interaction.

Docking of the core-head group adduct to the aforementioned G12D protein receptor model was achieved via alignment to bound literature structures involving KRAS G12C. Enumeration of the substituent groups X, R_6-1, R_4-1, R₄-2, R_4-3, R_4-4 and/or R_4-5 in Formulas I'a -1-1, I'a -2-1a, I'a -4-1a, I'a -5-1a, II'a -2-2a or II'a -3-2a was then performed using Bash scripts. The resultant adducts were subjected to minimization and refinement in the aforementioned G12D protein receptor model binding site using the Induced Fit GBVI/WSA dG scoring methodology, the AMBERKFEHT force field, and the Born implicit aqueous solvation model as implemented in the MOE 2020.0901 program package (Molecular Operating Environment, Chemical Computing Group, Montreal, CA). Binding affinities are in arbitrary units. Selection of particular example compounds for synthesis and testing may be based on a combination of predicted binding affinities and/or visual inspection and subsequent analyses that would be within the skill of the ordinary artisan. To perform the above, the atom for X was selected from C and N, and when X was N, R_4-1 was absent; the substituent for R_4-1 was selected from H, NH₂, OH and methyl; the substituent for R₄-2 was selected from H, C1, F, CN, cyclopropyl, enthynyl, methyl and ethyl; the substituent for R_4-3 was selected from H, methyl, C1 and F; the substituent for R_4-4 was selected from H, C1 and F; the substituent for R_4-5 was selected from H, C1 and F; and the substituent for R_6-1 was selected from the chemical structures (“Structure”) of Table A, wherein denotes the point of attachment of each chemical structure, and the reference names (“R₆ference”) were used to refer to those chemical structures, as done in the listings of Tables 3, 4, 5 and 6 below.

Table A.

Specific embodiments of compounds of Formula I'a -2-1a include those compounds listed in Table 3. Each row pertains to a specific compound. The identifying number for each compound is disclosed in the column titled “Cmpd”, the chemical substituent for each of R_6-1, R₄-2 and R_4-4 are listed in the column titled “R_6-1”, “R₄-2” and “R_4-4” respectively, and the predicted binding affinity for KRAS G12D (in arbitrary units, A.U.) is disclosed in the column titled “Score”.

Specific embodiments of compounds of Formula I'a -4-1a include those compounds listed in Table 4. Each row pertains to a specific compound. The identifying number for each compound is disclosed in the column titled “Cmpd”, the chemical substituent for each of X, R_6-1, R_4-1, R₄-2 and R_4-3 are listed in the column titled “X”, “R_6-1”, R_4-1”, “R₄-2” and “R_4-3” respectively, and the predicted binding affinity for KRAS G12D (in arbitrary units, A.U.) is disclosed in the column titled “Score”.

Specific embodiments of compounds of Formula I'a -5-1a include those compounds listed in Table 5. Each row pertains to a specific compound. The identifying number for each compound is disclosed in the column titled “Cmpd”, the chemical substituent for each of X, R_6-1, R_4-1, R₄-2 and R_4-3 are listed in the column titled “X”, “R_6-1”, R_4-1”, “R₄-2” and “R_4-3” respectively, and the predicted binding affinity for KRAS G12D (in arbitrary units, A.U.) is disclosed in the column titled “Score”.

Specific embodiments of compounds of Formula II'a -2-2a include those compounds listed in Table 6. Each row pertains to a specific compound. The identifying number for each compound is disclosed in the column titled “Cmpd”, the chemical substituent for each of X, R_6-1, R_4-1, R_4-3, R_4-4 and R_4-5 are listed in the column titled “X”, “R_6-1”, R_4-1”, “R_4-3”, “R_4-4” and “R_4-5” respectively, and the predicted binding affinity for KRAS G12D (in arbitrary units, A.U.) is disclosed in the column titled “Score”.

Specific embodiments of compounds of Formula II'a -3-2a include those compounds listed in Table 7. Each row pertains to a specific compound. The identifying number for each compound is disclosed in the column titled “Cmpd”, the chemical substituent for each of X, R_6-1, R_4-1, R_4-3, R_4-4 and R_4-5 are listed in the column titled “X”, “R_6-1”, R₄-I”,“R_4-3”, “R_4-4” and “R_4-5” respectively, and the predicted binding affinity for KRAS G12D (in arbitrary units, A.U.) is disclosed in the column titled “Score”.

Table 3.

Table 4.

Table 5.

Table 6.

Table 7.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated by reference in their entirety 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.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

EXEMPLIFICATION Synthetic Protocols

Compounds as disclosed herein can be synthesized via a number of specific methods. The examples, which outline specific synthetic routes, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.

Example 1: Synthesis of Spiro-tetralin Compounds

Schematization for the Preparation of Intermediates 1-1 through 1-9

Preparation of Intermediate 1-1 (7-(Benzyloxy)-3,4-dihydronaphthalen-l(2H)-one)

7-hydroxytetralin-1-one (10. Og, 61.7mmol) was dissolved in DMF (62mL) and treated with benzyl bromide (8.0mL, 67.4mm ol) and powdered K2CO3 (17.04g, 123.31 mmol), and the mixture was stirred vigorously at rt for 19hrs. The mixture was poured into chipped ice (400g) and stirred for approximately 15min. The solids were collected by filtration, washed with a little water, dried under suction, and further dried in vacuo at 50°C to give the title compound (15.19g, 97.6%) as a tan colored solid. Rf = 0.40 (85:15 hexane s:EtO Ac). ¹H NMR (400 MHz, CDCI₃) σ 7.62 (d, J = 2.7 Hz, 1H), 7.48 - 7.28 (m, 5H), 7.18 (dq, J = 8.4, 0.8 Hz, 1H), 7.13 (dd, J = 8.4, 2.8 Hz, 1H), 5.10 (s, 2H), 2.91 (t, J = 6.2 Hz, 2H), 2.68 - 2.60 (m, 2H), 2.19 - 2.07 (m, 2H).

Preparation of Intermediate 1-2 (2-(7-(Benzyloxy)-3,4-dihydronaphthalen-l(2H)~ ylidene )malononitrile )

Intermediate 1-1 (7-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one) (20.77g, 82.3 lmmol) was treated with malononitrile (7.07g, 107mmol), toluene (102mL), NH₄Oac (2.54g, 32.9mmol) and AcOH (9.41mL, 164.6mmol), and the mixture was heated to reflux on a Dean-Stark apparatus under N2 atmosphere for 2.5hrs. Additional malononitrile (3.5g), AcOH (4.5mL), and NH₄Oac (1.25g) was added and heating continued for 1.5hrs. Additional malononitrile (3.5g), NH₄Oac (1.25g), and AcOH (4.5mL) was again added and heating continued for lhr. Additional malononitrile (7.0g) was added and heating continued for lhr. The mixture was cooled and washed with H₂O. The wash was extracted with two small volumes of EtOAc and the combined extract was washed with brine, dried over Na2SO4, and filtered through a thin pad of silica gel, and concentrated. This residue was triturated with EtOAc and the solids were collected by filtration, and washed with a little EtOAc. The solids were dried under suction and further dried in vacuo to give the title compound (19.69g, 79.7%) as a tan colored crystalline solid. Preparation of Intermediate 1-3 (2-(7-(Benzyloxy)-l-(pent-4-en-l-yl)-l,2,3,4- tetrahydronaphthalen-l-yl)malononitrile)

A flame-dried 500mL round bottom flask was charged with CuBr*mE₂S (1.35g, 6.56mmol) and evacuated and backfilled with N2 (x3) then charged with anhydrous THF (50mL) and cooled to -40 °C. pent-4-en-1-ylmagnesium bromide, 1M solution in THF (112mL) was introduced via cannula, and the resulting mixture was stirred for 15min then Intermediate 1-2 (2-(7-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)- ylidene)malononitrile) (19.69g, 65.56mmol) was added as a solution in THF (lOOmL). After 4hrs, the reaction was quenched by the addition of sat. H4C1 and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The oily residue was taken up in 9: 1 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same. The filtrate was concentrated to give the title compound (22.32 g, 91.9%) as an off-white colored solid. Rf = 0.37 (9:1 hexanes :EtO Ac). LC/MS, ESI [M-H]^' = 369.2 m/z. ¹H NMR (400 MHz, CDCI₃) δ 7.47 - 7.28 (m, 5H), 7.07 (dt, J = 9.1, 1.1 Hz, 1H), 6.91 - 6.86 (m, 2H), 5.68 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.09 (d, J = 11.7 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 5.02 - 4.94 (m, 2H), 3.90 (s, 1H), 2.85 - 2.66 (m, 2H), 2.13 - 1.78 (m, 8H), 1.43 - 1.30 (m, 1H), 1.17 - 1.02 (m, 1H).

Preparation of Intermediate 1-4 (Methyl 2-(7-(henzyloxy)-l-(pent-4-en-l-yl)-l,2,3,4- tetrahydronaphthalen-l-yl)acetate)

In 250mL PFA round bottom flask, Intermediate 1-3 (2-(7-(Benzyloxy)-1-(pent-4- en-1-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)malononitrile) (20.39g, 55.04mmol) was treated with ethylene glycol (55mL), water (22 mL), and KOH (54.48g, 825.5mmol) and the mixture was heated to 190°C under N2. The mixture was allowed to cool slightly then poured into chipped ice containing H2SO4. The mixture was extracted with EtOAc (x4) and the combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was treated with 3N HC1 in MeOH and to 50°C for 4hrs. The mixture was concentrated and co-evaporated from toluene once, and the residue was taken up in 9:1 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same to give methyl 2-(7-benzyloxy- l-pent-4-enyl-tetralin-1-yl)acetate (18.687 g, 49.371 mmol, 89.708% yield) as a faintly red- brown oil. Observed [M+Na]⁺ = 401.2 m/z. Preparation of Intermediate 1-5 b/lethyl 2-(7-(benzyloxy)-l-(4-oxobutyl)-l,2,3,4- tetrahydronaphthalen-l-yl)acetate)

Intermediate 1-4 (methyl 2-(7-(benzyloxy)-1-(pent-4-en-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)acetate) (9.03g, 23.9mmol) was dissolved in DCM (160mL) and cooled to -78 °C, then ozone was passed through the solution for 20min after whih TLC analysis indicated complete conversion. The mixture was sparged with N2 for 5min then PPI13 (9.39g, 35.8mmol) was added and the cooling bath was removed and the mixture was stirred at rt for 4hrs. The mixture was directly adsorbed onto silica gel and purified by flash column chromatography on silica gel eluted with 0→35% EtOAc in hexanes to give the title compound (7.477g, 82.4%) as a faintly yellow colored oil. Rf = 0.15 (9:1 hexanes:EtOAc). LC/MS, ESI [M+Na]⁺ = 403.2 m/z.

Preparation of Intermediate 1-6 (Methyl 4-(7-(benzyloxy)-l-(2-methoxy-2-oxoethyl)-l,2, 3,4- tetrahydronaphthalen-l-yl)butanoate

Intermediate 1-5 (methyl 2-(7-(benzyloxy)-1-(4-oxobutyl)-1,2,3,4- tetrahydronaphthalen-1-yl)acetate) (7.4g, 19.5mmol) was dissolved in tert-butanol (39mL) and treated with H₂O (39 mL), 2-methyl-2 -butene (10.3mL, 97.25 mmol), and NaC1O₂ (5.28g, 58.4mmol). The mixture was cooled to 0 °C then KH₂PO₄ (9.52g, 58.4mmol) was added. After 50min, the mixture was poured into aq. NaHSO₄ and extracted with EtOAc (x3). The combined extract was washed with dilute Na₂S₂O₃, brine, dried over Na2SO4, filtered, and concentrated. The residue was treated with 3N HC1 in MeOH and warmed to 50°C for 4.5hrs. The mixture was concentrated and co-evaporated from toluene twice then purified by flash column chromatography on silica gel eluted with 0→20% EtOAc in hexanes to give the title compound (7.257g, 90.9%). Rf = 0.40 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 411.2 m/z.

Preparation of Intermediate 1-7 (Methyl 7’-(benzyloxy)-3-oxo-3’,4’-dihydro-2’H- spiro [cyclohexane- 1, 1 ' -naphthalene] -4-carboxylate)

NaH (3.63g, 90.75 mmol) was suspended in anhydrous toluene (41mL), treated with MeOH (600μL) dropwise, and stirred until gas evolution ceased. The mixture was warmed to 70 °C and Intermediate 1-6 (methyl 4-(7-(benzyloxy)-1-(2-methoxy-2-oxoethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)butanoate) (12.43g, 30.27mmol) was added dropwise as a solution in anhydrous toluene (110mL) containing MeOH (600μL) over a period of approximately 45min. After 12.5hrs, the mixture was cooled to rt, poured into sat NH₄C1, and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (13.595g, >100%) as a tan colored oily residue which was used without purification. LC/MS, [M+H]⁺ = 379.2 m/z.

Preparation of Intermediate 1-8 (7-(Benzyloxy)-2'-mercapto-3,4,5',8'-tetrahydro-2H,3'H- spiro[ naphthalene- 1, 7 '-quinazolin ] -4 '( 6 'H)-one )

Intermediate 1-7 (methyl 7'-(benzyloxy)-3-oxo-3',4'-dihydro-2'H- spiro[cyclohexane-1,l'-naphthalene]-4-carboxylate) (11.46g, 30.27mmol) was dissolved in anhydrous MeCN (lOOmL) and treated with thiourea (2.77g, 36.4mmol) and DBU (4.6mL, 30.8mmol) and the mixture was heated to reflux under N2. After 24hrs, the mixture was cooled to rt then poured into cold 2% NaHCO₃ and the resulting solids were collected by filtration. The solids were dissolved in warm DMF then cooled to rt and treated with Mel (2.8mL, 44.98 mmol) and NaOAc, 1M (151. mL, 151 mmol). After lhr, additional NaOAc (2.49g, 30.3mmol) and Mel (188μL, 3.27mmol) were added, followed by three additional charges of Mel (250μL, 4.35mmol). AcOH (1300uL) was added and the mixture was concentrated to approximately one half the initial volume then poured into a vigorously stirred solution of ice cold one-third saturated aqueous NaHCO₃. The mixture was stirred for 5min and the resulting solids were collected by filtration. The cake was slurried with H2O (x2) then 100% hexanes (x3) and the solids were dried under suction and further dried in vacuo at 50°C to give the title compound (11.544g, 91.1%) as a white powder. LC/MS, ESI [M+H]⁺ = 419.2 m/z.

Preparation of Intermediate 1-9 (7-(Benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro-2H,6'H- spiro [naphthalene- 1, 7 ’-quinazolin] -4' -yl trifluorome thane sulfonate)

Intermediate 1-8 (7-(Benzyloxy)-2'-mercapto-3,4,5',8'-tetrahydro-2H,3H- spiro[naphthalene-1,7'-quinazolin]-4'(6'H)-one) (478mg, 1.14mmol) was dissolved in anhydrous DCM (5.7mL) and treated with iPnEtN (497μL, 2.85mmol). The mixture was cooled to 0°C and triflic anhydride, 1M in DCM (1 ,72mL) was added dropwise. After lOmin, the mixture was diluted with lvol hexanes and filtered through a pad of silica gel rinsing with 8:2 hexanes:EtOAc. The filtrate was concentrated to give the title compound (556.3mg, 88.5%). LC/MS, ESI [M+H]⁺ = 551.1 m/z. Preparation of Intermediate 1-9 Analogs

It is understood by the artisan of ordinary skill that Intermediate 1-9 Analogs can be prepared by following these schematized procedures:

Analogs Examples of R include, but are not limited to, F, C1, CH₂CH₃, CEE and NEE, and one, two or three instances of R can occur, each of which is independently selected from one another. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of naphthalenones used for this procedure include, but are not limited to:

5-ethyl-7-hydroxy-3,4-dihydronaphthalen- 1 (2H )-one, 7-hydroxy-5-methyl-3,4- dihydronaphthalen- 1 ( 2H)-one , 7-amino-5-fluoro-3,4-dihydronaphthalen- 1 (2H )-one, 7- amino-5-methyl-3,4-dihydronaphthalen-1(2H )-one, 7-amino-5-chloro-3,4- dihydronaphthalen- 1 (2H )-one, 7-ami no-3, 4-dihydronaphthalen-1 (2H )-one, 5-chloro-7- hydroxy-3, 4-dihydronaphthalen-1(2H )-one and 5-fluoro-7-hydroxy-3,4-dihydronaphthalen- 1 (2H )-one. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired naphthalenones, or obtain them from chemical vendors. Schematization for the Preparation of Intermediates 1-10 through 1-13

Intermediate 1-9 Intermediate 1-10 Intermediate 1-11

Intermediate 1-12 Intermediate 1-13

Preparation of Intermediate 1-10 (tert-Butyl (lR,5S)-3-(7-(benzyloxy)-2'-(methylthio)- 3, 4, 5 ',8 '-te trahydro-2H, 6 'H-spiro[ naphthalene- 1, 7 '-quinazolin ] -4 ’-yl) -3, 8- diazabicyclo[ 3.2.1 ]octane-8-carboxylate)

Intermediate 1-9 (7-(Benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) (139. lmg,

0.253mmol) was dissolved in anhydrous DMF (1.3mL) and treated with iPnEtN (62μL, 0.356mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (59mg, 0.278mmol) at rt. After lhr, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. TLC analysis showed a major spot. The residue was dissolved in DCM:hexanes and purified by flash column chromatography on silica gel (12g) eluted with 0→40% EtOAc in hexanes to give the title compound (114.4mg, 73.9%) as a white foam. Rf = 0.37 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 613.3 m/z. 1H NMR (400 MHz, CDCI₃) δ 7.43 - 7.27 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.77 (dd, J = 8.3, 2.6 Hz, 1H), 4.97 (s, 2H), 4.40 - 4.20 (m, 2H), 4.05 - 3.87 (m, 1H), 3.70 - 3.54 (m, 1H), 3.48 - 3.27 (m, 1H), 3.14 - 2.86 (m, 3H), 2.78 - 2.60 (m, 3H), 2.56 - 2.45 (m, 4H), 2.04 - 1.88 (m, 4H), 1.88 - 1.68 (m, 5H), 1.67 - 1.55 (m, 1H), 1.49 (s, 9H).

Preparation of Intermediate 1-11 (tert-Butyl ( lR,5S)-3-(7-(benzyloxy)-2'-(methylsulfinyl)- 3, 4, 5 ',8 '-te trahydro-2H, 6 'H-spiro[ naphthalene- 1, 7 '-quinazolin ] -4 ’-yl) -3, 8- diazabicyclo[ 3.2.1 ]octane-8-carboxylate)

Intermediate 1-10 (tert-Butyl (lR,5S)-3-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate) (114.4mg, 0.187mmol) was dissolved in DCM (lmL) and treated with mCPBA (58mg, 0.168mmol) at 0 °C. After 50min, the mixture was diluted with Et20 and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (113.8 mg, 96.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 629.3 m/z.

Preparation of Intermediate 1-12 (tert-Butyl (lR,5S)-3-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3, 4, 5', 8 '-tetrahydro-2H, 6'H-spiro [naphthalene -1 , 7' -quinazolin ]-4'-yl)-3, 8- diazabicyclo[ 3.2.1 ]octane-8-carboxylate)

Intermediate 1-11 (tert-Butyl (lR,5S)-3-(7-(benzyloxy)-2'-(methylsulfmyl)- 3,4,5',8'-tetrahydro-2H,6H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) (60.0mg, 0.0954mmol) was dissolved in anhydrous THF (0.5mL) and cooled to -40 °C. [(2S)-pyrrolidin-2-yl]methanol (19.3mg, 0.191mmol) in anhydrous THF (0.5mL) was treated with KotBu, 1M in THF (124μL, 0.124mmol) and the resulting solution was added dropwise to the reaction. After 5min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 40→0% hexanes then 0→10% MeOH in DCM+2%Et3N to give the title compound (54.3mg, 85.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 666.3 m/z. Preparation of Intermediate 1-13 (tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate Intermediate 1-12 (tert-Butyl (1R,5S)-3-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) (54.3mg, 0.0815mmol) was dissolved in MeOH (1mL), amended with Pd/C 10% (wetted) (50mg), and sparged with H₂ gas. After 15min, the mixture was filtered through Celite and concentrated to give the title compound (40.6mg, 86.5%) as a white residue. LC/MS, ESI [M+H]⁺ = 576.3 m/z. Preparation of Intermediate 1-12 Analogs It is understood by the artisan of ordinary skill that Intermediate 1-12 Analogs can be prepared using Intermediate 1-9 or Intermediate 1-9 Analogs by following these schematized procedures:

Intermediate 1-9 or Intermediate 1-9 Analogs

Intermediate 1-12 Analogs wherein, examples of Ring A include, but are not limited to

where indicates the point of attachment to the pyrimidine; examples of R include, but are not limited to, F, C1, CH₂CH₃, CH₃ and NH₂, and zero, one, two or three instances of R can occur, each of which is independently selected from one another; examples of R6 include, but are not limited to, halogen, amino, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, wherein each of amino, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, hexahydro-1H-pyrrolizinyl, l-azabicyclo[2.2.1]heptanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl or piperazinyl may be optionally substituted with one or more R₇; examples of R₇ include, but are not limited to, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cyano, -(CH₂)_nN(R₃)₂, -N(R₃)₂, -C(O)N(R₃)₂, -OC(O)N(R₃)₂, -N(H)C(O)R₃, -CH₂N(H)C(O)R₃, -CH₂OC(O)N(R₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, and each instance of R₇ is independently selected from other instances; examples of R₃ include, but are not limited to, H and C₁-C₃ alkyl, and each instance of R3 is independently selected from other instances; and n in each occurrence is independently 1, 2 or 3. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of Ring A species that can be used to prepare Intermediate 1-12 Analogs include, but are not limited to: tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-3-methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-6- methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-5-methylpiperazine-1- carboxylate, tert-butyl (1S,5S,6S)-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-(2-cyanoethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-carbamoyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, 8-(tert-butyl) 1-methyl 3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate, tert-butyl (1S,5S,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-chloro-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate, tert-butyl (1S,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5R,6R)-6-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1S,5S,6S)-6-(1H-1,2,4-triazol-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Ring A species, or obtain them from chemical vendors. Examples of alcohols used to prepare Intermediate 1-12 Analogs include, but are not limited to: (1-isopropylpyrrolidin-2-yl)methanol, (1-ethylpyrrolidin-2-yl)methanol, (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol and (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Preparation of Compound 1-1 (4'-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-7- ol) Intermediate 1-13 (tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) (13.5mg, 0.0234mmol) was treated with TFA (166.26uL, 2.17 mmol) for 60min at rt. The mixture was concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to yield the title compound as its trifluoroacetate salt (17.2 mg, 100%). LC/MS, ESI [M+H]⁺ = 476.2 m/z. ¹H NMR (400 MHz, Methanol-d4, 1:1 mixture of diastereomers) δ 6.92 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 6.59 (dd, J = 8.3, 2.5 Hz, 1H), 4.88 – 4.76 (m, 1H), 4.64 (ddd, J = 12.0, 7.8, 1.8 Hz, 1H), 4.38 (dt, J = 14.1, 2.5 Hz, 1H), 4.22 (dd, J = 15.1, 2.8 Hz, 2H), 4.18 – 4.06 (m, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.54 (d, J = 13.6 Hz, 1H), 3.45 – 3.35 (m, 2H), 2.99 (d, J = 18.7 Hz, 1H), 2.96 – 2.85 (m, 2H), 2.79 – 2.60 (m, 3H), 2.38 – 2.26 (m, 1H), 2.24 – 1.62 (m, 14H). Preparation of Compound 1-2 (4'-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-7-ol) Step 1. Intermediate 1-13 (tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) (13.5mg, 0.0234mmol) was dissolved in THF (300µL) and treated with formaldehyde, 37% aqueous (5.2µL, 0.070mmol), AcOH (1.3uL, 0.023mmol), and NaBH(Oac)₃ (14.91mg, 0.070mmol) and the mixture was stirred at rt for 4hr. The mixture was poured into 10% K2CO3 and extracted with DCM (x4). The combined extract was dried over Na₂SO₄, filtered and concentrated to give tert-Butyl (1R,5S)-3-(7- hydroxy-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.3 mg,0.0259 mmol, >100%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 590.3 m/z. Step 2. Tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (crude, 0.0234mmol) was treated with TFA (451µL, 5.89 mmol) at rt for 60min then concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (18mg,100%). LC/MS, ESI [M+H]⁺ = 490.3 m/z. ¹H NMR (400 MHz, Methanol-d₄, 1:1 mixture of diastereomers) δ 6.92 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.87 – 4.78 (m, 1H), 4.74 (ddd, J = 12.3, 7.4, 3.8 Hz, 1H), 4.38 (d, J = 14.1 Hz, 1H), 4.26 – 4.18 (m, 2H), 4.00 – 3.89 (m, 1H), 3.87 – 3.72 (m, 2H), 3.53 (d, J = 14.0 Hz, 1H), 3.28 – 3.19 (m, 1H), 3.13 – 2.84 (m, 6H), 2.79 – 2.61 (m, 3H), 2.49 – 2.36 (m, 1H), 2.25 – 1.98 (m, 8H), 1.96 – 1.64 (m, 5H). Preparation of Compound 1-3 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-7-ol) Step 1. Intermediate 1-13 (tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) (13.5mg, 0.0234mmol) was dissolved in THF (300µL) and treated with acetone (5.2µL, 0.070mmol), AcOH (1.3uL, 0.0200 mmol), and NaBH(Oac)₃ (14.9mg, 0.070mmol) and the mixture was stirred at rt for 4hrs. The mixture was poured into 10% K2CO3 and extracted with DCM (x4). The combined extract was dried over Na2SO4, filtered and concentrated to give tert-Butyl (1R,5S)-3-(7-hydroxy-2'- (((S)-1-isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene- 1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16.5 mg, >100%) as a colorless residue which was used without purification. LC/MS, ESI [M+H]⁺ = 618.3 m/z. Step 2. Tert-Butyl (1R,5S)-3-(7-hydroxy-2'-(((S)-1-isopropylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (16.5mg, 0.0267mmol) was treated with TFA (500µL) at rt for 60min then concentrated. The residue was purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound (18.8mg, 94.4%) as a colorless film. LC/MS, ESI [M+H]⁺ = 518.3 m/z.¹H NMR (400 MHz, Methanol-d₄, 1:1 mixture of diastereomers) δ 6.92 (d, J = 8.4 Hz, 1H), 6.72 (t, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.87 – 4.70 (m, 3H), 4.38 (dq, J = 14.1, 2.8 Hz, 1H), 4.26 – 4.14 (m, 3H), 3.83 (dt, J = 12.9, 2.8 Hz, 2H), 3.67 – 3.57 (m, 1H), 3.53 (d, J = 14.5 Hz, 1H), 3.43 – 3.32 (m, 1H), 3.10 – 2.85 (m, 3H), 2.80 – 2.60 (m, 3H), 2.34 (dq, J = 12.6, 8.3, 7.8 Hz, 1H), 2.26 – 1.97 (m, 8H), 1.94 – 1.64 (m, 5H), 1.44 (dd, J = 6.6, 2.1 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H). Schematization for the Preparation of Intermediates 1-14 through 1-17

Intermediate 1-9 Intermediate 1-14 Intermediate 1-15

Intermediate 1-16 Intermediate 1-17 Preparation of Intermediate 1-14 (tert-Butyl 4-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate) Intermediate 1-9 (7-(Benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) (139.1mg, 0.253mmol) was dissolved in anhydrous DMF (1.25mL) and treated with iPr₂EtN (62µL, 0.360mmol) and piperazine (108.8mg, 1.26mmol) at rt. After 45min, the mixture was diluted with 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMF (500µL) and treated with Boc2O (82.7mg, 0.379mmol). After 2hrs, the mixture was diluted with EtOAc and washed with sat NaHCO3 (x3), brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→50% EtOAc in hexanes to give the title compound (113.9 mg, 76.8%). Rf = 0.34 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 587.3 m/z.¹H NMR (400 MHz, Chloroform-d) δ 7.43 – 7.26 (m, 5H), 7.01 (dd, J = 8.4, 3.0 Hz, 1H), 6.84 – 6.74 (m, 2H), 4.98 (s, 2H), 3.68 – 3.29 (m, 8H), 3.10 – 2.94 (m, 1H), 2.83 – 2.47 (m, 8H), 2.09 – 1.95 (m, 1H), 1.90 – 1.69 (m, 5H), 1.67 – 1.52 (m, 2H), 1.49 (s, 7H). Preparation of Intermediate 1-15 (tert-Butyl 4-(7-(benzyloxy)-2'-(methylsulfinyl)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate) Intermediate 1-14 (tert-Butyl 4-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro- 2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate) (113.9mg, 0.194mmol) was dissolved in DCM (1mL) and treated with mCPBA (60.3mg, 0.175mmol) at 0 °C. After 45min, the mixture was diluted with Et2O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (116.8 mg, 99.8%) as a white foam. LC/MS, ESI [M+H]⁺ = 603.3 m/z. Preparation of Intermediate 1-16 (tert-Butyl 4-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate) Intermediate 1-15 (tert-Butyl 4-(7-(benzyloxy)-2'-(methylsulfinyl)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate) (57mg, 0.095mmol) was dissolved in anhydrous THF (0.5mL) and cooled to -40°C. [(2S)- pyrrolidin-2-yl]methanol (19.1mg, 0.189mmol) in anhydrous THF (0.5mL) was treated with KotBu, 1M in THF (123µL) and the resulting solution was added dropwise to the reaction. After 5min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 40→0% hexanes then 0→10% MeOH in DCM+2%Et₃N to give the title compound (42.4mg, 70.1%) as a colorless film. LC/MS, ESI [M+H]⁺ = 640.4 m/z. Preparation of Intermediate 1-17 (tert-Butyl 4-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate) Intermediate 1-16 (tert-Butyl 4-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1- carboxylate) (42.4mg, 0.0663mmol) was dissolved in MeOH (1mL), amended with Pd/C, 10% (wetted) (45mg), and sparged with H₂ for 60min. The mixture was filtered through Celite and concentrated to give the title compound (31.3mg, 85.9%). LC/MS, ESI [M+H]⁺ = 550.3 m/z. Preparation of Compound 1-4 (4'-(Piperazin-1-yl)-2'-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-7-ol) Intermediate 1-17 (tert-Butyl 4-(7-hydroxy-2'-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1- carboxylate) (10.4mg, 0.0189mmol) was treated with TFA (200µL) at rt for 60min. The mixture was concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (19.3 mg) as a colorless film. LC/MS, ESI [M+H]⁺ = 450.2 m/z.1H NMR (400 MHz, Methanol-d4) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 6.59 (dd, J = 8.3, 2.5 Hz, 1H), 4.91 – 4.77 (m, 1H), 4.63 (dt, J = 12.0, 8.4 Hz, 1H), 4.22 – 4.08 (m, 3H), 4.08 – 3.96 (m, 2H), 3.52 – 3.36 (m, 6H), 3.01 (d, J = 18.9 Hz, 1H), 2.96 – 2.83 (m, 2H), 2.79 – 2.59 (m, 3H), 2.37 – 2.25 (m, 1H), 2.25 – 2.01 (m, 3H), 1.98 – 1.66 (m, 6H). Preparation of Compound 1-5 (2'-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-4'-(piperazin-1- yl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-7-ol) Step 1. Intermediate 1-17 (tert-Butyl 4-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate) (10.4mg, 0.0189mmol) was dissolved in THF (400µL) and treated with formaldehyde, 37% aqueous (4.2µL, 0.0564mmol), AcOH (1.1uL, 0.0192mmol), and NaBH(Oac)₃ (12.0mg, 0.0568mmol) and the mixture was stirred at rt overnight. The mixture was poured into 10% K2CO3 and extracted with DCM (x4). The combined extract was dried over Na2SO4, filtered and concentrated to give tert-Butyl 4-(7- hydroxy-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (11.4mg, >100%) as a colorless film which was used without purification. LC/MS, ESI [M+H]⁺ = 564.3 m/z. Step 2. Tert-Butyl 4-(7-hydroxy-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1-carboxylate (11.4mg, 0.0202mmol) was treated with TFA (500µL) at rt for 60min then concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (13.9 mg, 99.4%). LC/MS, ESI [M+H]⁺ = 464.3 m/z. ¹H NMR (400 MHz, Methanol-d4, 1:1 mixture of diastereomers) δ 6.92 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 2.8 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.95 – 4.82 (m, 1H), 4.72 (td, J = 12.1, 7.3 Hz, 1H), 4.16 (ddd, J = 14.6, 7.2, 3.5 Hz, 2H), 4.03 (ddd, J = 14.8, 7.0, 3.6 Hz, 2H), 3.94 (s, 1H), 3.78 (d, J = 7.4 Hz, 1H), 3.52 – 3.35 (m, 4H), 3.30 – 3.21 (m, 1H), 3.07 (s, 3H), 3.02 (d, J = 19.1 Hz, 1H), 2.97 – 2.84 (m, 2H), 2.76 – 2.59 (m, 3H), 2.49 – 2.35 (m, 1H), 2.28 – 1.98 (m, 4H), 1.94 – 1.66 (m, 5H). Preparation of Compound 1-6 (2'-(((S)-1-Isopropylpyrrolidin-2-yl)methoxy)-4'-(piperazin- 1-yl)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-7-ol) Step 1. Intermediate 1-17 (tert-Butyl 4-(7-hydroxy-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate (10.4mg, 0.0189mmol) was dissolved in THF (400µL) and treated with acetone (4.2µL, 0.0567mmol), AcOH (1.1µL, 0.019mmol), and NaBH(Oac)3 (12.0mg, 0.0568mmol) and the mixture was stirred at rt for 3.5hr. The mixture was poured into 10% K₂CO₃ and extracted with DCM (x4). The combined extract was dried over Na₂SO₄, filtered and concentrated to give tert-butyl 4-(7-hydroxy-2'-(((S)-1-isopropylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate (13.0mg, >100%) as a colorless residue which was used without purification. LC/MS, ESI [M+H]⁺ = 592.3 m/z. Step 2. Tert-Butyl 4-(7-hydroxy-2'-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazine-1- carboxylate (13mg, 0.022mmol) was treated with TFA (500µL) at rt for 60min then concentrated and purified by preparative HPLC (C18, 20x250mm, 5u, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (10.5 mg, 66.4%). LC/MS, ESI [M+H]⁺ = 492.3 m/z. ¹H NMR (400 MHz, Methanol-d₄) δ 6.82 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 4.74 – 4.57 (m, 2H), 4.14 – 3.99 (m, 3H), 3.97 – 3.86 (m, 2H), 3.72 (pd, J = 6.7, 2.4 Hz, 1H), 3.55 – 3.45 (m, 1H), 3.41 – 3.23 (m, 5H), 2.92 (dd, J = 18.9, 5.3 Hz, 1H), 2.86 – 2.74 (m, 2H), 2.67 – 2.50 (m, 3H), 2.24 (dq, J = 12.4, 7.6 Hz, 1H), 2.11 – 1.89 (m, 4H), 1.83 – 1.57 (m, 5H), 1.34 (dd, J = 6.6, 1.0 Hz, 3H), 1.29 (d, J = 6.5 Hz, 3H). Preparation of Compound 1-35 (4’-(Piperazin-1-yl)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol) Step 1. Intermediate 1-15 (tert-Butyl 4-(7-(benzyloxy)-2’-(methylsulfinyl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate; 62.2mg, 0.103mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (22mg, 0.156mmol) were dissolved in anhydrous THF (690µL) and cooled to -40 °C, then KotBu, 1M in THF (125µL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 55→0% hexanes then 0→10% MeOH in DCM+2%Et3N to give tert-Butyl 4-(7- hydroxy-2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate (46.2mg, 65.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 680.4 m/z. Step 2. Tert-Butyl 4-(7-hydroxy-2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate (46.2mg, 0.068mmol) was dissolved in MeOH (450µL) and treated with Pd/C, 10% (wetted) (40mg) and the mixture was gently sparged with H₂. After 60min, the mixture was filtered through Celite and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min then concentrated, redissolved in H₂O and washed with Et2O and the aqueous phase was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (50.5 mg) as a white powder. LC/MS, ESI [M+H]⁺ = 490.3 m/z. ¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.79 – 4.65 (m, 2H), 4.27 (ddd, J = 14.8, 7.2, 3.5 Hz, 2H), 4.13 (ddd, J = 14.8, 7.1, 3.7 Hz, 2H), 3.74 – 3.64 (m, 2H), 3.53 – 3.36 (m, 4H), 3.27 (dd, J = 12.1, 5.9 Hz, 2H), 3.08 – 2.85 (m, 3H), 2.80 – 2.60 (m, 3H), 2.39 – 2.06 (m, 9H), 1.94 – 1.65 (m, 5H). Schematization of the Preparation of Intermediates 1-18 through 1-21

I_{ntermediate 1-9 Intermediate 1-18 Intermediate 1-19}

I_{ntermediate 1-20 Intermediate 1-21} Preparation of Intermediate 1-18 (tert-Butyl (2S)-4-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2-(cyanomethyl)piperazine-1- carboxylate) Intermediate 1-9 (7-(Benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) (139.1mg, 0.253mmol) was dissolved in anhydrous DMF (1.26mL) and treated with iPr2EtN (154µL, 0.884mmol) and 2-[(2S)-piperazin-2-yl]acetonitrile dihydrochloride (55.4mg, 0.280mmol) at rt. After 45min, Boc₂O (83.mg, 0.3800 mmol) was added and the mixture was warmed to 40ºC. After 3hrs, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→50% EtOAc in hexanes to give the title compound (109.2 mg, 69.1%) as a white foam. Rf = 0.24 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 626.3 m/z. ¹H NMR (400 MHz, CDCl₃) δ 7.42 – 7.27 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H), 6.81 – 6.74 (m, 2H), 5.04 – 4.95 (m, 2H), 4.66 – 4.55 (m, 1H), 4.17 – 3.83 (m, 2H), 3.46 – 3.27 (m, 1H), 3.19 – 2.85 (m, 4H), 2.81 – 2.64 (m, 5H), 2.61 – 2.47 (m, 4H), 2.11 – 1.99 (m, 1H), 1.93 – 1.72 (m, 4H), 1.70 – 1.56 (m, 2H), 1.51 (s, 9H). Preparation of Intermediate 1-19 (tert-Butyl (2S)-4-(7-(benzyloxy)-2'-(methylsulfinyl)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2- (cyanomethyl)piperazine-1-carboxylate) Intermediate 1-18 (tert-butyl (2S)-4-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2-(cyanomethyl)piperazine-1- carboxylate) (109.2mg, 0.175mmol) was dissolved in DCM (1mL) and treated with mCPBA (54.2mg, 0.157mmol) at 0 °C. After 45min, the mixture was diluted with Et2O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (106.7mg, 95.3%) as a white foam. LC/MS, ESI [M+H]⁺ = 642.3 m/z. Preparation of Intermediate 1-20 (tert-Butyl (2S)-4-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2- (cyanomethyl)piperazine-1-carboxylate) Intermediate 1-19 (tert-butyl (2S)-4-(7-(benzyloxy)-2'-(methylsulfinyl)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2-(cyanomethyl)piperazine-1- carboxylate) (61.mg, 0.095mmol) was dissolved in anhydrous THF (0.5mL) and cooled to - 40 °C. [(2S)-pyrrolidin-2-yl]methanol (19.2mg, 0.190mmol) in anhydrous THF (0.5mL) was treated with KotBu, 1M in THF (124µL) and the resulting solution was added dropwise to the reaction. After 5min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 40→0% hexanes then 0→10% MeOH in DCM+2%Et₃N to give the title compound (53.9 mg, 83.5%) as a colorless film. LC/MS, ESI [M+H]⁺ = 679.3 m/z. Preparation of Intermediate 1-21 (tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]- 4'-yl)piperazine-1-carboxylate) Intermediate 1-20 (tert-butyl (2S)-4-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-2- (cyanomethyl)piperazine-1-carboxylate (53.9mg, 0.0794mmol) was dissolved in MeOH (1mL) and treated with Pd/C, 10% (wetted) (55mg) and the mixture was sparged with H₂ for 1.25hr. The mixture was filtered through Celite and concentrated to give the title compound (38 mg, 81.3%) as a white film. LC/MS, ESI [M+H]⁺ = 589.3 m/z. Preparation of Compound 1-7 (2-((2S)-4-(7-Hydroxy-2'-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazin-2- yl)acetonitrile) Intermediate 1-21 (tert-butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate (12.7mg, 0.0216mmol) was treated with TFA (200µL) at rt for 60min. The mixture was concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (14.6mg, 94.4% yield). LC/MS, ESI [M+H]⁺ = 489.3 m/z. ¹H NMR (400 MHz, Methanol-d4, 1:1 mixture of diastereomers) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 14.6, 2.5 Hz, 1H), 6.59 (dd, J = 8.3, 2.4 Hz, 1H), 4.88 – 4.55 (m, 3H), 4.53 – 4.45 (m, 1H), 4.17 – 3.88 (m, 2H), 3.88 – 3.36 (m, 6H), 3.21 – 2.81 (m, 5H), 2.79 – 2.59 (m, 3H), 2.36 – 2.23 (m, 1H), 2.23 – 2.01 (m, 3H), 1.99 – 1.68 (m, 6H). Preparation of Compound 1-8 (2-((2S)-4-(7-Hydroxy-2'-(((S)-1-methylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazin-2-yl)acetonitrile) Step 1. Intermediate 1-21 (tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate) (12.7mg, 0.0216mmol) was dissolved in THF (400µL) and treated with formaldehyde, 37% aqueous (4.8µL, 0.065mmol), AcOH (1.2µL, 0.021mmol), and NaBH(Oac)3 (13.7mg, 0.0647mmol) and the mixture was stirred at rt for 2hrs then poured into 10% K₂CO₃ and extracted with DCM (x4). The combined extract was dried over Na₂SO₄, filtered and concentrated to give tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'- (((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-4'-yl)piperazine-1-carboxylate (14.7 mg, >100%) as a colorless residue which was used without purification. LC/MS, ESI [M+H]⁺ = 603.3 m/z. Step 2. Tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)-1-methylpyrrolidin- 2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate (35.8mg, 0.0594mmol) was treated with 4N HCl in dioxane (1mL) at rt for 30min then concentrated and co-evaporated once from toluene and further dried in vacuo. Half of this material was purified by preparative HPLC to give the title compound as its trifluoroacetate salt (17.4 mg, 40.1%) as a colorless film.¹H NMR (400 MHz, Acetonitrile-d3, 1:1 mixture of diastereomers) δ 6.84 (d, J = 8.2 Hz, 1H), 6.62 (dd, J = 11.6, 2.5 Hz, 1H), 6.51 (dt, J = 8.2, 2.5 Hz, 1H), 4.79 – 4.56 (m, 2H), 4.46 – 4.21 (m, 2H), 3.86 – 3.55 (m, 4H), 3.54 – 3.46 (m, 1H), 3.35 (dt, J = 13.3, 3.1 Hz, 1H), 3.23 (ddd, J = 13.1, 10.8, 3.3 Hz, 1H), 3.14 – 2.91 (m, 4H), 2.88 – 2.82 (m, 3H), 2.81 – 2.53 (m, 4H), 2.52 – 2.40 (m, 1H), 2.29 – 2.15 (m, 1H), 2.09 – 1.87 (m, 4H), 1.78 – 1.51 (m, 5H). Preparation of Compound 1-9 (2-((2S)-4-(7-hydroxy-2'-(((S)-1-methylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-1- methylpiperazin-2-yl)acetonitrile) Compound 1-8 (2-((2S)-4-(7-Hydroxy-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)piperazin-2- yl)acetonitrile) (14.9mg, 0.0297mmol) was suspended in THF (300µL) and treated with Et₃N (12.4µL, 0.0890mmol), AcOH (1.7µL, 0.030mmol), formaldehyde, 37% aqueous (6.6µL, 0.089mmol), and NaBH(Oac)3 (19.mg, 0.090mmol) and the mixture was stirred at rt for 5hrs. The mixture was diluted with aqueous 0.25% TFA and purified by preparative HPLC to give the title compound (11.6 mg, 52.4%) as a colorless film. LC/MS, ESI [M+H]⁺ = 517.3 m/z.¹H NMR (400 MHz, Acetonitrile-d3, 1:1 mixture of diastereomers) δ 6.93 (d, J = 8.3 Hz, 2H), 6.71 (dd, J = 16.7, 2.5 Hz, 2H), 6.59 (dt, J = 8.2, 2.8 Hz, 2H), 4.88 (dd, J = 12.4, 7.3 Hz, 1H), 4.74 (td, J = 12.4, 6.3 Hz, 1H), 4.65 (ddd, J = 27.2, 12.4, 3.0 Hz, 2H), 4.56 (d, J = 14.1 Hz, 0H), 4.41 – 4.33 (m, 1H), 4.30 – 4.15 (m, 2H), 3.84 (ddd, J = 14.4, 11.0, 3.1 Hz, 1H), 3.78 – 3.63 (m, 7H), 3.57 (dd, J = 14.1, 9.9 Hz, 1H), 3.51 – 3.42 (m, 1H), 3.39 – 3.25 (m, 2H), 3.20 – 3.02 (m, 5H), 3.01 – 2.86 (m, 13H), 2.85 – 2.65 (m, 12H), 2.60 – 2.49 (m, 2H), 2.29 (dddd, J = 15.9, 12.8, 6.2, 3.2 Hz, 2H), 2.16 – 1.96 (m, 8H), 1.89 – 1.60 (m, 11H). Preparation of Compound 1-10 (2-((2S)-4-(7-Hydroxy-2'-(((S)-1-isopropylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazin-2-yl)acetonitrile) Step 1. Intermediate 1-21 (tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'- yl)piperazine-1-carboxylate) (12.7mg, 0.0216mmol) was dissolved in THF (400µL) and treated with acetone (4.8µL, 0.0648mmol), AcOH (1.2µL, 0.021mmol), and NaBH(Oac)₃ (13.7mg, 0.0648mmol) and the mixture was stirred at rt for 2hrs then poured into 10% K2CO3 and extracted with DCM (x4). The combined extract was dried over Na2SO4, filtered and concentrated to give tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-4'-yl)piperazine-1-carboxylate (14.8 mg, >100%) as a colorless residue which was used without purification. LC/MS, ESI [M+H]⁺ = 631.3 m/z. Step 2. Tert-Butyl (2S)-2-(cyanomethyl)-4-(7-hydroxy-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-4'-yl)piperazine-1-carboxylate (14.8mg, 0.0235mmol) was treated with TFA (500µL) at rt for 60min then concentrated and purified by preparative HPLC (C18, 20x250mm, 5µ, 20mL/min 5→25%; 25→70% ACN in H₂O+0.25%TFA) to give the title compound as its trifluoroacetate salt (16.1mg, 90.4%). LC/MS, ESI [M+H]⁺ = 492.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 13.7, 2.6 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.88 – 4.69 (m, 3H), 4.60 – 4.43 (m, 1H), 4.25 – 4.15 (m, 1H), 4.07 – 3.88 (m, 1H), 3.88 – 3.33 (m, 7H), 3.20 – 2.98 (m, 3H), 2.97 – 2.81 (m, 2H), 2.80 – 2.59 (m, 3H), 2.39 – 2.24 (m, 1H), 2.23 – 2.01 (m, 4H), 1.93 – 1.65 (m, 5H), 1.44 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.6 Hz, 3H). Preparation of Intermediate 1-22 (Allyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) Schematization of the Preparation of Intermediate 1-22.

Intermediate 1-22 Step 1. Tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (514.8mg, 2.42mmol) and Et3N (507µL, 3.64mmol) were dissolved in anhydrous DCM (8mL) and allyl chloroformate (284µL, 2.67 mmol) was added dropwise at 0 °C. After 20 min, the mixture was diluted with Et₂O and washed with half-saturated NaHCO₃ (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel and concentrated. The residue was dissolved in hexanes and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give 3-Allyl 8-(tert-butyl) (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (742.2 mg, quant.) as a colorless oil. Rf = 0.31 (8:2 hexanes:EtOAc). LC/MS, ESI [M+Na]⁺ = 319.2 m/z. Step 2. 3-Allyl 8-(tert-butyl) (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (718.7mg, 2.43mmol) was treated with TFA (4mL) at rt. After 40 min, the mixture was concentrated and the residue was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give the title compound (441.7mg, 92.8%) as a colorless oil. LC/MS, ESI [M+H]⁺ = 197.1 m/z.¹H NMR (400 MHz, CDCl3) δ 5.92 (ddt, J = 17.2, 10.6, 5.5 Hz, 1H), 5.35 – 5.25 (m, 1H), 5.20 (dq, J = 10.5, 1.4, 1.3 Hz, 1H), 4.58 (dt, J = 5.5, 1.6 Hz, 2H), 3.80 (dd, J = 30.2, 12.1 Hz, 2H), 3.54 (d, J = 18.2 Hz, 2H), 3.09 (dd, J = 28.4, 12.7 Hz, 2H), 1.85 – 1.71 (m, 4H). Schematization of the Preparation of Intermediates 1-23 through 1-25

Intermediate 1-9 Intermediate 1-23 Intermediate 1-24

Preparation of Intermediate 1-23 (Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 1-9 (7-(Benzyloxy)-2'-(methylthio)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) (139.1mg, 0.253mmol) was dissolved in anhydrous DMF (1.3mL) and treated with iPr2EtN (62µL, 0.356mmol) and Intermediate 1-22 (allyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) (54.5mg, 0.278mmol) at rt. After 45min, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), 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 eluted with 0→50% EtOAc in hexanes to give the title compound (113.7 mg, 75.4%) as a white foam. Rf = 0.30 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 597.3 m/z. Preparation of Intermediate 1-24 (Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(methylsulfinyl)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 1-23 (allyl (1R,5S)-8-(7-(benzyloxy)-2'-(methylthio)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate) (113.7mg, 0.191mmol) was dissolved in DCM (1mL) and treated with mCPBA (59.2mg, 0.172mmol) at 0 °C. After 45min, the mixture was diluted with Et₂O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (117.8mg, 100%) as a white foam. LC/MS, ESI [M+H]⁺ = 613.3 m/z. Preparation of Intermediate 1-25 (Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 1-24 (Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(methylsulfinyl)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate) (58mg, 0.095mmol) was dissolved in anhydrous THF (0.5mL) and cooled to - 40 °C. [(2S)-pyrrolidin-2-yl]methanol (19.2mg, 0.189mmol) in anhydrous THF (0.5mL) was treated with KotBu, 1M in THF (123µL) and the resulting solution was added dropwise to the reaction. After 5min, HPLC analysis showed complete conversion to a single major product showing The mixture was poured into 5% K2CO3 and extracted with DCM (x3) and the combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 40→0% hexanes then 0→10% MeOH in DCM+2%Et₃N to give the title compound (55.4mg, 90.1%). LC/MS, ESI [M+H]⁺ = 650.3 m/z. Preparation of Compound 1-11 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-7- ol) Step 1. Intermediate 1-25 (allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) (20.1mg, 0.0309mmol) and PhSiH3 (38.1µL, 0.309mmol) were dissolved in THF (350µL) and sparged with N₂ for 5min with vigorous stirring then treated with Pd(PPh₃)₄ (1.8mg, 0.0016mmol) and sparging continued for 5min. The mixture was diluted with 1N HCl and washed with Et2O (x2) and the aqueous phase was basified with K₂CO₃ and back-extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give 7-(Benzyloxy)-4'-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro- 2H,6'H-spiro[naphthalene-1,7'-quinazoline] (11.2mg, 64.0%) as a colorless film. LC/MS, ESI [M+H]⁺ = 566.3 m/z. Step 2. 7-(Benzyloxy)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazoline] (11.2mg, 0.0198mmol) was dissolved in MeOH (200µL), treated with Pd/C, 10% (wetted) (15mg), and the mixture was gently sparged with H₂ for 2hrs. The mixture was filtered through Celite, concentrated, and purified by preparative HPLC to give the title compound as its trifluoroacetate salt (6.2 mg, 44.5%) as a white powder. LC/MS, ESI [M+H]⁺ = 476.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 6.93 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.4, 2.5 Hz, 1H), 5.29 (d, J = 6.3 Hz, 1H), 5.17 (d, J = 7.0 Hz, 1H), 4.82 (td, J = 8.1, 3.9 Hz, 1H), 4.63 (ddd, J = 12.0, 7.9, 2.5 Hz, 1H), 4.12 (tq, J = 8.1, 4.8, 4.0 Hz, 1H), 3.69 – 3.59 (m, 1H), 3.51 – 3.33 (m, 5H), 3.11 – 2.98 (m, 1H), 2.84 (dd, J = 19.0, 1.8 Hz, 2H), 2.78 – 2.62 (m, 3H), 2.46 – 2.26 (m, 3H), 2.25 – 2.03 (m, 5H), 2.00 – 1.79 (m, 4H), 1.78 – 1.65 (m, 2H). Preparation of Compound 1-12 (4'-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-7-ol) Step 1. Intermediate 1-25 (allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) (18.5mg, 0.0285mmol) was dissolved in THF (300µL) and treated with formaldehyde, 37% aqueous (10.6µuL, 0.142mmol), AcOH (1.6µL, 0.028mmol), and NaBH(Oac)3 (30.2mg, 0.142mmol) and the mixture was stirred at rt overnight. The mixture was poured into 10% K2CO3 and extracted with DCM (x3) and the combined extract was dried over Na₂SO₄, filtered, and concentrated to give allyl (1R,5S)-8- (7-(benzyloxy)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H- spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (16.8 mg, 88.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 664.3 m/z. Step 2. Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (16.8mg, 0.0253mmol) was dissolved in THF (250µL) and treated with PhSiH3 (16µL, 0.130mmol). The mixture was sparged with N2 for 5 min then Pd(PPh3)4 (1.5mg, 0.0013mmol) was added and sparging was continued for 5min. After 20min, the mixture was concentrated then diluted with 1N HCl and washed with Et₂O (x3). The aqueous was basified with K2CO3 and back-extracted with DCM (x3) and the combined extract was dried over Na2SO4, filtered, and concentrated to give 7-(Benzyloxy)- 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazoline] (14.6mg, 99.5%) as an off- white foam. LC/MS, ESI [M+H]⁺ = 580.3 m/z. Step 3. 7-(Benzyloxy)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazoline] (14.6mg, 0.0252mmol) was dissolved in MeOH (250µL) and treated with Pd/C, 10% (wetted) (20mg) and the mixture was sparged with H₂. After 1hr, the mixture was filtered through Celite, concentrated, and purified by preparative HPLC to give the title compound as its trifluoroacetate salt (11.6 mg, 64.2%) as a white powder. LC/MS, ESI [M+H]⁺ = 490.3 m/z. Preparation of Compound 1-13 (4'-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-7-ol) Step 1. Intermediate 1-25 (allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) (18.5mg, 0.0285mmol) was dissolved in THF (300µL) and treated with NaBH(Oac)3 (30.2mg, 0.142mmol), acetone (10.5µL, 0.142mmol), and AcOH (1.6µL, 0.028mmol) and the mixture was stirred at rt overnight. The mixture was poured into 10% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (20.3mg, quant.) as a colorless film. LC/MS, ESI [M+H]⁺ = 692.4 m/z. Step 2. Allyl (1R,5S)-8-(7-(benzyloxy)-2'-(((S)-1-isopropylpyrrolidin-2- yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (20.3mg, 0.0293mmol) and 1,3-dimethylbarbituric acid (23mg, 0.15mmol) were dissolved in THF (300µL) and treated with 4-methylpiperidine (35µL, 0.296mmol) and PhSiH₃ (18µL, 0.1500 mmol) and the mixture was sparged with N₂ for 5min then amended with Pd(PPh3)4 (1.7mg, 0.0015mmol) and sparging continued for 5min. The mixture was diluted with 1N HCl and washed with Et2O (x3) and the aqueous was basified with K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give 7-(benzyloxy)-4'-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'- tetrahydro-2H,6'H-spiro[naphthalene-1,7'-quinazoline] (17.2 mg, 96.4%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 608.4 m/z. Step 3. 7-(Benzyloxy)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-2H,6'H-spiro[naphthalene-1,7'- quinazoline] (17.2mg, 0.0283mmol) was dissolved in MeOH (300µL) and treated with Pd/C, 10% (wetted) (17mg) and AcOH (6.5µL, 0.114mmol) and the mixture was sparged with H₂ for 5min then held under positive pressure with a balloon. Afer 1hr, additional Pd/C, 10% (wetted) (17mg) was added and the reaction re-charged with H₂. After 1hr, the mixture was filtered through Celite, concentrated, and purified by preparative HPLC to give the title compound as its trifluoroacetate salt (13 mg, 61.6%) as a white powder. LC/MS, ESI [M+H]⁺ = 518.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 6.93 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 2.7 Hz, 1H), 6.60 (dd, J = 8.3, 2.4 Hz, 1H), 5.30 (dd, J = 7.3, 2.1 Hz, 1H), 5.18 (dd, J = 7.4, 2.3 Hz, 1H), 4.85 – 4.67 (m, 2H), 4.25 – 4.14 (m, 1H), 3.82 (pd, J = 6.6, 4.3 Hz, 1H), 3.72 – 3.56 (m, 2H), 3.51 – 3.32 (m, 4H), 3.03 (dd, J = 18.5, 6.5 Hz, 1H), 2.93 – 2.79 (m, 2H), 2.79 – 2.64 (m, 3H), 2.48 – 2.25 (m, 3H), 2.24 – 2.01 (m, 6H), 1.93 – 1.64 (m, 5H), 1.45 (dd, J = 6.6, 1.4 Hz, 3H), 1.39 (d, J = 6.5 Hz, 3H). Preparation of Intermediate 1-46 ((R)-3-(Methoxymethyl)-1-tritylpiperazine) (2R)-2-(Methoxymethyl)piperazine dihydrochloride (370.4mg, 1.82mmol) was suspended in anhydrous DCM (7mL) and treated with trityl chloride (610mg, 2.19 mmol) followed by iPr₂EtN (741µL, 6.4mmol). After 2.5hrs, the mixture was diluted with EtOAc and washed with 5% K2CO3 (x2), brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→60% EtOAc + 2% Et₃N in hexanes + 2% Et₃N to give the title compound (583.5mg, 85.9%) as a white foam. Rf = 0.27 (7:3 hexanes:EtOAc + 2% Et3N, x2).¹H NMR (400 MHz, CD3CN) δ 7.71 – 7.37 (m, 6H), 7.36 – 7.23 (m, 6H), 7.24 – 7.12 (m, 3H), 3.22 (s, 7H), 2.86 (d, J = 10.6 Hz, 3H), 2.25 – 2.01 (m, 1H), 1.17 – 0.96 (m, 1H), 0.95 (s, 1H). Schematization of the Preparation of Intermediates 1-47 through 1-49

Intermediate 1-9 Intermediate 1-47 Intermediate 1-48

Intermediate 1-49 Preparation of Intermediate 1-47 (7-(Benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Intermediate 1-9 (7-(Benzyloxy)-2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl trifluoromethanesulfonate; 196.2mg, 0.356mmol) was dissolved in anhydrous DMF (2mL) and treated with iPr₂EtN (188µL, 1.08mmol) and (R)-3-(methoxymethyl)-1-tritylpiperazine (146.0mg, 0.392mmol) and the mixture was heated to 50°C for 2hrs then the temperature was raised to 70ºC and stirring continued for 4hrs. The mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluted with 0→50% EtOAc in hexanes to give the title compound (169.9mg, 61.7%) as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 7.55 – 7.41 (m, 5H), 7.41 – 7.23 (m, 12H), 7.22 – 7.11 (m, 3H), 6.98 (dd, J = 8.5, 3.3 Hz, 1H), 6.82 – 6.68 (m, 2H), 4.95 (d, J = 13.3 Hz, 2H), 4.42 – 4.03 (m, 2H), 3.99 – 3.65 (m, 2H), 3.64 – 3.51 (m, 1H), 3.49 – 3.38 (m, 3H), 3.36 – 2.89 (m, 4H), 2.80 – 2.61 (m, 2H), 2.56 – 2.33 (m, 4H), 2.02 – 1.64 (m, 6H), 1.63 – 1.47 (m, 3H). Preparation of Intermediate 1-48 (7-(Benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazoline]) Intermediate 1-47 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1- yl)-2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]; 169.9mg, 0.220mmol) was dissolved in DCM (1.5mL) and treated with mCPBA (68.3mg, 0.198mmol) at 0°C. After 10min, the mixture was diluted with Et₂O and washed with half- saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (176.9 mg, >100%) as a white foam which was used without purification. Preparation of Intermediate 1-49 (7-(Benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline]) Intermediate 1-48 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1- yl)-2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]; 130.2mg, 0.165mmol) was dissolved in anhydrous THF (700µL) and a solution of [(2S)- pyrrolidin-2-yl]methanol (25.0mg, 0.248mmol) and KotBu, 1M in THF (200µL) in THF (800µL) was added dropwise at -40°C. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on basic alumina eluted with 0→100% EtOAc in hexanes then 5% iPrOH in EtOAc to give the title compound (96.5mg, 70.8%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 826.4 m/z. Preparation of Compound 1-74 (4’-((R)-2-(Methoxymethyl)piperazin-1-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]- 7-ol) Step 1. Intermediate 1-49 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline]; 27.4mg, 0.0332mmol) was dissolved in MeOH (1mL) and treated with Pd/C, 10% (wetted) (40mg) and the mixture was gently sparged with H₂. After 30min, additional Pd/C (45mg) was added and sparging continued. After an additional 60min, the mixture was filtered through Celite and concentrated to give 4’-((R)-2- (methoxymethyl)-4-tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol (14.1mg, 57.8%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 736.3 m/z. Step 2. 4’-((R)-2-(Methoxymethyl)-4-tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol (14.1mg, 0.0192mmol) was treated with MeOH (8µL) and 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et₂O. HPLC analysis of the aqueous phase showed a major product showing the aqueous phase was filtered and purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (15.2mg) as a colorless residue. LC/MS, ESI [M+H]⁺ = 494.3 m/z.¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 3.9, 2.4 Hz, 1H), 6.59 (dd, J = 8.3, 2.5 Hz, 1H), 4.82 (ddd, J = 12.0, 7.3, 3.4 Hz, 1H), 4.65 – 4.34 (m, 2H), 4.12 (qd, J = 8.0, 3.4 Hz, 1H), 4.05 – 3.71 (m, 4H), 3.71 – 3.61 (m, 1H), 3.55 – 3.36 (m, 7H), 3.30 – 3.20 (m, 1H), 3.09 – 2.83 (m, 3H), 2.75 – 2.57 (m, 3H), 2.30 (dtdd, J = 12.5, 7.8, 4.4, 1.4 Hz, 1H), 2.24 – 2.01 (m, 3H), 2.01 – 1.65 (m, 6H). Preparation of Compound 1-75 (4’-((R)-2-(Methoxymethyl)piperazin-1-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazolin]-7-ol) Step 1. Intermediate 1-49 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline]; 27.4mg, 0.0332mmol) was dissolved in THF (500µL) and treated with AcOH (1.9uL, 0.033mmol), formaldehyde, 37% aqueous (1.8uL, 0.065mmol), and NaBH(Oac)₃ (14.1mg, 0.067mmol). After 4hrs, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give 7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazoline] (28.8 mg, >100%) as a colorless residue that was used without purification. LC/MS ESI [M+H]⁺ = 840.4 m/z. Step 2. 7-(Benzyloxy)-4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline] (28.8mg, 0.0343mmol) was dissolved in MeOH (500µL) and treated with Pd/C, 10% (wetted) (40mg) and the mixture was gently sparged with H₂. After 40min, additional Pd/C (50mg) was added and sparging continued. After an additional 40min, the mixture was filtered through Celite and concentrated to give 4’-((R)-2-(methoxymethyl)-4-tritylpiperazin- 1-yl)-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-7-ol (18.8mg, 73.1%) as a white powdery residue. LC/MS, ESI [M+H]⁺ = 750.4 m/z. Step 3. 4’-((R)-2-(Methoxymethyl)-4-tritylpiperazin-1-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazolin]-7-ol (18.8mg, 0.0251mmol) was treated with MeOH (10µL) and 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et₂O and the aqueous phase was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (19.1 mg) as a colorless residue. LC/MS, ESI [M+H^]+ = 508.3 m/z. ¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 4.1, 2.4 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.89 – 4.81 (m, 1H), 4.71 (dt, J = 12.4, 7.0 Hz, 1H), 4.64 – 4.36 (m, 1H), 4.05 – 3.61 (m, 7H), 3.57 – 3.37 (m, 6H), 3.29 – 3.19 (m, 1H), 3.03 (d, J = 30.9 Hz, 4H), 2.95 – 2.84 (m, 2H), 2.79 – 2.58 (m, 3H), 2.49 – 2.35 (m, 1H), 2.25 – 1.98 (m, 4H), 1.92 – 1.65 (m, 5H). Preparation of Compound 1-76 (2’-(((S)-1-Isopropylpyrrolidin-2-yl)methoxy)-4’-((R)-2- (methoxymethyl)piperazin-1-yl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazolin]-7-ol) Step 1. Intermediate 1-49 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline; 41.6mg, 0.0504mmol) was dissolved in THF (750µL) and treated with AcOH (2.9µL, 0.0507mmol), acetone (11.2µL, 0.151mmol), and NaBH(Oac)₃ (32.mg, 0.151mmol) at rt. After 3hrs, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give 7-(benzyloxy)-2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-4’- ((R)-2-(methoxymethyl)-4-tritylpiperazin-1-yl)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[397cenaphthyl-1,7’-quinazoline] (33.5mg, 76.6%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 868.4 m/z. Step 2. 7-(Benzyloxy)-2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-4’-((R)-2- (methoxymethyl)-4-tritylpiperazin-1-yl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[ 397 cenaphthyl- 1,7’-quinazoline] (33.5mg, 0.0386mmol) was dissolved in MeOH (500µL) and treated with Pd/C, 10% (wetted) (70mg) and the mixture was gently sparged with H₂. After 40min, the mixture was filtered through Celite and concentrated to give 2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1-yl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol (24.0mg, 79.9%) as a white solid. LC/MS, ESI [M+H]⁺ =778.4 m/z. Step 3. 2-(1,2,3,5,6,7-Hexahydropyrrolizin-8-ylmethoxy)-4-[(2R)-2- (methoxymethyl)-4-trityl-piperazin-1-yl]spiro[6,8-dihydro-5H-quinazoline-7,4’-tetralin]-6’- ol (31.0mg, 0.040mmol) was treated with MeOH (16.2µL) and 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et₂O and the aqueous phase was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (29.4mg, 96.7%) as a white residue. LC/MS, ESI [M+H]⁺ = 534.3 m/z.¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 6.1, 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 5.11 – 4.83 (m, 1H), 4.83 – 4.66 (m, 2H), 4.62 – 4.34 (m, 1H), 4.25 – 4.14 (m, 1H), 4.04 – 3.71 (m, 4H), 3.70 – 3.32 (m, 9H), 3.03 (dd, J = 18.9, 5.8 Hz, 1H), 2.96 – 2.83 (m, 2H), 2.79 – 2.68 (m, 2H), 2.68 – 2.58 (m, 1H), 2.41 – 2.27 (m, 1H), 2.25 – 1.99 (m, 4H), 1.93 – 1.65 (m, 5H), 1.44 (d, J = 6.6 Hz, 3H), 1.39 (d, J = 6.5 Hz, 3H). Preparation of Compound 1-77 (4’-((R)-2-(Methoxymethyl)piperazin-1-yl)-2’-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazolin]-7-ol) Step 1. Intermediate 1-48 (7-(benzyloxy)-4’-((R)-2-(methoxymethyl)-4- tritylpiperazin-1-yl)-2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazoline]; 43.4mg, 0.0550mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (11.7mg, 0.0829mmol) were dissolved in anhydrous THF (500µL) and cooled to -40 °C then KotBu, 1M in THF (66µL) was added dropwise. After 10min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on basic alumina eluted with 0→100% EtOAc in hexanes to give 7-(benzyloxy)-4’-((R)-2- (methoxymethyl)-4-tritylpiperazin-1-yl)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline] (39.7 mg,0.0458 mmol, 83.332% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 866.4 m/z. Step 2. 7-(Benzyloxy)-4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline] (39.7mg, 0.0458mmol) was dissolved in MeOH (0.5mL) and THF (0.5mL) and treated with Pd/C, 10% (wetted) (60mg) and the mixture was gently sparged with H₂. After 90min, the mixture was filtered through Celite and concentrated to give 4’-((R)-2-(methoxymethyl)-4-tritylpiperazin-1-yl)-2’-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol (31.0mg, 87.2%) as a white powder. LC/MS, ESI [M+H]+ = 776.4 m/z. Step 3. 4’-((R)-2-(Methoxymethyl)-4-tritylpiperazin-1-yl)-2’-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazolin]-7-ol (31.0mg, 0.040mmol) was treated with MeOH (16.2µL) and 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et2O. The aqueous was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (29.4mg, 96.7%) as a white residue. LC/MS, ESI [M+H]⁺ = 534.3 m/z.¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (dd, J = 4.3, 2.4 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 5.16 – 4.84 (m, 1H), 4.74 – 4.38 (m, 3H), 4.05 – 3.61 (m, 6H), 3.57 – 3.33 (m, 6H), 3.29 – 3.19 (m, 2H), 3.02 (d, J = 19.2 Hz, 1H), 2.95 – 2.83 (m, 2H), 2.79 – 2.58 (m, 3H), 2.38 – 2.06 (m, 9H), 1.91 – 1.65 (m, 5H). Preparation of Intermediate 1-50 ((S)-2-(4-Tritylpiperazin-2-yl)acetonitrile) 2-[(2S)-Piperazin-2-yl]acetonitrile dihydrochloride (304.6mg, 1.54mmol) was suspended in anhydrous DCM (6mL) and treated with trityl chloride (514mg, 1.84mmol) followed by iPr₂EtN (625µL, 5.4mmol). After 5hrs, the mixture was diluted with EtOAc and washed with 5% K2CO3 (x2), brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→60% EtOAc + 2% Et₃N in hexanes + 2% Et₃N to give the title compound (405.6mg, 71.8% yield) as a white foam. Rf = 0.24 (7:3 hexanes:EtOAc + 2% Et₃N, x2).¹H NMR (400 MHz, Acetonitrile-d₃, 60ºC) δ 7.55 – 7.43 (m, 6H), 7.35 – 7.26 (m, 6H), 7.24 – 7.15 (m, 3H), 3.32 (dtd, J = 9.1, 6.3, 2.8 Hz, 1H), 3.09 (td, J = 11.2, 10.3, 2.9 Hz, 1H), 2.93 (dt, J = 11.9, 3.2 Hz, 2H), 2.87 – 2.70 (m, 1H), 2.47 – 2.35 (m, 2H), 1.63 (s, 2H), 1.51 – 1.32 (m, 1H). Schematization of the Preparation of Intermediates 1-51 through 1-53

Intermediate 1-9 Intermediate 1-51 Intermediate 1-52

Intermediate 1-53 Preparation of Intermediate 1-51 (2-((2S)-1-(7-(Benzyloxy)-2’-(methylthio)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile) Intermediate 1-9 ((7’-benzyloxy-2-methylsulfanyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-tetralin]-4-yl) trifluoromethanesulfonate; 196.2mg, 0.3600 mmol) was dissolved in anhydrous DMF (2 mL) and treated with iPr2EtN (188µL, 1.08mmol) and (S)- 2-(4-Tritylpiperazin-2-yl)acetonitrile (144mg, 0.392mmol) then heated to 50 °C overnight. The mixture was diluted with EtOAc and washed with half-saturated NaHCO₃ (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→30% EtOAc in hexanes to give: unknown stereoisomer 1 (52.6 mg, 19.2%) as a faintly yellow residue. Rf = 0.38 (8:2 hexanes:EtOAc).¹H NMR (400 MHz, CD3CN) δ 7.60 – 7.37 (m, 5H), 7.37 – 7.23 (m, 12H), 7.23 – 7.13 (m, 3H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.71 (dd, J = 8.4, 2.6 Hz, 1H), 5.04 – 4.89 (m, 1H), 4.64 – 4.54 (m, 1H), 3.75 – 3.59 (m, 1H), 3.54 – 3.28 (m, 2H), 3.16 – 3.06 (m, 1H), 3.05 – 2.78 (m, 3H), 2.75 (d, J = 2.0 Hz, 1H), 2.73 – 2.51 (m, 4H), 2.47 – 2.30 (m, 4H), 2.16 (s, 1H), 1.92 – 1.84 (m, 1H), 1.76 – 1.49 (m, 6H); and unknown stereoisomer 2 (68.0mg, 24.8%) as a faintly yellow residue. Rf = 0.33 (8:2 hexanes:EtOAc). ¹H NMR (400 MHz, CD3CN) δ 7.64 – 7.38 (m, 5H), 7.36 – 7.21 (m, 12H), 7.21 – 7.14 (m, 3H), 6.93 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 6.69 (dd, J = 8.4, 2.6 Hz, 1H), 4.97 – 4.87 (m, 2H), 4.39 – 4.31 (m, 1H), 3.73 – 3.62 (m, 1H), 3.59 – 3.25 (m, 3H), 3.17 – 2.86 (m, 2H), 3.19 – 2.76 (m, 2H), 2.73 – 2.60 (m, 3H), 2.60 – 2.45 (m, 1H), 2.39 (s, 3H), 2.32 – 2.19 (m, 1H), 1.92 – 1.81 (m, 1H), 1.77 – 1.57 (m, 4H), 1.57 – 1.45 (m, 2H). Preparation of Intermediate 1-52 (2-((2S)-1-(7-(Benzyloxy)-2’-(methylsulfinyl)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile, Stereoisomer 1) Intermediate 1-51 (2-((2S)-1-(7-(benzyloxy)-2’-(methylthio)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2-yl)acetonitrile, stereoisomer 1; 52.6mg, 0.0700 mmol) was dissolved in DCM (700µL) and treated with mCPBA (21.3mg, 0.0617mmol) at 0 °C. After 10min, the mixture was diluted with Et₂O and washed with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (54.4mg, quant.) as a white foam. Preparation of Intermediate 1-53 (2-((2S)-1-(7-(Benzyloxy)-2’-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4- tritylpiperazin-2-yl)acetonitrile, Stereoisomer 1) Intermediate 1-52 (2-((2S)-1-(7-(Benzyloxy)-2’-(methylsulfinyl)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile, stereoisomer 1; 26.5mg, 0.0338mmol) and [(2S)-1-methylpyrrolidin-2- yl]methanol (7.8mg, 0.068mmol) were dissolved in anhydrous THF (250µL) and cooled to - 40 °C then KotBu, 1M in THF (44µL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→100% EtOAc+2% Et₃N in hexanes+2% Et₃N to give the title compound (22.4mg, 79.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 835.4 m/z. Preparation of Compound 1-78 (2-((2S)-1-(7-Hydroxy-2’-(((S)-1-methylpyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazin-2-yl)acetonitrile, Stereoisomer 1) Step1. Intermediate 1-53 (2-((2S)-1-(7-(benzyloxy)-2’-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4- tritylpiperazin-2-yl)acetonitrile, stereoisomer 1; 22.4mg, 0.0268mmol) was dissolved in MeOH (300µL) and THF (300µL) and treated with Pd/C, 10% (wetted) (50mg) and the mixture was gently sparged with H₂ for 5min then positive pressure maintained with a balloon. After 1.5hr, the mixture was filtered through Celite rinsing with THF and concentrated to give 2-((2S)-1-(7-hydroxy-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile, Stereoisomer 1 (19.4mg, 97.1%) as a white powdery residue. LC/MS, ESI [M+H]⁺ = 745.4 m/z. Step 2. 2-((2S)-1-(7-Hydroxy-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile stereoisomer 1 (19.4mg, 0.0260mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et2O and the aqueous phase was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate) salt (17.9mg, 94.1%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 503.3 m/z.¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 6.59 (dd, J = 8.3, 2.1 Hz, 1H), 5.15 – 5.07 (m, 1H), 4.89 – 4.83 (m, 1H), 4.66 (dd, J = 12.5, 7.3 Hz, 1H), 4.08 (dt, J = 14.8, 3.8 Hz, 1H), 3.97 – 3.88 (m, 1H), 3.84 – 3.39 (m, 6H), 3.36 – 3.16 (m, 2H), 3.10 – 2.96 (m, 5H), 2.96 – 2.83 (m, 2H), 2.79 – 2.68 (m, 3H), 2.49 – 2.36 (m, 1H), 2.25 – 1.98 (m, 4H), 1.91 – 1.66 (m, 5H). Preparation of Compound 1-79 (-((2S)-1-(7-Hydroxy-2’-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazin-2-yl)acetonitrile, Stereoisomer 1) Step 1. Intermediate 1-52 (2-((2S)-1-(7-(benzyloxy)-2’-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4- tritylpiperazin-2-yl)acetonitrile, stereoisomer 1; 27.1mg, 0.0346mmol) and 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (7.3mg, 0.052mmol) were dissolved in anhydrous THF (250µL) and cooled to -40°C then KotBu, 1M in THF (41µL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→100% EtOAc+2% Et3N in hexanes+2% Et3N to give 2-((2S)-1-(7-(benzyloxy)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile, Stereoisomer 1 (21.3mg, 71.6%) as a colorless residue. LC/MS, [ESI M+H]⁺ = 861.4 m/z. Step 2. 2-((2S)-1-(7-(Benzyloxy)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4- tritylpiperazin-2-yl)acetonitrile stereoisomer 1 (21.3mg, 0.0247mmol) was dissolved in MeOH (300µL) and THF (300µL) and treated with Pd/C, 10% (wetted) (65mg). The mixture was gently sparged with H₂ for 5min then positive pressure maintained with a balloon. After 1hr, additional Pd/C, 10% (wetted) (35mg) was added. After an additional 1hr, the mixture was filtered through Celite and concentrated to give 2-((2S)-1-(7-hydroxy-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2-yl)acetonitrile, Stereoisomer 1 (16.4mg, 86.0%) as a colorless film. LC/MS, ESI [M+H]⁺ = 771.3 m/z. Step 3. 2-((2S)-1-(7-Hydroxy-2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-4-tritylpiperazin-2- yl)acetonitrile stereoisomer 1 (16.4mg, 0.0213mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 60min. The mixture was diluted with H₂O and washed with Et2O and the aqueous phase was purified by preparative HPLC to give the title compound as its bis(trifluoroacetate (11.6mg, 72.1%) as a colorless film. LC/MS, ESI [M+H]⁺ = 529.3 m/z. ¹H NMR (400 MHz, MeOD) δ 6.92 (d, J = 8.3 Hz, 1H), 6.72 – 6.67 (m, 1H), 6.61 – 6.56 (m, 1H), 5.03 – 4.82 (m, 1H), 4.72 – 4.55 (m, 1H), 4.20 – 3.92 (m, 1H), 3.75 – 3.37 (m, 7H), 3.30 – 3.13 (m, 4H), 3.09 – 2.98 (m, 2H), 2.96 – 2.80 (m, 2H), 2.79 – 2.68 (m, 3H), 2.38 – 2.05 (m, 9H), 1.92 – 1.64 (m, 5H). Schematization of the Preparation of Intermediates 1-26 through 1-33

Intermediate 1-26

Intermediate 1-27 Intermediate 1-28

Intermediate 1-29 Intermediate 1-30

Intermediate 1-31 Intermediate 1-32 Intermediate 1-33 Preparation of Intermediate 1-26 (2-(3,4-Dihydronaphthalen-1(2H)-ylidene)malononitrile) Tetralin-1-one (10.0g, 68.4mmol), malononitrile (5.87g, 88.9mmol), NH4Oac (1.05g, 13.7mmol), and AcOH (4.9mL, 85.5 mmol) were dissolved in toluene (50 mL) and heated to reflux on a Dean-Stark apparatus under N₂. After 2hrs, the mixture was cooled, diluted with EtOAc, and washed with water (x2), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, and concentrated to give the title compound (12.346g, 92.9%) as a tan colored crystalline solid. Rf = 0.31 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 195.1 m/z. Preparation of Intermediate 1-27 (2-(1-(Pent-4-en-1-yl)-1,2,3,4-tetrahydronaphthalen-1- yl)malononitrile) A flame-dried 500mL round bottom flask was charged with CuBr•Me2S (1.31g, 6.36mmol) and evacuated and backfilled with N₂ (x3). Anhydrous THF (50mL) was added and the mixture was cooled to -40 °C and pent-4-en-1-ylmagnesium bromide, 0.5M in THF (216mL) was added via cannula. The resulting mixture was stirred for 15min then Intermediate 1-26 (2-(3,4-Dihydronaphthalen-1(2H)-ylidene)malononitrile) (12.35g, 63.6mmol) was added as a solution in anhydrous THF (75mL). The mixture was stirred for 3hrs then allowed to warm to rt and quenched with sat NH4Cl. The mixture was diluted with EtOAc and the organic phase was collected and washed sequentially with sat NH₄C1, brine, dried over Na₂SO₄, filtered, and concentrated. The residue was suspended in 85:15 hexanes:EtOAc and filtered through a thin pad of silica gel. The filtrate was concentrated to give the title compound (16.69 g, 99.3%) as a yellow colored viscous oil. LC/MS, ESI [M- H]- = 263.2. Preparation of Intermediate 1-28 (Methyl 2-(1-(pent-4-en-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl)acetate) Intermediate 1-27 (2-(1-(Pent-4-en-1-yl)-1,2,3,4-tetrahydronaphthalen-1- yl)malononitrile) (16.69g, 63.13mmol) was treated with ethylene glycol (63mL), H₂O (27mL), and KOH (62.5g, 947mmol) and the mixture was heated to 190 °C under N₂ for 30hrs. The mixture was cooled slightly and poured into chipped ice containing H₂SO₄ and extracted with EtOAc (x3). The combined extract was washed with brine (x2), dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 3N HCl in MeOH (140mL) and heated to 50°C for 3hrs. The mixture was concentrated and co-evaporated from toluene then taken up in 85:15 hexanes:EtOAc and filtered through a thin pad of silica, and concentrated to give the title compound (15.47g, 90.0%) as a faintly orange oil. Rf = 0.51 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 273.2 m/z. Preparation of Intermediate 1-29 (Methyl 2-(1-(4-oxobutyl)-1,2,3,4-tetrahydronaphthalen- 1-yl)acetate) Intermediate 1-28 (methyl 2-(1-(pent-4-en-1-yl)-1,2,3,4-tetrahydronaphthalen-1- yl)acetate) (15.47g, 56.8mmol) was dissolved in DCM (350mL) and cooled to -78 °C then ozone was passed through the solution for 50min. Ozone introduction was then stopped and the mixture was sparged vigorously with N2 for approximately 10min and PPh3 (19.37g, 73.8mmol) was added and the mixture was allowed to warm to rt and stirred overnight. The mixture was filtered through a pad of silica gel rinsing with 100% DCM and the filtrate was purified by flash column chromatography on silica gel eluted with 0→25% EtOAc in hexanes to give the title compound (12.701g, 81.5%) as a colorless oil. LC/MS, ESI [M+H]⁺ = 275.2 m/z.¹H NMR (400 MHz, Chloroform-d) δ 9.69 (td, J = 1.7, 0.5 Hz, 1H), 7.19 (dd, J = 7.7, 1.8 Hz, 1H), 7.15 – 7.03 (m, 3H), 3.57 (s, 3H), 2.83 – 2.73 (m, 2H), 2.69 (d, J = 13.9 Hz, 1H), 2.56 (d, J = 13.9 Hz, 1H), 2.38 (td, J = 7.3, 1.7 Hz, 2H), 2.07 – 1.97 (m, 1H), 1.92 (ddd, J = 13.8, 12.5, 4.4 Hz, 1H), 1.86 – 1.77 (m, 3H), 1.72 (ddd, J = 13.8, 12.4, 4.5 Hz, 1H), 1.64 – 1.48 (m, 1H), 1.46 – 1.30 (m, 1H).¹³C NMR (101 MHz, CDCl3) δ 202.50, 172.15, 141.30, 137.50, 129.56, 126.57, 126.03, 126.00, 51.39, 46.57, 44.39, 40.46, 39.82, 32.07, 30.44, 19.43, 17.26. Preparation of Intermediate 1-30 (Methyl 4-(1-(2-methoxy-2-oxoethyl)-1,2,3,4- tetrahydronaphthalen-1-yl)butanoate) Intermediate 1-29 (methyl 2-(1-(4-oxobutyl)-1,2,3,4-tetrahydronaphthalen-1- yl)acetate) (12.7g, 46.3mmol) was dissolved in tert-butanol (46mL) and treated with H₂O (46 mL), NaClO₂ (12.56g, 138.9mmol), and 2-methyl-2-butene (24.5mL, 231mmol) then cooled to 0 °C and amended with KH₂PO₄ (22.65g, 138.9mmol). After 40min, the mixture was poured into aq NaHSO4 and extracted with EtOAc (x2). The combined extract was washed with aq Na₂S₂O₃, brine, dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 3N HCl in MeOH (160mL) and heated to 50°C for 2.5hr. The mixture was concentrated, co-evaporated from toluene once, purified by flash column chromatography on silica gel eluted with 0→30% EtOAc in hexanes to give the title compound (12.562g, 89.1%) as a colorless oil. Rf = 0.31 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 305.2 m/z.¹H NMR (400 MHz, CDCl3) δ 7.24 – 7.17 (m, 1H), 7.17 – 7.01 (m, 3H), 3.63 (s, 3H), 3.56 (s, 3H), 2.79 – 2.73 (m, 2H), 2.70 (d, J = 14.0 Hz, 1H), 2.55 (d, J = 14.0 Hz, 1H), 2.25 (ddd, J = 8.1, 7.2, 1.2 Hz, 2H), 2.12 – 1.76 (m, 5H), 1.69 (ddd, J = 13.7, 12.4, 4.4 Hz, 1H), 1.62 – 1.47 (m, 1H), 1.45 – 1.32 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 173.98, 172.15, 141.43, 137.44, 129.47, 126.61, 125.94 (2), 51.55, 51.33, 46.55, 40.56, 39.73, 34.49, 31.98, 30.44, 20.04, 19.43. Preparation of Intermediate 1-31 (methyl 3-oxo-3’,4’-dihydro-2’H-spiro[cyclohexane-1,1’- naphthalene]-4-carboxylate) NaH (4.06g, 102mmol) was suspended in anhydrous toluene (85mL) and treated with MeOH (680µL) then warmed to 70 °C. Intermediate 1-30 (methyl 4-(1-(2-methoxy-2- oxoethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)butanoate) (10.3g, 33.9mmol) was then added dropwise over approximately 90min as a solution in anhydrous toluene (85mL) containing additional MeOH (680µL) and heating was continued for 14.5hrs. The mixture was poured into sat NH4C1, the organic phase was collected, and the aqueous was extracted with EtOAc once. The combined extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (11.08g, >100%) as a faintly yellow oil which was used without purification. Preparation of Intermediate 1-32 (2’-(Methylthio)-3,4,5’,8’-tetrahydro-2H,3’H- spiro[naphthalene-1,7’-quinazolin]-4’(6’H)-one) Intermediate 1-31 (methyl 3-oxo-3’,4’-dihydro-2’H-spiro[cyclohexane-1,1’- naphthalene]-4-carboxylate) (9.22g, 33.9mmol) was dissolved in anhydrous MeCN (110mL) and treated with thiourea (3.09g, 40.6mmol) and DBU (5.1mL, 34.2mmol) and the mixture was heated to reflux under N2 for 19hr. Additional thiourea (514mg, 6.75mmol) and DBU (2.5mL, 16.7mmol) was added and the reaction continued for 5hr then cooled to rt and poured into ice cold one-third saturated NaHCO3 and the resulting solids were collected by filtration and washed liberally with H₂O and freed of excess liquid under suction. The material was suspended in warm DMF (250mL), amended with NaOAc (5.55g, 67.7mmol), and cooled to rt. MeI (1.26mL, 20.2mmol) was added. Seven additional charges of MeI (250µL, 4.02mmol) were made over the course of 6hrs at which point the mixture was poured into ice cold one-third saturated NaHCO3 and stirred for 5min then filtered. The cake was slurried with H₂O (x3), 1:1 hexanes:EtOH (x3), and hexanes (x3) and the solids were dried under suction and further dried in vacuo at 50ºC to give the title compound (7.895g, 74.7%) as an off white powder. LC/MS, ESI [M+H]⁺ = 313.1 m/z. Preparation of Intermediate 1-33 (2’-(Methylthio)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) Intermediate 1-32 (2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,3’H-spiro[naphthalene- 1,7’-quinazolin]-4’(6’H)-one) (775mg, 2.48mmol) was suspended in anhydrous DCM (12mL), treated with iPr2EtN (1.1mL, 6.3mmol), cooled to 0°C, and triflic anhydride (542µL, 3.23 mmol) was added dropwise. After 5min, the mixture was diluted with 1vol hexanes and filtered through a pipet column of silica gel rinsing with 8:2 hexanes:EtOAc and concentrated to give the title compound (1.1596g, >100%) as a pale yellow residue. LC/MS, ESI [M+H]⁺ = 445.1 m/z. Schematization of the Preparation of Intermediates 1-34 through 1-36

Intermediate 1-33 Intermediate 1-34 Intermediate 1-35

Intermediate 1-36 Preparation of Intermediate 1-34 (tert-Butyl (1R,5S)-3-(2’-(methylthio)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 1-33 (2’-(Methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) (275.7mg, 0.620mmol) was dissolved in anhydrous DMF (3mL) and treated with iPr2EtN (180µL, 1.55mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (144.9mg, 0.682mmol) at rt. After 12hr, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concenentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (309.2 mg, 98.4%) as a white foam. Rf = 0.41 (8:2 hexanes:EtOAc). [M+H]⁺ = 507.3 m/z. ¹H NMR (400 MHz, Acetonitrile-d3) δ 7.33 – 7.26 (m, 1H), 7.18 – 7.05 (m, 3H), 4.22 (d, J = 3.8 Hz, 2H), 4.04 – 3.97 (m, 1H), 3.58 (ddd, J = 12.6, 2.8, 1.4 Hz, 1H), 3.32 – 3.24 (m, 1H), 3.00 – 2.88 (m, 2H), 2.84 – 2.67 (m, 4H), 2.57 – 2.47 (m, 1H), 2.45 (s, 3H), 2.12 – 1.96 (m, 2H), 1.89 – 1.64 (m, 8H), 1.45 (s, 9H). Preparation of Intermediate 1-35 (tert-Butyl (1R,5S)-3-(2’-(methylsulfinyl)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 1-34 (tert-Butyl (1R,5S)-3-(2’-(methylthio)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate) (309.2mg, 0.610mmol) was dissolved in DCM (3mL) and treated with mCPBA (190mg, 0.550mmol) at 0 °C. After 30min, HPLC analysis showed complete conversion to a single major product showing The mixture was diluted with Et2O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (327mg, 103%) as a white foam. LC/MS, ESI [M+H]⁺ = 523.2 m/z. Preparation of Intermediate 1-36 (tert-Butyl (1R,5S)-3-(2’-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 1-35 (tert-Butyl (1R,5S)-3-(2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate) (131mg, 0.250mmol) was dissolved in anhydrous THF (1.5mL) and cooled to - 40 °C. [(2S)-pyrrolidin-2-yl]methanol (51mg, 0.500mmol) was dissolved in anhydrous THF (1mL) and treated with KotBu, 1M in THF (325µL, 0.330mmol) and the resulting mixture was added dropwise to the reaction. After 10min, the mixture was poured into 10% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (142.8mg, 102%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 560.3 m/z. Preparation of Compound 1-14 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-14 was prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 1-36 instead of Intermediate 1-13, and was obtained (16.9 mg, 82.3%) as a white foam. LC/MS ESI, [M+H]⁺ = 460.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.28 – 7.22 (m, 1H), 7.16 – 7.02 (m, 3H), 4.34 – 4.18 (m, 2H), 4.17 – 4.08 (m, 1H), 3.73 – 3.64 (m, 1H), 3.56 – 3.41 (m, 3H), 3.37 – 3.32 (m, 1H), 3.08 – 2.84 (m, 4H), 2.85 – 2.70 (m, 4H), 2.54 (dt, J = 16.0, 4.8 Hz, 1H), 2.16 – 1.92 (m, 3H), 1.92 – 1.65 (m, 10H), 1.58 (ddt, J = 12.3, 8.8, 7.1 Hz, 1H). Preparation of Compound 1-15 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-15 was prepared following the general procedures used to prepare Compound 1-2 and using Intermediate 1-36 instead of Intermediate 1-13 in step 1, and was obtained (17.4mg, 88.9%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 474.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.25 (d, J = 7.5 Hz, 1H), 7.16 – 7.03 (m, 3H), 4.35 (ddd, J = 10.9, 7.1, 6.0 Hz, 1H), 4.25 (ddd, J = 10.9, 7.8, 5.8 Hz, 1H), 4.17 – 4.08 (m, 1H), 3.69 (ddt, J = 12.4, 3.0, 1.6 Hz, 1H), 3.56 – 3.49 (m, 2H), 3.37 – 3.31 (m, 1H), 3.11 – 2.98 (m, 2H), 2.92 (d, J = 18.4 Hz, 1H), 2.86 – 2.66 (m, 5H), 2.59 – 2.51 (m, 1H), 2.49 (d, J = 0.8 Hz, 3H), 2.33 (q, J = 9.1 Hz, 1H), 2.16 – 1.97 (m, 3H), 1.94 – 1.61 (m, 11H). Preparation of Compound 1-16 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-16 was prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 1-36 instead of Intermediate 1-13 in step 1, and was obtained (16.3mg, 73.8%) as a white foam. LC/MS, ESI [M+H]⁺ = 502.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.15 (dd, J = 7.4, 1.4 Hz, 1H), 7.05 – 6.91 (m, 3H), 4.21 (ddd, J = 10.5, 7.1, 4.7 Hz, 1H), 4.07 – 3.90 (m, 2H), 3.63 – 3.53 (m, 1H), 3.45 – 3.38 (m, 2H), 3.28 – 3.22 (m, 1H), 3.12 (tdd, J = 8.4, 4.8, 3.5 Hz, 1H), 2.97 – 2.61 (m, 8H), 2.55 – 2.37 (m, 2H), 2.06 – 1.87 (m, 2H), 1.86 – 1.55 (m, 12H), 1.06 (d, J = 6.5 Hz, 3H), 0.98 (dd, J = 6.4, 1.7 Hz, 3H). Schematization of the Preparation of Intermediates 1-37 through 1-39

Intermediate 1-33 Intermediate 1-37 Intermediate 1-38

Intermediate 1-39 Preparation of Intermediate 1-37 (tert-Butyl 4-(2’-(methylthio)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 1-33 (2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) (275.7mg, 0.620mmol) was dissolved in anhydrous DMF (3mL) and treated with tert-butyl piperazine-1-carboxylate (127.1mg, 0.682mmol) and iPr₂EtN (180µL, 1.55mmol) and stirred overnight. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel (12g) eluted with 0→40% EtOAc in hexanes to give the title compound (296.5mg, 99.4%) as a white foam. Rf = 0.40 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]+ = 481.3 m/z. ¹H NMR (400 MHz, Acetonitrile-d3) δ 7.33 – 7.26 (m, 1H), 7.18 – 7.06 (m, 3H), 3.58 – 3.38 (m, 6H), 3.34 – 3.23 (m, 2H), 2.91 (s, 1H), 2.84 – 2.65 (m, 4H), 2.56 – 2.44 (m, 4H), 2.12 – 2.02 (m, 1H), 1.91 – 1.64 (m, 5H), 1.44 (s, 9H). Preparation of Intermediate 1-38 (tert-Butyl 4-(2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 1-37 (tert-butyl 4-(2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) (296.5mg, 0.617mmol) was dissolved in DCM (3.0mL) and treated with mCPBA (192mg, 0.556mmol) at 0 °C. After 35min, the mixture was diluted with Et₂O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (306.9 mg, 100%) as a white foam. LC/MS, ESI [M+H]⁺ = 497.2 m/z. Preparation of Intermediate 1-39 (tert-Butyl 4-(2’-(((S)-pyrrolidin-2-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 1-38 (tert-butyl 4-(2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) (124.2mg, 0.250mmol) was dissolved in anhydrous THF (0.5mL) and cooled to -40 °C. [(2S)- Pyrrolidin-2-yl]methanol (50.6mg, 0.500mmol) was dissolved in anhydrous THF (0.75mL) and treated with KotBu, 1M in THF (250µL) and the resulting mixture was added dropwise to the reaction. After 5min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (141 mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 534.3 m/z. Preparation of Compound 1-17 (4’-(piperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]) Compound 1-17 was prepared following the general procedures used to prepare Compound 1-4 and using Intermediate 1-39 instead of Intermediate 1-17, and was obtained (15.9 mg, 78.3%) as a white foam. LC/MS ESI, [M+H]⁺ = 434.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.25 (d, J = 8.0 Hz, 1H), 7.16 – 7.02 (m, 3H), 4.32 – 4.20 (m, 2H), 3.56 (ddd, J = 13.3, 6.9, 3.3 Hz, 2H), 3.51 – 3.43 (m, 1H), 3.39 (ddd, J = 13.1, 6.8, 3.2 Hz, 2H), 3.03 – 2.93 (m, 3H), 2.93 – 2.85 (m, 4H), 2.85 – 2.69 (m, 4H), 2.53 (dt, J = 16.1, 4.8 Hz, 1H), 2.17 – 2.04 (m, 1H), 1.97 (dtd, J = 12.4, 7.9, 5.1 Hz, 1H), 1.90 – 1.66 (m, 7H), 1.58 (ddt, J = 12.3, 8.9, 7.1 Hz, 1H). Preparation of Compound 1-18 (2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4’-(piperazin-1- yl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]) Compound 1-18 was prepared following the general procedures used to prepare Compound 1-5 and using Intermediate 1-39 instead of Intermediate 1-17 in step 1, and was obtained (15.3mg, 70.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 448.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.25 (dd, J = 7.3, 1.3 Hz, 1H), 7.16 – 7.02 (m, 3H), 4.36 (ddd, J = 11.0, 8.0, 6.1 Hz, 1H), 4.26 (ddd, J = 10.9, 9.2, 5.8 Hz, 1H), 3.56 (ddd, J = 13.3, 7.0, 3.3 Hz, 2H), 3.40 (ddd, J = 13.1, 6.8, 3.3 Hz, 2H), 3.06 (ddd, J = 9.5, 5.8, 3.6 Hz, 1H), 2.98 (ddd, J = 12.5, 6.8, 3.1 Hz, 2H), 2.93 – 2.67 (m, 8H), 2.53 (ddd, J = 16.3, 5.1, 3.6 Hz, 1H), 2.49 (d, J = 1.0 Hz, 3H), 2.33 (q, J = 9.0 Hz, 1H), 2.15 – 2.01 (m, 2H), 1.93 – 1.61 (m, 8H). Preparation of Compound 1-19 (2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-4’- (piperazin-1-yl)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]) Compound 1-19 was prepared following the general procedures used to prepare Compound 1-6 and using Intermediate 1-39 instead of Intermediate 1-17 in step 1, and was obtained (17.2mg, 81.0%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 476.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 7.25 (d, J = 7.5 Hz, 1H), 7.16 – 7.02 (m, 3H), 4.34 (ddd, J = 11.9, 10.6, 4.7 Hz, 1H), 4.05 (ddd, J = 11.8, 10.6, 8.3 Hz, 1H), 3.62 – 3.50 (m, 2H), 3.38 (ddd, J = 13.1, 6.8, 3.2 Hz, 2H), 3.22 (tq, J = 7.0, 3.4 Hz, 1H), 3.09 – 2.68 (m, 11H), 2.65 – 2.46 (m, 2H), 2.10 (ddd, J = 13.1, 10.4, 5.1 Hz, 1H), 1.96 – 1.66 (m, 9H), 1.16 (dd, J = 6.6, 1.7 Hz, 3H), 1.08 (dd, J = 6.4, 2.0 Hz, 3H). Schematization of the Preparation of Intermediates 1-40 through 1-42

Intermediate 1-38 Intermediate 1-40 Intermediate 1-41

Intermediate 1-42 Preparation of Intermediate 1-40 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(methylthio)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) Intermediate 1-38 (2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) (275.7mg, 0.620mmol) was dissolved in anhydrous DMF (3.1mL) and treated with 2-[(2S)-piperazin-2-yl]acetonitrile dihydrochloride (135.2mg, 0.682mmol) and iPr2EtN (252µL, 2.17mmol) at rt. After 30min Boc₂O (203.1mg, 0.930mmol) was added and the mixture was stirred for 10hrs then diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (339.7mg, >100%) as an off-white foam. Rf = 0.27 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 520.3 m/z.¹H NMR (400 MHz, Acetonitrile-d3) δ 7.37 – 7.24 (m, 1H), 7.19 – 7.06 (m, 3H), 4.66 – 4.52 (m, 1H), 4.02 – 3.71 (m, 3H), 3.15 – 2.49 (m, 11H), 2.47 (s, 3H), 2.13 – 2.02 (m, 1H), 1.92 – 1.54 (m, 5H), 1.49 – 1.38 (m, 9H). Preparation of Intermediate 1-41 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) Intermediate 1-40 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(methylthio)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) (322.4mg, 0.620mmol) was dissolved in DCM (3.1mL) and treated with mCPBA (193mg, 0.559mmol) at 0 °C. After 30min, the mixture was diluted with Et2O and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (328mg, 98.7%) as a white foam. LC/MS, ESI [M+H]⁺ = 536.3 m/z. Preparation of Intermediate 1-42 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(((S)-pyrrolidin-2- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazine-1-carboxylate) Intermediate 1-41 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) (134mg, 0.250mmol) was dissolved in anhydrous THF (0.75mL) and cooled to - 40 °C. [(2S)-pyrrolidin-2-yl]methanol (50.6mg, 0.500mmol) was dissolved in anhydrous THF (0.5mL) and treated with KotBu, 1M in THF (330µL) and the resulting mixture was added dropwise to the reaction. After 5min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (160.3mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 573.3 m/z. Preparation of Compound 1-20 (2-((2S)-4-(2’-(((S)-Pyrrolidin-2-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile) Compound 1-20 was prepared following the general procedures used to prepare Compound 1-7 and using Intermediate 1-42 instead of Intermediate 1-21, and was obtained (10.8mg, 52.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 473.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.28 – 7.23 (m, 1H), 7.15 – 7.09 (m, 1H), 7.08 – 7.04 (m, 2H), 4.33 – 4.22 (m, 2H), 4.21 – 3.78 (m, 2H), 3.54 – 3.40 (m, 1H), 3.29 – 2.70 (m, 12H), 2.65 (ddd, J = 9.5, 6.8, 1.9 Hz, 2H), 2.61 – 2.51 (m, 1H), 2.21 – 2.05 (m, 1H), 2.03 – 1.66 (m, 8H), 1.59 (ddt, J = 11.5, 7.4, 2.4 Hz, 1H). Preparation of Compound 1-21 (2-((2S)-4-(2’-(((S)-1-Methylpyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazin-2- yl)acetonitrile) Compound 1-21 was prepared following the general procedures used to prepare Compound 1-8 and using Intermediate 1-42 instead of Intermediate 1-21 in step 1, and was obtained (10.2 mg, 51.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 487.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.29 – 7.21 (m, 1H), 7.18 – 7.03 (m, 3H), 4.38 (ddd, J = 11.0, 6.2, 1.9 Hz, 1H), 4.28 (ddd, J = 11.0, 5.6, 2.3 Hz, 1H), 4.18 – 3.77 (m, 2H), 3.30 – 3.17 (m, 1H), 3.15 – 3.00 (m, 3H), 2.99 – 2.90 (m, 2H), 2.90 – 2.69 (m, 6H), 2.68 – 2.63 (m, 2H), 2.60 – 2.51 (m, 1H), 2.50 (d, J = 1.5 Hz, 3H), 2.39 – 2.28 (m, 1H), 2.18 – 2.00 (m, 2H), 1.93 – 1.64 (m, 8H). Preparation of Compound 1-22 (2-((2S)-4-(2’-(((S)-1-Isopropylpyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazin-2- yl)acetonitrile) Compound 1-22 was prepared following the general procedures used to prepare Compound 1-9 and using Intermediate 1-42 instead of Intermediate 1-21 in step 1, and was obtained (11.5mg, 53.7%) as a white foam. LC/MS, ESI [M+H^]+ = 515.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 7.30 – 7.21 (m, 1H), 7.15 – 7.02 (m, 3H), 4.35 (ddd, J = 11.0, 6.3, 4.8 Hz, 1H), 4.12 – 3.75 (m, 3H), 3.28 – 3.15 (m, 2H), 3.13 – 2.70 (m, 11H), 2.69 – 2.50 (m, 4H), 2.18 – 2.05 (m, 1H), 1.97 – 1.63 (m, 9H), 1.17 (dd, J = 6.6, 1.2 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H). Schematization of the Preparation of Intermediates 1-43 through 1-45

Intermediate 1-38 Intermediate 1-43 Intermediate 1-44

Intermediate 1-45 Preparation of Intermediate 1-43 (Allyl (1R,5S)-8-(2’-(Methylthio)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) Intermediate 1-38 (2’-(methylthio)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) (275.7mg, 0.620mmol) was dissolved in anhydrous DMF (3mL) and treated with allyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (133.9mg, 0.682mmol) and iPr₂EtN (0.18mL, 1.55mmol) at rt for 11hr. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (241.5mg, 79.3%) as a white foam. Rf = 0.34 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 491.2 m/z.¹H NMR (400 MHz, Acetonitrile-d3) δ 7.35 – 7.28 (m, 1H), 7.18 – 7.05 (m, 3H), 5.96 (ddt, J = 17.4, 10.6, 5.3 Hz, 1H), 5.29 (dq, J = 17.4, 1.8 Hz, 1H), 5.19 (dq, J = 10.6, 1.5 Hz, 1H), 4.72 – 4.68 (m, 1H), 4.60 – 4.48 (m, 3H), 3.80 (d, J = 12.6 Hz, 2H), 3.48 – 3.29 (m, 1H), 3.19 – 2.99 (m, 1H), 2.98 – 2.89 (m, 1H), 2.83 – 2.67 (m, 4H), 2.61 – 2.50 (m, 1H), 2.45 (s, 3H), 2.16 – 1.99 (m, 2H), 1.90 – 1.62 (m, 8H). Preparation of Intermediate 1-44 (Allyl (1R,5S)-8-(2’-(Methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) Intermediate 1-43 (allyl (1R,5S)-8-(2’-(Methylthio)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate) (241.5mg, 0.492mmol) was dissolved in DCM (2.5mL) and treated with mCPBA (153mg, 0.443mmol) at 0 °C. After 35min, the mixture was diluted with Et₂O and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (245mg, 98.2%) as a white foam. LC/MS, ESI [M+H]⁺ = 507.2 m/z. Preparation of Intermediate 1-45 (Allyl (1R,5S)-8-(2’-(((S)-pyrrolidin-2-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 1-44 (allyl (1R,5S)-8-(2’-(Methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) (127mg, 0.251mmol) was dissolved in anhydrous THF (0.75mL) and cooled to - 40 °C. [(2S)-Pyrrolidin-2-yl]methanol (50.7mg, 0.501mmol) was dissolved in anhydrous THF (0.5mL) and treated with KotBu, 1M in THF (251µL) and the resulting solution was added dropwise to the reaction. After 5min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give the title compound (143.9 mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 544.3 m/z. Preparation of Compound 1-23 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-23 was prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 1-45 instead of Intermediate 1-25, and was obtained (8.9 mg, 42.1%). LC/MS, ESI [M+H]⁺ = 460.3 m/z.¹H NMR (400 MHz, Methanol- d₄) δ 7.28 (d, J = 7.8 Hz, 1H), 7.16 – 7.04 (m, 3H), 4.69 (d, J = 6.4 Hz, 1H), 4.55 (d, J = 5.8 Hz, 1H), 4.31 – 4.17 (m, 2H), 3.47 (qd, J = 7.4, 5.3 Hz, 1H), 3.20 (dt, J = 12.8, 2.1 Hz, 1H), 3.04 – 2.83 (m, 4H), 2.83 – 2.75 (m, 3H), 2.75 – 2.67 (m, 3H), 2.57 (ddd, J = 16.0, 5.6, 3.3 Hz, 1H), 2.21 – 2.06 (m, 2H), 2.06 – 1.91 (m, 4H), 1.92 – 1.65 (m, 7H), 1.64 – 1.52 (m, 1H). Preparation of Compound 1-24 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-24 was prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 1-45 instead of Intermediate 1-25 in step 1, and was obtained (13.4mg, 76.6%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 474.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.28 (d, J = 7.4 Hz, 1H), 7.17 – 7.02 (m, 3H), 4.69 (d, J = 6.8 Hz, 1H), 4.59 – 4.52 (m, 1H), 4.33 (ddd, J = 10.9, 7.5, 6.1 Hz, 1H), 4.23 (ddd, J = 11.0, 8.4, 5.9 Hz, 1H), 3.22 (dt, J = 12.8, 2.4 Hz, 1H), 3.06 (dt, J = 9.5, 4.5 Hz, 1H), 2.98 – 2.88 (m, 2H), 2.83 – 2.77 (m, 3H), 2.76 – 2.66 (m, 4H), 2.57 (ddd, J = 16.0, 5.5, 3.3 Hz, 1H), 2.48 (s, 3H), 2.33 (q, J = 9.0 Hz, 1H), 2.20 – 1.93 (m, 6H), 1.92 – 1.61 (m, 8H). Preparation of Compound 1-25 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’- quinazoline]) Compound 1-25 was prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 1-45 instead of Intermediate 1-25 in step 1, and was obtained (15.3mg, 80.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 502.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 7.27 (d, J = 7.4 Hz, 1H), 7.15 – 7.08 (m, 1H), 7.08 – 7.03 (m, 2H), 4.73 – 4.65 (m, 1H), 4.55 (d, J = 5.4 Hz, 1H), 4.29 (ddd, J = 10.6, 4.8, 2.8 Hz, 1H), 4.05 (ddd, J = 10.9, 8.3, 2.9 Hz, 1H), 3.21 (ddd, J = 12.4, 4.1, 2.1 Hz, 2H), 3.08 – 2.87 (m, 4H), 2.86 – 2.65 (m, 6H), 2.65 – 2.51 (m, 2H), 2.20 – 1.64 (m, 14H), 1.16 (dd, J = 6.5, 1.0 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H). Preparation of Compound 1-26 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-7-ol) Step 1. Intermediate 1-11 (tert-Butyl 4-(7-(benzyloxy)-2’-(methylsulfinyl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) (21.0mg, 0.0334mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (7.1mg, 0.050mmol) were dissolved in anhydrous THF (250µL) and cooled to - 40°C then KotBu, 1M in THF (40µL) was added dropwise. After 15min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 55→0% hexanes then 0→10% MeOH in DCM+2%Et₃N to give tert-Butyl (1R,5S)-3-(7-(benzyloxy)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’- tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (19.6mg, 83.1%) as a white foam. LC/MS, ESI [M+H]⁺ = 706.4 m/z. Step 2. Tert-Butyl (1R,5S)-3-(7-(benzyloxy)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (19.6mg, 0.0278mmol) was dissolved in Methanol (300µL) and treated with Pd/C, 10% (wetted) (15mg) and the mixture was gently sparged with H₂. After 30min, a second charge of Pd/C, 10% (wetted) (15mg) was added. After an additional 60min, the mixture was filtered through Celite and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min then concentrated, dissolved in H₂O, and purified by preparative HPLC to give the title compound as its trifluoroacetate salt (18.0mg, 87.2%) as a white powder. LC/MS, ESI [M+H]⁺ = 516.2 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 6.92 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.4 Hz, 1H), 4.82 (dt, J = 14.5, 2.6 Hz, 1H), 4.68 (s, 2H), 4.39 (dt, J = 14.1, 2.5 Hz, 1H), 4.21 (dt, J = 12.5, 2.9 Hz, 2H), 3.81 (dd, J = 14.2, 1.8 Hz, 1H), 3.69 (dt, J = 11.6, 6.7 Hz, 2H), 3.52 (d, J = 13.1 Hz, 1H), 3.30 – 3.23 (m, 1H), 3.02 (d, J = 19.1 Hz, 1H), 2.97 – 2.84 (m, 2H), 2.79 – 2.60 (m, 3H), 2.38 – 1.97 (m, 14H), 1.95 – 1.65 (m, 5H). Preparation of Compound 1-27 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2’- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-7-ol) Compound 1-27 was prepared following the general procedures used to prepare Compound 1-26 and using [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol instead of 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol in step 1, and was obtained as its trifluoroacetate salt (33.4mg, 98.2%) as a white powder. LC/MS, ESI [M+H]+ = [M+H]⁺ = 634.3 m/z.¹H NMR (400 MHz, Methanol-d4) δ 6.92 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.4 Hz, 1H), 5.57 (dt, J = 51.0, 3.1 Hz, 1H), 4.92 – 4.86 (m, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.71 (d, J = 11.9 Hz, 1H), 4.43 (dt, J = 14.1, 2.6 Hz, 1H), 4.26 – 4.17 (m, 2H), 4.01 – 3.80 (m, 4H), 3.55 (d, J = 13.9 Hz, 1H), 3.45 (td, J = 10.8, 6.1 Hz, 1H), 3.02 (d, J = 19.0 Hz, 1H), 2.98 – 2.85 (m, 2H), 2.79 – 2.54 (m, 5H), 2.49 – 1.95 (m, 9H), 1.94 – 1.65 (m, 5H).¹⁹F NMR (376 MHz, Methanol-d₄) δ -77.02, -174.27, -174.28. Preparation of Compound 1-28 (2-((2S)-4-(7-Hydroxy-2’-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazin-2-yl)acetonitrile) Compound 1-28 was prepared following the general procedures used to prepare Compound 1-26 and using Intermediate 1-19 instead of Intermediate 1-11 in step 1, and was obtained as its trifluoroacetate salt (40.7mg, 99.1%) as a colorless film. LC/MS, ESI [M+H]⁺ = 529.2 m/z.¹H NMR (400 MHz, Methanol-d4) δ 6.93 (d, J = 8.8 Hz, 1H), 6.72 (dd, J = 17.3, 2.5 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 4.87 – 4.52 (m, 4H), 4.09 – 3.77 (m, 3H), 3.74 – 3.62 (m, 2H), 3.62 – 3.42 (m, 2H), 3.32 – 3.24 (m, 2H), 3.23 – 2.84 (m, 5H), 2.79 – 2.60 (m, 3H), 2.43 – 2.30 (m, 2H), 2.28 – 2.03 (m, 7H), 1.86 (td, J = 10.4, 5.3 Hz, 5H). Preparation of Compound 1-29 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-7-ol) Compound 1-29 was prepared following the general procedures used to prepare Compound 1-26 and using Intermediate 1-24 instead of Intermediate 1-11 in step 1, and was obtained as its trifluoroacetate salt (22.3mg, 36.3%) as a colorless film. LC/MS, ESI [M+H]⁺ = 516.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 6.93 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 6.60 (dd, J = 8.3, 2.5 Hz, 1H), 5.32 (dd, J = 45.0, 7.0 Hz, 2H), 4.74 (d, J = 11.8 Hz, 1H), 4.70 (d, J = 11.8 Hz, 1H), 3.74 – 3.62 (m, 3H), 3.47 (dd, J = 13.1, 2.3 Hz, 1H), 3.39 (ddd, J = 12.9, 5.2, 2.2 Hz, 2H), 3.29 – 3.23 (m, 1H), 3.03 (d, J = 18.5 Hz, 1H), 2.94 – 2.80 (m, 2H), 2.78 – 2.64 (m, 3H), 2.47 – 2.06 (m, 14H), 1.91 – 1.79 (m, 3H), 1.78 – 1.64 (m, 2H). Preparation of Compound 1-30 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline]) Intermediate 1-35 (tert-Butyl (1R,5S)-3-(2’-(methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate) (26.8mg, 0.0513mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (11.mg, 0.078mmol) were dissolved in anhydrous THF (300µL) and cooled to 0°C, then KotBu, 1M in THF (62µL) was added dropwise. After 40min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then concentrated, dissolved in H₂O, then washed with Et₂O (x2). The aqueous phase was purified by preparative HPLC to give the title compound (20.6 mg, 80.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 500.2 m/z.¹H NMR (400 MHz, Methanol- d₄) δ 7.24 (d, J = 7.4 Hz, 1H), 7.15 – 7.01 (m, 3H), 4.18 – 4.03 (m, 3H), 3.74 – 3.66 (m, 1H), 3.56 – 3.45 (m, 2H), 3.37 – 3.28 (m, 1H), 3.10 – 2.98 (m, 3H), 2.91 (d, J = 18.5 Hz, 1H), 2.84 – 2.71 (m, 4H), 2.67 (dt, J = 10.4, 6.5 Hz, 2H), 2.54 (dt, J = 16.1, 4.9 Hz, 1H), 2.13 – 1.97 (m, 4H), 1.95 – 1.64 (m, 14H). Preparation of Compound 1-31 (4’-(Piperazin-1-yl)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazoline]) Compound 1-31 was prepared following the general procedures used to prepare Compound 1-30 and using Intermediate 1-38 instead of Intermediate 1-35, and was obtained (18.8mg, 69.7%) as a white foam. LC/MS, ESI [M+H]⁺ = 474.2 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 7.25 (d, J = 7.3 Hz, 1H), 7.16 – 7.02 (m, 3H), 4.12 (d, J = 10.4 Hz, 1H), 4.08 (d, J = 10.5 Hz, 1H), 3.56 (ddd, J = 13.3, 7.0, 3.2 Hz, 2H), 3.39 (ddd, J = 13.1, 6.8, 3.2 Hz, 2H), 3.05 (dt, J = 10.4, 6.0 Hz, 2H), 3.01 – 2.93 (m, 2H), 2.93 – 2.71 (m, 7H), 2.67 (dt, J = 10.5, 6.5 Hz, 2H), 2.58 – 2.48 (m, 1H), 2.10 (ddd, J = 13.1, 10.9, 5.2 Hz, 1H), 2.05 – 1.98 (m, 2H), 1.97 – 1.64 (m, 11H). Preparation of Compound 1-32 (2-((2S)-4-(2’-((Tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazin-2-yl)acetonitrile) Step1. Intermediate 1-40 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) (51.9mg, 0.969mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (20.5mg, 0.145mmol) were dissolved in anhydrous THF (600µL) and cooled to 0°C then KotBu, 1M in THF (116µL) was added dropwise. After 30min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give tert-Butyl (2S)-2-(cyanomethyl)-4-(2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate (31.8mg, 53.6%) as a pale yellow foam. LC/MS, ESI [M+H]⁺ = 613.3 m/z. Step 2. Tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’- yl)piperazine-1-carboxylate (31.8mg, 0.0519mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 40min then concentrated, dissolved in H₂O, and washed with Et₂O (x2). The aqueous phase was purified by preparative HPLC to give the title compound (6.1mg, 22.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 513.2 m/z.¹H NMR (400 MHz, Methanol- d₄) δ 7.26 (dd, J = 7.3, 3.2 Hz, 1H), 7.15 – 7.04 (m, 3H), 4.19 – 3.77 (m, 4H), 3.29 – 3.15 (m, 1H), 3.14 – 2.99 (m, 4H), 2.99 – 2.89 (m, 2H), 2.89 – 2.73 (m, 5H), 2.73 – 2.61 (m, 4H), 2.55 (dt, J = 16.3, 4.2 Hz, 1H), 2.20 – 1.98 (m, 3H), 1.98 – 1.65 (m, 11H). Preparation of Compound 1-33 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazoline]) Step 1. Intermediate 1-44 (allyl (1R,5S)-8-(2’-(Methylsulfinyl)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate) (26.9mg, 0.0531mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (11.2mg, 0.0793mmol) were dissolved in anhydrous THF (300µL) and cooled to - 40°C then KotBu, 1M in THF (64µL) was added dropwise. After 20min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 50→0 hexanes then 0→10% MeOH in DCM+2%Et₃N to give allyl (1R,5S)-8- (2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H- spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (26.5mg, 85.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 584.3 m/z. ¹H NMR (400 MHz, Acetonitrile-d3) δ 7.32 (dd, J = 7.3, 1.3 Hz, 1H), 7.20 – 7.06 (m, 3H), 5.98 (ddt, J = 17.4, 10.5, 5.3 Hz, 1H), 5.31 (dq, J = 17.3, 1.8 Hz, 1H), 5.21 (dq, J = 10.5, 1.5 Hz, 1H), 4.74 – 4.66 (m, 1H), 4.65 – 4.48 (m, 3H), 3.99 – 3.89 (m, 2H), 3.87 – 3.78 (m, 2H), 3.50 – 3.28 (m, 1H), 3.19 – 3.00 (m, 1H), 3.00 – 2.89 (m, 3H), 2.86 – 2.68 (m, 4H), 2.64 – 2.51 (m, 3H), 2.16 – 2.01 (m, 2H), 1.94 – 1.66 (m, 14H), 1.58 (dt, J = 12.0, 7.4 Hz, 2H). Step 2. Allyl (1R,5S)-8-(2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (26.5mg, 0.0454mmol) was dissolved in anhydrous THF (350µL) and treated with PhSiH₃ (28µL, 0.23mmol) and 4-methylpiperidine (107µL, 0.904mmol) and the mixture was sparged with N2 for 2min then Pd(PPh3)4 (2.6mg, 0.0023mmol) was added and sparging continued for 2min. After 60min, the mixture was carefully diluted with 1N HCl and washed with Et₂O (x3). The aqueous phase was purified by preparative HPLC to give the title compound (17.9mg, 78.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 500.4 m/z.¹H NMR (400 MHz, Methanol-d4) δ 7.28 (d, J = 7.4 Hz, 1H), 7.17 – 7.00 (m, 3H), 4.73 – 4.66 (m, 1H), 4.56 (d, J = 6.0 Hz, 1H), 4.12 – 4.02 (m, 2H), 3.21 (dd, J = 12.8, 2.1 Hz, 1H), 3.05 (dt, J = 10.6, 5.9 Hz, 2H), 2.97 – 2.88 (m, 2H), 2.84 – 2.64 (m, 8H), 2.58 (ddd, J = 16.0, 5.5, 3.3 Hz, 1H), 2.23 – 1.63 (m, 18H). Preparation of Compound 1-34 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-2’- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5’,8’-tetrahydro- 2H,6’H-spiro[naphthalene-1,7’-quinazoline]) Compound 1-34 was prepared following the general procedures used to prepare Compound 1-30 and using [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol instead of 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol, and was obtained (34 mg, 88.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 518.3 m/z.¹H NMR (400 MHz, Methanol-d₄) δ 7.28 – 7.18 (m, 1H), 7.15 – 7.01 (m, 3H), 5.26 (ddq, J = 55.3, 4.1, 1.8 Hz, 1H), 4.18 – 4.08 (m, 2H), 4.03 (t, J = 10.3 Hz, 1H), 3.69 (dt, J = 12.5, 1.4 Hz, 1H), 3.55 – 3.47 (m, 2H), 3.36 – 3.32 (m, 1H), 3.29 – 3.11 (m, 3H), 3.05 – 2.95 (m, 2H), 2.91 (d, J = 18.9 Hz, 1H), 2.85 – 2.69 (m, 4H), 2.59 – 2.49 (m, 1H), 2.31 – 1.63 (m, 16H).¹⁹F NMR (376 MHz, Methanol-d₄) δ -173.54, -173.54. Example 2: Synthesis of Spiro-indane Compounds Preparation of Intermediates 2-1 through 2-8

Intermediate 2-1 Intermediate 2-2

Intermediate 2-5 Intermediate 2-6

Intermediate 2-7 Intermediate 2-8 Intermediate 2-8 (6-(benzyloxy)-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) is used in subsequent syntheses without purification. [M+H]⁺ = 537.1 m/z. Preparation of Intermediate 2-8 Analogs It is understood by the artisan of ordinary skill that Intermediate 2-8 Analogs can be prepared by following these schematized procedures:

Intermediate 2-8 Analogs Examples of R include, but are not limited to, F, C1, CH₂CH₃, CH₃ and NH₂, and one, two or three instances of R can occur, each of which is independently selected from one another. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of dihydroindenones used for this procedure include, but are not limited to: 6-amino-2,3-dihydro-1H-inden-1-one, 6-amino-4-chloro-2,3-dihydro-1H-inden-1-one, 6- amino-4-fluoro-2,3-dihydro-1H-inden-1-one, 6-amino-4-methyl-2,3-dihydro-1H-inden-1- one, 6-amino-4-ethyl-2,3-dihydro-1H-inden-1-one, 4-chloro-6-hydroxy-2,3-dihydro-1H- inden-1-one, 4-fluoro-6-hydroxy-2,3-dihydro-1H-inden-1-one, 6-hydroxy-4-methyl-2,3- dihydro-1H-inden-1-one and 4-ethyl-6-hydroxy-2,3-dihydro-1H-inden-1-one. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired dihydroindenones, or obtain them from chemical vendors. Preparation of Intermediates 2-9 through 2-12

Intermediate 2-8 Intermediate 2-9 Intermediate 2-10

Intermediate 2-11 Intermediate 2-12 Preparation of Intermediate 2-11 Analogs It is understood by the artisan of ordinary skill that Intermediate 2-11 Analogs can be prepared using Intermediate 2-8 or Intermediate 2-8 Analogs by following these schematized procedures:

Intermediate 2-8 or Intermediate 2-8 Analogs

Intermediate 2-11 Analogs wherein, examples of Ring A include, but are not limited to

indicates the point of attachment to the pyrimidine; examples of R include, but are not limited to, F, C1, CH₂CH3, CH3 and NH₂, and zero, one, two or three instances of R can occur, each of which is independently selected from one another; examples of R6 include, but are not limited to, halogen, amino, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, wherein each of amino, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, hexahydro-1H-pyrrolizinyl, 1-azabicyclo[2.2.1]heptanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl or piperazinyl may be optionally substituted with one or more R7; examples of R7 include, but are not limited to, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cyano, -(CH₂)_nN(R₃)₂, -N(R₃)₂, -C(O)N(R₃)₂, -OC(O)N(R₃)₂, -N(H)C(O)R₃, -CH₂N(H)C(O)R₃, -CH₂OC(O)N(R₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, and each instance of R7 is independently selected from other instances; examples of R3 include, but are not limited to, H and C₁-C₃ alkyl, and each instance of R3 is independently selected from other instances; and n in each occurrence is independently 1, 2 or 3. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of Ring A species that can be used to prepare Intermediate 2-11 Analogs include, but are not limited to: tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-3-methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-6- methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-5-methylpiperazine-1- carboxylate, tert-butyl (1S,5S,6S)-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-(2-cyanoethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-carbamoyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, 8-(tert-butyl) 1-methyl 3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate, tert-butyl (1S,5S,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-chloro-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate, tert-butyl (1S,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5R,6R)-6-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1S,5S,6S)-6-(1H-1,2,4-triazol-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Ring A species, or obtain them from chemical vendors. Examples of alcohols used to prepare Intermediate 2-11 Analogs include, but are not limited to: (1-isopropylpyrrolidin-2-yl)methanol, (1-ethylpyrrolidin-2-yl)methanol, (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol and (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Preparation of Compound 2-1 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-6-ol) Compound 2-1 is prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 2-12 instead of Intermediate 1-13. Preparation of Compound 2-2 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-6- ol) Compound 2-2 is prepared following the general procedures used to prepare Compound 1-2 and using Intermediate 2-12 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-3 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]- 6-ol) Compound 2-3 is prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 2-12 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-31 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-6-ol) Compound 2-31 is prepared following the general procedures used to prepare Compound 1-26 and using Intermediate 2-10 instead of Intermediate 1-11 in step 1. Preparation of Compound 2-32 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-6-ol) Compound 2-32 is prepared following the general procedures used to prepare Compound 1-27 and using Intermediate 2-10 instead of Intermediate 1-11 in step 1 of the procedures for preparing Compound 1-26. Preparation of Intermediates 2-13 through 2-16

Intermediate 2-8 Intermediate 2-13 Intermediate 2-14

Intermediate 2-15 Intermediate 2-16 Preparation of Compound 2-4 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-6-ol) Compound 2-4 is prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 2-16 instead of Intermediate 1-25. Preparation of Compound 2-5 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-6- ol) Compound 2-5 is prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 2-16 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-6 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]- 6-ol) Compound 2-6 is prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 2-16 instead of Intermediate 1-25 in step 1. Schematization for the Preparation of Intermediates 2-17 through 2-24

Intermediate 2-17 Intermediate 2-18

Intermediate 2-19 Intermediate 2-20

Intermediate 2-21 Intermediate 2-22

Intermediate 2-23 Intermediate 2-24 Preparation of of Intermediate 2-17 (2-(2,3-Dihydro-1H-inden-1-ylidene)malononitrile) Indan-1-one (8.05g, 60.9mmol) and malononitrile (4.83g, 73.1mmol) were dissolved in EtOH (80mL) and treated with NaOAc•3H₂O (8.29g, 60.9mmol) and the mixture was stirred at rt for 9hrs. The reaction mixture was diluted with 1N HCl (30mL) and the solids were collected by filtration and washed with H₂O and a little EtOH then dried under suction and further dried in vacuo at 45°C overnight to give the title compound (9.925g, 90.4%) as a pale yellow solid. Rf = 0.38 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 181.1 m/z.¹H NMR (500 MHz, CDCl₃) δ 8.40 (d, J = 8.1 Hz, 1H), 7.61 (td, J = 7.6, 1.2 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.44 (td, J = 7.8, 1.0 Hz, 1H), 3.29 (ddt, J = 5.9, 3.9, 2.1 Hz, 2H), 3.23 – 3.18 (m, 2H). Preparation of of Intermediate 2-18 (2-(1-(Pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)malononitrile) A 500mL round bottom flask was charged with CuBr•Me2S (1.13g, 5.5 mmol) and evacuated and backfilled with N₂ (x3) then amended with anhydrous THF (30mL) and cooled to -40 °C. A solution of pent-4-en-1-ylmagnesium bromide (0.5M in THF, 186mL) was added and the mixture was stirred cold for 15min then Intermediate 2-17 (2-(2,3-dihydro- 1H-inden-1-ylidene)malononitrile; 9.93g, 55.1mmol) was added as a suspension in anhydrous THF (100mL). The mixture was stirred cold for 1hr then allowed to warm to rt over a period of 2 hr. The reaction was quenched with sat NH₄Cl then diluted with EtOAc and washed with sat NH4Cl (x2), brine, dried over Na2SO4, filtered, and concentrated. The residue was taken up in 8:2 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same to give the title compound (14.1g, quant.). Rf = 0.28 (9:1 hexanes:EtOAc). LC/MS, ESI [M-H]- = 249.1 m/z.¹H NMR (500 MHz, CDCl3) δ 7.38 – 7.25 (m, 4H), 5.72 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.04 – 4.93 (m, 2H), 3.85 (s, 1H), 3.11 (ddd, J = 15.9, 8.9, 6.8 Hz, 1H), 3.00 (ddd, J = 16.5, 9.0, 5.1 Hz, 1H), 2.39 – 2.21 (m, 2H), 2.14 – 1.91 (m, 4H), 1.47 – 1.36 (m, 1H), 1.25 – 1.14 (m, 1H). Preparation of of Intermediate 2-19 (Methyl 2-(1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)acetate) In a 250mL PFA round bottom flask, Intermediate 2-18 (2-(1-(pent-4-en-1-yl)-2,3- dihydro-1H-inden-1-yl)malononitrile; 13.79g, 55.08mmol) was treated with ethylene glycol (55mL), H₂O (25mL), and KOH (54.5g, 826mmol), and the mixture was heated to 180 °C under N2 for 24hrs. The mixture was cooled slightly then poured into chipped ice containing H₂SO4 and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was heated to 200ºC under N2 for 10min then cooled to rt and treated with 3N HCl in MeOH (180mL) and warmed to 45ºC for 2hr then cooled, concentrated, and co-evaporated from toluene once. The residue was taken up in 85:15 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same. The filtrate was concentrated to give the title compound (12.36g, 86.9%) as an orange colored oil. Rf = 0.59 (9:1 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 259.2 m/z. Preparation of of Intermediate 2-20 (Methyl 2-(1-(4-oxobutyl)-2,3-dihydro-1H-inden-1- yl)acetate) Intermediate 2-19 (methyl 2-(1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)acetate; 4.1g, 15.9mmol) was dissolved in DCM (106mL) and cooled to -78°C then ozone was passed through the solution for 40min. The mixture was sparged with N2 for 5min then PPh3 (5.83g, 22.2mmol) was added, the cooling bath was removed, and the mixture was stirred at rt overnight. The mixture was directly adsorbed onto silica gel and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (3.724g, 90.1%). Rf = 0.31 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]+ = 261.1 m/z.¹H NMR (500 MHz, cdcl₃) δ 9.70 (t, J = 1.7 Hz, 1H), 7.23 – 7.13 (m, 3H), 7.10 (dt, J = 4.5, 3.2 Hz, 1H), 3.60 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 2.70 (d, J = 14.2 Hz, 1H), 2.54 (d, J = 14.2 Hz, 1H), 2.42 – 2.35 (m, 2H), 2.29 – 2.18 (m, 1H), 2.15 – 2.05 (m, 1H), 1.82 (td, J = 12.7, 4.2 Hz, 1H), 1.73 – 1.56 (m, 2H), 1.56 – 1.46 (m, 1H). Preparation of of Intermediate 2-21 (Methyl 4-(1-(2-methoxy-2-oxoethyl)-2,3-dihydro-1H- inden-1-yl)butanoate) Intermediate 2-20 (methyl 2-(1-(4-oxobutyl)-2,3-dihydro-1H-inden-1-yl)acetate; 3.72g, 14.3mmol) was dissolved in H₂O (15mL) and tBuOH (15mL), cooled to 0 °C, and treated with NaClO2 (3.88g, 42.9mmol), 2-methyl-2-butene (7.6mL, 71.7mmol), and KH₂PO₄ (7.0g, 42.9mmol) and stirred cold for 75min. The mixture was poured into aq NaHSO4 and extracted with EtOAc (x2). The combined extract was washed with dilute Na2S2O3, brine, dried over Na2SO4, filtered, and concentrated. The residue was treated with 3N HCl in MeOH (40mL) then heated to 50°C for 2hr. The mixture was concentrated and co-evaporated from toluene then taken up in 6:4 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same. Purification by flash column chromatography on silica gel eluted with 0→30% EtOAc in hexanes afforded the title compound (3.762g, 90.6%) as a colorless oil. Rf = 0.42 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]+ = 291.1 m/z. Preparation of of Intermediate 2-22 (Methyl 3-oxo-2’,3’-dihydrospiro[cyclohexane-1,1’- indene]-4-carboxylate) A 500mL round bottom flask fitted with an addition funnel was charged with NaH, 60% dispersion (6.02g, 151mmol) then evacuated and backfilled with N2 (x3) and amended with anhydrous toluene (135mL) and MeOH (1.0mL). The addition funnel was charged with a solution of Intermediate 2-21 (methyl 4-(1-(2-methoxy-2-oxoethyl)-2,3-dihydro-1H- inden-1-yl)butanoate; 14.57g, 50.17mmol) in anhydrous toluene (115mL) containing additional MeOH (1.0mL) and this solution was added dropwise over a period of approximately 90min and stirring continued for 13hrs. The mixture was poured into sat NH4Cl and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (13.2g, >100%) which was used without purification. LC/MS, ESI [M+H]⁺ = 259.1 m/z. Preparation of of Intermediate 2-23 (2’-(Methylthio)-2,3,5’,8’-tetrahydro-3’H- spiro[indene-1,7’-quinazolin]-4’(6’H)-one) Intermediate 2-22 (methyl 3-oxo-2’,3’-dihydrospiro[cyclohexane-1,1’-indene]-4- carboxylate; 12.96g, 50.17mmol) was dissolved in MeCN (165mL) and treated with thiourea (4.96g, 65.2mmol) and DBU (9.0mL, 60mmol) and the mixture was heated to reflux for 21hr. The mixture was cooled slightly and poured into a stirred solution of cold one-third saturated NaHCO3 and stirred for 5min then the solids were collected by filtration, washed with H₂O, and freed of excess moisture under suction. The solids were solubilized in DMF (250 mL) and THF (150 mL) and treated with NaOAc (8.23g, 100mmol) and MeI (3.1mL, 49.8mmol). Several additional charges of MeI and NaOAc were made until high conversion was observed by HPLC. The volatiles were removed by rotary evaporation and the remainder was poured into ice cold one-third saturated NaHCO₃ and stirred for 5min then filtered. The cake was washed with H₂O (x3), hexanes (x3), then dried under suction and further dried in vacuo at 50ºC overnight to give the title compound (9.996g, 66.8%) as an off-white powder. LC/MS, ESI [M+H]⁺ = 299.1 m/z. Preparation of of Intermediate 2-24 (2’-(Methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) Intermediate 2-23 (2’-(methylthio)-2,3,5’,8’-tetrahydro-3’H-spiro[indene-1,7’- quinazolin]-4’(6’H)-one; 753mg, 2.52mmol) was suspended in anhydrous DCM (12.5mL) and treated with iPr2EtN (1.3mL, 7.46mmol). The mixture was cooled to 0 °C and triflic anhydride (550.uL, 3.28 mmol) was added dropwise. After 10min, the mixture was diluted with 1vol hexanes and filtered through a pad of silica gel rinsing with 8:2 hexanes:EtOAc and concentrated to give the title compound (1.168g, >100%) as a pale orange solid which was used without further purification. LC/MS, ESI [M+H]⁺ = 431.0 m/z. Schematization for the Preparation of Intermediates 2-25 through 2-27

Intermediate 2-24 Intermediate 2-25 Intermediate 2-26

Intermediate 2-27 Preparation of Intermediate 2-25 (tert-Butyl 4-(2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediatee 2-24 ((2-methylsulfanylspiro[6,8-dihydro-5H-quinazoline-7,1’- indane]-4-yl) trifluoromethanesulfonate; 244.9mg, 0.569mmol) was dissolved in anhydrous DMF (2mL) and treated with iPr₂EtN (200µL, 1.73mmol) and tert-butyl piperazine-1-carboxylate (127mg, 0.682mmol) at rt for 13hrs. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (248.2mg, 93.5%) as a colorless residue. Rf = 0.46 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 467.2 m/z. Preparation of Intermediate 2-26 (tert-Butyl 4-(2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro- 6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-25 (tert-butyl 4-(2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 248.2mg, 0.532mmol) was dissolved in DCM (3.5mL) and treated with mCPBA (165.3mg, 0.479mmol) at 0 °C for 15min. The mixture was diluted with Et2O and washed with half-saturated NaHCO3 (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (246.6mg, 96.1%) as a white foam. LC/MS, ESI [M+H]⁺ = 483.2 m/z. Preparation of Intermediate 2-27 (tert-Butyl 4-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-26 (tert-butyl 4-(2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 125.5mg, 0.260mmol) was dissolved in anhydrous THF (700µL) and cooled to -40 °C then a solution of [(2S)- pyrrolidin-2-yl]methanol (52.6mg, 0.520mmol) and KotBu, 1M in THF (338µL) in THF (600uL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give the title compound (154.1mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 520.3 m/z. Preparation of Compound 1-36 (4’-(Piperazin-1-yl)-2’-(((S)-pyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-27 (tert-butyl 4-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 45.2mg, 0.087mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (27.8mg, 76.2% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 420.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.26 – 7.18 (m, 1H), 7.18 – 7.10 (m, 2H), 7.06 (dt, J = 5.3, 3.1 Hz, 1H), 4.34 – 4.20 (m, 2H), 3.58 – 3.37 (m, 5H), 3.04 – 2.79 (m, 8H), 2.79 – 2.66 (m, 3H), 2.58 (dt, J = 16.1, 5.1 Hz, 1H), 2.09 – 1.65 (m, 7H), 1.59 (ddt, J = 12.4, 8.9, 7.2 Hz, 1H). Preparation of Compound 1-37 (2’-(((S)-1-Methylpyrrolidin-2-yl)methoxy)-4’-(piperazin-1- yl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-27 (tert-butyl 4-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 45.2mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.09mmol), formaldehyde, 37% aqueous (19.4µL, 0.261mmol), and NaBH(Oac)₃ (55.3mg, 0.261mmol) at rt for 6hr. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (30.5mg, 80.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 434.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.10 (m, 2H), 7.06 (dt, J = 5.1, 3.0 Hz, 1H), 4.37 (ddd, J = 11.0, 6.0, 4.1 Hz, 1H), 4.27 (ddd, J = 10.9, 5.9, 4.5 Hz, 1H), 3.53 (ddd, J = 13.1, 6.8, 3.6 Hz, 2H), 3.43 (ddd, J = 13.1, 6.5, 3.4 Hz, 2H), 3.06 (ddd, J = 9.5, 5.8, 3.6 Hz, 1H), 3.01 – 2.86 (m, 6H), 2.80 – 2.66 (m, 4H), 2.58 (dt, J = 16.1, 5.3 Hz, 1H), 2.48 (s, 3H), 2.32 (q, J = 9.0 Hz, 1H), 2.13 – 1.92 (m, 4H), 1.88 – 1.62 (m, 4H). Preparation of Compound 1-38 (2’-(((S)-1-Isopropylpyrrolidin-2-yl)methoxy)-4’- (piperazin-1-yl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-27 (tert-butyl 4-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 45.2mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.087mmol), acetone (19µL, 0.261mmol), and NaBH(Oac)3 (55.3mg, 0.261mmol) at rt for 6hr. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (32.9mg, 81.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 462.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.09 (m, 2H), 7.05 (dt, J = 5.1, 3.0 Hz, 1H), 4.34 (ddd, J = 11.0, 6.6, 4.6 Hz, 1H), 4.06 (ddd, J = 10.8, 8.3, 6.6 Hz, 1H), 3.59 – 3.47 (m, 2H), 3.42 (ddd, J = 13.3, 6.5, 3.5 Hz, 2H), 3.28 – 3.17 (m, 1H), 3.09 – 2.85 (m, 8H), 2.79 – 2.66 (m, 3H), 2.64 – 2.52 (m, 2H), 2.08 – 1.67 (m, 8H), 1.16 (d, J = 6.6 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H). Preparation of Compound 1-39 (4’-(Piperazin-1-yl)-2’-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediatee 2-26 (tert-butyl 4-(2-methylsulfinylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)piperazine-1-carboxylate; 38.6mg, 0.080mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (16.9mg, 0.120mmol) were dissolved in anhydrous THF (500µL) and cooled to -40 °C then KotBu, 1M in THF (96µL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (29.9mg, 81.3%) as a white foam. LC/MS, ESI [M+H]⁺ = 460.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.09 (m, 2H), 7.08 – 7.03 (m, 1H), 4.10 (d, J = 1.5 Hz, 2H), 3.53 (ddd, J = 13.3, 6.6, 3.5 Hz, 2H), 3.43 (ddd, J = 13.1, 6.4, 3.5 Hz, 2H), 3.05 (dt, J = 10.3, 5.9 Hz, 2H), 3.00 – 2.85 (m, 6H), 2.80 – 2.63 (m, 5H), 2.58 (dt, J = 16.0, 5.3 Hz, 1H), 2.09 – 1.64 (m, 12H). Schematization for the Preparation of Intermediates 2-28 through 2-30

Intermediate 2-24 Intermediate 2-28 Intermediate 2-29

Intermediate 2-30 Preparation of Intermediate 2-28 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(methylthio)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-24 (2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-4’-yl trifluoromethanesulfonate; 244.9mg, 0.569mmol) and 2-[(2S)-piperazin-2- yl]acetonitrile dihydrochloride (135.2mg, 0.683mmol) were dissolved in DMF (1mL) and treated with iPr₂EtN (264µL, 2.28mmol). After 20min, Boc₂O (186.25mg, 0.8500 mmol) was added and stirring continued for 14hrs. Additional Boc2O (58mg, 0.27mmol) and iPr2EtN (200uL, 1.7mmol) were added and the mixture was warmed to 50 ºC. After 2hrs, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHO₃ (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes. Combined fractions 72-76 to give the title compound (286mg, 99.4%) as a white foam. Rf = 0.24 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 506.2 m/z. Preparation of Intermediate 2-29 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-28 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(methylthio)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 286.mg, 0.566mmol) was dissolved in DCM (3.5mL) and treated with mCPBA (175.7mg, 0.509mmol) at 0°C for 10min. The mixture was diluted with Et2O and washed with half- saturated NaHCO3 (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (268.3mg, 90.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 522.2 m/z. Preparation of Intermediate 2-30 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(((S)-pyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate) Intermediate 2-29 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 135.6mg, 0.260mmol) was dissolved in anhydrous THF (800µL) and cooled to -40 °C then a solution of [(2S)-pyrrolidin-2-yl]methanol (52.6mg, 0.520mmol) and KotBu, 1M in THF (338µL) in anhydrous THF (700µL) was added dropwise. After 35min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (157.1mg, >100%) as a pale brown foam which was used without purification. LC/MS, ESI [M+H]⁺ = 559.3 m/z. Preparation of Compound 1-40 (2-((2S)-4-(2’-(((S)-Pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile) Intermediate 2-30 (tert-Butyl (2S)-2-(cyanomethyl)-4-(2’-(((S)-pyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate; 48.6mg, 0.087mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (22.5mg, 56.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 459.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.26 – 7.19 (m, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.03 (m, 1H), 4.37 – 4.22 (m, 2H), 4.19 – 3.99 (m, 1H), 3.95 – 3.79 (m, 1H), 3.50 (qdd, J = 7.0, 5.2, 1.3 Hz, 1H), 3.29 – 3.09 (m, 2H), 3.09 – 2.54 (m, 14H), 2.10 – 1.68 (m, 7H), 1.61 (ddtd, J = 12.3, 8.6, 7.1, 1.4 Hz, 1H). Preparation of Compound 1-41 (2-((2S)-4-(2’-(((S)-1-Methylpyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile) Intermediate 2-30 (tert-butyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]piperazine-1-carboxylate; 48.61mg, 0.0900 mmol) was dissolved in THF (870 uL) and treated with AcOH (5.uL, 0.0900 mmol), formaldehyde, 37% aqueous (19.4uL, 0.2600 mmol), and NaBH(Oac)3 (55.32mg, 0.2600 mmol) at rt for 6hrs. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (22.9mg, 55.7%) as a white foam. LC/MS, ESI [M+H]⁺ = 473.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.26 – 7.19 (m, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.03 (m, 1H), 4.44 – 4.33 (m, 1H), 4.33 – 4.22 (m, 1H), 4.15 – 3.77 (m, 2H), 3.30 – 2.53 (m, 15H), 2.52 – 2.48 (m, 3H), 2.33 (qd, J = 8.9, 1.6 Hz, 1H), 2.20 – 1.93 (m, 4H), 1.88 – 1.63 (m, 4H). Preparation of Compound 1-42 (2-((2S)-4-(2’-(((S)-1-Isopropylpyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2-yl)acetonitrile) Intermediate 2-30 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(((S)-pyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate; 48.61mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.087mmol), acetone (19.3µL, 0.260mmol), and NaBH(Oac)₃ (55.3mg, 0.261mmol) at rt for 6hrs. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (18.6 mg, 42.7%) as a white foam. LC/MS, ESI [M+H]⁺ = 501.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.26 – 7.19 (m, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.03 (m, 1H), 4.40 – 4.30 (m, 1H), 4.13 – 3.75 (m, 3H), 3.28 – 2.54 (m, 16H), 2.52 – 2.47 (m, 1H), 2.08 – 1.69 (m, 8H), 1.17 (dd, J = 6.6, 1.3 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H). Preparation of Compound 1-43 (2-((2S)-4-(2’-((Tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2- yl)acetonitrile) Intermediate 2-29 (tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(methylsulfinyl)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 41.7mg, 0.080mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.9mg, 0.120mmol) were dissolved in anhydrous THF (500µL) and cooled to -40 °C then KotBu, 1M in THF (96µL) was added dropwise. After 35min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL, 2 mmol) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (24.5mg, 61.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 499.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.26 – 7.19 (m, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.04 (m, 1H), 4.11 (s, 4H), 3.28 – 2.97 (m, 5H), 2.97 – 2.54 (m, 12H), 2.10 – 1.64 (m, 12H). Schematization for the Preparation of Intermediates 2-31 through 2-33

Intermediate 2-24 Intermediate 2-31 Intermediate 2-32

Intermediate 2-33 Preparation of Intermediate 2-31 (tert-Butyl 3-(2-methylsulfanylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 2-24 (2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-4’-yl trifluoromethanesulfonate; 244.9mg, 0.569mmol) was dissolved in anhydrous DMF (2mL) and treated with iPr₂EtN (200µL, 1.73mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (144.93mg, 0.6800 mmol) at rt for 13hrs. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (264.5mg, 94.4%) as a white foam. Rf = 0.44 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 493.3 m/z. Preparation of Intermediate 2-32 (tert-Butyl 3-(2-methylsulfinylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 2-31 (tert-butyl 3-(2-methylsulfanylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 264.5mg, 0.537mmol) was dissolved in DCM (3.5mL) and treated with mCPBA (166.8mg, 0.483mmol) at 0°C. After 10min, the mixture was diluted with Et₂O and washed with half- saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (277.3mg, quant.) as a white foam. LC/MS, ESI [M+H]⁺ = 509.2 m/z. Preparation of Intermediate 2-33 (tert-Butyl 3-[2-[[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 2-32 (tert-butyl 3-(2-methylsulfinylspiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 128.3mg, 0.252mmol) was dissolved in anhydrous THF (800µL) and cooled to -40 °C then a solution of [(2S)- pyrrolidin-2-yl]methanol (51.0mg, 0.504mmol) and KotBu, 1M in THF (330µL) in THF (500µL) was added dropwise. After 15min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give the title compound (146.5mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 546.3 m/z. Preparation of Compound 1-44 (4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)-pyrrolidin- 2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-33 (tert-butyl 3-[2-[[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 47.5mg, 0.087mmol) was treated with 4N HCl in dioxane (0.5mL) for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was filtered and purified by preparative HPLC to give the title compound (25.4mg, 65.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 446.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.26 – 7.18 (m, 1H), 7.18 – 7.10 (m, 2H), 7.09 – 7.01 (m, 1H), 4.36 – 4.20 (m, 2H), 4.01 (dd, J = 12.6, 2.7 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.56 – 3.44 (m, 3H), 3.26 (d, J = 12.5 Hz, 1H), 3.10 (d, J = 12.4 Hz, 1H), 3.05 – 2.85 (m, 4H), 2.83 – 2.66 (m, 3H), 2.59 (dt, J = 15.8, 5.1 Hz, 1H), 2.09 – 1.68 (m, 11H), 1.66 – 1.53 (m, 1H). Preparation of Compound 1-45 (4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-33 (tert-butyl 3-[2-[[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 47.5mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5uL, 0.087mmol), formaldehyde, 37% aqueous (19uL, 0.26mmol), and NaBH(Oac)₃ (55.3mg, 0.26mmol) at rt for 4hr. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (29.6 mg, 74.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 460.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.09 (m, 2H), 7.08 – 7.03 (m, 1H), 4.35 (ddd, J = 9.8, 6.0, 3.6 Hz, 1H), 4.30 – 4.20 (m, 1H), 4.02 (dt, J = 12.6, 3.9 Hz, 1H), 3.78 (dt, J = 12.5, 3.0 Hz, 1H), 3.55 – 3.50 (m, 2H), 3.27 (d, J = 12.6 Hz, 1H), 3.10 (d, J = 12.6 Hz, 1H), 3.08 – 3.01 (m, 1H), 2.93 (t, J = 7.1 Hz, 2H), 2.83 – 2.66 (m, 4H), 2.59 (dt, J = 15.6, 5.1 Hz, 1H), 2.48 (s, 3H), 2.32 (q, J = 9.0 Hz, 1H), 2.17 – 1.90 (m, 5H), 1.90 – 1.61 (m, 7H). Preparation of Compound 1-46 (4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)-1- isopropylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-33 (tert-butyl 3-[2-[[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 47.5mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.087mmol), acetone (19µL, 0.26mmol), and NaBH(Oac)₃ (55.3mg, 0.26mmol) at rt for 4hr. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (31mg, 73.1%) as a white foam. LC/MS, ESI [M+H]⁺ = 488.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.17 (m, 1H), 7.17 – 7.10 (m, 2H), 7.09 – 7.01 (m, 1H), 4.31 (dt, J = 10.8, 4.3 Hz, 1H), 4.10 – 3.96 (m, 2H), 3.82 – 3.72 (m, 1H), 3.56 – 3.48 (m, 2H), 3.31 – 3.16 (m, 2H), 3.10 (dt, J = 12.5, 2.1 Hz, 1H), 3.06 – 2.88 (m, 4H), 2.83 – 2.67 (m, 3H), 2.65 – 2.52 (m, 2H), 2.08 – 1.67 (m, 12H), 1.16 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H). Preparation of Compound 1-47 (4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethoxy)spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-32 (tert-Butyl 3-(2-methylsulfinylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 40.7mg, 0.080mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.9mg, 0.120mmol) were dissolved in anhydrous THF (500µL) and KotBu, 1M in THF (96µL) was added dropwise at -40 °C. After 10min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (30.3mg, 78.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 486.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.09 (m, 2H), 7.09 – 7.01 (m, 1H), 4.09 (dd, J = 11.9, 10.5 Hz, 2H), 4.03 (ddd, J = 12.4, 2.9, 1.4 Hz, 1H), 3.79 (ddd, J = 12.5, 2.9, 1.5 Hz, 1H), 3.55 – 3.48 (m, 2H), 3.26 (dd, J = 12.6, 1.9 Hz, 1H), 3.14 – 2.99 (m, 3H), 2.93 (t, J = 7.1 Hz, 2H), 2.83 – 2.54 (m, 6H), 2.10 – 1.64 (m, 16H). Preparation of Compound 1-48 (4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]) Intermediate 2-32 (tert-butyl 3-(2-methylsulfinylspiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 40.4mg, 0.0794mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (19.mg, 0.119mmol) were dissolved in anhydrous THF (500µL) and cooled to -40 °C then KotBu, 1M in THF (96µL) was added dropwise. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (31.3mg, 78.2%) as a white foam. LC/MS, ESI [M+H]⁺ = 504.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.17 – 7.10 (m, 2H), 7.08 – 7.03 (m, 1H), 5.35 – 5.17 (m, 1H), 4.14 (dd, J = 10.4, 4.3 Hz, 1H), 4.08 – 3.97 (m, 2H), 3.79 (ddd, J = 12.5, 2.9, 1.5 Hz, 1H), 3.55 – 3.49 (m, 2H), 3.30 – 3.04 (m, 5H), 3.02 – 2.89 (m, 3H), 2.83 – 2.68 (m, 3H), 2.59 (dt, J = 15.8, 5.3 Hz, 1H), 2.32 – 1.68 (m, 14H). ¹⁹F NMR (376 MHz, MeOD) δ -173.57. Schematization for the Preparation of Intermediates 2-34 through 2-37 and Compound 1- 49

Intermediate 2-24 Intermediate 2-34 Intermediate 2-35

Intermediate 2-36 Compound 1-49 Preparation of Intermediate 2-33 (Allyl 8-(2-methylsulfanylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-24 (2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-4’-yl trifluoromethanesulfonate; 107.mg, 0.2500 mmol) was dissolved in anhydrous DMF (1 mL) and treated with iPr2EtN (100.78uL, 0.8700 mmol) and allyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (53.66mg, 0.2700 mmol) at rt overnight. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHO3 (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (110.4mg, 93.2%) as a white foam. Rf = 0.32 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 477.2 m/z. Preparation of Intermediate 2-34 (Allyl 8-(2-methylsulfinylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-33 (allyl 8-(2-methylsulfanylspiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 110.4mg, 0.232mmol) was dissolved in DCM (1.5mL) and treated with mCPBA (72.mg, 0.209mmol) at 0°C for 10min. The mixture was diluted with Et₂O and washed with half-saturated NaHCO₃ (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (114.5mg, quant.) as a white foam. LC/MS, ESI [M+H]⁺ = 493.2m/z. Preparation of Intermediate 2-35 (Allyl 8-[2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-34 (allyl 8-(2-methylsulfinylspiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 38.3mg, 0.078mmol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (17.9mg, 0.1600 mmol) were dissolved in anhydrous THF (500 uL), cooled to -40 °C, and KotBu, 1M in THF (101.uL, 0.1000 mmol) was added dropwise. After 15min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→100% EtOAc+2% Et3N in hexanes+2%Et3N to give the title compound (34.9 mg,0.0642 mmol, 82.564% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 544.3 m/z. Preparation of Intermediate 2-36 (Allyl 8-[2-[[(2S)-1-methylpyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-35 (Allyl 8-(2-methylsulfinylspiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (38.3mg, 0.078mmol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (17.9mg, 0.1600 mmol) were dissolved in anhydrous THF (500 uL), cooled to -40 °C, and KotBu, 1M in THF (101.uL, 0.1000 mmol) was added dropwise. After 15min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→100% EtOAc+2% Et₃N in hexanes+2%Et₃N to give the title compound (34.9 mg,0.0642 mmol, 82.564% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 544.3 m/z. Preparation of Compound 1-49 (4-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-36 (allyl 8-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 34.9mg, 0.064mmol) was dissolved in THF (500µL) and treated with 4-methylpiperidine (150µL, 1.27 mmol) and PhSiH3 (39µL, 0.316mmol). The mixture was sparged with N2 for 2min then Pd(PPh₃)₄ (3.7mg, 0.0032mmol) was added and the mixture stirred for 40min. The mixture was carefully diluted with 2N HCl (2mL) and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (33.1 mg) as a white solid. LC/MS, ESI [M+H]⁺ = 460.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.17 (m, 1H), 7.17 – 7.10 (m, 2H), 7.08 – 7.03 (m, 1H), 4.66 (d, J = 6.4 Hz, 1H), 4.63 – 4.55 (m, 1H), 4.38 – 4.18 (m, 3H), 3.15 (dt, J = 12.9, 2.6 Hz, 1H), 3.10 – 2.99 (m, 2H), 2.93 (t, J = 7.1 Hz, 2H), 2.78 – 2.67 (m, 2H), 2.61 (dq, J = 15.9, 5.4 Hz, 1H), 2.48 (s, 3H), 2.33 (q, J = 9.1 Hz, 1H), 2.17 – 1.91 (m, 8H), 1.88 – 1.61 (m, 5H), 1.54 – 1.24 (m, 2H). Preparation of Compound 1-50 (4-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-2-(1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethoxy)spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Step 1. Intermediate 2-35 (allyl 8-(2-methylsulfinylspiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 38.9mg, 0.079mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (16.7mg, 0.118mmol) were dissolved in anhydrous THF (500µL), cooled to -40 °C, and KotBu, 1M in THF (95µL) was added dropwise. After 15min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→100% EtOAc+2% Et₃N in hexanes+2%Et3N to give allyl 8-[2-(1,2,3,5,6,7-hexahydropyrrolizin-8- ylmethoxy)spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (36.2mg, 80.5%) as a white foam. LC/MS, ESI [M+H]+ = 570.3 m/z. Step 2. Allyl 8-[2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (36.2mg, 0.0635mmol) was dissolved in THF (500µL) and treated with 4-methylpiperidine (150µL, 1.27mmol) and PhSiH₃ (39µL, 0.32mmol) and the mixture was gently sparged with N₂ for 2min then amended with Pd(PPh₃)₄ (3.7mg, 0.0032mmol) and stirred for 40min. The reaction was carefully diluted with 2N HCl (2mL) and washed with Et2O. The aqueous phase was purified by preparative HPLC to give the title compound (25.8mg, 83.6%) as a white solid. LC/MS, ESI [M+H]⁺ = 460.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.18 (m, 1H), 7.18 – 7.09 (m, 2H), 7.09 – 7.03 (m, 1H), 4.70 – 4.62 (m, 1H), 4.61 – 4.55 (m, 1H), 4.07 (s, 2H), 3.14 (dd, J = 12.9, 2.0 Hz, 1H), 3.10 – 2.99 (m, 3H), 2.94 (t, J = 7.2 Hz, 2H), 2.77 – 2.55 (m, 8H), 2.14 – 1.64 (m, 16H). Schematization for the Preparation of Intermediates 2-38 through 2-40

Intermediate 2-24 Intermediate 2-38 Intermediate 2-39

Intermediate 2-40 Preparation of Intermediate 2-38 (tert-Butyl 3-(2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) Intermediate 2-24 (2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-4’-yl trifluoromethanesulfonate; 244.9mg, 0.569mmol) was dissolved in anhydrous DMF (2mL) and treated with iPr₂EtN (200µL, 1.73mmol) and tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (135.4mg, 0.683mmol) at rt. After 13hr, the mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (277mg, quant.) as a white foam. Rf = 0.34 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 479.2 m/z. Preparation of Intermediate 2-39 (tert-Butyl 3-(2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro- 6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) Intermediate 2-38 (tert-butyl 3-(2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 277.mg, 0.579mmol) was dissolved in DCM (3.5mL) and treated with mCPBA (179.8mg, 0.521mmol) at 0°C. The mixture was diluted with Et2O and washed with half-saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (286.7mg, quant.) as a white foam. LC/MS, ESI [M+H]⁺ = 495.2 m/z. Preparation of Intermediate 2-40 (tert-Butyl 3-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate) Intermediate 2-39 (tert-butyl 3-(2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 128.6mg, 0.260mmol) was dissolved in anhydrous THF (800µL) and cooled to -40 °C and a solution of [(2S)-pyrrolidin-2-yl]methanol (52.6mg, 0.520mmol) and KotBu, 1M in THF (338µL) in THF (500µL) was added dropwise. After 15min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (145.3 mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 532.3 m/z. Preparation of Compound 1-51 (4’-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2’-(((S)- pyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-40 (tert-butyl 3-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate; 46.3mg, 0.087mmol) was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (25.1 mg, 66.9%) as a white foam. LC/MS, ESI [M+H]⁺ = 432.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.24 – 7.19 (m, 1H), 7.17 – 7.07 (m, 3H), 4.38 – 4.20 (m, 3H), 4.17 – 4.04 (m, 2H), 4.01 – 3.93 (m, 1H), 3.80 – 3.71 (m, 2H), 3.52 (qd, J = 7.4, 5.1 Hz, 1H), 3.09 – 2.85 (m, 6H), 2.78 – 2.63 (m, 3H), 2.09 – 1.71 (m, 7H), 1.71 – 1.55 (m, 2H). Preparation of Compound 1-52 (4’-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2’-(((S)-1- methylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-40 (tert-butyl 3-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate; 46.3mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.087mmol), formaldehyde, 37% aqueous (19µL, 0.26mmol), and NaBH(Oac)3 (55.3mg, 0.261mmol) at rt for 13hr. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (25.6mg, 66.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 446.3 m/z.¹H NMR (400 MHz, MeOD) δ 7.25 – 7.05 (m, 4H), 4.36 (ddd, J = 10.9, 6.1, 2.1 Hz, 1H), 4.32 – 4.23 (m, 2H), 4.18 – 4.04 (m, 2H), 4.01 – 3.93 (m, 1H), 3.80 – 3.71 (m, 2H), 3.13 – 2.89 (m, 5H), 2.77 – 2.63 (m, 4H), 2.49 (s, 3H), 2.32 (q, J = 9.1 Hz, 1H), 2.16 – 1.92 (m, 4H), 1.88 – 1.59 (m, 5H). Preparation of Compound 1-53 (4’-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2’-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) Intermediate 2-40 (tert-butyl 3-(2’-(((S)-pyrrolidin-2-yl)methoxy)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate; 46.3mg, 0.087mmol) was dissolved in THF (870µL) and treated with AcOH (5µL, 0.087mmol), acetone (19.3µL, 0.260mmol), and NaBH(Oac)₃ (55.3mg, 0.261mmol) at rt for 13hr. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et₂O. The aqueous phase was purified by preparative HPLC to give the title compound (26.8mg, 65.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 474.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.24 – 7.18 (m, 1H), 7.17 – 7.08 (m, 3H), 4.32 (ddd, J = 10.6, 4.8, 1.6 Hz, 1H), 4.30 – 4.24 (m, 1H), 4.17 – 4.03 (m, 3H), 3.96 (d, J = 12.5 Hz, 1H), 3.74 (d, J = 6.3 Hz, 2H), 3.22 (tt, J = 8.3, 3.9 Hz, 1H), 3.10 – 2.87 (m, 6H), 2.74 (s, 2H), 2.68 (dt, J = 9.0, 6.1 Hz, 1H), 2.59 (td, J = 9.1, 7.1 Hz, 1H), 2.07 – 1.86 (m, 4H), 1.85 – 1.70 (m, 4H), 1.67 (d, J = 9.0 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H), 1.07 (dd, J = 6.4, 1.3 Hz, 3H). Preparation of Compound 1-54 (4’-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2’-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) Intermediate 2-39 (tert-butyl 3-(2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 40.5mg, 0.0819mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (17.3mg, 0.123mmol) were dissolved in anhydrous THF (500µL) and cooled to -40 °C then KotBu, 1M in THF (100µL) was added dropwise. After 20min, HPLC analysis showed complete conversion to a major product. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with 4N HCl in dioxane (0.5mL) at rt for 60min then diluted with H₂O and washed with Et2O. The aqueous phase was filtered and purified by preparative HPLC to give the title compound (27.6mg, 71.5%) as a white foam. LC/MS, ESI [M+H]⁺ = 472.3 m/z. ¹H NMR (400 MHz, MeOD) δ 7.24 – 7.18 (m, 1H), 7.17 – 7.08 (m, 3H), 4.31 – 4.23 (m, 1H), 4.18 – 4.04 (m, 4H), 3.97 (dt, J = 13.0, 1.4 Hz, 1H), 3.74 (d, J = 6.1 Hz, 2H), 3.10 – 2.89 (m, 6H), 2.75 (s, 2H), 2.68 (ddd, J = 10.5, 7.2, 6.1 Hz, 3H), 2.08 – 1.63 (m, 13H). Schematization for the Preparation of Intermediates 2-41 through 2-48

Intermediate 2-41 Intermediate 2-42

Intermediate 2-43 Intermediate 2-44

Intermediate 2-45 Intermediate 2-46

Intermediate 2-47 Intermediate 2-48 Preparation of Intermediate 2-41 (2-(4-Chloro-2,3-dihydro-1H-inden-1- ylidene)malononitrile) 4-Chloroindan-1-one (30.0g, 180mmol) was dissolved in EtOH (180mL) and treated with malononitrile (17.85g, 270mmol), AcOH (20.6mL, 360mmol), and NH₄Oac (13.9g, 180mmol) at rt for 17hrs. The mixture was diluted with 1N HCl (180mL) and stirred for 5min and the solids were collected by filtration and washed with H₂O, 1:1 hexanes:EtOH, 100% hexanes, and dried under suction then further dried in vacuo at 50ºC to give the title compound (37.42g, 96.8%) as a tan colored powder. LC/MS, ESI [M-H]- = 213.0/215.0 m/z (3:1).¹H NMR (400 MHz, CDCl3) δ 8.31 (dd, J = 7.9, 0.9 Hz, 1H), 7.60 (dd, J = 7.9, 0.9 Hz, 2H), 7.42 (tt, J = 7.9, 0.8 Hz, 2H), 3.36 – 3.28 (m, 3H), 3.25 – 3.17 (m, 3H). Preparation of Intermediate 2-42 (2-(4-Chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)malononitrile) A 2L round bottom flask was charged with CuBr•Me₂S (3.58g, 17.4mmol) and evacuated and backfilled with N2 (x3) then amended with anhydrous THF (30mL) and cooled to -78°C. Pent-4-en-1-ylmagnesium bromide, 0.5M in THF (590mL) was added and the mixture was stirred for 15min then a suspension of Intermediate 2-41 (2-(4-chloroindan-1- ylidene)propanedinitrile; 37.4g, 174mmol) in anhydrous THF (30mL) was added. The cooling bath was removed and the mixture was allowed to warm to 0ºC and held at the same temperature. After 5hrs, the reaction was quenched by addition of sat NH₄Cl (150mL). The mixture was filtered and the filtrate was washed with sat NH₄Cl (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, and concentrated. The residue was taken up in 8:2 hexanes:EtOAc and again filtered through a thin pad of silica gel rinsing with the same. The filtrate was concentrated to give the title compound (49.89 g, quant.) as a red colored viscous oil. Rf = 0.68 (toluene). LC/MS, ESI [M-H]- = 283.1/285.1 m/z (3:1).¹H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 7.6, 1.4 Hz, 1H), 7.25 (tt, J = 7.6, 0.9 Hz, 1H), 7.21 (dd, J = 7.6, 1.4 Hz, 1H), 5.72 (ddt, J = 17.0, 10.3, 6.8 Hz, 1H), 5.05 – 4.95 (m, 2H), 3.19 – 2.97 (m, 2H), 2.42 – 2.22 (m, 2H), 2.16 – 1.87 (m, 5H), 1.48 – 1.30 (m, 1H), 1.24 – 1.09 (m, 1H).¹³C NMR (101 MHz, CDCl3) δ 143.64, 142.15, 137.46, 131.61, 129.30, 129.06, 121.83, 115.76, 111.90, 111.87, 55.17, 36.53, 33.74, 33.62, 33.58, 29.71, 23.62. Preparation of Intermediate 2-43 (Methyl 2-(4-chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H- inden-1-yl)acetate) In a PFA round bottom flask, Intermediate 2-42 (2-(4-Chloro-1-(pent-4-en-1-yl)- 2,3-dihydro-1H-inden-1-yl)malononitrile; 24.8g, 87.1mmol) was treated with ethylene glycol (75mL), H₂O (35mL), and KOH (69g, 1.05mol) and heated to 190 °C under N₂ for 22hrs. The mixture was cooled slightly then poured into chipped ice (750g) containing H₂SO₄ (37.5mL, 0.70mol), amended with EtOAc (500mL) and vigorously mixed for 5min then filtered. The organic phase was collected and the aqueous was extracted with EtOAc (500mL). The combined extract was washed with H₂O (x2), brine, dried over Na₂SO₄, filtered, and concentrated. The residue was heated to 200°C under N2 atmosphere for 20min then cooled to rt. The material was dissolved in MeOH (175mL), cooled to 0°C, and acetyl chloride (37.5mL, 0.525mmol) was added dropwise. The mixture was then warmed to 45ºC for 2hrs then concentrated, diluted with toluene, and washed with H₂O. The aqueous was extracted with Et2O (x2), and the combined extract was washed with brine, dried over Na₂SO₄, and filtered. The solvent was exchanged to 8:2 hexanes:EtOAc and the mixture was filtered through a thin pad of silica gel and concentrated to give the title compound (19.74g, 77.4%) as an dark red oil. Rf = 0.49 (9:1 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 293.1/295.1 m/z (3:1). Preparation of Intermediate 2-44 (Methyl 2-(4-chloro-1-(4-oxobutyl)-2,3-dihydro-1H- inden-1-yl)acetate) Intermediate 2-43 (methyl 2-(4-chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)acetate; 19.74g, 67.42mmol) was dissolved in DCM (330mL) and cooled to -78 °C then ozone was passed through the solution for 70min. Ozone introduction was halted and the mixture was sparged with N2 for 5min then PPh3 (22.92g, 87.4mmol) was added and the mixture was allowed to warm to rt and stirred for 4.5hrs. The mixture was diluted with hexanes (140mL), filtered through a pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 100% hexanes followed by 20→30% EtOAc in hexanes to give the title compound (16.10g, 81.0%) as a yellow-orange oil. LC/MS, ESI [M+H]⁺ = 295.1/297.1 m/z (3:1). Preparation of Intermediate 2-45 (Methyl 4-(4-chloro-1-(2-methoxy-2-oxoethyl)-2,3- dihydro-1H-inden-1-yl)butanoate) Intermediate 2-44 (methyl 2-(4-chloro-1-(4-oxobutyl)-2,3-dihydro-1H-inden-1- yl)acetate; 32.19g, 109.2mmol) was dissolved in tBuOH (110mL) and treated with H₂O (110mL), 2-methyl-2-butene (58mL, 548mmol), and KH₂PO₄ (53.5g, 328mmol) and stirred vigorously at 0°C then NaClO2 (29.6g, 327mmol) was added in several portions over a period of approximately 15min. After 45min, the mixture was poured into 5% NaHSO4 and extracted with EtOAc (x2). The combined extract was washed with 5% Na₂S₂O₃, brine, dried over Na2SO4, filtered, and concentrated. The residue was taken up in MeOH (280mL), cooled to 0°C, and acetyl chloride (60mL, 841mmol) was added dropwise then the mixture was warmed to 45ºC for 5hrs. The mixture was concentrated, taken up toluene, washed with H₂O, brine, dried over Na₂SO₄, filtered, and concentrated. The residue was reconstituted in 85:15 hexanes:EtOAc, and filtered through a thin pad of silica gel rinsing with the same. The filtrate was concentrated to give the title compound (34.3g, 96.7%) as a pale yellow oil. Rf = 0.26 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 325.1/327.1 m/z (3:1). Preparation of Intermediate 2-46 (Methyl 4’-chloro-3-oxo-2’,3’-dihydrospiro[cyclohexane- 1,1’-indene]-4-carboxylate) A 1L flask fitted with an addition funnel was charged with NaH (12.67g, 316.8mmol) and evacuated and backfilled with N2 (x3) then amended with anhydrous toluene (300mL) and anhydrous MeOH (2.2ml) and heated to 70 °C. The addition funnel was charged with a solution of Intermediate 2-45 (methyl 4-(4-chloro-1-(2-methoxy-2-oxoethyl)-2,3- dihydro-1H-inden-1-yl)butanoate; 34.28g, 105.6mmol) in anhydrous toluene (230mL) containing MeOH (2.1mL) and this solution was added dropwise over a period of 2.5hrs. The mixture was heated for 11hrs then cooled and poured into a stirred solution of half saturated NH4Cl and EtOAc. The aqueous phase was neutralized be the addition of solid NaHSO4 and the organic phase was collected. The aqueous was extracted with EtOAc once and the combined extract was washed with sat NH₄C1, brine, dried over Na₂SO₄, filtered through a pad of Celite, and concentrated to give the title compound (35.4g, >100%) as a red oil which crystallized upon standing and was used without purification. LC/MS, ESI, [M+H]⁺ = 293.1/295.1 m/z (3:1). Preparation of Intermediate 2-47 (4-Chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-3’H- spiro[indene-1,7’-quinazolin]-4’(6’H)-one) Intermediate 2-46 (methyl 4’-chloro-3-oxo-2’,3’-dihydrospiro[cyclohexane-1,1’- indene]-4-carboxylate; 30.9g, 105.6mmol) was dissolved in anhydrous MeCN (350mL) and treated with thiourea (10.46g, 137.4mmol) and DBU (19mL, 127.3mmol) and heated to reflux under N₂ for 18hrs. The mixture was cooled slightly and reduced to approximately one-third the initial volume by then poured into stirred one-third saturated NaHCO3 (600mL) at 0ºC. The resulting precipitate was collected by filtration and washed with H₂O (x2), hexanes (x2), and freed of excess water under suction. The solids were dissolved in a mixture of DMSO (100mL), DMF (300mL), and THF (200mL) then treated with NaOAc (17.32g, 211.1mmol) followed by MeI (6.5mL, 104mmol). After 25min, the mixture was reduced to approximately 200mL by rotary evaporation then carefully poured into stirred ice-cold one- third saturated NaHCO₃ (600mL) containing hexanes (100mL). The resulting precipitate was collected by filtration and washed with H₂O (x3), 8:2 hexanes:EtOH (3x50mL), and hexanes (x2) then dried under suction and further dried in vacuo at 50ºC to give the title compound (24.43g, 69.5%) as a tan colored powder. LC/MS, ESI [M+H]⁺ = 333.1/335.0 m/z (3:1).¹H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.27 – 7.23 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.11 (dd, J = 7.1, 1.4 Hz, 1H), 2.93 (t, J = 7.3 Hz, 2H), 2.71 (dt, J = 17.8, 1.9 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.44 (s, 5H), 2.02 – 1.81 (m, 3H), 1.72 – 1.61 (m, 1H). Preparation of Intermediate 2-48 (4-Chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) Intermediate 2-47 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-3’H-spiro[indene- 1,7’-quinazolin]-4’(6’H)-one; 2.17g, 6.51mmol) was suspended in anhydrous DCM (32mL) and treated with iPr2EtN (3.4mL, 19.5mmol). The mixture was cooled to 0°C and triflic anhydride (1.6mL, 9.5mmol) was added dropwise. After 15min, the mixture was diluted with 1vol hexanes and filtered through a pad of silica gel rinsing with 8:2 hexanes:EtOAc. The filtrate was concentrated to give the title compound (2.61g, 86.1%) as a pale yellow solid. LC/MS, ESI [M+H]⁺ = 465.0/467.0 m/z (~3:1). Preparation of (R)-1-phenylethan-1-aminium (R)-2-(4-chloro-1-(pent-4-en-1-yl)-2,3- dihydro-1H-inden-1-yl)acetate

(rac)-2-(4-chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetic acid (230 g, 825 mmol) was added to a vessel and dissolved in ethyl acetate (460 mL). The solution was heated to 45–55 ^C and (S)-methylbenzylamine (110 g, 1.1 equiv) was added over 30 min. The resulting mixture was stirred for 1 h at 45–55 ^C, then cooled to 38–42 ^C. Product seed (1.72 g, 0.005 equiv) was added and the reaction mixture was allowed to cool to 20–25 ^C over 2–3 h. The reaction was stirred at this temperature for 12–16 h, then filtered. The filter cake was washed with ethyl acetate (460 mL), which was combined with the mother liquor. The combined mother liquor was washed with citric acid solution (10 wt%, 2.3 L). The organic phase was concentrated to 1.5–2.0 V under reduced pressure, ethyl acetate (2.53 L) was added and the solution was warmed to 45–55 ^C. (R)-methylbenzylamine (79.98 g, 0.8 equiv) was added over 30 min and the reaction was allowed to stir for 1 h. The mixture was cooled to 38–42 ^C and crystalline seed material (1.72 g, 0.005 equiv) was added. The suspension was cooled to 20–25 ^C over 2–3 h and allowed to stir at this temperature for 12–16 h. The solid was collected by filtration and rinsed with ethyl acetate (460 mL). The solid was dried under vacuum to afford (R)-1-phenylethan-1-aminium (R)-2- (1-(3-carboxypropyl)-4-chloro-2,3-dihydro-1H-inden-1-yl)acetate (94.3 g, 27.3%, 95.5% ee). Uses for (R)-1-phenylethan-1-aminium (R)-2-(4-chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H- inden-1-yl)acetate Following the procedures of Preparation of Intermediates 2-41 through 2-48 or Preparation of Intermediate 2-8 Analogs, (R)-1-phenylethan-1-aminium (R)-2-(4-chloro-1- (pent-4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetate is used for the synthesis of compounds described herein after treatment with strong base to yield free acid, (R)-2-(4-chloro-1-(pent- 4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetic acid. More specifically, (R)-2-(4-chloro-1- (pent-4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetic acid can be used in Step 4 of Preparation of Intermediates 2-41 through 2-48 in place of Intermediate 2-43 for the synthesis of compounds described herein. Also more specifically, (R)-2-(4-chloro-1-(pent-4-en-1-yl)-2,3- dihydro-1H-inden-1-yl)acetic acid can be used in Step 4 of Preparation of Intermediate 2-8 Analogs for the enantioenriched synthesis of compounds described herein. Enantioenriched forms of Intermediate 2-47 are afforded with the use of (R)-2-(4- chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetic acid to make the respective starting material for each intermediate (see Step A of Preparation of Intermediate 2-48F’ ((1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline])). Preparation of Intermediate 2-48F’ ((1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline])

Intermediate 2-47’ Intermediate 2-48F’ Step A: (S)-4,4'-dichloro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline] Intermediate 2-47’ was made by following the procedures of Preparation of Intermediates 2-41 through 2-48 and beginning at Step 4 (Preparation of Intermediate 2- 44) while using (R)-2-(4-chloro-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1-yl)acetic acid as the starting material. (R)-4-chloro-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene-1,7'-quinazolin]- 4'(6'H)-one was suspended in DCE (1.5mL, 19mmol) and TEA (90.2mg, 0.89mmol), and was treated with POCl3 (453.2mg, 2.96mmol) at RT. The reaction was slightly exothermic. The reaction was stirred at RT, then warmed to 60°C for 3 hours. LC/MS showed conversion to a new peak. The reaction was poured into 1N NaOH aqueous (20mL), stirred 10 min, and washed three times with DCM (10mL portions). The combined organic was dried over Na₂SO₄, filtered and concentrated on a rotovap. The mixture was wet loaded with DCM and purified by flash silica gel chromatography (12G ISCO Column, 0-50% Hex/EA) to give the title compound (225mg, 86.7% yield) as a white solid. Step B: Intermediate 2-48F’ ((1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline]) To a dry 250 mL round-bottom flask containing a magnetic stirbar under nitrogen was added (S)-4,4'-dichloro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline] (10.18 g, 95.03 wt% potency, 27.54 mmol). The solid was dissolved in tetrahydrofuran (104 mL) and the flask was cooled to 0 ^C in an ice water bath. Lithium diisopropylamide (2M, 17.9 mL, 35.8 mmol, 1.3 equiv) was added over 10 min and the solution was then cooled to –78 ^C in a dry ice/acetone bath. To a dry 100 mL heart-shaped flask under nitrogen was added N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (11.17 g, 35.4 mmol, 1.3 equiv), which was dissolved in tetrahydrofuran (52 mL) and added dropwise to the first solution over 10 min. The reaction was stirred for 1 h and then quenched with saturated aqueous ammonium chloride (10 mL). The mixture was allowed to warm to 23 ^C and partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were agitated and separated and the organic layer was washed with water (50 mL) and brine (50 mL). The solution was dried over sodium sulfate, filtered, and concentrated in vacuo to a semi solid foam. The residue was dissolved in acetone (91 mL) and stirred at 23 ^C. Water (10 mL) was added dropwise followed by product seed material (101 mg, 0.275 mmol, 0.01 equiv) and the solution was allowed to age over 12 h, during which a white slurry developed. Water (21 mL) was added over 15 min and the mixture was allowed to stir for 2 h. The solid was filtered and rinsed with 1:1 acetone:water (20 mL). The isolated white solid was dried over 12 h under vacuum at 70 ^C to render the title compound (7.91 g, 89.4 wt% potency, 19.15 mmmol, 69.5% yield). Preparation of Compound 1-91 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-bromo-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline]) Compound 1-91 was prepared following the general procedures used to prepare Compound 1-65 and using 4-bromo-2,3-dihydro-1H-inden-1-one instead of 4-chloro-2,3- dihydro-1H-inden-1-one when synthesizing Intermediate 2-48. LC/MS, ESI [M+H]⁺ = 564/566 m/z. ¹H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 4.33 (s, 2H), 3.91 – 3.69 (m, 4H), 3.58 (dt, J = 12.0, 6.4 Hz, 2H), 3.31 (dd, J = 36.9, 12.8 Hz, 2H), 3.11 – 2.91 (m, 2H), 2.84 (h, J = 6.6 Hz, 4H), 2.70 – 2.40 (m, 2H), 2.27 (dtd, J = 13.1, 6.5, 3.1 Hz, 2H), 2.18 – 1.78 (m, 13H), 1.71 (dq, J = 13.0, 6.4 Hz, 1H). Preparation of Compound 1-92 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4- cyclopropyl-2'-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazoline]) Compound 1-92 was prepared following the general procedures used to prepare Compound 1-91, except that a Negishi coupling was performed before the last step (i.e., before deprotection of the diazabicyclo with TFA). The Negishi coupling was performed using cycloproylzinc(II)bromide. LC/MS, ESI [M+H]⁺ = 526.2 m/z. ¹H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 4.60 (s, 2H), 4.30 (s, 2H), 4.03 – 3.63 (m, 4H), 3.42 – 3.08 (m, 2H), 3.00 (dt, J = 10.1, 6.7 Hz, 4H), 2.88 (d, J = 10.3 Hz, 2H), 2.67 – 2.47 (m, 2H), 2.44 – 2.33 (m, 2H), 2.23 (dp, J = 13.5, 6.7 Hz, 3H), 2.17 – 1.81 (m, 11H), 1.71 (dt, J = 12.1, 5.4 Hz, 1H), 0.99 – 0.86 (m, 2H), 0.74 – 0.62 (m, 2H). Preparation of Compound 1-93 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline]-4-carbonitrile) Compound 1-93 was prepared following the general procedures used to prepare Compound 1-91, except that a Negishi coupling was performed before the last step (i.e., before deprotection of the diazabicyclo with TFA). The Negishi coupling was performed using dicyanozinc. LC/MS, ESI [M+H]⁺ = 511.1 m/z. ¹H NMR (400 MHz, MeOD) δ 7.52 (dd, J = 7.6, 3.0 Hz, 1H), 7.42 (dd, J = 7.7, 2.9 Hz, 1H), 7.33 (td, J = 7.7, 3.1 Hz, 1H), 4.79 – 4.48 (m, 3H), 4.44 (d, J = 14.1 Hz, 1H), 4.15 (s, 3H), 3.75 (d, J = 14.1 Hz, 1H), 3.68 – 3.50 (m, 5H), 3.12 (ddd, J = 14.5, 7.2, 3.7 Hz, 6H), 2.86 (d, J = 3.1 Hz, 2H), 2.65 (d, J = 16.0 Hz, 1H), 2.31 – 1.94 (m, 12H), 1.87 – 1.71 (m, 1H). Preparation of Compound 1-94 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-ethyl-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline]) Compound 1-94 was prepared following the general procedures used to prepare Compound 1-91, except that a Suzuki coupling was performed before the last step (i.e., before deprotection of the diazabicyclo with TFA). The Suzuki coupling was performed using triethylborane. LC/MS, ESI [M+H]⁺ = 514 m/z. Preparation of Compound 1-95 (((3S,7aS)-7a-(((4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-4-chloro-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-2'- yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate), Compound 1-96 (((3S,7aS)-7a-(((4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-2'-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3- yl)methanol), and Compound 1-97 (((3S,7aS)-7a-(((4'-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazolin]-2'-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl acetate) The triflate of Intermediate 2-47’ was used to synthesize the desired diasteromer of Intermediate 2-56 by following the general procedures of Preparation of Intermediate 2-55 and then the general procedures of Preparation of Intermediate 2-56. The desired diastereomer of Intermediate 2-56 was then used while following the general procedures for the synthesis of Compound 1-65, except that ((3S,7aS)-3-(((tert- butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol was used instead of (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, and before the last step (i.e., before deprotection of the diazabicyclo with TFA), the intermediate product was treated with TBAF and then dimethylcarbamic chloride. Compounds 1-95, 1-96 and 1-97 were then separated by HPLC. Compound 1-95: LC/MS, ESI [M+H]⁺ = 621 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.13 (m, 2H), 7.08 – 7.00 (m, 1H), 4.57 – 4.35 (m, 2H), 4.30 (ddd, J = 12.3, 7.8, 5.0 Hz, 1H), 4.24 – 4.09 (m, 3H), 3.99 (dd, J = 14.2, 6.5 Hz, 1H), 3.87 – 3.66 (m, 1H), 3.61 – 3.40 (m, 2H), 3.35 (d, J = 4.0 Hz, 1H), 3.01 (td, J = 6.9, 2.7 Hz, 2H), 2.97 – 2.88 (m, 3H), 2.85 (d, J = 3.1 Hz, 4H), 2.80 (t, J = 4.5 Hz, 1H), 2.66 (dt, J = 16.1, 5.1 Hz, 1H), 2.39 (dt, J = 8.5, 5.0 Hz, 1H), 2.33 – 2.00 (m, 16H), 1.99 (s, 1H), 1.90 – 1.75 (m, 1H). Compound 1-96: LC/MS, ESI [M+H]⁺ = 550 m/z. ¹H NMR (400 MHz, MeOD) δ 7.25 – 7.14 (m, 2H), 7.06 (dd, J = 6.8, 1.7 Hz, 1H), 4.19 (s, 2H), 4.08 (d, J = 12.8 Hz, 1H), 3.83 (d, J = 12.8 Hz, 1H), 3.65 (s, 2H), 3.60 (d, J = 5.5 Hz, 2H), 3.19 – 2.89 (m, 7H), 2.84-2.70 (m, 3H), 2.67 – 2.54 (m, 1H), 2.26 – 2.20 (m, 1H), 2.18 – 1.70 (m, 16H). Compound 1-97: LC/MS, ESI [M+H]⁺ = 592 m/z. ¹H NMR (400 MHz, MeOD) δ 7.24 – 7.13 (m, 2H), 7.04 (dt, J = 6.9, 1.7 Hz, 1H), 4.24 – 3.86 (m, 7H), 3.50 – 3.42 (m, 1H), 3.32 – 3.24 (m, 1H), 3.19 – 3.04 (m, 1H), 3.00 (t, J = 7.2 Hz, 2H), 2.92 (dt, J = 10.7, 5.4 Hz, 1H), 2.86 – 2.73 (m, 3H), 2.63 (dt, J = 16.1, 5.0 Hz, 1H), 2.26 – 2.15 (m, 2H), 2.15 – 1.86 (m, 16H), 1.85 – 1.65 (m, 3H). Preparation of Compound 1-98 (((3S,7aS)-7a-(((4-chloro-4'-((1R,5S)-8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-2'- yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate) Compound 1-98 was prepared by treating Compound 1-95 with formaldehyde. LC/MS, ESI [M+H]⁺ = 635.1 m/z.¹H NMR (400 MHz, MeOD) δ 7.38 – 7.11 (m, 2H), 7.05 (d, J = 7.2 Hz, 1H), 4.64 – 4.47 (m, 1H), 4.36 (d, J = 14.4 Hz, 1H), 4.10 (d, J = 26.9 Hz, 3H), 3.89 (dd, J = 12.2, 3.8 Hz, 1H), 3.78 (dt, J = 12.4, 6.3 Hz, 1H), 3.71 – 3.51 (m, 4H), 3.50 – 3.36 (m, 5H), 3.02 (t, J = 7.3 Hz, 2H), 2.96-2.76 (m, 6H), 2.68 (d, J = 16.7 Hz, 1H), 2.45 – 2.22 (m, 5H), 2.22 – 1.96 (m, 13H), 1.85 (d, J = 12.8 Hz, 1H). Preparation of Compound 1-99 (4-bromo-4'-((1R,5S)-8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)-2'-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline]) Compound 1-99 was prepared by treating Compound 1-91 with formaldehyde. LC/MS, ESI [M+H]⁺ = 579 m/z. Preparation of Compound 1-100 ((1S,8'R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4-chloro-8'-fluoro-2'-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro- 6'H-spiro[indene-1,7'-quinazoline]) Compound 1-100 was prepared following the general procedures used to prepare Compound 1-65 and using Intermediate 2-48F’ instead of Intermediate 2-48. LC/MS, ESI [M+H]⁺ = 538.3/540.3 m/z (3:1). ¹H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 5.11 (d, J = 48.3 Hz, 1H), 4.13 (q, J = 10.4 Hz, 2H), 3.93 – 3.77 (m, 2H), 3.56 (d, J = 9.0 Hz, 2H), 3.25 – 2.91 (m, 8H), 2.73 – 2.56 (m, 3H), 2.52 – 2.35 (m, 2H), 2.21 – 2.02 (m, 3H), 1.96 – 1.76 (m, 9H), 1.68 (dt, J = 12.6, 7.5 Hz, 2H).¹⁹F NMR (376 MHz, CDCl₃) δ -178.12. Preparation of Compound 1-101 ((1S,8'R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4-chloro-8'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]) Compound 1-101 was prepared following the general procedures used to prepare Compound 1-66 and using Intermediate 2-48F’ instead of Intermediate 2-48. LC/MS, ESI [M+H]⁺ = 556.3/558.3 m/z (3:1). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 5.35 – 5.01 (m, 2H), 4.13 – 3.98 (m, 2H), 3.92 – 3.76 (m, 2H), 3.68 – 3.56 (m, 2H), 3.31 – 3.11 (m, 6H), 3.11 – 2.89 (m, 5H), 2.71 – 2.55 (m, 1H), 2.50 – 2.35 (m, 2H), 2.32 – 2.02 (m, 5H), 2.02 – 1.87 (m, 6H).¹⁹F NMR (376 MHz, CDCl₃) δ -173.18, -177.68. Preparation of Compound 1-102 ((R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4- chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline]) Compound 1-102 was prepared following the general procedures used to prepare Compound 1-66 and using the triflate form of Intermediate 2-47’ instead of Intermediate 2-48. LC/MS, ESI [M+H]⁺ = 538.3/540.3 m/z (3:1).¹H NMR (400 MHz, CDCl₃) δ 7.17 (dd, J = 7.9, 1.0 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.91 (dd, J = 7.5, 1.0 Hz, 1H), 5.21 (d, J = 54.1 Hz, 1H), 4.09 (d, J = 10.2 Hz, 1H), 3.94 (d, J = 10.2 Hz, 1H), 3.86 (d, J = 12.4 Hz, 1H), 3.72 (d, J = 12.4 Hz, 1H), 3.65 – 3.54 (m, 2H), 3.29 – 3.18 (m, 3H), 3.18 – 3.07 (m, 2H), 3.03 – 2.91 (m, 3H), 2.91 – 2.78 (m, 2H), 2.69 – 2.44 (m, 3H), 2.32 – 2.08 (m, 3H), 2.08 – 1.98 (m, 2H), 1.98 – 1.76 (m, 8H), 1.71 (dt, J = 12.0, 5.5 Hz, 1H).¹⁹F NMR (376 MHz, CDCl3) δ - 173.22. Preparation of Compound 1-103 ((1S,8'R)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4-chloro-8'-fluoro-2'-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazoline]) Compound 1-103 was prepared following the general procedures used to prepare Compound 1-63 and using Intermediate 2-48F’ instead of Intermediate 2-48. LC/MS and NMR characterization performed with the TFA salt. LC/MS, ESI [M+H]⁺ = 512.3 m/z. ¹H NMR (400 MHz, DMSO) δ 7.33 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 5.37 (d, J = 48.2 Hz, 1H), 4.60 (dd, J = 12.5, 3.5 Hz, 1H), 4.47 (dd, J = 12.3, 6.5 Hz, 1H), 4.10 (d, J = 14.7 Hz, 4H), 3.90 (d, J = 13.7 Hz, 2H), 3.78 (s, 1H), 3.67 – 3.55 (m, 1H), 3.41 (d, J = 13.6 Hz, 1H), 3.28 (d, J = 13.6 Hz, 1H), 3.20 – 3.07 (m, 1H), 3.05 – 2.93 (m, 4H), 2.90 – 2.76 (m, 1H), 2.27 (dq, J = 13.0, 6.5 Hz, 2H), 2.15 – 2.01 (m, 4H), 2.00 – 1.78 (m, 6H). Preparation of Intermediate 2-48F (rac-(1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline])

Intermediate 2-48F Step A: 4,4'-dichloro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline] 4-chloro-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene-1,7'-quinazolin]- 4'(6'H)-one (246mg, 0.74mmol) was suspended in DCE (1.5mL, 19mmol) and TEA (90.2mg, 0.89mmol), and was treated with POCl3 (453.2mg, 2.96mmol) at RT. The reaction was slightly exothermic. The reaction was stirred at RT, then warmed to 60°C for 3 hours. LC/MS showed conversion to a new peak. The reaction was poured into 1N NaOH aqueous (20mL), stirred 10 min, and washed three times with DCM (10mL portions). The combined organic was dried over Na2SO4, filtered and concentrated on a rotovap. The mixture was wet loaded with DCM and purified by flash silica gel chromatography (12G ISCO Column, 0-50% Hex/EA) to give the title compound (225mg, 86.7% yield) as a white solid. Step B: rac-(1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazoline] Three vials were flame dried under vacuum and cooled under nitrogen atmosphere. The first was charged with N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (150.81mg, 0.48mmol), the second with (S)-4,4'-dichloro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H- spiro[indene-1,7'-quinazoline] (112mg, 0.32mmol), and the third with LDA (0.24mL, 0.48mmol). The LDA-containing vial was cooled to -78°C in an acetone dry ice bath. Heating was needed to dissolve the substrate in 2mL THF. The N-(benzenesulfonyl)-N-fluoro- benzenesulfonamide dissolved readily in 1mL THF. The substrate was added dropwise to the LDA solution via syringe. A color change from orange to clear solution occurred. The reaction was stirred 45 min and then allowed to come to RT for 5 min followed by re-cooling and injection of the fluoro reagent by syringe. The reaction became cloudy and yellow, then clear-yellow after warming to RT. After 15 mins, 1N NaOH and EtOAc were added (10 volumes each). The organic was separated and concentrated onto silica gel. The mixture was purified by flash chromatography (10-50% EtOAc/Hexanes). The product was barely retained and eluted in 2 column volumes to give the title compound (as a mixture of epimers). LC/MS, ESI [M+H] = 369 amu.¹H NMR (400 MHz, CDCl3): δ 7.32 – 7.15 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.69 (dd, J = 7.5, 0.9 Hz, 1H), 5.27 (d, J = 48.2 Hz, 1H), 3.15 – 2.94 (m, 2H), 2.94 – 2.80 (m, 1H), 2.78 – 2.65 (m, 1H), 2.58 (s, 3H), 2.35 (dddd, J = 13.3, 8.6, 6.9, 1.3 Hz, 1H), 2.15 – 2.00 (m, 3H). A portion of the product was transferred to a vial (10 mg) and triturated with pentane (~0.5mL). Acetone was added 5 drops at a time, followed by sealing the vial and heating to boiling, until a clear and colorless solution resulted. A small amount of pentane was allowed to evaporate, yielding a still boiling turbid solution that was removed from the heating block and allowed to cool. Over time, fine white needles crystallized, which proved suitable for X- ray diffraction analysis that confirmed the desired relative stereochemistry. See Tables X1, X2, X3, X4, X5, X6 and X7. See Fig.1. Preparation of Intermediate 2-48F’ (rac-(1R,8'S)-4,4'-dichloro-8'-fluoro-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline])

Intermediate 2-48F Intermediate 2-48F’ A flask charged with Intermediate 2-48F (rac-(1R,8'R)-4,4'-dichloro-8'-fluoro-2'- (methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]; 1,310mg, 2.67mmol) was injected with THF (0.12M, 25.13mL) and cooled to -78°C. LDA (2.67mL, 5.34mmol, 2 eq.) was injected dropwise and an orange solution resulted and was kept at -78°C in an acetone dry ice bath. The reaction was stirred for 45 minutes and allowed to warm to 0°C. The reaction was cooled back to -78°C and methanol was injected, followed by aqueous NH4Cl. The reaction was allowed to warm to r.t. The organic phase was diluted with ethyl acetate and transferred to a separatory funnel. The organic was separated, dried over Na₂SO₄ and concentrated to dryness on a rotovap. Reversed phase HPLC (70-100% ACN/H₂O + 0.25% AcOH) successfully separated the diastereomers. Peak 1 corresponded to Intermediate 2-48F (30.03% yield) and peak 2 corresponded to the title compound (38.07% yield). The products were concentrated on the rotovap and then lyophilizer. Peak 2: LC/MS, ESI [M+H] = 369 amu.¹H NMR (400 MHz, CDCl₃): δ 7.30 – 7.15 (m, 3H), 5.00 (d, J = 48.6 Hz, 1H), 3.12 – 2.89 (m, 3H), 2.74 (ddt, J = 18.0, 11.4, 6.3 Hz, 1H), 2.57 (s, 3H), 2.13 – 1.94 (m, 2H), 1.91 – 1.74 (m, 2H). Intermediate 2-48F or Intermediate 2-48F’ is used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro-indane Compounds. Preparation of Intermediate 2-48F Analogs Using the same synthetic scheme used to produce Intermediate 2-48F (rac- (1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'- quinazoline]) or Intermediate 2-48F’ (rac-(1R,8'S)-4,4'-dichloro-8'-fluoro-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]), other singly fluorinated Intermediate 2-48F Analogs where R₂ is CH₃, F or Br may be similarly synthesized using 4-methyl-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene-1,7'-quinazolin]-4'(6'H)-one, 4-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene-1,7'-quinazolin]-4'(6'H)-one or 4-bromo-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene-1,7'-quinazolin]-4'(6'H)- one, respectively, in place of 4-chloro-2'-(methylthio)-2,3,5',8'-tetrahydro-3'H-spiro[indene- 1,7'-quinazolin]-4'(6'H)-one. Intermediate 2-48F Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro- indane Compounds.

Preparation of Intermediate 2-48G (4,4'-dichloro-8',8'-difluoro-2'-(methylthio)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline])

Intermediate 2-48F Intermediate 2-48G Intermediate 2-48F (rac-(1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline] (205mg, 0.55mmoles)) was dissolved in THF (5mL) and cooled to -78 ºC in a dry ice/acetone bath. LDA (0.55mL, 2M, 1.11mmoles) was injected dropwise to afford a bright orange solution that was aged 45 minutes, allowed to warm to ambient temperature, re-cooled and treated with injection of the fluoro reagent by syringe (255mg, 2mL THF). The reaction became cloudy and yellow, then clear-yellow after warming to RT. After 15 mins, 1N NaOH and EtOAc were added (10 volumes each). The organic was separated and concentrated onto silica gel. The mixture was purified by flash chromatography (10-50% EtOAc/Hexanes). The product was barely retained and eluted in 2 column volumes to give the title compound. LC/MS, ESI [M+H] = 387 amu.¹H NMR (400 MHz, CDCl3): δ 7.64 – 7.57 (m, 1H), 7.30 – 7.07 (m, 2H), 3.37 (t, J = 6.3 Hz, 1H), 3.09 – 2.88 (m, 2H), 2.83 – 2.69 (m, 1H), 2.44 (q, J = 7.4 Hz, 1H), 2.22 (ddd, J = 12.8, 8.3, 4.1 Hz, 1H), 1.98 (m, 5H). Intermediate 2-48G is used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro-indane Compounds. Preparation of Intermediate 2-48G Analogs Using the same synthetic scheme used to produce Intermediate 2-48G from Intermediate 2-48F, other difluoro Intermediate 2-48G Analogs where R2 is CH3, F or Br may be similarly synthesized using (8'R)-4'-chloro-8'-fluoro-4-methyl-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline], (8'R)-4'-chloro-4,8'-difluoro-2'- (methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]or (8'R)-4-bromo-4'- chloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline], respectively, in place of (8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro- 6'H-spiro[indene-1,7'-quinazoline]. Intermediate 2-48G Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro- indane Compounds. Preparation of Intermediate 2-48D (4,4'-dichloro-8'-fluoro-8'-methyl-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline])

Intermediate 2-48F Intermediate 2-48D Intermediate 2-48-F (rac-(1R,8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'- tetrahydro-6'H-spiro[indene-1,7'-quinazoline]; 4.06g, 75% pure crude from fluorination, 8.246mmoles) was dissolved in dry THF (100mL) and cooled in a dry ice/acetone bath to - 78 ºC. LDA (2M, 8.2mL, 16.4mmoles) was injected dropwise and the clear orange solution was stirred cold for one hour. Without warming, methyl iodide (0.74mL, 11.89mmoles) was added via syringe and the reaction was stirred for one hour cold and then allowed to warm to ambient temperature. After two hours at ambient temperature LC/MS showed clean formation of the expected product (M+H+=383amu). The reaction was poured into 50% aqueous saturated ammonium chloride (100mL) and diluted with ethyl acetate (200mL). The biphasic mixture was transferred to a separatory funnel and the organic phase was separated, dried over magnesium sulfate, filtered and concentrated on the rotovap. The crude residue was dissolved in a minimum amount of DCM and loaded onto silica gel. Flash chromatography (220g ISCO gold, 0-30% Hexanes/EtOAc) yielded the title compound as a statistical mixture (~1:1) of racemic diastereomers (2.39g, 75%). The resulting orange solid was separated into its constituent stereoisomers by SFC (4 peaks), which could be independently converted into the final compounds by means of the general procedure. Mixture of diastereomers: ¹H NMR (400 MHz, CDCl₃): δ 7.34 – 7.13 (m, 3H), 3.11 – 2.86 (m, 3H), 2.86 – 2.73 (m, 1H), 2.71 – 2.61 (m, 1H), 2.58 (s, 3H), 2.13 – 1.97 (m, 1H), 1.89 – 1.76 (m, 2H), 1.60 – 1.49 (m, 3H) ppm. LC/MS – M+H+ = 383.1amu, found 383.1amu. Intermediate 2-48D is used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro-indane Compounds. Preparation of Intermediate 2-48D Analogs Using the same synthetic scheme used to produce Intermediate 2-48D from Intermediate 2-48F, other difluoro Intermediate 2-48D Analogs where R2 is CH3, F or Br may be similarly synthesized using (8'R)-4'-chloro-8'-fluoro-4-methyl-2'-(methylthio)- 2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline], (8'R)-4'-chloro-4,8'-difluoro-2'- (methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]or (8'R)-4-bromo-4'- chloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline], respectively, in place of (8'R)-4,4'-dichloro-8'-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro- 6'H-spiro[indene-1,7'-quinazoline]. Intermediate 2-48D Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro- indane Compounds. Preparation of Intermediate 2-48P (4-chloro-7-fluoro-2'-(methylthio)-2,3,5',8'-tetrahydro- 3'H-spiro[indene-1,7'-quinazolin]-4'(6'H)-one)

Intermediate 2-48P Individual stereoisomers of the above intermediates may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. Intermediates obtained by this synthetic route include, but are not limited to, those where R2 is F, C1, Br or CH3. The skilled artisan would use the corresponding starting material to make such intermediates, for example, the skilled artisan would use 4-bromo-7-fluoro-2,3- dihydro-1H-inden-1-one as the starting material when making the analogous intermediate where R₂ is Br. Similarly, the skilled artisan would use 4,7-difluoro-2,3-dihydro-1H-inden- 1-one as the starting material when making the analogous intermediate where R2 is F or 4- methyl-7-fluoro-2,3-dihydro-1H-inden-1-one as the starting material when making the analogous intermediate where R_X1 is CH₃. Intermediate 2-48P is used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 2-11 Analogs, and more generally, the procedures detailed throughout section Example 2: Synthesis of Spiro-indane Compounds. Schematization for the Preparation of Intermediates 2-49 through 2-51

Intermediate 2-48 Intermediate 2-49 Intermediate 2-50

Intermediate 2-51 Preparation of Intermediate 2-49 (tert-Butyl 4-(4-chloro-2’-(methylthio)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-48 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate trifluoromethanesulfonate; 241.4mg, 0.519mmol) was dissolved in anhydrous DMF (2.6mL) and treated with tert-butyl piperazine-1-carboxylate (106mg, 0.569mmol) and iPr₂EtN (181µL, 1.04mmol) at rt. After 40min, the mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (x2), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→50% EtOAc in hexanes to give the title compound (248.5mg, 95.5%) as a white foam. Rf = 0.37 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 501.2/503.2 m/z (5:3). Preparation of Intermediate 2-50 (tert-Butyl 4-(4-chloro-2’-(methylsulfinyl)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) Intermediate 2-49 (tert-butyl 4-(4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 248.5mg, 0.496mmol) was dissolved in DCM (2.5mL) and treated with mCPBA (154.1mg, 0.446mmol) and at 0 °C. After 30min, the mixture was diluted with Et2O and washed with dilute NaHCO3 (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (255.3mg, 99.6%) as a white foam. LC/MS, [M+H]⁺ = 517.2/519.2 m/z (5:3). Preparation of Intermediate 2-51 (tert-Butyl 4-(4-chloro-2’-(((S)-pyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate) In a dry vial, [(2S)-pyrrolidin-2-yl]methanol (29.6mg, 0.292mmol) was dissolved in THF (650µL) and treated with KotBu, 1M in THF (272µL) and the resulting mixture was added dropwise to a stirred solution of Intermediate 2-50 (tert-butyl 4-(4-chloro-2’- (methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1- carboxylate; 100.7mg, 0.195mmol) in anhydrous THF (650µL) at 0 °C. After 10min, the mixture was diluted with EtOAc and washed with 5% K₂CO₃ (x2), brine, dried over Na₂SO₄, filtered and concentrated to give the title compound (104.4mg, 96.7%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 554.3/556.3 m/z (2:1). Preparation of Compound 1-55 (4-Chloro-4’-(piperazin-1-yl)-2’-(((S)-pyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-51 (tert-butyl 4-(4-chloro-2’-(((S)-pyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 15.4mg, 0.0278mmol) was treated with TFA (300µL) at rt for 60min then concentrated, dissolved in H₂O, washed with Et2O, and purified by preparative HPLC to give the title compound (8.0mg, 63.4%) as a colorless film. LC/MS, ESI [M+H]⁺ = 454.2/456.2 m/z. Preparation of Compound 1-56 (4-Chloro-2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4’- (piperazin-1-yl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-51 (tert-butyl 4-(4-chloro-2’-(((S)-pyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 21.3mg, 0.0384mmol) was dissolved in THF (375µL) and treated with formaldehyde, 37% aqueous (8.6µL, 0.116mmol), AcOH (2.2µL, 0.038mmol), Et₃N (16.1µL, 0.115mmol), and NaBH(Oac)3 (24.4mg, 0.115mmol) and the mixture was stirred at rt overnight. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (300µL) at rt for 60min then concentrated, dissolved in H₂O, washed with Et₂O, and purified by preparative HPLC to give the title compound (11.2 mg, 62.1%) as a white foam. LC/MS, ESI [M+H]⁺ = 468.2/470.2 m/z (3:1). ¹H NMR (400 MHz, ) δ 7.25 – 7.13 (m, 2H), 7.05 (dt, J = 7.2, 1.0 Hz, 1H), 4.30 – 4.13 (m, 2H), 3.67 – 3.58 (m, 1H), 3.40 (ddd, J = 13.2, 6.7, 3.2 Hz, 2H), 3.34 – 3.23 (m, 2H), 3.04 – 2.95 (m, 4H), 2.94 – 2.78 (m, 4H), 2.77 – 2.63 (m, 3H), 2.60 – 2.46 (m, 2H), 2.14 – 1.88 (m, 2H), 1.88 – 1.68 (m, 4H), 1.63 – 1.49 (m, 1H). Preparation of Compound 1-57 (4-Chloro-2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-4’- (piperazin-1-yl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-51 (tert-butyl 4-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]piperazine-1-carboxylate; 20.2mg, 0.037mmol) was dissolved in THF (350µL) and treated with AcOH (2.1µL, 0.037mmol), acetone (8.1uL, 0.11mmol), and NaBH(Oac)₃ (23.18mg, 0.109mmol) and the mixture was stirred at rt overnight. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with TFA (300µL) for 60min then concentrated, dissolved in H₂O, and purified by preparative HPLC to give the title compound (12.1 mg, 64.9%) as a colorless film. LC/MS, ESI [M+H]⁺ = 496.2/498.2 m/z (3:1).¹H NMR (400 MHz, CD3CN) δ 7.26 – 7.13 (m, 2H), 7.12 – 7.03 (m, 1H), 4.23 (dt, J = 10.8, 4.2 Hz, 1H), 3.89 (ddd, J = 10.8, 8.2, 5.4 Hz, 1H), 3.51 – 3.13 (m, 5H), 3.05 – 2.63 (m, 11H), 2.61 – 2.46 (m, 3H), 2.09 – 1.96 (m, 3H), 1.85 – 1.67 (m, 4H), 1.10 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H). Preparation of Compound 1-58 (4-Chloro-4’-(piperazin-1-yl)-2’-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) Intermediate 2-50 (tert-butyl 4-(4-chloro-2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro- 6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate; 27.5mg, 0.0532mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (11.3mg, 0.080mmol) were dissolved in anhydrous THF (330µL) and cooled to 0 °C and KotBu, 1M in THF (64µL) was added dropwise. After 20min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min then concentrated, taken up in H₂O, and washed with Et2O (x2). The aqueous phase was purified by preparative HPLC to give the title compound (20.5mg, 78.0%) as a white foam. LC/MS, ESI+ = 494.1/496.1 m/z (3:1). ¹H NMR (400 MHz, MeOD) δ 7.22 – 7.12 (m, 2H), 7.05 – 7.00 (m, 1H), 4.16 – 4.05 (m, 2H), 3.54 (ddd, J = 13.3, 6.7, 3.4 Hz, 2H), 3.43 (ddd, J = 13.3, 6.5, 3.4 Hz, 2H), 3.05 (dt, J = 10.4, 5.9 Hz, 2H), 3.01 – 2.87 (m, 6H), 2.81 – 2.65 (m, 5H), 2.58 (dt, J = 16.3, 5.3 Hz, 1H), 2.13 – 1.96 (m, 5H), 1.96 – 1.75 (m, 5H), 1.75 – 1.66 (m, 2H). Schematization for the Preparation of Intermediates 2-52 through 2-54

Intermediate 2-48 Intermediate 2-52 Intermediate 2-53

Intermediate 2-54 Preparation of Intermediate 2-52 (tert-Butyl (2S)-4-(4-chloro-2’-(methylthio)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2-(cyanomethyl)piperazine-1- carboxylate) Intermediate 2-48 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate; 1.47g, 3.15mmol) was dissolved in anhydrous DMF (16mL) and treated with 2-[(2S)-piperazin-2-yl]acetonitrile (686.9mg, 3.47mmol) and iPr₂EtN (1.9mL, 10.9mmol) at rt and stirred for 30min then Boc₂O (1.03g, 4.72mmol) was added and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→45% EtOAc in hexanes to give the title compound (1.644g, 96.5%) as a white foam. Rf = 0.25 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 574.2/576.2 m/z (5:2). Preparation of Intermediate 2-53 (tert-Butyl (2S)-4-(4-chloro-2’-(methylsulfinyl)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2-(cyanomethyl)piperazine-1- carboxylate) Intermediate 2-52 (tert-butyl (2S)-4-(4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro- 6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2-(cyanomethyl)piperazine-1-carboxylate; 1.64g, 3.04mmol) was dissolved in DCM (15.5mL), cooled to 0°C, and treated with mCPBA (700mg, 3.04mmol). After 40min, the mixture was diluted with Et₂O and washed with dilute NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (1.746g, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 556.2/558.2 m/z (3:1). Preparation of Intermediate 2-54 (tert-Butyl (2S)-4-(4-chloro-2’-(((S)-1-methylpyrrolidin- 2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2- (cyanomethyl)piperazine-1-carboxylate) Intermediate 2-53 (tert-butyl (2S)-4-(4-chloro-2’-(methylsulfinyl)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2-(cyanomethyl)piperazine-1- carboxylate; 1.69g, 3.04mmol) and [(2S)-1-methylpyrrolidin-2-yl]methanol (471µL, 3.96 mmol) were dissolved in anhydrous THF (15mL) and cooled to 0°C then KotBu, 1.7M in THF (2.1mL, 3.57mmol) was added dropwise. After 15min, the mixture was diluted with Et₂O (200mL) and washed with 5% K₂CO₃ (3x25mL), brine, dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on basic alumina eluted with 0→50% EtOAc in hexanes to give the title compound (1.276g, 69.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 607.3/609.3 m/z (3:1). Preparation of Compound 1-59 (2-((2S)-4-(4-Chloro-2’-(((S)-1-methylpyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2- yl)acetonitrile) Intermediate 2-54 (tert-butyl (2S)-4-(4-chloro-2’-(((S)-1-methylpyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-2- (cyanomethyl)piperazine-1-carboxylate; 1.28g, 2.1mmol) was treated with TFA (10mL) at rt for 75min then concentrated. The residue was dissolved in 1N HCl (100mL) and washed with Et2O (2x25mL). The aqueous phase was carefully basified with K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated to give the title compound (1.08g, quant.) as a white foam. LC/MS, ESI [M+H]⁺ = 507.3/509.2 m/z (3:1).¹H NMR (400 MHz, CD3CN) δ 7.23 – 7.14 (m, 2H), 7.06 (ddd, J = 7.1, 2.1, 1.3 Hz, 1H), 4.33 – 4.22 (m, 1H), 4.11 – 4.02 (m, 1H), 3.90 – 3.60 (m, 2H), 3.21 – 2.45 (m, 15H), 2.36 (d, J = 0.9 Hz, 3H), 2.25 – 2.15 (m, 2H), 2.11 – 1.91 (m, 3H), 1.79 – 1.57 (m, 4H). Preparation of Compound 1-60 (2-((2S)-4-(4-Chloro-2’-(((S)-1-isopropylpyrrolidin-2- yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)piperazin-2- yl)acetonitrile) Compound 1-60 is prepared following the general procedures used to prepare Compound 1-57 and using Intermediate 2-54 instead of Intermediate 2-51. Preparation of Compound 1-61 (2-((2S)-4-(4-Chloro-2’-((tetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’- yl)piperazin-2-yl)acetonitrile) Compound 1-61 is prepared following the general procedures used to prepare Compound 1-58 and using Intermediate 2-53 instead of Intermediate 2-50. Schematization for the Preparation of Intermediates 2-55 through 2-57

Intermediate 2-48 Intermediate 2-55 Intermediate 2-56

Intermediate 2-57 Preparation of Intermediate 2-55 (tert-Butyl 3-(4’-chloro-2-methylsulfanyl-spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 2-48 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate; 311.2mg, 0.669mmol) was dissolved in anhydrous DMF (3.3mL) and treated with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (156mg, 0.735mmol) and iPr2EtN (233µL, 1.34mmol) at rt. After 20min, the mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (x2), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (354.1mg, quant.) as a white foam. Rf = 0.40 (8:2 hexanes:EtOAc). LCMS, ESI [M+H]⁺ = 527.2/529.2 m/z (2:1). Preparation of Intermediate 2-56 (tert-Butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) Intermediate 2-55 (tert-butyl 3-(4’-chloro-2-methylsulfanyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 354.1mg, 0.672mmol) was dissolved in DCM (3.4mL) and treated with mCPBA (208.7mg, 0.605mmol) at 0 °C. After 30min, the mixture was diluted with Et₂O and washed with half- saturated NaHCO3 (x3), brine, dried over Na2SO4, filtered, and concentrated to give the title compound (371.2mg, quant.) as a white foam. LC/MS, ESI [M+H]⁺ = 543.2/545.2 m/z (10:7). Preparation of Intermediate 2-57 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) In a dry vial, [(2S)-pyrrolidin-2-yl]methanol (30.1mg, 0.297mmol) was dissolved in anhydrous THF (650µL) and treated with KotBu, 1M in THF (278uL) and the resulting solution was added dropwise to a solution of Intermediate 2-56 (tert-butyl 3-(4’-chloro-2- methylsulfinyl-spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 107.7mg, 0.198mmol) in anhydrous THF (650µL) at 0 °C. After 10min, the mixture was diluted with EtOAc and washed with 5% K2CO3 (x2), brine, dried over Na₂SO₄, filtered and concentrated to give the title compound (109.3mg, 95.0%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 580.3/582.3 m/z (5:3). Preparation of Compound 1-62 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)- pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-57 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 10.9mg, 0.0188mmol) was treated with TFA (300µL) at rt for 60min then concentrated. The residue was dissolved in H₂O, washed with Et₂O, and purified by preparative HPLC (C18 20x250mm, 10µ, 5→80% ACN in H₂O+0.25%TFA, 25mL/min) to give the title compound (7.6 mg, 84.3%) as a colorless residue. LC/MS, ESI [M+H]+ = 480.2/482.2 m/z (3:1).¹H NMR (400 MHz, CD3CN) δ 7.21 (dd, J = 7.9, 1.3 Hz, 1H), 7.17 (tt, J = 7.9, 0.9 Hz, 1H), 7.06 (dt, J = 7.0, 0.6 Hz, 1H), 4.17 – 4.04 (m, 2H), 3.85 (d, J = 12.2 Hz, 1H), 3.59 (d, J = 12.4 Hz, 1H), 3.49 – 3.40 (m, 3H), 3.15 – 3.04 (m, 1H), 3.02 – 2.93 (m, 3H), 2.93 – 2.62 (m, 6H), 2.53 (dt, J = 16.1, 5.1 Hz, 1H), 2.11 – 1.98 (m, 3H), 1.97 – 1.83 (m, 2H), 1.82 – 1.62 (m, 6H). Preparation of Compound 1-63 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)- 1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-57 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 49.5mg, 0.0853mmol) was dissolved in THF (600µL) and treated with formaldehyde, 37% aqueous (7.1µL, 0.258mmol), AcOH (4.9µL, 0.086mmol), and NaBH(Oac)₃ (54mg, 0.255mmol) and the mixture was stirred at rt overnight. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (300µL) at rt for 30min then concentrated. One third of the material was dissolved in H₂O and purified by preparative HPLC to give the title compound (13.8 mg, 98.1%) as a colorless residue. LC/MS, ESI [M+H]⁺ = 494.2/496.3 m/z (3:1). ¹H NMR (400 MHz, CD₃CN) δ 7.19 (d, J = 1.3 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 – 7.01 (m, 1H), 4.27 (ddd, J = 10.9, 4.8, 3.4 Hz, 1H), 4.06 (ddd, J = 10.8, 6.2, 4.5 Hz, 1H), 3.91 – 3.82 (m, 1H), 3.66 – 3.56 (m, 1H), 3.51 – 3.45 (m, 2H), 3.14 (dt, J = 12.1, 1.7 Hz, 1H), 3.03 – 2.92 (m, 4H), 2.82 – 2.64 (m, 3H), 2.60 – 2.45 (m, 5H), 2.36 (s, 3H), 2.21 (td, J = 9.1, 7.8 Hz, 1H), 2.09 – 1.98 (m, 2H), 1.97 – 1.87 (m, 1H), 1.81 – 1.56 (m, 7H). Preparation of Compound 1-64 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2S)- 1-isopropylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-57 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (20mg, 0.0345mmol) was dissolved in THF (240µL) and treated with acetone (7.7µL, 0.104mmol), AcOH (2µL, 0.035mmol), and NaBH(Oac)3 (22mg, 0.104mmol) and stirred at rt overnight. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (300µL) at rt for 60min then concentrated, diluted with H₂O, and purified by preparative HPLC to give the title compound (13.4mg, 71.3%) as a white foam. LC/MS, ESI [M+H]⁺ = 522.3/524.2 m/z (3:1). ¹H NMR (400 MHz, CD₃CN) δ 7.20 (dd, J = 7.9, 1.3 Hz, 1H), 7.16 (tt, J = 7.5, 0.7 Hz, 1H), 7.04 (dt, J = 7.2, 1.2 Hz, 1H), 4.19 (dt, J = 10.6, 3.9 Hz, 1H), 3.89 – 3.78 (m, 2H), 3.59 (ddt, J = 12.1, 3.1, 1.8 Hz, 1H), 3.48 – 3.41 (m, 2H), 3.17 – 3.06 (m, 2H), 3.02 – 2.84 (m, 5H), 2.81 – 2.62 (m, 3H), 2.60 – 2.45 (m, 2H), 2.09 – 1.97 (m, 2H), 1.95 – 1.88 (m, 2H), 1.83 – 1.62 (m, 8H), 1.08 (dd, J = 6.6, 1.5 Hz, 3H), 0.99 (dd, J = 6.4, 1.2 Hz, 3H). Preparation of Compound 1-65 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)spiro[6,8-dihydro-5H-quinazoline-7,1’- indane]) Intermediate 2-56 (tert-butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 35.3mg, 0.065mmol) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (13.8mg, 0.098mmol) were dissolved in anhydrous THF (400µL) and cooled to 0°C then KotBu, 1M in THF (78µL) was added dropwise. After 20min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated, and the residue was treated with TFA (0.5mL) at rt for 60min, concentrated, taken up in H₂O and washed with Et2O (x2), and the aqueous phase was purified by preparative HPLC to give the title compound (25.9mg, 76.6%) as a white foam. LC/MS, ESI [M+H]+ = 520.2/522.2 m/z (3:1).¹H NMR (400 MHz, MeOD) δ 7.54 – 7.44 (m, 2H), 7.35 (dd, J = 6.6, 2.0 Hz, 1H), 4.47 – 4.34 (m, 3H), 4.16 – 4.08 (m, 1H), 3.90 – 3.80 (m, 2H), 3.61 (dd, J = 12.6, 1.9 Hz, 1H), 3.43 (dd, J = 12.5, 1.8 Hz, 1H), 3.38 (dt, J = 10.5, 6.0 Hz, 2H), 3.31 (t, J = 7.3 Hz, 2H), 3.18 – 2.96 (m, 5H), 2.92 (dt, J = 16.0, 5.1 Hz, 1H), 2.46 – 1.97 (m, 16H). Preparation of Compound 1-66 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]) Intermediate 2-56 (tert-butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 38.5mg, 0.0709mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (17.0mg, 0.107mmol) were dissolved in anhydrous THF (400µL) and cooled to -40 °C then KotBu, 1M in THF (85µL) was added dropwise. After 20min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min then concentrated, taken up in H₂O and washed with Et2O (x2), and the aqueous was purified by preparative HPLC to give the title compound (31.9 mg, 83.6%) as a white foam. LC/MS, ESI [M+H]⁺ = 538.2/540.2 m/z (3:1). ¹H NMR (400 MHz, MeOD) δ 7.21 – 7.10 (m, 2H), 7.01 (dd, J = 6.8, 1.9 Hz, 1H), 5.36 – 5.16 (m, 1H), 4.13 (dd, J = 10.4, 5.4 Hz, 1H), 4.08 – 3.99 (m, 2H), 3.82 – 3.73 (m, 1H), 3.55 – 3.48 (m, 2H), 3.29 – 3.06 (m, 5H), 3.04 – 2.91 (m, 3H), 2.84 – 2.69 (m, 3H), 2.58 (dt, J = 15.8, 5.1 Hz, 1H), 2.31 – 1.71 (m, 14H). ¹⁹F NMR (376 MHz, MeOD) δ -173.59. Schematization for the Preparation of Intermediates 2-58 through 2-60

Intermediate 2-48 Intermediate 2-58 Intermediate 2-59

Intermediate 2-60 Preparation of Intermediate 2-58 (Allyl 8-(4’-chloro-2-methylsulfanyl-spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-48 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate; 297.6mg, 0.640mmol) was dissolved in anhydrous DMF (3.2mL) and treated with allyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (139.mg, 0.708mmol) and iPr₂EtN (223µL, 1.28mmol) and stirred at rt for 90min. The mixture was diluted with EtOAc and washed with half-saturated NaHCO3 (x2), 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 eluted with 0→40% EtOAc in hexanes to give the title compound (300mg, 91.7%) as a white foam. Rf = 0.33 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 511.1/513.2 m/z (2:1). Preparation of Intermediate 2-59 (Allyl 8-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate) Intermediate 2-58 (allyl 8-(4’-chloro-2-methylsulfanyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 300mg, 0.587mmol) was dissolved in DCM (2.5mL) and treated with mCPBA (183mg, 0.530mmol) at rt. After 10min, the mixture was diluted with Et2O and washed with half- saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (301.5mg, 97.4%) as a white foam. LC/MS, ESI [M+H]⁺ = 527.2/529.2 m/z (3:1). Preparation of Intermediate 2-60 (Allyl 8-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate) [(2S)-Pyrrolidin-2-yl]methanol (46mg, 0.45mmol) was dissolved in anhydrous THF (0.5mL) and treated with KotBu, 1M in THF (424µL) and the resulting mixture was added to a solution of Intermediate 2-59 (allyl 8-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 159.6mg, 0.303mmol) in anhydrous THF (1.0mL) at -20 °C. After 10min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 0→10% MeOH in DCM+2% Et₃N to give the title compound (144.8mg, 84.8%) as a white foam. LC/MS, ESI [M+H]⁺ = 564.2/566.3 m/z (3:1). Preparation of Compound 1-67 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-[[(2S)- pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-60 (allyl 8-[4’-chloro-2-[[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate; 20mg, 0.036mmol) was dissolved in THF (175µL) and treated with PhSiH₃ (44µL, 0.36mmol) and sparged with N2 for 5min then Pd(PPh3)4 (2.0mg, 0.0017mmol) was added and sparging continued for 5min. After an additional 10min, the mixture was diluted with Et₂O and extracted with 1N HCl (2x1mL) and the aqueous extract was filtered and purified by preparative HPLC (C1820x250mm, 10µ, 5→80% ACN in H₂O+0.25%TFA, 25mL/min) to give the title compound (8.2mg, 48.2%) as a colorless film. LC/MS, ESI [M+H]⁺ = 480.2/482.2 m/z (3:1).¹H NMR (400 MHz, MeOD) δ 7.22 – 7.11 (m, 2H), 7.03 (dt, J = 6.9, 1.6 Hz, 1H), 4.66 (d, J = 6.1 Hz, 1H), 4.58 (s, 1H), 4.31 (ddd, J = 10.9, 5.1, 1.8 Hz, 1H), 4.24 (ddd, J = 11.0, 6.9, 2.5 Hz, 1H), 3.54 (qd, J = 7.4, 5.1 Hz, 1H), 3.14 (dt, J = 12.9, 2.3 Hz, 1H), 3.09 – 2.86 (m, 5H), 2.78 – 2.67 (m, 5H), 2.61 (dt, J = 16.0, 5.3 Hz, 1H), 2.15 – 1.76 (m, 12H), 1.70 – 1.56 (m, 1H). Preparation of Compound 1-68 (4’-Chloro-4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-[[(2S)- 1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Step 1. Intermediate 1-60 (allyl 8-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate; 36.7mg, 0.0651mmol) was dissolved in THF (325µL) and treated with AcOH (3.7uL, 0.065mmol), formaldehyde, 37% aqueous (154.6L, 0.196mmol), and NaBH(Oac)3 (41.4mg, 0.195mmol) and the mixture was stirred at rt for 4hrs. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 60→100% DCM+2% Et3N in hexanes to give allyl 8-[4’-chloro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline- 7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (29.1mg, 77.4%) as a colorless film. LC/MS, ESI [M+H]⁺ = 578.3/580.2 m/z (2:1). Step 2. Allyl 8-[4’-chloro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (29.1mg, 0.0503mmol) was dissolved in THF (250µL) and treated with PhSiH3 (31µL, 0.25mmol) and the mixture was sparged with N₂ for 5min then amended with Pd(PPh₃)₄ (2.9mg, 0.0025mmol) and sparging was continued for 5min. After an additional 30min, the mixture was diluted with Et2O and extracted with 1N HCl (2x1mL) and the aqueous extract was filtered and purified by preparative HPLC (C18 20x250mm, 10u, 5→80% ACN in H₂O+0.25%TFA, 25mL/min) to give the title compound (15.8mg, 63.5%) as a colorless film. LC/MS, ESI [M+H]⁺ = 494.2/496.2 m/z (3:1). ¹H NMR (400 MHz, MeOD) δ 7.22 – 7.11 (m, 2H), 7.03 (dd, J = 6.8, 1.8 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.64 – 4.56 (m, 1H), 4.34 (ddd, J = 10.6, 6.1, 4.4 Hz, 1H), 4.26 (dt, J = 11.0, 4.7 Hz, 1H), 3.17 (dt, J = 12.9, 2.4 Hz, 1H), 3.10 (dt, J = 9.6, 4.5 Hz, 1H), 3.06 – 2.93 (m, 3H), 2.84 – 2.68 (m, 6H), 2.68 – 2.54 (m, 1H), 2.52 (s, 3H), 2.38 (q, J = 8.9 Hz, 1H), 2.16 – 1.95 (m, 8H), 1.92 – 1.62 (m, 4H). Preparation of Compound 1-69 (4’-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-4-chloro- 2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) Step 1. Intermediate 1-60 (allyl 8-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate; 41.mg, 0.0700 mmol) was dissolved in THF (360µL) and treated with AcOH (4.2µL, 0.073mmol), acetone (16.2µL, 0.219mmol), and NaBH(Oac)3 (46.2mg, 0.218mmol) and the mixture was stirred at rt overnight. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, concentrated, and purified by flash column chromatography on silica gel eluted with 60→100% DCM+2% Et3N in hexanes to give allyl (1R,5S)-8-(4-chloro- 2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (17.2mg, 39.0%) as a white foam. LC/MS, ESI [M+H]⁺ 606.3/608.3 m/z. Step 2. Allyl (1R,5S)-8-(4-chloro-2’-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (17.2mg, 0.0284mmol) was dissolved in THF (200µL) and treated with PhSiH3 (17.5µL, 0.142mmol) and the mixture was sparged with N2 for 5min then amended with Pd(PPh3)4 (1.64mg, 0.0014mmol) and sparging was continued for 5min. After an additional 40min, the mixture was diluted with Et₂O and extracted with 1N HCl (2x1mL) and the aqueous extract was purified by preparative HPLC (C18 20x250mm, 10u, 5→80% ACN in H₂O+0.25%TFA, 25mL/min) to give the title compound (8.0mg, 54.0%) as a colorless film. LC/MS, ESI [M+H]⁺ = 522.3/524.3 m/z (3:1).¹H NMR (400 MHz, MeOD) δ 7.22 – 7.12 (m, 2H), 7.03 (dt, J = 6.9, 1.6 Hz, 1H), 4.67 (d, J = 6.0 Hz, 1H), 4.58 (s, 1H), 4.30 (ddd, J = 10.9, 4.9, 2.3 Hz, 1H), 4.13 – 4.04 (m, 1H), 3.20 – 2.91 (m, 6H), 2.78 – 2.55 (m, 7H), 2.14 – 1.74 (m, 13H), 1.17 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H). Schematization for the Preparation of Intermediates 2-61 through 2-63

Intermediate 2-48 Intermediate 2-61 Intermediate 2-62

Intermediate 2-63 Preparation of Intermediate 2-61 (tert-Butyl 3-(4’-chloro-2-methylsulfanyl-spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) Intermediate 2-48 (4-chloro-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazolin]-4’-yl trifluoromethanesulfonate; 212.8mg, 0.458mmol) was dissolved in anhydrous DMF (2mL) and treated with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (100mg, 0.504mmol) and iPr₂EtN (160µL, 1.38mmol) at rt for 45min. The mixture was diluted with EtOAc and washed sequentially with half-saturated NaHCO3 (x3), brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (274.7mg, >100%). Rf = 0.31 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 513.2/515.2 m/z (3:1). Preparation of Intermediate 2-62 (tert-butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8- dihydro-5H-quinazoline-7,1’-indane]-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate) Intermediate 2-61 (tert-butyl 3-(4’-chloro-2-methylsulfanyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 234.8mg, 0.458mmol) was dissolved in DCM (2.3mL) and treated with mCPBA (142.2mg, 0.412mmol) at 0°C. After 50min, the mixture was diluted with Et2O and washed sequentially with half-saturated NaHCO₃ (x3), brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (252.7mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 529.2/531.2 m/z (3:2). Preparation of Intermediate 2-63 (tert-Butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate) Intermediate 2-62 (tert-butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 87.5mg, 0.165mmol) was dissolved in anhydrous THF (400µL) and cooled to -40°C then a mixture of [(2S)-pyrrolidin-2-yl]methanol (25mg, 0.25mmol) and KotBu, 1M in THF (200µL) in THF (400µL) was added dropwise. After 10min, the mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated to give the title compound (100.6mg, >100%) as a white foam which was used without purification. LC/MS, ESI [M+H]⁺ = 566.3/568.3 m/z (3:2). Preparation of Compound 1-70 (4’-Chloro-4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2- [[(2S)-pyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-63 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 31.2mg, 0.0551mmol) was treated with TFA (0.5mL) at rt for 60min. The mixture was concentrated, re-dissolved in H₂O, and purified by preparative HPLC to give the title compound (20.7mg, 80.6%) as a white foam. LC/MS, ESI [M+H]⁺ = 466.2/468.2 m/z (3:1).¹H NMR (400 MHz, Methanol-d₄) δ 7.21 – 7.11 (m, 2H), 7.09 – 7.03 (m, 1H), 4.33 – 4.20 (m, 3H), 4.18 – 4.03 (m, 2H), 3.96 (d, J = 12.6 Hz, 1H), 3.75 (d, J = 6.1 Hz, 2H), 3.51 – 3.40 (m, 1H), 3.10 – 2.78 (m, 6H), 2.76 (s, 2H), 2.68 (dt, J = 9.1, 6.1 Hz, 1H), 2.15 – 1.72 (m, 7H), 1.67 (d, J = 9.0 Hz, 1H), 1.64 – 1.48 (m, 1H). Preparation of Compound 1-71 (4’-Chloro-4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2- [[(2S)-1-methylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-63 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 31.2mg, 0.0551mmol) was dissolved in THF (300µL) and treated with formaldehyde, 37% aqueous (12.3µL, 0.165mmol), AcOH (3.2µL, 0.056mmol), and NaBH(Oac)₃ (35mg, 0.165mmol) at rt for 15hrs. The mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min then concentrated, re-dissolved in H₂O, and purified by preparative HPLC to give the title compound (23.1mg, 87.3%) as a white foam. LC/MS, ESI [M+H]⁺ = 480.2/482.2 m/z (3:1). ¹H NMR (400 MHz, Methanol-d4) δ 7.21 – 7.11 (m, 2H), 7.06 (dd, J = 6.5, 2.1 Hz, 1H), 4.36 (ddd, J = 11.0, 6.1, 3.2 Hz, 1H), 4.27 (ddt, J = 10.8, 5.6, 2.5 Hz, 2H), 4.15 (d, J = 12.5 Hz, 1H), 4.11 – 4.04 (m, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.75 (d, J = 6.0 Hz, 2H), 3.11 – 2.89 (m, 5H), 2.76 (s, 2H), 2.75 – 2.60 (m, 2H), 2.48 (s, 3H), 2.32 (q, J = 9.1 Hz, 1H), 2.13 – 1.94 (m, 4H), 1.87 – 1.73 (m, 3H), 1.72 – 1.62 (m, 2H). Preparation of Compound 1-72 (4’-Chloro-4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2- [[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]) Intermediate 2-63 (tert-butyl 3-[4’-chloro-2-[[(2S)-pyrrolidin-2- yl]methoxy]spiro[6,8-dihydro-5H-quinazoline-7,1’-indane]-4-yl]-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 31.2mg, 0.0551mmol) was dissolved in THF (300µL) and treated with acetone (12.3µL, 0.166mmol), AcOH (3.2µL, 0.056mmol), and NaBH(Oac)₃ (35mg, 0.165mmol) at rt for 15hrs. The mixture was poured into 5% K₂CO₃ and extracted with DCM (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min, concentrated, re- dissolved in H₂O, and purified by preparative HPLC to give the title compound (24.1mg, 86.0%) as a white foam. LC/MS, ESI [M+H]⁺ = 508.3/510.3 m/z (3:1).¹H NMR (400 MHz, Methanol-d4) δ 7.21 – 7.11 (m, 2H), 7.05 (dd, J = 6.4, 2.2 Hz, 1H), 5.49 (s, 0H), 4.36 – 4.23 (m, 2H), 4.14 (d, J = 12.5 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.96 (d, J = 12.3 Hz, 1H), 3.74 (d, J = 6.1 Hz, 2H), 3.26 – 3.16 (m, 1H), 3.09 – 2.88 (m, 6H), 2.75 (s, 2H), 2.68 (dt, J = 9.0, 6.2 Hz, 1H), 2.58 (td, J = 9.1, 7.1 Hz, 1H), 2.12 – 1.94 (m, 3H), 1.94 – 1.72 (m, 5H), 1.67 (d, J = 9.0 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H), 1.07 (dd, J = 6.4, 1.0 Hz, 3H). Preparation of Compound 1-73 (4’-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-4-chloro-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) Intermediate 2-62 (tert-butyl 3-(4’-chloro-2-methylsulfinyl-spiro[6,8-dihydro-5H- quinazoline-7,1’-indane]-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate; 30.2mg, 0.0571mmol) and (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (12.1mg, 0.0856mmol) were dissolved in anhydrous THF (275µL) and KotBu, 1M in THF (70µL) was added dropwise at -40 °C. After 20min, the mixture was poured into 5% K2CO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated. The residue was treated with TFA (0.5mL) at rt for 60min, concentrated, redissolved in H₂O, and purified by preparative HPLC to give the title compound (18.8mg, 65.1%) as a white foam. LC/MS, ESI [M+H]⁺ = 506.3/508.2 m/z (3:1). ¹H NMR (400 MHz, Methanol-d₄) δ 7.21 – 7.11 (m, 2H), 7.06 (dd, J = 6.5, 2.1 Hz, 1H), 5.49 (s, 1H), 4.31 – 4.24 (m, 1H), 4.18 – 4.04 (m, 4H), 3.96 (d, J = 12.3 Hz, 1H), 3.75 (d, J = 6.0 Hz, 2H), 3.10 – 2.89 (m, 6H), 2.76 (s, 2H), 2.67 (dt, J = 10.4, 6.4 Hz, 3H), 2.13 – 1.74 (m, 9H), 1.74 – 1.64 (m, 3H). Schematization for the Preparation of Intermediates 2-63 through 2-70

Intermediate 2-63 Intermediate 2-64

Intermediate 2-65 Intermediate 2-66

Intermediate 2-69 Intermediate 2-70 Preparation of of Intermediate 2-63 (2-(4-Methyl-2,3-dihydro-1H-inden-1- ylidene)malononitrile) 4-Methylindan-1-one (10.0g, 68.4mmol) and malononitrile (5.0g, 75.7mmol) were treated with EtOH (100mL) and treated with NaOAc•3H₂O (9.31g, 68.4mmol) and the mixture was stirred at room temperature overnight. 1M HCl (50mL) was added and the resulting solids were collected by filtration, washed with H₂O and a small amount of EtOH then dried under suction and further dried in vacuo at 50ºC to give the title compound (11.61g, 87.4%) as a tan colored powder. LC/MS, [M+H]⁺ = 195.1 m/z. Preparation of of Intermediate 2-64 (2-(4-Methyl-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden- 1-yl)malononitrile) An 500 mL flask was charged with CuBr•Me2S (1.23g, 5.98mmol) and anhydrous THF (35mL) then cooled to -40ºC and pent-4-en-1-ylmagnesium bromide, 0.5M in THF (180mL) was added. The mixture was stirred for 15min then Intermediate 2-63 (2-(4- methyl-2,3-dihydro-1H-inden-1-ylidene)malononitrile; 11.61g, 59.8mmol) was added as a solution in THF (130mL). After 1hr, the cooling bath was removed and the mixture was allowed to warm to rt over a period of approximately 1hr. The mixture was poured into sat NH4Cl and extracted with EtOAc (x2). The combined extract was washed with saturated NH4C1, brine, dried over Na2SO4, filtered through a thin pad of silica gel, concentrated, and purified by flash column chromatography on silica gel eluted with 0→30% EtOAc in hexanes to give the title compound (14.87g, 94.1%) as a yellow oil.¹H NMR (600 MHz, cdcl3) δ 7.20 (t, J = 7.5 Hz, 1H), 7.15 – 7.10 (m, 2H), 5.72 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.03 – 4.94 (m, 2H), 3.83 (s, 1H), 3.04 – 2.94 (m, 1H), 2.90 (ddd, J = 16.7, 9.1, 5.0 Hz, 1H), 2.37 – 2.23 (m, 5H), 2.12 – 1.99 (m, 3H), 1.94 (ddd, J = 13.9, 12.4, 4.2 Hz, 1H), 1.46 – 1.34 (m, 1H), 1.23 – 1.13 (m, 1H). Preparation of of Intermediate 2-65 (Methyl 2-(4-methyl-1-(pent-4-en-1-yl)-2,3-dihydro- 1H-inden-1-yl)acetate) Intermediate 2-64 (2-(4-methyl-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)malononitrile; 14.87g, 56.25mmol) was treated with ethylene glycol (56mL), H₂O (25 mL), and KOH (55.69g, 843.7mmol), and the mixture was heated to 175°C and stirred overnight. The mixture was cooled slightly then poured into chipped ice containing H₂SO4 and extracted with EtOAc (x2). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was heated to 200°C for 25 min then cooled to rt. The residue was dissolved in MeOH (120mL) was cooled to 0°C and acetyl chloride (40.1mL, 562mmol) was added dropwise and the mixture was heated to 50°C for 3hr then concentrated. The residue was co-evaporated from toluene once then taken up in 8:2 hexanes:EtOAc and filtered through a thin pad of silica gel and concentrated to give the title compound (14.21g, 92.7%) as a pale yellow oil. ¹H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 5.75 (ddt, J = 16.8, 10.1, 6.7 Hz, 1H), 5.00 – 4.94 (m, 1H), 4.92 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 3.60 (s, 3H), 2.86 – 2.77 (m, 2H), 2.68 (d, J = 14.1 Hz, 1H), 2.52 (d, J = 14.1 Hz, 1H), 2.26 (s, 3H), 2.25 – 2.19 (m, 1H), 2.13 – 2.06 (m, 1H), 2.05 – 1.95 (m, 2H), 1.78 (ddd, J = 13.6, 12.5, 4.7 Hz, 1H), 1.65 (ddd, J = 13.6, 12.5, 4.2 Hz, 1H), 1.36 (tddd, J = 12.7, 8.1, 6.7, 4.7 Hz, 1H), 1.25 (tddd, J = 12.6, 8.1, 6.8, 4.1 Hz, 1H). Preparation of of Intermediate 2-66 (Methyl 2-(4-methyl-1-(4-oxobutyl)-2,3-dihydro-1H- inden-1-yl)acetate) Intermediate 2-65 (methyl 2-(4-methyl-1-(pent-4-en-1-yl)-2,3-dihydro-1H-inden-1- yl)acetate; 14.21g, 52.2mmol) was dissolved in DCM (260mL) and cooled to -78 °C then ozone was passed through the solution for 30min. Ozone introduction was halted and the mixture was sparged with N₂ for 5min then PPh₃ (16.42g, 62.6 mmol) was added and the mixture was allowed to warm to rt and stirred overnight. The mixture was directly adsorbed onto silica gel and purified by flash column chromatography on silica gel eluted with 0→60% EtOAc in hexanes to give the title compound (12.94g, 90.4%) as a faintly yellow oil. LC/MS, [M+H]⁺ = 273.2 m/z. Preparation of of Intermediate 2-67 (Methyl 4-(1-(2-methoxy-2-oxoethyl)-4-methyl-2,3- dihydro-1H-inden-1-yl)butanoate) Intermediate 2-66 (methyl 2-(4-methyl-1-(4-oxobutyl)-2,3-dihydro-1H-inden-1- yl)acetate; 12.94g, 47.2mmol) was dissolved in tBuOH (120mL) and treated with 2-metyl- 2-butene (25mL, 236mmol) and cooled to 0ºC. A solution of NaClO2 (12.8g, 141.5 mmol) and KH₂PO4 (19.26g, 141.5mmol) in H₂O (120mL) was added and the mixture was allowed to warm to rt and stirred for 16hrs. The mixture was acidified with 1 M HCl and extracted with EtOAc (x3). The combined extract was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in in MeOH (230mL) acetyl chloride (27mL, 377mmol) was added dropwise at 0ºC then the mixture was warmed to 40 °C for 2hr. The mixture was concentrated, co-evaporated from toluene once then purified by flash column chromatography on silica gel eluted with 0→50% EtOAc in hexanes to give the title compound (13.01g, 90.7%) as a colorless oil. LC/MS, [M+H]⁺ = 305.2 m/z. Preparation of of Intermediate 2-68 (Methyl 4’-methyl-3-oxo-2’,3’- dihydrospiro[cyclohexane-1,1’-indene]-4-carboxylate) A 250mL round bottom flask fitted with an addition funnel was charged with NaH (5.13g, 128.3mmol) and evacuated and backfilled with N2 (x3) then amended with anhydrous toluene (35mL) and MeOH (300µL) and warmed to 70 °C. The addition funnel was charged with a solution of Intermediate 2-67 (methyl 4-(1-(2-methoxy-2-oxoethyl)-4-methyl-2,3- dihydro-1H-inden-1-yl)butanoate; 13.01g, 42.7mmol) and MeOH (300µL) in anhydrous toluene (40mL) and this solution was added dropwise over a period of approximately 90min and the reaction was stirred overnight. The mixture was cooled to room temperature and quenched with aq. NH₄Cl and extracted with EtOAc (x2). The combined extract was washed with sat NH4C1, brine, dried with Na2SO4, and concentrated to give the title compound (11.64g, quant.) as a tan colored turbid oil which was used without further purification. LC/MS, [M+H]⁺ = 273.1 m/z. Preparation of of Intermediate 2-69 (4-Methyl-2’-(methylthio)-2,3,5’,8’-tetrahydro-3’H- spiro[indene-1,7’-quinazolin]-4’(6’H)-one) Intermediate 2-68 (methyl 4’-methyl-3-oxo-2’,3’-dihydrospiro[cyclohexane-1,1’- indene]-4-carboxylate; 11.64g, 42.7mmol) was dissolved in MeCN (143mL) and treated with thiourea (4.23g, 55.6mmol) and DBU (7.7mL, 51.6mmol) and the mixture was heated to reflux overnight. The mixture was cooled slightly then poured into ice cold one-third saturated NaHCO₃ and stirred for 5min and the resulting solids were collected by filtration, washed with H₂O, and freed of excess water under suction. The solids were dissolved in warm DMF (390mL) and THF (195mL) then cooled and treated with NaOAc (7.01g, 85.5mmol) and MeI (2.66mL, 42.7mmol). After 30min, the mixture was poured into ice cold one-third saturated NaHCO3 and stirred for 5min and the resulting solids were collected by filtration, washed with H₂O, hexanes:EtOH (9:1, x3), hexanes (x3), dried under suction, and further dried in vacuo at 50ºC to give the title (8.0g, 59.9%) as an off-white powder. LC/MS, ESI [M+H]⁺ = 313.1 m/z. Preparation of of Intermediate 2-70 (4-Methyl-2’-(methylthio)-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazolin]-4’-yl trifluoromethanesulfonate) Intermediate 2-69 (4-methyl-2’-(methylthio)-2,3,5’,8’-tetrahydro-3’H- spiro[indene-1,7’-quinazolin]-4’(6’H)-one; 0.50g, 1.6mmol) was suspended in anhydrous DCM (8mL) and treated with iPr₂EtN (0.84mL, 4.82mmol) and cooled to 0°C. Triflic anhydride, 1M in DCM (2.66mL) was added and the mixture was stirred for 20min then diluted with 1vol hexanes and filtered through a pad of silica gel rinsing with 20% EtOAc in hexanes and concentrated to give the title compound (710mg, 99.8%) as a pale yellow residue. LC/MS, ESI [M+H]⁺ = 445.1 m/z. Schematization for the Preparation of Intermediates 2-71 and 2-72

Intermediate 2-70 Intermediate 2-71 Intermediate 2-72 Preparation of Intermediate 2-71 (tert-butyl (1R,5S)-3-(4-methyl-2’-(methylthio)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate) To a solution of Intermediate 2-70 ((4’-methyl-2-methylsulfanyl-spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl) trifluoromethanesulfonate; 355 mg, 0.80 mmol) in DMF (4 mL) was added iPr₂EtN (0.28 mL, 1.61 mmol) followed by tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (187 mg, 0.88 mmol). The mixture was stirred at room temperature for 1h before EtOAc was added and the resulting mixture was poured into sat NaHCO₃ (aq)., the organics were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were dried with Na2SO4, filtered, and concentrated. The crude material was then purified using flash column chromatography on silica gel (0 – 50% EtOAc in hexanes) to yield the title compound (372 mg, 0.73 mmol, 92% yield) as an off- white foam. LC/MS, ESI [M+H]⁺ = 507.3 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.08 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 4.43 – 4.17 (m, 2H), 3.95 – 3.63 (m, 2H), 3.38 – 3.10 (m, 2H), 2.98 – 2.79 (m, 4H), 2.70 – 2.53 (m, 2H), 2.51 (s, 3H), 2.28 (s, 3H), 2.08 – 1.87 (m, 6H), 1.87 – 1.78 (m, 1H), 1.78 – 1.67 (m, 1H), 1.49 (s, 9H). Preparation of Intermediate 2-72 (tert-butyl (1R,5S)-3-(4-methyl-2’-(methylsulfinyl)- 2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate) To a cooled (0 °C) solution of Intermediate 2-71 (tert-butyl (1R,5S)-3-(4-methyl-2’- (methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 372 mg, 0.73 mmol) in DCM (3.8 mL) was added mCPBA (152 mg, 0.66 mmol). The mixture was stirred for 1h before being poured into half saturated NaHCO₃ (aq) and extracting with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated to yield the crude title compound (383 mg, 0.73 mmol, 99.8% yield), which was taken on to the next step without further purification. LC/MS, ESI [M+H]⁺ = 523.3 m/z. Preparation of Compound 1-80 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methyl- 2’-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene- 1,7’-quinazoline]) To a cooled (-40 °C) solution of Intermediate 2-72 (tert-butyl (1R,5S)-3-(4-methyl- 2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 40 mg, 0.08 mmol) and 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (16 mg, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to the title compound (22 mg, 0.045 mmol, 59% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 500.3 m/z.¹H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 4.14 – 4.00 (m, 2H), 3.87 (d, J = 12.1 Hz, 1H), 3.74 (d, J = 12.4 Hz, 1H), 3.61 – 3.46 (m, 2H), 3.24 – 3.04 (m, 4H), 2.93 – 2.77 (m, 4H), 2.78 – 2.46 (m, 6H), 2.27 (s, 3H), 2.10 (dtd, J = 12.4, 6.0, 3.2 Hz, 2H), 2.06 – 1.94 (m, 2H), 1.96 – 1.73 (m, 8H), 1.73 – 1.58 (m, 3H). Preparation of Compound 1-81 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2’- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methyl-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) To a cooled (-40 °C) solution of Intermediate 2-72 (tert-butyl (1R,5S)-3-(4-methyl- 2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 40 mg, 0.08 mmol) and [(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (18 mg, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na2SO4 and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to yield the title compound (26 mg, 0.05 mmol, 65% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 518.3 m/z. ¹H NMR (400 MHz, CDCl₃) δ 7.07 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.4, 1H), 6.87 (d, J = 7.4, 1H), 5.35 – 5.12 (m, 1H), 4.08 (dd, J = 10.2, 7.8 Hz, 1H), 3.94 (dd, J = 10.2, 7.9 Hz, 1H), 3.84 (d, J = 11.8 Hz, 1H), 3.72 (d, J = 12.5 Hz, 1H), 3.55 (s, 2H), 3.29 – 3.04 (m, 5H), 3.00 – 2.89 (m, 1H), 2.90 – 2.80 (m, 4H), 2.67 – 2.47 (m, 2H), 2.47 – 2.31 (m, 2H), 2.27 (s, 3H), 2.26 – 1.61 (m, 13H).¹⁹F NMR (376 MHz, CDCl3) δ -173.19, -173.21. Preparation of Compound 1-82 (4’-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methyl- 2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) To a cooled (-40 °C) solution of Intermediate 2-72 (tert-butyl (1R,5S)-3-(4-methyl- 2’-(methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 40 mg, 0.08 mmol) and (S)-(1-methylpyrrolidin-2- yl)methanol (0.01 mL, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to yield the title compound (27 mg, 0.056 mmol, 73% yield) as a off- white foam. LC/MS, ESI [M+H]⁺ = 474.3 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.08 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 4.38 (ddd, J = 10.6, 4.8, 4.8 Hz, 1H), 4.09 (ddd, J = 10.6, 7.4, 5.6 Hz, 1H), 3.85 (d, J = 12.7 Hz, 1H), 3.71 (d, J = 12.3 Hz, 1H), 3.62 – 3.50 (m, 2H), 3.20 (d, J = 12.5 Hz, 1H), 3.15 – 3.03 (m, 2H), 2.91 – 2.79 (m, 4H), 2.72 – 2.50 (m, 4H), 2.47 (s, 3H), 2.27 (s, 4H), 2.12 – 1.64 (m, 12H). Schematization for the Preparation of Intermediates 2-73 and 2-74

Intermediate 2-70 Intermediate 2-73 Intermediate 2-74 Preparation of Intermediate 2-73 (tert-butyl 3-(4-methyl-2’-(methylthio)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate) To a solution of Intermediate 2-70 ((4’-methyl-2-methylsulfanyl-spiro[6,8-dihydro- 5H-quinazoline-7,1’-indane]-4-yl) trifluoromethanesulfonate; 355 mg, 0.80 mmol) in DMF (4 mL) was added iPr₂EtN (0.28 mL, 1.61 mmol), followed by tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (174 mg, 0.88 mmol). The mixture was stirred at room temperature for 1h before EtOAc was added and the resulting mixture was poured into sat NaHCO₃ (aq). The organics were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were dried with Na2SO4 and concentrated. The crude material was then purified using flash column chromatography on silica gel (0 – 65% EtOAc in hexanes) to yield the title compound (364 mg, 0.74 mmol, 92.5% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 493.3 m/z. ¹H NMR (400 MHz, CDCl₃) δ 7.08 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.69 – 4.16 (m, 4H), 3.99 – 3.61 (m, 2H), 3.02 – 2.72 (m, 6H), 2.61 (ddd, J = 6.8, 6.8, 6.6 Hz, 1H), 2.52 (s, 3H), 2.28 (s, 3H), 2.11 – 1.87 (m, 3H), 1.79 – 1.68 (m, 1H), 1.53 – 1.46 (m, 1H), 1.41 (s, 9H). Preparation of Intermediate 2-74 (tert-butyl 3-(4-methyl-2’-(methylsulfinyl)-2,3,5’,8’- tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate) To a cooled (0 °C) solution of Intermediate 2-73 (tert-butyl 3-(4-methyl-2’- (methylthio)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 364 mg, 0.74 mmol) in DCM (3.8 mL) was added mCPBA (153 mg, 0.66 mmol). The mixture was stirred for 1h before being poured into half saturated NaHCO₃ (aq) and extracting with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated to yield the crude title compound (375 mg, 0.73 mmol, 99.8% yield), which was taken on to the next step without further purification. LC/MS, ESI [M+H]⁺ = 509.2 m/z. Preparation of Compound 1-83 (4’-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-methyl-2’- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’- quinazoline]) To a cooled (-40 °C) solution of Intermediate 1-74 (tert-butyl 3-(4-methyl-2’- (methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 40 mg, 0.08 mmol) and 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (16 mg, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to yield the title compound (22 mg, 0.045 mmol, 59% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 486.3 m/z. ¹H NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 4.22 – 3.64 (m, 8H), 3.17 (ddd, J = 10.9, 5.7, 5.7 Hz, 2H), 2.96 – 2.76 (m, 6H), 2.74 – 2.58 (m, 4H), 2.26 (s, 3H), 2.12 (ddd, J = 12.4, 6.0, 6.0 Hz, 2H), 2.06 – 1.78 (m, 7H), 1.78 – 1.54 (m, 4H). Preparation of Compound 1-84 (4’-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2’-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-methyl-2,3,5’,8’-tetrahydro-6’H- spiro[indene-1,7’-quinazoline]) To a cooled (-40 °C) solution of Intermediate 1-74 (tert-butyl 3-(4-methyl-2’- (methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 40 mg, 0.08 mmol) and [(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (18 mg, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na2SO4 and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to yield the title compound (26 mg, 0.05 mmol, 65% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 504.3 m/z. ¹H NMR (400 MHz, CDCl₃) δ 7.08 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 5.33 – 5.14 (m, 1H), 4.25 – 3.64 (m, 8H), 3.33 – 3.08 (m, 3H), 3.04 – 2.62 (m, 9H), 2.35 – 2.09 (m, 6H), 2.07 – 1.77 (m, 6H), 1.77 – 1.57 (m, 2H).¹⁹F NMR (376 MHz, CDCl₃) δ - 173.20. Preparation of Compound 1-85 (4’-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-methyl-2’-(((S)- 1-methylpyrrolidin-2-yl)methoxy)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazoline]) To a cooled (-40 °C) solution of Intermediate 1-74 (tert-butyl 3-(4-methyl-2’- (methylsulfinyl)-2,3,5’,8’-tetrahydro-6’H-spiro[indene-1,7’-quinazolin]-4’-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 39 mg, 0.08 mmol) and (S)-(1-methylpyrrolidin- 2-yl)methanol (0.01 mL, 0.11 mmol) in THF (0.5 mL) was added KotBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K₂CO₃ (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 – 65% ACN in H₂O + 0.25% TFA) to yield the title compound (33 mg, 0.073 mmol, 95% yield) as an off- white foam. LC/MS, ESI [M+H]⁺ = 460.3 m/z.¹H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.41 (ddd, J = 10.7, 4.8, 1.8 Hz, 1H), 4.23 – 4.09 (m, 2H), 4.09 – 3.99 (m, 2H), 3.96 – 3.85 (m, 1H), 3.85 – 3.75 (m, 2H), 3.18 – 3.06 (m, 1H), 2.96 – 2.64 (m, 9H), 2.49 (s, 3H), 2.35 – 2.23 (m, 4H), 2.12 – 1.88 (m, 5H), 1.88 – 1.56 (m, 4H). Example 3: Synthesis of Spiro-Benzylictetralin & Spiro-Benzylicquinoline Compounds Preparation of Intermediate 3-1 (3-allyl 1-(tert-butyl) 3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4- dihydroquinoline-1,3(2H)-dicarboxylate)

Intermediate 3-1 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 give tert-butyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (8.26 g, 33.4 mmol, 98% yield) as a colorless oil which crystallized upon standing.¹H NMR (400 MHz, CDCl3) δ 7.25 – 7.14 (m, 2H), 7.05 (td, J = 7.4, 1.3 Hz, 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.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. Freshly prepared LDA, 1M in THF (4.85 mmol) was cooled to -78ºC, 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), and the mixture was stirred for 40 minutes before adding allyl imidazole-1-carboxylate (738 mg, 4.85 mmol) 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, then quenched with saturated NH₄Cl. The mixture was partitioned between saturated NH4Cl and EtOAc and the organic phase was collected and washed with saturated NH4C1, 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. ¹H NMR (500 MHz, CDCl₃) δ 7.23 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 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.¹³C 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. 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-bromobutanoate (2.23 mL, 16 mmol), KI (1.73 g, 10.4 mmol), and K₂CO₃ (4.3 g, 31 mmol), and the mixture was stirred at room temperature. After 23 hours, the mixture was diluted with H₂O and extracted with EtOAc (3 times). The combined extract was 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→40% EtOAc in hexanes) to give Intermediate 3-1, 3-allyl 1-(tert-butyl) 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. LCMS: [M+2H-Boc]⁺ m/z = 346.1 amu. Preparation of Intermediate 3-1 Analogs It is readily apparent to a person of ordinary skill in the art that Intermediate 3-1 Analogs having groups alternative to that imparted by the use of 3,4-dihydroquinolin-2(1H)- one can be made by using a different dihydroquinolinones. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare desired dihydroquinolinones, or obtain them from chemical vendors. Intermediate 3-1 Analogs are used in subsequent steps to prepare the corresponding Intermediate 3-2 Analogs. Further, Intermediate 3-2 Analogs are used to prepare compounds (see below) that are key intermediates for preparing inhibitors of KRAS G12D. Preparation of Intermediate 3-2 ((R)-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinolin]-4-yl trifluoromethanesulfonate)

Intermediate 3-2 To an oven-dried flask containing Intermediate 3-1 (3-allyl 1-(tert-butyl) 3-(4- ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1,3(2H)-dicarboxylate) (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), followed by THF (50 mL). The headspace was purged with argon and the flask was fitted with a condenser. The mixture was stirred at room temperature for 30 minutes before being warmed to 50°C and stirring 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 using flash column chromatography on silica gel (0→60% EtOAc in hexanes) to yield tert-butyl (S)-3-allyl-3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.78 mg, 4.43 mmol, 89% yield) as an off white solid. LCMS: [M+H]⁺ m/z = 402.2 amu. To a solution of tert-butyl (S)-3-allyl-3-(4-ethoxy-4-oxobutyl)-2-oxo-3,4- dihydroquinoline-1(2H)-carboxylate (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 vigorously stirred at room temperature for 20 minutes, at which point an additional 2 equivalents of NaIO₄ was added. After 20 more minutes, an additional 1 equivalent of NaIO₄ was added and the reaction was stirred for a final 1 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 using EtOAc (30 mL * 3) and the combined organics were dried using Na₂SO₄, filtered, and concentrated to afford the crude acid, which was taken on without further purification. LCMS: [M+H]⁺ m/z= 420.2 amu. The crude acid was taken up in MeOH (45 mL) and cooled to 0°C. To the cooled solution was added SOCl2 (3.9 mL, 53 mmol) dropwise, and the reaction was warmed to room temperature and stirred overnight. Upon completion, H₂O (100 mL) was slowly added before being extracted with EtOAc (60 mL * 3). The combined organics were dried using Na2SO4, filtered, and concentrated to afford the crude methyl (R)-4-(3-(2-methoxy-2- oxoethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)butanoate, which was taken on to the next step without further purification. LCMS: [M+H]⁺ m/z = 320.1 amu. To a solution of the crude methyl (R)-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 gas bubbles were observed. After an additional 20 minutes of stirring, the aqueous was made basic using 2 M NaOH. the mixture was extracted with DCM (100 mL * 3) and the combined organics were dried using Na₂SO₄, filtered, and concentrated in vacuo to afford the crude methyl (R)-4-(3-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydroquinolin-3- yl)butanoate, which was taken on without further purification. LCMS: [M+H]⁺ m/z = 306.1 amu. To a cooled (0°C) solution of the crude methyl (R)-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 before NaBH(OAc)3 (1.88 g, 8.9 mmol) was added and the mixture was warmed to room temperature. After 4 hours of additional stirring, the reaction was quenched with half-saturated NaHCO₃ (100 mL) and extracted using 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 yield methyl (R)-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 pale- yellow foam.¹H 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. LCMS: [M+H]⁺ m/z = 320.1 amu. To a cooled (-78°C) solution of methyl (R)-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 using flash column chromatography on silica gel (0→40% EtOAc in hexanes) to yield methyl (1R)-1'-methyl-3-oxo-1',4'-dihydro- 2'H-spiro[cyclohexane-1,3'-quinoline]-4-carboxylate (270 mg, 0.94 mmol, 75% yield) as a pale yellow-foam. LCMS: [M+H]⁺ m/z = 288.1 amu. To a vial containing a solution of methyl (1R)-1'-methyl-3-oxo-1',4'-dihydro-2'H- 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 (R)-2-mercapto-1'-methyl-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'- quinolin]-4-ol was taken on to the next step without further purification. LCMS: [M+H]⁺ m/z = 314.1 amu. To a vial containing the crude (R)-2-mercapto-1'-methyl-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinolin]-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 fully dissolved, MeI (33 µL, 0.52 mmol) was added. The reaction was stirred for 1 hour, after which 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 (R)-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinolin]- 4-ol was taken on to the next step without further purification. LCMS: [M+H]⁺ m/z = 328.1 amu. To a solution of the crude (R)-1'-methyl-2-(methylthio)-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinolin]-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 triflic anhydride (380 µL, 0.38 mmol, 1M in DCM) was added. The reaction was stirred for 2 hours, after which hexanes (2 mL) was added and the mixture was passed through a plug of silica gel, rinsing with 30% EtOAc in hexanes (20 mL). The combined organics were concentrated in vacuo and Intermediate 3-2, (R)-1'-methyl-2- (methylthio)-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinolin]-4-yl trifluoromethanesulfonate, was used in subsequent reaction without further purification. LCMS: [M+H]⁺ m/z = 460.1 amu. Preparation of Intermediate 3-3

I_{ntermediate 3-2 Intermediate 3-2a Intermediate 3-2b}

Intermediate 3-3 Preparation of Intermediate 3-4 ((S)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H- spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate)

Intermediate 3-4 (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) under N₂ atmosphere and the mixture was stirred for 30 minutes at room temperature. Separately, allyl 2-(4-ethoxy-4- oxobutyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (2.68 g, 7.8 mmol) was dissolved in toluene (30 mL) and sparged with N₂ for 20 minutes then added to the catalyst mixture. After 13 hours, the reaction was warmed to 40°C. After an additional 24 hours, the mixture was cooled, opened to air, and amended with a small amount of silica gel and stirred for 10 minutes, then 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 ethyl (S)-4-(2-allyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoate (2.39 g, >100% yield) as a yellow oil.¹H NMR matched that of the R enantiomer. LCMS: [M+H]⁺ m/z = 301.2 amu. Ethyl (S)-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 0.5M NaHSO₄ and extracted with EtOAc (3 times). The combined extract was washed with brine, dried over Na2SO4, filtered through Celite, and concentrated. The residue was dissolved in Methanol (35 mL), cooled to 0ºC, and SOCl₂ (5.3 mL, 73 mmol) was added dropwise. The mixture 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 extract was 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 methyl (S)-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 pale yellow oil.¹H NMR matched that of the R enantiomer. LCMS: [M+H]⁺ m/z = 319.1 amu. Methyl (S)-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, 10wt% (wetted) (240 mg) and HClO4 (62 µL, 0.57 mmol) and the vessel was charged with H₂. After 17 hours, the reaction mixture was filtered through Celite and concentrated. The residue was taken up in MeOH (10 mL), cooled to 0°C, and treated with SOCl2 (1.5 mL, 19 mmol), then warmed to room temperature. After 1.5 hours, the mixture was concentrated, diluted with H₂O, and extracted with Et₂O (3 times). The combined extract was washed with sat 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 give methyl (R)-4-(2-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydronaphthalen-2- yl)butanoate (1.02 g, 3.36 mmol, 88% yield). ¹H NMR matched that of the S enantiomer. LCMS: [M+H]⁺ m/z = 305.2 amu. To a cooled (-78°C) solution of methyl (R)-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 methyl (1R)-3-oxo-3',4'-dihydro-1'H- spiro[cyclohexane-1,2'-naphthalene]-4-carboxylate was used in the next step without further purification. LCMS: [M+H]⁺ m/z = 273.1 amu. To a vial containing a solution of the crude methyl (1R)-3-oxo-3',4'-dihydro-1'H- 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 (S)-2'-mercapto-3,4,5',8'-tetrahydro-1H,6'H- spiro[naphthalene-2,7'-quinazolin]-4'-ol was taken on to the next step without further purification. LCMS: [M+H]⁺ m/z = 299.1 amu. To a vial containing the crude (S)-2'-mercapto-3,4,5',8'-tetrahydro-1H,6'H- spiro[naphthalene-2,7'-quinazolin]-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 fully dissolved, MeI (65 µL, 1.04 mmol) was added. The reaction was stirred for 1 h, after which 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 (S)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-ol was taken on to the next step without further purification. LCMS: [M+H]⁺ m/z = 313.1 amu. To solution of the crude (S)-2'-(methylthio)-3,4,5',8'-tetrahydro-1H,6'H- spiro[naphthalene-2,7'-quinazolin]-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 triflic anhydride (432 µL, 0.43 mmol, 1M in DCM) was added. The reaction was stirred for 2 hours, after which hexanes (2.4 mL) was added and the mixture was passed through a plug of silica gel, rinsing with 30% EtOAc in hexanes (20 mL). The combined organics were concentrated in vacuo to give Intermediate 3-4, (S)-2'- (methylthio)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazolin]-4'-yl trifluoromethanesulfonate, which was used in subsequent reactions without further purification. LCMS: [M+H]⁺ m/z = 445.1 amu. Preparation of Intermediate 3-5

I_{ntermediate 3-4 Intermediate 3-4a Intermediate 3-4b}

Intermediate 3-5 Preparation of Intermediate 3-3 Analogs and Intermediate 3-5 Analogs It is understood by the artisan of ordinary skill that Intermediate 3-3 Analogs can be prepared using Intermediate 3-2 or Intermediate 3-2 Analogs by following these schematized procedures, and that Intermediate 3-5 Analogs can be prepared using Intermediate 3-4 or Intermediate 3-4 Analogs by following these schematized procedures:

Intermediate 3-2/3-4 or Intermediate 3-2/3-4 Analogs

Intermediate 3-3/3-5 Analogs wherein, examples of X include, but are not limited to, CH₂, CH(CH3), N(H) and N(CH3); examples of Ring A include, but are not limited to

where indicates the point of attachment to the pyrimidine; examples of R include, but are not limited to, F, C1, OH, CH₂CH3, CH3 and NH₂, and zero, one, two or three instances of R can occur, each of which is independently selected from one another; examples of R6 include, but are not limited to, halogen, amino, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, wherein each of amino, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, hexahydro-1H-pyrrolizinyl, 1-azabicyclo[2.2.1]heptanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl or piperazinyl may be optionally substituted with one or more R7; examples of R7 include, but are not limited to, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cyano, -(CH₂)_nN(R₃)₂, -N(R₃)₂, -C(O)N(R₃)₂, -OC(O)N(R₃)₂, -N(H)C(O)R₃, -CH₂N(H)C(O)R₃, -CH₂OC(O)N(R₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, and each instance of R7 is independently selected from other instances; examples of R3 include, but are not limited to, H and C₁-C₃ alkyl, and each instance of R3 is independently selected from other instances; and n in each occurrence is independently 1, 2 or 3. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of Ring A species that can be used to prepare Intermediate 3-3 Analogs and Intermediate 3-5 Analogs include, but are not limited to: tert-butyl 2- (cyanomethyl)piperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-3-methylpiperazine-1- carboxylate, tert-butyl 2-(cyanomethyl)-6-methylpiperazine-1-carboxylate, tert-butyl 2- (cyanomethyl)-5-methylpiperazine-1-carboxylate, tert-butyl (1S,5S,6S)-6-fluoro-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-(2-cyanoethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-methyl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate, tert-butyl 1-carbamoyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 8-(tert- butyl) 1-methyl 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate, tert-butyl (1S,5S,6S)-6- methoxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-chloro-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5S,6S)-6-hydroxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5R,6R)-6-(cyanomethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1S,5S,6S)-6-(1H-1,2,4-triazol-1-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Ring A species, or obtain them from chemical vendors. Examples of alcohols used to prepare Intermediate 3-3 Analogs and Intermediate 3-5 Analogs include, but are not limited to: (1-isopropylpyrrolidin-2-yl)methanol, (1- ethylpyrrolidin-2-yl)methanol, (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, (2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and (2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Preparation of Compound 2-7 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'-quinazoline]) Compound 2-7 is prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 3-5 instead of Intermediate 1-13. Preparation of Compound 2-8 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- 1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'- quinazoline]) Compound 2-8 is prepared following the general procedures used to prepare Compound 1-2 and using Intermediate 3-5 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-9 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- 1-isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'- quinazoline]) Compound 2-9 is prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 3-5 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-33 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H- spiro[naphthalene-2,7'-quinazoline]) Compound 2-33 is prepared following the general procedures used to prepare Compound 1-30 and using Intermediate 3-4b instead of Intermediate 1-35. Preparation of Compound 2-34 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,5',8'-tetrahydro- 1H,6'H-spiro[naphthalene-2,7'-quinazoline]) Compound 2-34 is prepared following the general procedures used to prepare Compound 1-34 and using Intermediate 3-4b instead of Intermediate 1-35. Preparation of Compound 2-35 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1'- methyl-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinoline]) Compound 2-35 is prepared following the general procedures used to prepare Compound 1-30 and using Intermediate 3-2b instead of Intermediate 1-35. Preparation of Compound 2-36 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1'-methyl-1',4',5,8- tetrahydro-2'H,6H-spiro[quinazoline-7,3'-quinoline]) Compound 2-36 is prepared following the general procedures used to prepare Compound 1-34 and using Intermediate 3-2b instead of Intermediate 1-35. Preparation of Intermediate 3-6

Intermediate 3-4

Intermediate 3-6 Preparation of Compound 2-10 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'- (((S)-pyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'- quinazoline]) Compound 2-10 is prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 3-6 instead of Intermediate 1-25. Preparation of Compound 2-11 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'- (((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene-2,7'- quinazoline]) Compound 2-11 is prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 3-6 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-12 ((S)-4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'- (((S)-1-isopropylpyrrolidin-2-yl)methoxy)-3,4,5',8'-tetrahydro-1H,6'H-spiro[naphthalene- 2,7'-quinazoline]) Compound 2-12 is prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 3-6 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-13 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1'- methyl-2-(((S)-pyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'- quinoline]) Compound 2-13 is prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 3-3 instead of Intermediate 1-13. Preparation of Compound 2-14 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1'- methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinoline]) Compound 2-14 is prepared following the general procedures used to prepare Compound 1-2 and using Intermediate 3-3 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-15 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)- 1-isopropylpyrrolidin-2-yl)methoxy)-1'-methyl-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinoline]) Compound 2-15 is prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 3-3 instead of Intermediate 1-13 in step 1. Preparation of Intermediate 3-7

Intermediate 3-4

Intermediate 3-7 Preparation of Compound 2-16 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1'- methyl-2-(((S)-pyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2'H,6H-spiro[quinazoline-7,3'- quinoline]) Compound 2-16 is prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 3-7 instead of Intermediate 1-25. Preparation of Compound 2-17 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1'- methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinoline]) Compound 2-17 is prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 3-7 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-18 ((R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(((S)- 1-isopropylpyrrolidin-2-yl)methoxy)-1'-methyl-1',4',5,8-tetrahydro-2'H,6H- spiro[quinazoline-7,3'-quinoline]) Compound 2-18 is prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 3-7 instead of Intermediate 1-25 in step 1. Example 4: Synthesis of Spiro-Acenaphthene Compounds Scheme for the Preparation of Intermediates 4-1 through 4-8

Intermediate 4-1 Intermediate 4-2

Intermediate 4-3 Intermediate 4-4 Intermediate 4-5

Intermediate 4-6 Intermediate 4-7

Intermediate 4-8 Preparation of Intermediate 4-1 (2-(Acenaphthylen-1(2H)-ylidene)malononitrile) 2H-Acenaphthylen-1-one (3.0g, 17.8mmol) was dissolved in EtOH (30mL) and treated with malononitrile (1.5mL, 27.0mmol), AcOH (2.0mL, 35.7mmol), and NH₄OAc (1.38g, 17.9mmol), and the mixture was stirred at rt, shielded from light. After 16hr, the mixture was diluted with 1N HCl (30mL), stirred for 5min, and the resulting precipitate was collected by filtration and washed with 1:1 hexanes:EtOH, hexanes, then dried under suction and further dried in vacuo at 50 ºC to give the title compound (3.303g, 85.6%) as a dark yellow solid. LC/MS, ESI [M-H]- = 215.1 m/z. Preparation of Intermediate 4-1 Analogs It is readily apparent to a person of ordinary skill in the art that Intermediate 4-1 Analogs having groups alternative to that imparted by the use of acenaphthylen-1(2H)-one can be made by using a different acenaphthylenone. Examples of alternative acenaphthylenone that can be used include, but are not limited to: 7-hydroxyacenaphthylen- 1(2H)-one, 7-aminoacenaphthylen-1(2H)-one, 6-fluoro-7-hydroxyacenaphthylen-1(2H)- one, 7-amino-6-fluoroacenaphthylen-1(2H)-one, 6-chloro-7-hydroxyacenaphthylen-1(2H)- one, 7-amino-6-chloroacenaphthylen-1(2H)-one, 6-chloro-3-fluoro-7- hydroxyacenaphthylen-1(2H)-one, 7-amino-6-chloro-3-fluoroacenaphthylen-1(2H)-one, 3,6-difluoro-7-hydroxyacenaphthylen-1(2H)-one, 7-amino-3,6-difluoroacenaphthylen- 1(2H)-one, 6-chloro-3-fluoroacenaphthylen-1(2H)-one, 3,6-difluoroacenaphthylen-1(2H)- one, 6-fluoroacenaphthylen-1(2H)-one, 3-fluoroacenaphthylen-1(2H)-one, 6- chloroacenaphthylen-1(2H)-one, 3-chloroacenaphthylen-1(2H)-one, 8- methylacenaphthylen-1(2H)-one, 8-fluoroacenaphthylen-1(2H)-one, 8- chloroacenaphthylen-1(2H)-one, 7-hydroxy-8-methylacenaphthylen-1(2H)-one, 8-fluoro-7- hydroxyacenaphthylen-1(2H)-one, 8-chloro-7-hydroxyacenaphthylen-1(2H)-one, 7-amino- 8-methylacenaphthylen-1(2H)-one, 7-amino-8-fluoroacenaphthylen-1(2H)-one and 7- amino-8-chloroacenaphthylen-1(2H)-one. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired acenaphthylenone, or obtain them from chemical vendors. Intermediate 4-1 Analogs are used in subsequent steps to prepare the corresponding Intermediate 4-8 Analogs. Further, Intermediate 4-8 Analogs are used to prepare compounds (see below) that are key intermediates for preparing inhibitors of KRAS G12D. Preparation of Intermediate 4-2 (2-(1-(Pent-4-en-1-yl)-1,2-dihydroacenaphthylen-1- yl)malononitrile) A flame-dried 250mL round bottom flask was charged with CuBr•Me2S (471mg, 2.29mmol) and evacuated and backfilled with Ar (x3), amended with anhydrous THF (10mL), and cooled to -40 °C. Pent-4-en-1-ylmagnesium bromide, 0.5M in THF (52.4mL, 26.2mmol) was added and the mixture was stirred for 15min, then a suspension of Intermediate 4-1 (3.3g, 15.3mmol) in THF (40mL) was added. The cooling bath was allowed to slowly warm to rt. After 2hrs, the mixture was partitioned between EtOAc and sat NH4Cl. The organic phase was further washed with sat NH4C1, brine, then diluted with 1vol hexanes and 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 eluted with 0→15% EtOAc in hexanes to give the title compound (2.89g, 66.1%) as a yellow oil. Rf = 0.30 (9:1 hexanes:EtOAc). LC/MS, ESI [M-H]- = 285.1 m/z.¹H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 8.1, 0.9 Hz, 1H), 7.71 (dq, J = 8.3, 1.0 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.50 (dd, J = 7.1, 0.9 Hz, 1H), 7.38 – 7.34 (m, 1H), 5.66 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.01 – 4.86 (m, 2H), 3.93 (s, 1H), 3.60 (dt, J = 17.7, 1.2 Hz, 1H), 3.52 (dt, J = 17.9, 1.2 Hz, 1H), 2.27 – 1.97 (m, 4H), 1.38 – 1.22 (m, 1H), 1.10 – 0.95 (m, 1H). Preparation of Intermediate 4-3 (Methyl 2-(1-(pent-4-en-1-yl)-1,2-dihydroacenaphthylen- 1-yl)acetate) In a PFA round bottom flask, Intermediate 4-2 (2.89g, 10.09 mmol) was treated with ethylene glycol (10.mL, 10.09 mmol), water (5 mL), and KOH (9.99g, 151.36 mmol), and the mixture was heated to 185 °C for 24hrs. The mixture was poured into chipped ice containing H₂SO4 and extracted with EtOAc (x3). The combined extract was washed with H₂O, brine, dried over Na₂SO₄, filtered, and concentrated. The residue was heated to 200 ºC for 30min then cooled to rt. The residue was treated with 3N HC1, warmed to 50 ºC for 2.5 hrs, and then the mixture was concentrated, co-evaporated from toluene once, triturated with 8:2 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same to give the title compound (2.62g, 88.2% yield) as a red colored oil. LC/MS, ESI [M+H]⁺ = 295.2 m/z.¹H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 8.2, 0.7 Hz, 1H), 7.62 (dd, J = 8.2, 0.9 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.29 – 7.25 (m, 1H), 7.20 (dd, J = 6.9, 0.8 Hz, 1H), 5.67 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H), 4.97 – 4.81 (m, 2H), 3.61 (dt, J = 17.5, 1.2 Hz, 1H), 3.54 (s, 3H), 3.35 (dt, J = 17.5, 1.2 Hz, 1H), 2.84 (d, J = 14.7 Hz, 1H), 2.72 (d, J = 14.5 Hz, 1H), 2.02 – 1.77 (m, 4H), 1.36 – 1.21 (m, 1H), 1.08 – 0.92 (m, 1H). Preparation of Intermediate 4-4 (Methyl 2-(1-(4-oxobutyl)-1,2-dihydroacenaphthylen-1- yl)acetate) Intermediate 4-3 (2.62g, 8.9mmol) was dissolved in DCM (59mL) and cooled to -78 °C, then ozone was passed through the solution for 10min. The mixture was then vigorously sparged with N2 for 5min, PPh3 (3.03g, 11.6mmol) was added, and the mixture was warmed to rt and stirred for 14hrs. The mixture was directly adsorbed onto silica gel and purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (1.419 g, 53.8%). Rf = 0.26 (8:2 hexanes:EtOAc). LC/MS, ESI [M+Na]+ = 319.1 m/z.¹H NMR (400 MHz, CDCl₃) δ 9.63 (t, J = 1.7 Hz, 1H), 7.65 (dd, J = 8.2, 0.7 Hz, 1H), 7.64 – 7.61 (m, 1H), 7.51 – 7.45 (m, 2H), 7.30 – 7.27 (m, 1H), 7.20 (dd, J = 7.0, 0.7 Hz, 1H), 3.61 (dt, J = 17.7, 1.4 Hz, 1H), 3.56 (s, 3H), 3.39 (dt, J = 17.6, 1.2 Hz, 1H), 2.84 (d, J = 14.7 Hz, 1H), 2.73 (d, J = 14.8 Hz, 1H), 2.32 (tt, J = 7.2, 1.5 Hz, 2H), 2.02 – 1.78 (m, 2H), 1.60 – 1.44 (m, 1H), 1.30 – 1.13 (m, 1H). Preparation of Intermediate 4-5 (Methyl 4-(1-(2-methoxy-2-oxoethyl)-1,2- dihydroacenaphthylen-1-yl)butanoate) Intermediate 4-4 (1.41g, 4.76mmol) was dissolved in tBuOH (5mL) and H₂O (5mL), and the mixture was cooled to 0 °C and treated with 2-methyl-2-butene (2.5mL, 24mmol), NaClO2 (1.29g, 14.26 mmol), and KH₂PO4 (2.33g, 14.3mmol). After 40min, the mixture was poured into aq. NaHSO4 and extracted with EtOAc (x2). The combined extract was washed with aq Na₂S₂O₃, brine, dried over Na₂SO₄, filtered, and concentrated. The residue was treated with 3N HCl in MeOH and heated to 50 °C. After 2hrs, the mixture was concentrated, co-evaporated from toluene once, then taken up in 8:2 hexanes:EtOAc and filtered through a thin pad of silica gel rinsing with the same. The residue was purified by flash column chromatography on silica gel eluted with 0→40% EtOAc in hexanes to give the title compound (1.312 g, 84.5%). Rf = 0.37 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]+ = 327.2 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.64 (dd, J = 8.2, 0.9 Hz, 1H), 7.63 – 7.60 (m, 1H), 7.50 – 7.45 (m, 2H), 7.29 – 7.26 (m, 1H), 7.20 (dd, J = 6.9, 0.8 Hz, 1H), 3.64 – 3.57 (m, 4H), 3.54 (s, 3H), 3.39 (dt, J = 17.5, 1.2 Hz, 1H), 2.83 (d, J = 14.8 Hz, 1H), 2.73 (d, J = 14.7 Hz, 1H), 2.21 (td, J = 7.3, 1.0 Hz, 2H), 2.00 – 1.81 (m, 2H), 1.60 – 1.44 (m, 1H), 1.31 – 1.15 (m, 1H). Preparation of Intermediate 4-6 (Methyl 3'-oxo-2H-spiro[acenaphthylene-1,1'- cyclohexane]-4'-carboxylate) A flame-dried 100mL round bottom flask was charged with NaH (482mg, 12.1mmol) and evacuated and backfilled with N2 (x3) then amended with anhydrous toluene (10mL) and MeOH (80µL) and warmed to 70 °C. A solution of Intermediate 4-5 (1.31g, 4.02mmol) and additional anhydrous MeOH (80µL) in anhydrous toluene (10mL) was added dropwise via syringe pump over a period of 90min. After 18hrs, the mixture was cooled slightly then poured into half saturated NH₄Cl and extracted with EtOAc (x3). The combined extract was washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (1.36g, >100%) as a pale brown oil which was used without purification. LC/MS, ESI [M+H]+ = 295.1 m/z. Preparation of Intermediate 4-7 (2'-(Methylthio)-5',8'-dihydro-2H,3'H- spiro[acenaphthylene-1,7'-quinazolin]-4'(6'H)-one) Intermediate 4-6 (1.18g, 4.02mmol) was dissolved in anhydrous MeCN (14mL) and treated with thiourea (398mg, 5.23mmol) and DBU (720µL, 4.82mmol) and heated to 90 °C in a sealed vial under Ar for 14hrs. The mixture was reduced in volume to approximately 3mL then diluted with aq KH₂PO4, and the solids were collected by filtration then suspended in THF (9mL) and DMF (18mL), and treated with NaOAc (660mg, 8.05mmol) and MeI (250µL, 4.02mmol). After 1hr, additional MeI (200µL) and a small amount of K2CO3 were added. After an additional 30min, DMSO (10mL) was added and the mixture was heated to affect dissolution. The volatiles were removed by rotary evaporation and the high boiling remainder was poured into ice cold one-third saturated NaHCO3. The resulting solids were collected by filtration and washed with H₂O, 1:1 hexanes:acetone, and hexanes, then dried under suction and further dried in vacuo at 50 ºC to give the title compound (724.5mg, 54%) as a white powder. LC/MS, ESI [M+H]⁺ = 335.1 m/z. Preparation of Intermediate 4-7F and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 4-7F and analogs thereof can be prepared using Intermediate 4-7 or analogs thereof by following these schematized procedures:

Intermediate 4-7 Intermediate 4-7F or Intermediate 4-7 Analogs (wherein R is absent) or Intermediate 4-7F Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 4-7F), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 4-7F or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 4-7F and 4-7F Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 4-11 Analogs, and more generally, the procedures detailed throughout section Example 4: Synthesis of Spiro-Acenaphthene Compounds. Preparation of Intermediate 4-7F’ and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 4-7F’ and analogs thereof can be prepared using Intermediate 4-7 or analogs thereof by following these schematized procedures:

Intermediate 4-7 Intermediate 4-7F’ or Intermediate 4-7 Analogs (wherein R is absent) or Intermediate 4-7F’ Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 4-7F’), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 4-7F’ or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 4-7F’ and 4-7F’ Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 4-11 Analogs, and more generally, the procedures detailed throughout section Example 4: Synthesis of Spiro-Acenaphthene Compounds. Preparation of Intermediate 4-7G and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 4-7G and analogs thereof can be prepared using Intermediate 4-7F or analogs thereof by following these schematized procedures:

Intermediate 4-7F Intermediate 4-7G or Intermediate 4-7F Analogs (wherein R is absent) or Intermediate 4-7G Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH3, CH3 and NH₂, and zero (which corresponds to Intermediate 4-7G), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 4-7G or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 4-7G and 4-7G Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 4-11 Analogs, and more generally, the procedures detailed throughout section Example 4: Synthesis of Spiro-Acenaphthene Compounds. Preparation of Intermediate 4-7D and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 4-7D and analogs thereof can be prepared using Intermediate 4-7F or analogs thereof by following these schematized procedures:

Intermediate 4-7F Intermediate 4-7D or Intermediate 4-7F Analogs (wherein R is absent) or Intermediate 4-7D Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 4-7D), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 4-7D or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 4-7D and 4-7D Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 4-11 Analogs, and more generally, the procedures detailed throughout section Example 4: Synthesis of Spiro-Acenaphthene Compounds. Preparation of Intermediate 4-7P and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 1-7P and analogs thereof can be prepared by following these schematized procedures:

Intermediate 4-7P (wherein R is absent) or Intermediate 4-7P Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 4-7P), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 4-7P or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Furthermore, the skilled artisan would recognize that the acenaphthylenone chosen corresponds to that Intermediate 4-7P Analog that the skilled artisan wishes to make, for example, 8-fluoro-3-methylacenaphthylen-1(2H)-one or 8- fluoro-7-hydroxyacenaphthylen-1(2H)-one. Intermediate 4-7P and 4-7P Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 4-11 Analogs, and more generally, the procedures detailed throughout section Example 4: Synthesis of Spiro-Acenaphthene Compounds. Preparation of Intermediate 4-8 (2'-(Methylthio)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) Intermediate 4-7 (387.5mg, 1.16mmol) was suspended in anhydrous DCM (6mL), iPr2EtN (605µL, 3.47mmol) was added, and the mixture was cooled to 0 °C then triflic anhydride, 1M in DCM (1.9mL, 1.9 mmol) was added dropwise. After 30min, the mixture was diluted with 1vol hexanes and filtered through a thin pad of silica gel rinsing with 85:15 hexanes:EtOAc, and concentrated to give the title compound (507.5mg, 93.9%) as a faintly red oil. Rf = 0.42 (9:1 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 467.1 m/z. Preparation of Intermediates 4-9 through 4-11

Intermediate 4-8 Intermediate 4-9 Intermediate 4-10

Intermediate 4-11 Preparation of Intermediate 4-9 (tert-butyl (1R,5S)-3-(2'-(methylthio)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) To a solution of Intermediate 4-8 ((2'-methylsulfanylspiro[1H-acenaphthylene-2,7'- 6,8-dihydro-5H-quinazoline]-4'-yl) trifluoromethanesulfonate; 134 mg, 0.29 mmol) in DMF (1.5 mL) was added iPr2EtN (0.1 mL, 0.57 mmol) followed by tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (67 mg, 0.31 mmol). The mixture was stirred at room temperature for 1h before EtOAc was added and the resulting mixture was poured into sat NaHCO₃ (aq). the organics were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were dried with Na2SO4, filtered, and concentrated. The crude material was then purified using flash column chromatography on silica gel (0 - 50% EtOAc in hexanes) to yield the title compound (138 mg, 0.26 mmol, 91% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 529.2 m/z.¹H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.2, 5.1 Hz, 2H), 7.47 (dd, J = 7.6, 7.6 Hz, 2H), 7.27 (d, J = 6.7 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 4.49 – 4.18 (m, 2H), 3.92 (d, J = 12.4 Hz, 1H), 3.80 – 3.59 (m, 1H), 3.49 – 2.96 (m, 6H), 2.85 – 2.71 (m, 2H), 2.51 (s, 3H), 2.09 – 1.78 (m, 6H), 1.50 (s, 9H). Preparation of Intermediate 4-10 (tert-butyl (1R,5S)-3-(2'-(methylsulfinyl)-5',8'-dihydro- 2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate) To a cooled (0 °C) solution of Intermediate 4-9 (tert-butyl (1R,5S)-3-(2'- (methylthio)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 138 mg, 0.26 mmol) in DCM (2 mL) was added mCPBA (55 mg, 0.23 mmol). the mixture was stirred for 2h before being poured into half saturated NaHCO₃ (aq) and extracting with DCM (3x). The combined organics were dried with Na2SO4 and concentrated to yield the crude title compound (127 mg, 0.23 mmol, 89.3% yield), which was taken on to the next step without further purification. LC/MS, ESI [M+H]⁺ = 545.2 m/z. Preparation of Intermediate 4-11 Analogs It is understood by the artisan of ordinary skill that Intermediate 4-11 Analogs can be prepared using Intermediate 4-8 or Intermediate 4-8 Analogs by following these schematized procedures:

Intermediate 4-8 or Intermediate 4-8 Analogs

Intermediate 4-11 Analogs wherein, examples of Ring A include, but are not limited to and where

indicates the point of attachment to the pyrimidine; examples of R include, but are not limited to, F, C1, OH, CH₂CH3, CH3 and NH₂, and zero, one, two or three instances of R can occur, each of which is independently selected from one another; examples of R6 include, but are not limited to, halogen, amino, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, wherein each of amino, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, hexahydro-1H-pyrrolizinyl, 1-azabicyclo[2.2.1]heptanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl or piperazinyl may be optionally substituted with one or more R₇; examples of R₇ include, but are not limited to, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cyano, -(CH₂)nN(R₃)₂, -N(R₃)₂, -C(O)N(R₃)₂, -OC(O)N(R₃)₂, -N(H)C(O)R3, -CH₂N(H)C(O)R3, -CH₂OC(O)N(R₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, and each instance of R7 is independently selected from other instances; examples of R₃ include, but are not limited to, H and C₁-C₃ alkyl, and each instance of R3 is independently selected from other instances; and n in each occurrence is independently 1, 2 or 3. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of Ring A species that can be used to prepare Intermediate 4-11 Analogs include, but are not limited to: tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-3-methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-6- methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-5-methylpiperazine-1- carboxylate, tert-butyl (1S,5S,6S)-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-(2-cyanoethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-carbamoyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, 8-(tert-butyl) 1-methyl 3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate, tert-butyl (1S,5S,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-chloro-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate, tert-butyl (1S,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5R,6R)-6-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1S,5S,6S)-6-(1H-1,2,4-triazol-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Ring A species, or obtain them from chemical vendors. Examples of alcohols used to prepare Intermediate 4-11 Analogs include, but are not limited to: (1-isopropylpyrrolidin-2-yl)methanol, (1-ethylpyrrolidin-2-yl)methanol, (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol and (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Preparation of Compound 2-19 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazoline]) Compound 2-19 is prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 4-11 instead of Intermediate 1-13. Preparation of Compound 2-20 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) To a cooled (-40 °C) solution of Intermediate 4-10 (tert-butyl (1R,5S)-3-(2'- (methylsulfinyl)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 45 mg, 0.083 mmol) and (S)-(1-methylpyrrolidin- 2-yl)methanol (0.015 mL, 0.12 mmol) in THF (0.4 mL) was added KOtBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 - 65% ACN in H₂O + 0.25% TFA) to yield the title compound (32 mg, 0.065 mmol, 78% yield) as an off-white foam. LC/MS, ESI [M+H]⁺ = 496.3 m/z.¹H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 8.2, 5.0 Hz, 2H), 7.47 (ddd, J = 8.2, 6.9, 4.5 Hz, 2H), 7.27 (d, J = 6.2 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 4.39 (ddd, J = 10.6, 4.7, 2.2 Hz, 1H), 4.11 (ddd, J = 10.6, 7.4, 4.3 Hz, 1H), 3.95 (d, J = 12.4 Hz, 1H), 3.72 (d, J = 12.6 Hz, 1H), 3.59 (s, 2H), 3.41 (d, J = 17.0 Hz, 1H), 3.32 – 3.22 (m, 2H), 3.17 – 3.04 (m, 3H), 2.97 (d, J = 18.5 Hz, 1H), 2.83 – 2.62 (m, 3H), 2.53 – 2.42 (m, 4H), 2.32 – 2.21 (m, 1H), 2.13 – 1.68 (m, 10H). Preparation of Compound 2-21 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) Compound 2-21 is prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 4-11 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-37 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazoline]) Compound 2-37 is prepared following the general procedures used to prepare Compound 1-30 and using Intermediate 4-10 instead of Intermediate 1-35. Preparation of Compound 2-38 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazoline]) Compound 2-38 is prepared following the general procedures used to prepare Compound 1-34 and using Intermediate 4-10 instead of Intermediate 1-35. Preparation of Compound 1-88 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazoline]) To a cooled (-40 °C) solution of Intermediate 4-10 (tert-butyl (1R,5S)-3-(2'- (methylsulfinyl)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate; 40 mg, 0.073 mmol) and 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (16 mg, 0.11 mmol) in THF (0.4 mL) was added KOtBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K₂CO₃ (aq) and extracted with DCM (3x). The combined organics were dried with Na2SO4 and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 - 65% ACN in H₂O + 0.25% TFA) to yield the title compound (32 mg, 0.061 mmol, 84% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 522.3 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.68 – 7.60 (m, 2H), 7.46 (ddd, J = 8.2, 6.9, 5.9 Hz, 2H), 7.26 (d, J = 6.5 Hz, 1H), 7.14 (d, J = 6.8 Hz, 1H), 4.11 – 4.00 (m, 2H), 3.98 (d, J = 11.8 Hz, 1H), 3.76 (d, J = 12.1 Hz, 1H), 3.57 (d, J = 4.2 Hz, 2H), 3.41 (d, J = 17.0 Hz, 1H), 3.32 – 3.22 (m, 2H), 3.18 – 3.05 (m, 4H), 2.98 (d, J = 18.5 Hz, 1H), 2.82 – 2.70 (m, 2H), 2.67 – 2.57 (m, 2H), 2.42 (bs, 1H), 2.15 – 2.04 (m, 2H), 2.05 – 1.74 (m, 10H), 1.63 (ddd, J = 12.6, 7.6, 7.6 Hz, 2H). Preparation of Intermediates 4-12 through 4-14

Intermediate 4-8 Intermediate 4-12 Intermediate 4-13

Intermediate 4-14 Preparation of Compound 2-22 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazoline]) Compound 2-22 is prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 4-14 instead of Intermediate 1-25. Preparation of Compound 2-23 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) Compound 2-23 is prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 4-14 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-24 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) Compound 2-24 is prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 4-14 instead of Intermediate 1-25 in step 1. Schematization of the Preparation of Intermediates 4-17 and 4-18

Intermediate 4-8 Intermediate 4-17 Intermediate 4-18 Preparation of Intermediate 4-17 (tert-butyl 3-(2'-(methylthio)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate) To a solution of Intermediate 4-8 ((2'-methylsulfanylspiro[1H-acenaphthylene-2,7'- 6,8-dihydro-5H-quinazoline]-4'-yl) trifluoromethanesulfonate; 116 mg, 0.25 mmol) in DMF (1.5 mL) was added iPr2EtN (0.1 mL, 0.57 mmol) followed by tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (54 mg, 0.27 mmol). The mixture was stirred at room temperature for 1h before EtOAc was added and the resulting mixture was poured into sat NaHCO3 (aq). the organics were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were dried with Na₂SO₄, filtered, and concentrated. The crude material was then purified using flash column chromatography on silica gel (0 - 50% EtOAc in hexanes) to yield the title compound (117 mg, 0.23 mmol, 92% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 515.2 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J = 8.3, 5.3 Hz, 2H), 7.47 (dd, J = 7.0, 7.0 Hz, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 6.9 Hz, 1H), 4.71 – 4.09 (m, 5H), 3.96 (d, J = 12.0 Hz, 1H), 3.72 (d, J = 12.0 Hz, 1H), 3.40 (d, J = 17.0 Hz, 1H), 3.26 (d, J = 17.0 Hz, 1H), 3.16 (d, J = 18.6 Hz, 1H), 3.10 – 2.91 (m, 3H), 2.62 (dd, J = 7.2, 7.1 Hz, 1H), 2.52 (s, 3H), 2.08 – 1.89 (m, 2H), 1.51 (d, J = 8.6 Hz, 1H), 1.43 (s, 9H). Preparation of Intermediate 4-18 (tert-butyl 3-(2'-(methylsulfinyl)-5',8'-dihydro-2H,6'H- spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate) To a cooled (0 °C) solution of Intermediate 4-17 (tert-butyl 3-(2'-(methylthio)-5',8'- dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 117 mg, 0.23 mmol) in DCM (2 mL) was added mCPBA (47 mg, 0.20 mmol). The mixture was stirred for 2h before being poured into half saturated NaHCO3 (aq) and extracting with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated to yield the crude title compound (110 mg, 0.21 mmol, 91.2% yield), which was taken on to the next step without further purification. LC/MS, ESI [M+H]⁺ = 531.2 m/z. Preparation of Compound 1-89 (4'-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) To a cooled (-40 °C) solution of Intermediate 4-18 (tert-butyl 3-(2'-(methylsulfinyl)- 5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 36 mg, 0.068 mmol) and (S)-(1-methylpyrrolidin- 2-yl)methanol (0.012 mL, 0.10 mmol) in THF (0.4 mL) was added KOtBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 - 65% ACN in H₂O + 0.25% TFA) to yield the title compound (28 mg, 0.056 mmol, 83% yield) as an off- white foam. LC/MS, ESI [M+H]⁺ = 482.3 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J = 7.8, 5.7 Hz, 2H), 7.47 (ddd, J = 8.4, 6.9, 1.7 Hz, 2H), 7.26 (d, J = 6.4 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 4.41 (ddd, J = 10.6, 4.8, 1.8 Hz, 1H), 4.33 – 4.20 (m, 1H), 4.18 – 4.00 (m, 3H), 3.98 – 3.71 (m, 3H), 3.40 (d, J = 17.0 Hz, 1H), 3.26 (d, J = 17.3 Hz, 1H), 3.19 – 3.01 (m, 4H), 3.01 – 2.91 (m, 1H), 2.78 – 2.66 (m, 2H), 2.49 (s, 3H), 2.29 (td, J = 9.5, 7.1 Hz, 1H), 2.21 – 1.91 (m, 4H), 1.90 – 1.70 (m, 3H), 1.64 (d, J = 8.0 Hz, 1H). Preparation of Compound 1-90 (4'-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2'-((tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'- quinazoline]) To a cooled (-40 °C) solution of Intermediate 4-18 (tert-butyl 3-(2'-(methylsulfinyl)- 5',8'-dihydro-2H,6'H-spiro[acenaphthylene-1,7'-quinazolin]-4'-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate; 37 mg, 0.070 mmol) and 1,2,3,5,6,7- hexahydropyrrolizin-8-ylmethanol (15 mg, 0.11 mmol) in THF (0.4 mL) was added KOtBu (1 M in THF, 0.1 mL, 0.10 mmol) dropwise. The mixture was stirred for 1 h. Upon completion, the mixture was poured into 5% K2CO3 (aq) and extracted with DCM (3x). The combined organics were dried with Na₂SO₄ and concentrated. The crude intermediate was then taken up in DCM (0.35 mL) and TFA (0.35 mL, 4.57 mmol) was added and the mixture was stirred for 30 min. Upon completion, the mixture was concentrated and purified by preparative HPLC (30 - 65% ACN in H₂O + 0.25% TFA) to yield the title compound (25 mg, 0.049 mmol, 71% yield) as a white foam. LC/MS, ESI [M+H]⁺ = 508.3 m/z.¹H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 8.2, 5.1 Hz, 2H), 7.46 (ddd, J = 8.2, 6.9, 3.3 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 6.9 Hz, 1H), 4.24 (d, J = 12.4 Hz, 1H), 4.07 (d, J = 3.3 Hz, 4H), 3.92 (d, J = 12.3 Hz, 1H), 3.86 – 3.68 (m, 2H), 3.39 (d, J = 17.0 Hz, 1H), 3.25 (d, J = 17.0 Hz, 1H), 3.21 – 3.06 (m, 3H), 3.04 (t, J = 6.3 Hz, 2H), 2.97 (d, J = 18.1 Hz, 1H), 2.75 – 2.56 (m, 3H), 2.31 – 1.75 (m, 9H), 1.70 – 1.57 (m, 3H). Example 5: Synthesis of Spiro-Phenalene Compounds Scheme for the Preparation of Intermediates 5-1 through 5-9

Intermediate 5-1 Intermediate 5-2

Intermediate 5-3 Intermediate 5-4 Intermediate 5-5

Intermediate 5-8 Intermediate 5-9 Preparation of Intermediate 5-1 (2-(2,3-Dihydro-1H-phenalen-1-ylidene)malononitrile) 2,3-Dihydrophenalen-1-one (2.95g, 16.2mmol) was dissolved in EtOH (32mL) and treated with malononitrile (1.6g, 24.2mmol), AcOH (1.85mL, 32.4mmol), and NH₄OAc (1.25g, 16.2mmol) at rt and the mixture was stirred for 18hrs. The mixture was diluted with 1vol 1N HCl and stirred for 5min then the solids were collected by filtration and washed liberally with H₂O, 7:3 hexanes:EtOH, then hexanes. The material was dried under suction and further dried at 50 ºC in vacuo to give the title compound (3.432g, 92.2%) as a dull yellow solid. LC/MS, ESI [M-H]- = 229.1 m/z.1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 7.4, 1.2 Hz, 1H), 8.09 (dd, J = 8.3, 1.3 Hz, 1H), 7.84 – 7.72 (m, 1H), 7.56 (ddd, J = 27.6, 8.3, 7.2 Hz, 2H), 7.44 (dq, J = 7.1, 1.2 Hz, 1H), 3.42 – 3.35 (m, 2H), 3.29 – 3.22 (m, 2H). Preparation of Intermediate 5-1 Analogs It is readily apparent to a person of ordinary skill in the art that Intermediate 5-1 Analogs having groups alternative to that imparted by the use of 2,3-dihydro-1H-phenalen- 1-one can be made by using a different phenalenones. Examples of alternative phenalenones that can be used include, but are not limited to: 8-hydroxy-2,3-dihydro-1H-phenalen-1-one, 8-amino-2,3-dihydro-1H-phenalen-1-one, 7-fluoro-8-hydroxy-2,3-dihydro-1H-phenalen-1- one, 8-amino-7-fluoro-2,3-dihydro-1H-phenalen-1-one, 7-chloro-8-hydroxy-2,3-dihydro- 1H-phenalen-1-one, 8-amino-7-chloro-2,3-dihydro-1H-phenalen-1-one, 7-chloro-4-fluoro- 8-hydroxy-2,3-dihydro-1H-phenalen-1-one, 8-amino-7-chloro-4-fluoro-2,3-dihydro-1H- phenalen-1-one, 4,7-difluoro-8-hydroxy-2,3-dihydro-1H-phenalen-1-one, 8-amino-7- chloro-4-fluoro-2,3-dihydro-1H-phenalen-1-one, 7-chloro-4-fluoro-2,3-dihydro-1H- phenalen-1-one, 4,7-difluoro-2,3-dihydro-1H-phenalen-1-one, 7-fluoro-2,3-dihydro-1H- phenalen-1-one, 4-fluoro-2,3-dihydro-1H-phenalen-1-one, 7-chloro-2,3-dihydro-1H- phenalen-1-one, 4-chloro-2,3-dihydro-1H-phenalen-1-one, 9-methyl-2,3-dihydro-1H- phenalen-1-one, 9-fluoro-2,3-dihydro-1H-phenalen-1-one, 9-chloro-2,3-dihydro-1H- phenalen-1-one, 8-hydroxy-9-methyl-2,3-dihydro-1H-phenalen-1-one, 9-fluoro-8-hydroxy- 2,3-dihydro-1H-phenalen-1-one, 9-chloro-8-hydroxy-2,3-dihydro-1H-phenalen-1-one, 8- amino-9-methyl-2,3-dihydro-1H-phenalen-1-one, 8-amino-9-fluoro-2,3-dihydro-1H- phenalen-1-one and 8-amino-9-chloro-2,3-dihydro-1H-phenalen-1-one. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired phenalenones, or obtain them from chemical vendors. Intermediate 5-1 Analogs are used in subsequent steps to prepare the corresponding Intermediate 5-9 Analogs. Further, Intermediate 5-9 Analogs are used to prepare compounds (see below) that are key intermediates for preparing inhibitors of KRAS G12D. Preparation of Intermediate 5-2 (2-(1-(Pent-4-en-1-yl)-2,3-dihydro-1H-phenalen-1- yl)malononitrile) A flame-dried 250mL round bottom flask was charged with CuBr•Me₂S (306.2mg, 1.49mmol) and evacuated and backfilled with N2 (x3) then amended with anhydrous THF (5mL) and cooled to -78 °C. Pent-4-en-1-ylmagnesium bromide, 0.5M in THF (50.6mL, 25.3mmol) was added and the mixture was stirred for 15min, then a suspension of Intermediate 5-1 (3.43g, 14.9mmol) in anhydrous THF (25mL) was added and the cooling bath was removed. The mixture was allowed to warm to 0 ºC and stirred for 5hrs then quenched with sat NH₄Cl and partitioned between sat NH₄Cl and 1:1 hexanes:EtOAc. The organic phase was collected and washed with sat NH₄C1, 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 eluted with 0→25% EtOAc to give the title compound (3.758g, 84.0%) as an amber colored vitreous oil. Rf = 0.35 (85:15 hexanes:EtOAc). LC/MS, ESI [M- H]- = 299.1 m/z.¹H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 7.0, 2.5 Hz, 1H), 7.77 (dd, J = 8.1, 0.9 Hz, 1H), 7.54 – 7.44 (m, 3H), 7.36 (dq, J = 7.0, 1.3 Hz, 1H), 5.77 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.09 – 4.94 (m, 2H), 4.08 (s, 1H), 3.29 (dt, J = 17.6, 5.3 Hz, 1H), 3.16 (dddt, J = 17.4, 10.1, 5.9, 1.3 Hz, 1H), 2.49 – 2.26 (m, 3H), 2.22 – 1.97 (m, 3H), 1.54 – 1.32 (m, 2H). Preparation of Intermediate 5-3 (Methyl 2-(1-(pent-4-en-1-yl)-2,3-dihydro-1H-phenalen- 1-yl)acetate) In a PFA round bottom flask, Intermediate 5-2 (3.76g, 12.51 mmol) was treated with ethylene glycol (12.5mL), H₂O (6 mL), and KOH (12.38g, 187.7mmol), and the mixture was heated to 195 °C for 53hrs. The mixture was cooled slightly and poured into chipped ice containing H₂SO4 then extracted with EtOAc (x2). The combined extract was washed with brine (x2), dried over Na₂SO₄, filtered, and concentrated. The residue was heated to 200 ºC for 20min then cooled to rt, dissolved in MeOH (34mL), cooled to 0 ºC, and acetyl chloride (7.1mL, 99.5 mmol) was added dropwise. The mixture was warmed to 40 ºC for 4hrs then concentrated, co-evaporated from toluene once, triturated with 85:15 hexanes:EtOAc, and filtered through a thin pad of silica gel to give the title compound (3.604g, 93.4%) as an orange colored oil. Rf = 0.58 (85:15 hexanes:EtOAc). LC/MS, ESI [M+H]⁺ = 309.2 m/z. ¹H NMR (400 MHz, CDCl₃) δ 7.72 – 7.68 (m, 2H), 7.44 – 7.36 (m, 2H), 7.34 (dd, J = 7.3, 1.3 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 5.76 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.01 – 4.88 (m, 2H), 3.59 (s, 3H), 3.28 – 3.10 (m, 2H), 2.80 (d, J = 14.1 Hz, 1H), 2.68 (d, J = 14.1 Hz, 1H), 2.21 (ddd, J = 13.2, 7.0, 5.3 Hz, 1H), 2.13 – 1.97 (m, 4H), 1.79 (ddd, J = 14.1, 11.9, 5.0 Hz, 1H), 1.49 – 1.29 (m, 2H). Preparation of Intermediate 5-4 (Methyl 2-(1-(4,5-dihydroxypentyl)-2,3-dihydro-1H- phenalen-1-yl)acetate) In a 100mL flask, Intermediate 5-3 (3.41g, 11.0mmol) was dissolved in acetone (5.5mL) and treated with H₂O (5.5mL), NMO hydrate (2.98g, 22.0mmol), and OsO4, 4% aqueous (351µL, 0.055mmol) and the mixture was stirred vigorously at rt under N₂ for 1hr. The reaction was amended with a small amount of sodium sulfite and stirred for 10min then partitioned between EtOAc and H₂O. The organic phase was washed with brine, dried over Na₂SO₄, filtered through a thin pad of silica gel, and concentrated to give the title compound (3.81g, quant.) as a red oil. Rf = 0.25 (8:2 EtOAc:hexanes). LC/MS, ESI [M+H]⁺ = 343.2 m/z. Preparation of Intermediate 5-5 (Methyl 2-(1-(4-oxobutyl)-2,3-dihydro-1H-phenalen-1- yl)acetate) Intermediate 5-4 (3.78g, 11.0mmol) was dissolved in THF (38mL) and treated with H₂O (7.5mL) followed by NaIO₄ (3.07g, 14.4mmol) at 0 °C. After 2hrs, the mixture was filtered through Celite rinsing with EtOAc and the filtrate was washed with sat NaHCO₃, brine, dried over Na2SO4, filtered, and concentrated to give the title compound (3.389 g, 98.9%) as a dark yellow vitreous oil. LC/MS, ESI [M+Na]⁺ = 333.1 m/z. Rf = 0.19 (85:15 hexanes:EtOAc).¹H NMR (400 MHz, CDCl₃) δ 9.72 (t, J = 1.6 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.46 – 7.24 (m, 4H), 3.60 (s, 3H), 3.20 (s, 2H), 2.79 (d, J = 14.2 Hz, 1H), 2.71 (d, J = 14.2 Hz, 1H), 2.41 (td, J = 7.3, 1.7 Hz, 2H), 2.26 – 2.01 (m, 3H), 1.82 (ddd, J = 13.6, 12.2, 4.5 Hz, 1H), 1.75 – 1.50 (m, 2H). Preparation of Intermediate 5-6 (Methyl 4-(1-(2-methoxy-2-oxoethyl)-2,3-dihydro-1H- phenalen-1-yl)butanoate) Intermediate 5-5 (3.39g, 10.92 mmol) was dissolved in tBuOH (11mL) and treated with H₂O (11mL), NaClO2 (2.96g, 32.7mmol), 2-methyl-2-butene (5.8mL, 54.8mmol), and KH₂PO₄ (5.34g, 32.7mmol), and the mixture was stirred vigorously at 0 ºC for 4hrs. The mixture was diluted with 5% NaHSO₄ and extracted with EtOAc (x2). The combined extract was washed with dilute Na2S2O3, brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in MeOH (25mL) and acetyl chloride (5.5mL, 77.1mmol) was added dropwise at 0 °C, then the mixture was warmed to 45 ºC for 3hrs. The mixture was concentrated, taken up in 8:2 hexanes:EtOAc, and filtered through a thin pad of silica gel, then purified by flash column chromatography on silica gel eluted with 0→30% EtOAc in hexanes to give the title compound (2.859g, 76.9%) as a pale yellow oil. Rf = 0.32 (8:2 hexanes:EtOAc). LC/MS, ESI [M+H]+ = 341.2 m/z.¹H NMR (400 MHz, CDCl3) δ 7.72 – 7.68 (m, 2H), 7.45 – 7.34 (m, 3H), 7.32 – 7.24 (m, 1H), 3.63 (s, 3H), 3.59 (s, 3H), 3.24 – 3.16 (m, 2H), 2.80 (d, J = 14.2 Hz, 1H), 2.69 (d, J = 14.2 Hz, 1H), 2.35 – 2.16 (m, 3H), 2.16 – 2.00 (m, 2H), 1.81 (ddd, J = 13.6, 12.2, 4.6 Hz, 1H), 1.75 – 1.48 (m, 2H). Preparation of Intermediate 5-7 (Methyl 3-oxo-2',3'-dihydrospiro[cyclohexane-1,1'- phenalene]-4-carboxylate) NaH, 60% dispersion (50mg, 1.25mmol) was suspended in anhydrous toluene (1mL) and treated with MeOH (9µL) then heated to 70 °C. A solution of Intermediate 5-6 (139.2mg, 0.409mmol) in anhydrous toluene (1.5mL) containing additional MeOH (9µL) was added portionwise over a period of approximately 2hrs. After an additional 18hrs, the mixture was partitioned between EtOAc and sat NH4Cl and the organic phase was washed with sat NH₄C1, brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (146.1mg, >100%) as an oil, which was used without purification. LC/MS, ESI [M+H]⁺ = 309.1 m/z. Preparation of Intermediate 5-8 (2'-(Methylthio)-2,3,5',8'-tetrahydro-3'H- spiro[phenalene-1,7'-quinazolin]-4'(6'H)-one) Intermediate 5-7 (126.1mg, 0.409mmol) was dissolved in anhydrous MeCN (1.5mL) and treated with thiourea (40.5mg, 0.532mmol) and DBU (75µL, 0.503mmol) and the vessel was sealed and heated to 90 °C for 22hrs. The mixture was cooled to rt and reduced to approximately 250µL then diluted with aq KH₂PO4 and the resulting solids were collected by centrifugation and washed with H₂O once, then re-dissolved in THF:DMF. NaOAc (67.1mg, 0.818mmol) and MeI (26µL, 0.409mmol) were added and the mixture was stirred at rt for 20min. The mixture was poured into one-third saturated NaHCO3 and extracted with DCM (x3). The combined extract was dried over Na₂SO₄, filtered, and concentrated and the residue was triturated with 1:1 hexanes:Me₂CO and the solids were collected by centrifugation and washed with 1:1 hexanes:Me2CO (x2) then air dried and further dried in vacuo at 50 ºC to give the title compound (84.4 mg, 59.2%) as a tan colored powder. LC/MS, ESI [M+H]⁺ = 349.1 m/z. Preparation of Intermediate 5-8F and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 5-8F and analogs thereof can be prepared using Intermediate 5-8 or analogs thereof by following these schematized procedures:

Intermediate 5-8 Intermediate 5-8F or Intermediate 5-8 Analogs (wherein R is absent) or Intermediate 5-8F Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH3, CH3 and NH₂, and zero (which corresponds to Intermediate 5-8F), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 5-8F or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 5-8F and 5-8F Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 5-12 Analogs, and more generally, the procedures detailed throughout section Example 5: Synthesis of Spiro-Phenalene Compounds. Preparation of Intermediate 5-8F’ and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 5-8F’ and analogs thereof can be prepared using Intermediate 5-8 or analogs thereof by following these schematized procedures:

or Intermediate 5-8 Analogs (wherein R is absent) or Intermediate 5-8F’ Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 5-8F’), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 5-8F’ or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 5-8F’ and 5-8F’ Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 5-12 Analogs, and more generally, the procedures detailed throughout section Example 5: Synthesis of Spiro-Phenalene Compounds. Preparation of Intermediate 5-8G and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 5-8G and analogs thereof can be prepared using Intermediate 5-8F or analogs thereof by following these schematized procedures:

or Intermediate 5-8F Analogs (wherein R is absent) or Intermediate 5-8G Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 5-8G), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 5-8G or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 5-8G and 5-8G Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 5-12 Analogs, and more generally, the procedures detailed throughout section Example 5: Synthesis of Spiro-Phenalene Compounds. Preparation of Intermediate 5-8D and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 5-8D and analogs thereof can be prepared using Intermediate 5-8F or analogs thereof by following these schematized procedures:

Intermediate 5-8F Intermediate 5-8D or Intermediate 5-8F Analogs (wherein R is absent) or Intermediate 5-8D Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 5-8D), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 5-8D or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Intermediate 5-8D and 5-8D Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 5-12 Analogs, and more generally, the procedures detailed throughout section Example 5: Synthesis of Spiro-Phenalene Compounds. Preparation of Intermediate 5-8P and Analogs Thereof It is understood by the artisan of ordinary skill that Intermediate 5-8P and analogs thereof can be prepared by following these schematized procedures:

Intermediate 5-8P (wherein R is absent) or Intermediate 5-8P Analogs wherein, examples of R include, but are not limited to, OH, F, C1, Br, CH₂CH₃, CH₃ and NH₂, and zero (which corresponds to Intermediate 2-8P), one, two or three instances of R can occur, each of which is independently selected from one another. Individual stereoisomers of Intermediate 2-8P or analogs thereof may be prepared by catalytic and/or stereoselective variants of the above reaction sequence or may be resolved from the racemic form by chiral chromatography, diastereomeric crystallization, or other conventional techniques. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Furthermore, the skilled artisan would recognize that the dihydrophenalenone chosen corresponds to that Intermediate 5-8P Analog that the skilled artisan wishes to make, for example, 9-fluoro-4-methyl-2,3-dihydro-1H-phenalen-1-one or 9-fluoro-8-hydroxy-2,3-dihydro-1H-phenalen-1-one. Intermediate 5-8P and 5-8P Analogs are used to synthesize compounds of the invention by following the procedures detailed in section Preparation of Intermediate 5-12 Analogs, and more generally, the procedures detailed throughout section Example 5: Synthesis of Spiro-Phenalene Compounds. Preparation of Intermediate 5-9 (2'-(Methylthio)-2,3,5',8'-tetrahydro-6'H- spiro[phenalene-1,7'-quinazolin]-4'-yl trifluoromethanesulfonate) Intermediate 5-8 (84.4mg, 0.242mmol) was suspended in anhydrous DCM (1.2mL) and treated with iPr2EtN (140µL, 0.802mmol). The mixture was cooled to 0 °C and triflic anhydride, 1M in DCM (412µL, 0.412mmol) was added dropwise. After 25min, additional iPr2EtN (93uL) and triflic anhydride, 1M in DCM (200µL) were added. After an additional 20min, the mixture was diluted with 1vol hexanes and filtered through a pipet column of silica gel rinsing with 8:2 hexanes:EtOAc, and concentrated to give the title compound (114.5mg, 98.4%) as a faintly yellow foam. LC/MS, ESI [M+H]⁺ = 481.0m/z. Preparation of Intermediates 5-10 through 5-12

Preparation of Intermediate 5-12 Analogs It is understood by the artisan of ordinary skill that Intermediate 5-12 Analogs can be prepared using Intermediate 5-9 or Intermediate 5-9 Analogs by following these schematized procedures:

Intermediate 5-9 or Intermediate 5-9 Analogs

Intermediate 5-12 Analogs wherein, examples of Ring A include, but are not limited to

and , where indicates the point of attachment to the pyrimidine; examples of R include, but are not limited to, F, C1, OH, CH₂CH3, CH3 and NH₂, and zero, one, two or three instances of R can occur, each of which is independently selected from one another; examples of R6 include, but are not limited to, halogen, amino, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, wherein each of amino, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, cyclopropyl, cyclobutyl, cyclopentyl, hexahydro-1H-pyrrolizinyl, 1-azabicyclo[2.2.1]heptanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl or piperazinyl may be optionally substituted with one or more R7; examples of R7 include, but are not limited to, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cyano, -(CH₂)_nN(R₃)₂, -N(R₃)₂, -C(O)N(R₃)₂, -OC(O)N(R₃)₂, -N(H)C(O)R₃, -CH₂N(H)C(O)R₃, -CH₂OC(O)N(R₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrothiophenyl, piperidinyl and piperazinyl, and each instance of R7 is independently selected from other instances; examples of R3 include, but are not limited to, H and C₁-C₃ alkyl, and each instance of R3 is independently selected from other instances; and n in each occurrence is independently 1, 2 or 3. The person of ordinary skill in the art would recognize that some R groups may require additional steps or procedures (e.g., protection and deprotection) in addition to those schematized, and such additional steps or procedures are readily understood in the art and by the skilled artisan. Examples of Ring A species that can be used to prepare Intermediate 5-12 Analogs include, but are not limited to: tert-butyl 2-(cyanomethyl)piperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-3-methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-6- methylpiperazine-1-carboxylate, tert-butyl 2-(cyanomethyl)-5-methylpiperazine-1- carboxylate, tert-butyl (1S,5S,6S)-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-(2-cyanoethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-carbamoyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, 8-(tert-butyl) 1-methyl 3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate, tert-butyl (1S,5S,6S)-6-methoxy-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl 1-chloro-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate, tert-butyl (1S,5S,6S)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, tert-butyl (1S,5R,6R)-6-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1S,5S,6S)-6-(1H-1,2,4-triazol-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired Ring A species, or obtain them from chemical vendors. Examples of alcohols used to prepare Intermediate 5-12 Analogs include, but are not limited to: (1-isopropylpyrrolidin-2-yl)methanol, (1-ethylpyrrolidin-2-yl)methanol, (tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol and (2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol. Additionally, the skilled artisan could use procedures established by the art to synthesize or prepare these or other desired alcohols, or obtain them from chemical vendors. Preparation of Compound 2-25 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'-quinazoline]) Compound 2-25 is prepared following the general procedures used to prepare Compound 1-1 and using Intermediate 5-12 instead of Intermediate 1-13. Preparation of Compound 2-26 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'-quinazoline]) Compound 2-26 is prepared following the general procedures used to prepare Compound 1-2 and using Intermediate 5-12 instead of Intermediate 1-13 in step 1. Preparation of Compound 2-27 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'- quinazoline]) Compound 2-27 is prepared following the general procedures used to prepare Compound 1-3 and using Intermediate 5-12 instead of Intermediate 1-13 in step 1. Preparation of Intermediates 5-13 through 5-15

Intermediate 5-9 Intermediate 5-13 Intermediate 5-14

Intermediate 5-15 Preparation of Compound 2-28 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)- pyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'-quinazoline]) Compound 2-28 is prepared following the general procedures used to prepare Compound 1-11 and using Intermediate 5-15 instead of Intermediate 1-25. Preparation of Compound 2-29 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- methylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'-quinazoline]) Compound 2-29 is prepared following the general procedures used to prepare Compound 1-12 and using Intermediate 5-15 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-30 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2'-(((S)-1- isopropylpyrrolidin-2-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene-1,7'- quinazoline]) Compound 2-30 is prepared following the general procedures used to prepare Compound 1-13 and using Intermediate 5-15 instead of Intermediate 1-25 in step 1. Preparation of Compound 2-39 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- ((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H-spiro[phenalene- 1,7'-quinazoline]) Compound 2-39 wasprepared following the general procedures used to prepare Compound 1-30 and using Intermediate 5-11 instead of Intermediate 1-35. LC/MS, ESI [M+H]⁺ = 536.2 m/z.¹H NMR (400 MHz, CDCl3) δ 7.76 – 7.64 (m, 2H), 7.39 (dd, J = 8.2, 7.0 Hz, 1H), 7.34 (dd, J = 8.2, 7.2 Hz, 1H), 7.30 – 7.20 (m, 2H), 4.11 (d, J = 2.0 Hz, 2H), 3.91 – 3.66 (m, 3H), 3.62 – 3.49 (m, 2H), 3.47 – 3.14 (m, 5H), 3.14 – 3.04 (m, 2H), 2.99 – 2.87 (m, 1H), 2.66 (dt, J = 10.4, 6.8 Hz, 2H), 2.52 (dt, J = 15.8, 5.7 Hz, 1H), 2.30 (ddd, J = 14.7, 8.2, 4.9 Hz, 1H), 2.21 – 2.00 (m, 4H), 1.99 – 1.74 (m, 9H), 1.74 – 1.61 (m, 3H). Preparation of Compound 2-40 (4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydro-6'H- spiro[phenalene-1,7'-quinazoline]) Compound 2-40 was prepared following the general procedures used to prepare Compound 1-34 and using Intermediate 5-11 instead of Intermediate 1-35. LC/MS, ESI [M+H]⁺ = 554.2 m/z.¹H NMR (400 MHz, CDCl₃) δ 7.75 – 7.64 (m, 2H), 7.40 (dd, J = 8.1, 7.0 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.22 (ddd, J = 7.3, 2.6, 1.2 Hz, 1H), 5.27 (d, J = 54.7 Hz, 1H), 4.16 – 4.06 (m, 1H), 4.04 – 3.94 (m, 1H), 3.94 – 3.56 (m, 5H), 3.47 – 3.02 (m, 8H), 3.01 – 2.87 (m, 2H), 2.52 (dt, J = 15.9, 5.5 Hz, 1H), 2.37 – 2.01 (m, 6H), 1.99 – 1.61 (m, 9H).¹⁹F NMR (376 MHz, CDCl3) δ -173.13. Biological Experiments Inhibition of KRAS G12D GTP Binding Assay Test compounds were assayed for their ability to inhibit binding of GTP by KRAS^G12D protein. The assay was performed in assay buffer (pH 7.4) using 30 nM (final concentration) recombinant GST tagged KRAS^G12D protein (amino acids 2 – 169), 10 nM (final concentration) recombinant SOS1 protein (amino acids 564 – 1049), 150 nM (final concentration) fluorescent GTP analogue 2'/3'-O-(2-aminoethyl-carbamoyl)-guanosine-5'- triphosphate (GTP-DY-647P1; Jena Bioscience (Germany)) and approximately 0.5 to 2 nM (final concentration) anti-GST-terbium (Cisbio, France). To perform the assay, KRAS^G12D protein, anti-GST-terbium and test compound were first mixed and incubated for 1 hour at RT, then a mixture of SOS1 protein with GTP-DY-647P1 was added to begin the exchange reaction. Homogeneous time-resolved fluorescence (HTRF) using an Envision reader (Perkin Elmer, USA; excitation: 320-275 nm; emission 1: 665-667.5 nm, emission 2: 615- 618.5 nm) was used to measure the resonance energy transfer from anti-GST-terbium (FRET donor) to GTP-DY-647P1 (FRET acceptor). The data were normalized using DMSO as a control for 0% binding by GST tagged KRAS^G12D protein and by subtracting signal background, which was measured with all assay components present except the recombinant proteins. Test compounds were evaluated at 10 concentrations (3-fold serial dilution; 10 µM, 3.33 µM, 1.11 µM, 0.37 µM, 0.123 µM, 0.0412 µM, 0.0137 µM, 0.00457 µM, 0.00152 µM and 0.000508 µM). IC₅₀ values were calculated by fitting the data of each test compound to a 4-parameter logistic curve. See Table 8. “A” represents an IC₅₀ of 100 nM or less, “B” represents an IC50 of greater than 100 nM and less than 1 µM, and “C” represents an IC50 of 1 µM or greater. Caco-2 Assay (Papp A to B) The degree of bi-directional human intestinal permeability for compounds is estimated using a Caco-2 cell permeability assay. Caco-2 cells are seeded onto polyethylene membranes in 96-well plates. The growth medium is refreshed every 4 to 5 days until cells form a confluent cell monolayer. HBSS with 10 mM HEPES at pH 7.4 is used as the transport buffer. Compounds are tested at 2 μM bi-directionally in duplicate. Digoxin, nadolol and metoprolol are included as standards. Digoxin is tested at 10 μM bi- directionally in duplicate, while nadolol and metoprolol are tested at 2 μM in the A to B direction in duplicate. The final DMSO concentration is adjusted to less than 1% for all experiments. The plate is incubated for 2 hours in a CO₂ incubator at 37°C, with 5% CO₂ at saturated humidity. After incubation, all wells are mixed with acetonitrile containing an internal standard, and the plate is centrifuged at 4,000 rpm for 10 minutes.100 µL supernatant is collected from each well and diluted with 100 µL distilled water for LC/MS/MS analysis. Concentrations of test and control compounds in starting solution, donor solution, and receiver solution are quantified by LC/MS/MS, using peak area ratio of analyte to internal standard. The apparent permeability coefficient Papp (cm/s) is calculated using the equation: Papp = (dCr/dt) x Vr / (A x C0), where dC_r/dt is the cumulative concentration of compound in the receiver chamber as a function of time (µM/s); Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport, which is 0.0804 cm² for the area of the monolayer; and C₀ is the initial concentration in the donor chamber (µM). The efflux ratio is calculated using the equation: Efflux Ratio = P_app (BA) / P_app (AB) Percent recovery is calculated using the equation: % Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x C0), where Vd is the volume in the donor chambers, which are 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 transport compound in donor and receiver chambers, respectively. Measurement of Compound Metabolic Stability The metabolic stability of compounds is determined in hepatocytes from human, mice and rats. Compounds are diluted to 5 µM in Williams' Medium E from 10 mM stock solutions.10 µL of each compound is aliquoted into a well of a 96-well plate and reactions are started by aliquoting 40 µL of a 625,000 cells/mL suspension into each well. The plate is incubated at 37°C with 5% CO2. At each corresponding time point, the reaction is stopped by quenching with ACN containing internal standards (IS) at a 1:3. Plates are shaken at 500 rpm for 10 min, and then centrifuged at 3,220 x g for 20 minutes. Supernatants are transferred to another 96-well plate containing a dilution solution. Supernatants are analyzed by LC/MS/MS. The remaining percent of compound after incubation is calculated using the following equation: % Remaining Compound = Peak Area Ratios of Tested Compound vs. Internal Standard at End Point Peak Area Ratios of Tested Compound vs. Internal Standard at Start Point Compound half-life and CL_int are calculated using the following equations: Ct = C0*e^-k*t (first order kinetics); when Ct = ½C0, t½ = ln2/k = 0.693/k; and CL_int = k/(1,000,000 cells/mL) The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods described will become apparent from the description and teachings herein. Such variations may be practiced without departing from the true scope and spirit of the disclosure and are intended to fall within the scope of the present disclosure. Cell Line Growth Retardation Assay Cells were seeded at densities of 1,000-5,000 cells per well in 48-well tissue culture plates. After a 24 h rest period, cells were treated with compound at 10 µM, 2 ^M, 0.4 ^M, 0.08 ^M, 0.016 ^M, and 0.0032 ^M. A group of cells were treated with the vehicle in which the compound was prepared and served as a control. Prior to treatment, cells were counted and this count was used as a baseline for the calculation of growth inhibition. The cells were grown in the presence of compounds for 6 days and were counted on day 6. All cell counting was performed using a Synentec Cellavista plate imager. Growth inhibition was calculated as a ratio of cell population doublings in the presence of compound versus the absence of compound. If treatment resulted in a net loss of cells from baseline, percent lethality was defined as the decrease in cell numbers in treated wells compared with counts on day 1 of non-treated wells post-seeding. IC₅₀ values for each compound were calculated by fitting curves to data points from each dose–response assay using the Proc NLIN function in SAS for Windows version 9.2 (SAS Institute, Inc.). Average IC50s (“Avg Cellular IC₅₀s” in Table 8) were calculated as arithmetic means of the group, and said group included the following cell lines: A427, ASPC-1, NCI-H596, HPAC, HPAF-2, LS174T, LS513, PANC 02.03, PANC 04.03, PANC 05.04, PANC-1, PANC 10.05, PL45, SK-BR-3, SNU-C2B and SU.86.86.. See Table 8. “A” represents an IC50 of 0.5 µM or less, “B” represents an IC₅₀ of greater than 0.5 µM and less than 2 µM, “C” represents an IC₅₀ of 2 µM and less than 5 µM and “D” represents an IC50 of 5 µM or greater. Cell Viability Assay AGS or AsPC-1 cells were seeded at 500 cells per well in 384-well tissue culture plates. After about 24 hours, cells were treated with compound at 10 doses over a 3-fold dilution where the highest dose concentration was 10 µM. For a high signal control (“High Control”), wells with cells and 0.5% DMSO were prepared when treatment was introduced to experimental wells. For a low signal control (“Low Control”), only 50 μL of medium was added into wells when treatment was introduced to experimental wells. All treatment groups were done in duplicate and final DMSO concentration in wells was 0.5%. All groups were incubated for 72 hours. After the 72-hours treatment, 25 µL Cell Titer-Glo (Promega) luminescent cell viability reporter dye was added to each well according to the manufacture’s specifications, incubated for 1 hour at RT, and luminescence was measured in each well using an Envision system (Perkin Elmer) with the following parameters: emission filter = luminescence 700; mirror = luminescence; measurement time (s) = 0.5; and measurement height (mm) = 6.5. The average signal and standard deviation were calculated for the High Control and Low Control, and to calculate compound activity in each well, the following calculation was performed:

The dose response curves were fitted using a four-parameter dose-response curve by Graphpad Prism software, and the IC₅₀ value for each compound was calculated. See Table 8A. “A” represents an IC₅₀ of 1.0 µM or less, “B” represents an IC₅₀ of greater than 1.0 µM and less than 5 µM, “C” represents an IC50 of 5 µM or greater. Cellular pERK Assay AGS or AsPC-1 cells were seeded at 15,000 cells per well in 384-well tissue culture plates. After an overnight incubation, cells were treated with compound at 10 doses over a 3-fold dilution where the highest dose concentration was 10 µM. For a high signal control (“High Control”), wells with cells and 0.5% DMSO were prepared when treatment was introduced to experimental wells. For a low signal control (“Low Control”), wells with cells were treated with 1 µM Trametinib. All treatment groups were done in duplicate and final DMSO concentration in wells was 0.5%. All groups were incubated for 3 hours. After the 3-hours treatment, all wells were treated with 50 µL of 8% paraformaldehyde at RT for 20 – 30 mins. Wells were washed 5 times with 110 µL of Wash/Permeabilization Buffer (PBS containing 0.1% Trition X-100). Then 50 µL of Blocking Buffer (Li-Cor Biosciences, Cat. No.927-70001) was added to each well and incubated for 1 hour at RT. Primary antibody (phospho-ERK; Cell Signaling Technologies, Cat. No.4370L) was prepared in Blocking Buffer at 1:600 dilution. Blocking Buffer was removed from wells, 30 µL of diluted primary antibody was added to each well and the plate was incubated at least 16 hours at 4°C. After the primary antibody incubation, wells were washed 5 times with 110 µL of Wash/Permeabilization Buffer. A solution of secondary antibody (IR Dye 800CW goat anti-rabbit; Li-Cor Biosciences, Cat. No.926-32211) and DRAQ5 (VWR, Cat. No.10761- 508) was prepared in Blocking Buffer at 1:400 and 1:1000 dilutions, respectively. Wash/Permeabilization Buffer was removed from wells, 30 µL of diluted secondary antibody + DRAQ5 solution was added to each well and the plate was incubated for 2 hours at RT. After the secondary antibody + DRAQ5 solution incubation, wells were washed 5 times with 110 µL of Wash/Permeabilization Buffer. Wells were aspirated and the plate immediately scanned with a plate reader (Li-Cor Odyssey) using channels 700 nm and 800 nm. Fluorescence intensity for image capture was gated using Odessy software, and image analysis was performed with Odessy software. The average signal and standard deviation were calculated for the High Control and Low Control, and to calculate compound activity in each well, the following calculation was performed:

The dose response curves were fitted using a four-parameter dose-response curve by Graphpad Prism software, and the IC50 value for each compound was calculated. See Table 8A. “A” represents an IC50 of 1.0 µM or less, “B” represents an IC50 of greater than 1.0 µM and less than 5 µM, “C” represents an IC₅₀ of 5 µM or greater. Surface Plasmon Resonance (SPR) Assay A Biacore 8K+ (GE Healthcare) was used to acquire SPR measurements at 25 °C, a flow rate of 50 µL/mL, and biotinylated KRAS-G12D-GDP (MW 23 KDa, 5 mg/mL) recombinant protein was used for the assay. KRAS-G12D-GDP protein was diluted to 5µg/mL and captured on a neutravidin pre-coated CM5 sensor chip for a 350 seconds contact at 5 µL/min to reach an immobilization level of 1400-1900 response units (RU) and using Running Buffer (10 mM HEPES, 150 mM NaC1, 5 mM MgCl2, 0.05% Tween 20, 0.5 mM TCEP, 1µM GDP). During the course of the assay, different concentrations of compounds were injected, and the compounds were serially diluted (3- fold) in Dilution Buffer (10 mM HEPES, 150 mM NaC1, 5 mM MgCl2, 0.05% Tween 20, 0.5 mM TCEP, 1µM GDP, pH7.4, 2% DMSO). In each cycle, association time was 60 seconds, and dissociation time was 120 seconds. The final response was obtained by subtracting the blank channel (without KRAS-G12D-GDP protein, a buffer injection across the sample channel was measured). Raw data were analyzed in Biacore Insight Evaluation program by fitting the data to a simple 1:1 equilibrium and kinetic model. See Table 8A. “A” represents a KD of 100 nM or less, “B” represents an KD of greater than 100 nM and less than 1 µM, “C” represents an KD of 1 µM or greater. Activity-Guided Selection of Inhibitors Subgenera of KRAS G12D inhibitors having desirable properties were identified using one or more types of in vitro data. In particular, the results from the assays described above (e.g., Inhibition of KRAS G12D GTP Binding Assay, SPR Assay, Cellular pERK Assay, Cell Viability Assay, Cell Line Growth Retardation Assay, Caco-2 Assay (P_app A to B) and Measurement of Compound Metabolic Stability) were used to select compounds. A desirable property for compounds of the invention is having an average IC50 of about 100 nM or less for binding of GTP by KRAS^G12D protein (as measured, for example, by the Inhibition of KRAS G12D GTP Brinding Assay disclosed herein). A desirable property for compounds of the invention is having a KD of about 100 nM or less for binding of GTP by KRAS^G12D protein (as measured, for example, by the Inhibition of KRAS G12D GTP Brinding Assay disclosed herein). A more desirable property for compounds of the invention is having an average KD of about 10 nM or less for binding of GTP by KRAS^G12D protein. A desirable property for compounds of the invention is having an average IC₅₀ of about 500 nM or less for cellular pERK (as measured, for example, by the Cellular pERK Assay disclosed herein). A more desirable property for compounds of the invention is having an average IC50 of about 250 nM or less for cellular pERK. An even more desirable property for compounds of the invention is having an average IC₅₀ of about 100 nM or less for cellular pERK. A desirable property for compounds of the invention is having an average IC50 of about 500 nM or less against the group of cell lines A427, ASPC-1, NCI-H596, HPAC, HPAF-2, LS174T, LS513, PANC 02.03, PANC 04.03, PANC 05.04, PANC-1, PANC 10.05, PL45, SK-BR-3, SNU-C2B and SU.86.86. Another desirable property for compounds of the invention is having an average IC₅₀ of about 500 nM or less against cell lines AsPC-1 and AGS. A more desirable property for compounds of the invention is having an average IC50 of about 250 nM or less against cell lines AsPC-1 and AGS. An even more desirable property for compounds of the invention is having an average IC₅₀ of about 100 nM or less against cell lines AsPC-1 and AGS. The IC50 can be determined using either the Cell Line Growth Retardation Assay or the Cell Viability Assay. More preferably, the IC50 is determined using the Cell Line Growth Retardation Assay. The skilled artisan would readily recognize that the results of additional in vitro assays (e.g., CYP enzymatic inhibition, hERG inhibition, compound solubility, target- specificity analysis, Compound Metabolic Stability Assay, Caco-2 Assay), as well as the results of in vivo assays (e.g., rodent xenograft studies, rodent pharmacokinetic and single- dose saturation studies, rodent maximum tolerated dose studies, and oral bioavailability) could be used to identify other subgenera of KRAS G12D inhibitors, or to narrow subgenera determined using other results, for example, the subgenera identified with the average IC50 values for the group of cell lines A427, ASPC-1, NCI-H596, HPAC, HPAF-2, LS174T, LS513, PANC 02.03, PANC 04.03, PANC 05.04, PANC-1, PANC 10.05, PL45, SK-BR-3, SNU-C2B and SU.86.86. Table 8.

Table 8A.

Table X1. Crystal Data and Structure Refinement Empirical formula C17 H15 Cl2 F N2 S Formula weight 369.27 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2₁/c Unit cell dimensions a = 10.3855(18) Å a= 90°. b = 10.265(2) Å b= 94.109(10)°. c = 14.991(3) Å g = 90°. Volume 1594.1(5) Å³ Z 4 Density (calculated) 1.539 Mg/m3 Absorption coefficient 0.548 mm-1 F(000) 7 60 Crystal size 0.400 x 0.150 x 0.100 mm³ Theta range for data collection 2.407 to 36.323°. Index ranges -17<=h<=17, -17<=k<=17, -24<=l<=24 Reflections collected 63481 Independent reflections 7727 [R(int) = 0.0481] Completeness to theta = 25.242° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7471 and 0.6595 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7727 / 0 / 209 Goodness-of-fit on F² 1.034 Final R indices [I>2sigma(I)] R1 = 0.0297, wR2 = 0.0773 R indices (all data) R1 = 0.0383, wR2 = 0.0826 Extinction coefficient n/a Largest diff. peak and hole 0.918 and -0.601 e.Å^-3 Table X2. Atomic Coordinates (x10⁴) and Equivalent Isotropic Displacement Parameters (Å²x10³) __________________________________________________ x y z U(eq)^# __________________________________________________ S(1) 8396(1) 3280(1) 6283(1) 16(1) C(9) 7805(1) 3660(1) 7348(1) 22(1) C(1) 7640(1) 4476(1) 5591(1) 13(1) N(1) 6683(1) 5190(1) 5900(1) 13(1) C(2) 6184(1) 6074(1) 5333(1) 12(1) Cl(1) 4913(1) 6985(1) 5696(1) 15(1) C(3) 6580(1) 6304(1) 4478(1) 12(1) C(4) 6000(1) 7334(1) 3862(1) 15(1) C(5) 6820(1) 7585(1) 3072(1) 15(1) C(6) 7214(1) 6307(1) 2632(1) 12(1) C(10) 7920(1) 6510(1) 1790(1) 12(1) C(11) 8919(1) 7375(1) 1651(1) 15(1) C(12) 9479(1) 7361(1) 831(1) 17(1) C(13) 9058(1) 6474(1) 166(1) 17(1) C(14) 8053(1) 5625(1) 320(1) 14(1) Cl(2) 7514(1) 4512(1) -503(1)19(1) C(15) 7469(1) 5642(1) 1123(1) 13(1) C(16) 6370(1) 4828(1) 1409(1) 15(1) C(17) 6035(1) 5463(1) 2296(1) 15(1) C(7) 8105(1) 5590(1) 3328(1) 14(1) F(1) 8373(1) 4341(1) 3017(1) 21(1) C(8) 7558(1) 5465(1) 4234(1) 12(1) N(2) 8096(1) 4557(1) 4783(1) 13(1) __________________________________________________ ^#U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. Table X3. Bond lengths [Å] _____________________________________________________ S(1)-C(1) 1.7551(9) S(1)-C(9) 1.7952(10) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C(9)-H(9C) 0.9800 C(1)-N(2) 1.3350(11) C(1)-N(1) 1.3426(11) N(1)-C(2) 1.3235(11) C(2)-C(3) 1.3946(12) C(2)-Cl(1) 1.7366(8) C(3)-C(8) 1.3990(11) C(3)-C(4) 1.5010(12) C(4)-C(5) 1.5287(12) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(5)-C(6) 1.5370(12) C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-C(10) 1.5197(12) C(6)-C(7) 1.5329(12) C(6)-C(17) 1.5539(12) C(10)-C(11) 1.3925(12) C(10)-C(15) 1.3943(12) C(11)-C(12) 1.3973(13) C(11)-H(11) 0.9500 C(12)-C(13) 1.3963(13) C(12)-H(12) 0.9500 C(13)-C(14) 1.3920(12) C(13)-H(13) 0.9500 C(14)-C(15) 1.3874(12) C(14)-Cl(2) 1.7429(9) C(15)-C(16) 1.5013(12) C(16)-C(17) 1.5435(12) C(16)-H(16A) 0.9900 C(16)-H(16B) 0.9900 C(17)-H(17A) 0.9900 C(17)-H(17B) 0.9900 C(7)-F(1) 1.3982(10) C(7)-C(8) 1.5156(12) C(7)-H(7) 1.0000 C(8)-N(2) 1.3389(11) _____________________________________________________ Symmetry transformations used to generate equivalent atoms Table X4. Bond Angles [°] _____________________________________________________ C(1)-S(1)-C(9) 101.91(4) S(1)-C(9)-H(9A) 109.5 S(1)-C(9)-H(9B) 109.5 H(9A)-C(9)-H(9B) 109.5 S(1)-C(9)-H(9C) 109.5 H(9A)-C(9)-H(9C) 109.5 H(9B)-C(9)-H(9C) 109.5 N(2)-C(1)-N(1) 126.72(8) N(2)-C(1)-S(1) 113.98(6) N(1)-C(1)-S(1) 119.29(6) C(2)-N(1)-C(1) 114.77(7) N(1)-C(2)-C(3) 125.33(7) N(1)-C(2)-Cl(1) 116.10(6) C(3)-C(2)-Cl(1) 118.56(6) C(2)-C(3)-C(8) 113.77(7) C(2)-C(3)-C(4) 123.57(7) C(8)-C(3)-C(4) 122.65(7) C(3)-C(4)-C(5) 111.98(7) C(3)-C(4)-H(4A) 109.2 C(5)-C(4)-H(4A) 109.2 C(3)-C(4)-H(4B) 109.2 C(5)-C(4)-H(4B) 109.2 H(4A)-C(4)-H(4B) 107.9 C(4)-C(5)-C(6) 111.58(7) C(4)-C(5)-H(5A) 109.3 C(6)-C(5)-H(5A) 109.3 C(4)-C(5)-H(5B) 109.3 C(6)-C(5)-H(5B) 109.3 H(5A)-C(5)-H(5B) 108.0 C(10)-C(6)-C(7) 109.11(7) C(10)-C(6)-C(5) 113.50(7) C(7)-C(6)-C(5) 106.52(7) C(10)-C(6)-C(17) 102.88(7) C(7)-C(6)-C(17) 112.08(7) C(5)-C(6)-C(17) 112.82(7) C(11)-C(10)-C(15) 121.08(8) C(11)-C(10)-C(6) 128.37(8) C(15)-C(10)-C(6) 110.50(7) C(10)-C(11)-C(12) 119.09(8) C(10)-C(11)-H(11) 120.5 C(12)-C(11)-H(11) 120.5 C(13)-C(12)-C(11) 120.41(8) C(13)-C(12)-H(12) 119.8 C(11)-C(12)-H(12) 119.8 C(14)-C(13)-C(12) 119.37(8) C(14)-C(13)-H(13) 120.3 C(12)-C(13)-H(13) 120.3 C(15)-C(14)-C(13) 121.01(8) C(15)-C(14)-Cl(2) 119.00(7) C(13)-C(14)-Cl(2) 119.99(7) C(14)-C(15)-C(10) 119.01(8) C(14)-C(15)-C(16) 128.95(8) C(10)-C(15)-C(16) 112.03(7) C(15)-C(16)-C(17) 103.48(7) C(15)-C(16)-H(16A) 111.1 C(17)-C(16)-H(16A) 111.1 C(15)-C(16)-H(16B) 111.1 C(17)-C(16)-H(16B) 111.1 H(16A)-C(16)-H(16B) 109.0 C(16)-C(17)-C(6) 107.11(7) C(16)-C(17)-H(17A) 110.3 C(6)-C(17)-H(17A) 110.3 C(16)-C(17)-H(17B) 110.3 C(6)-C(17)-H(17B) 110.3 H(17A)-C(17)-H(17B) 108.5 F(1)-C(7)-C(8) 108.55(7) F(1)-C(7)-C(6) 109.77(7) C(8)-C(7)-C(6) 113.79(7) F(1)-C(7)-H(7) 108.2 C(8)-C(7)-H(7) 108.2 C(6)-C(7)-H(7) 108.2 N(2)-C(8)-C(3) 123.18(8) N(2)-C(8)-C(7) 116.25(7) C(3)-C(8)-C(7) 120.52(7) C(1)-N(2)-C(8) 116.18(7) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms Table X5. Anisotropic Displacement Parameters (Å²x10³) The anisotropic displacement factor exponent takes the form:

_________________________________________________________________ Table X6. Hydrogen Coordinates (x10⁴) and Isotropic Displacement Parameters (Å²x10³)

________________________________________________________________ Table X7. Torsion angles [°]

C(3)-C(4)-C(5)-C(6) 47.54(10) C(4)-C(5)-C(6)-C(10) 174.42(7) C(4)-C(5)-C(6)-C(7) -65.49(9) C(4)-C(5)-C(6)-C(17) 57.89(9) C(7)-C(6)-C(10)-C(11) -73.11(11) C(5)-C(6)-C(10)-C(11) 45.50(12) C(17)-C(6)-C(10)-C(11) 167.73(8) C(7)-C(6)-C(10)-C(15) 104.51(8) C(5)-C(6)-C(10)-C(15) -136.89(8) C(17)-C(6)-C(10)-C(15) -14.66(9) C(15)-C(10)-C(11)-C(12) -0.46(13) C(6)-C(10)-C(11)-C(12) 176.92(8) C(10)-C(11)-C(12)-C(13) -1.17(13) C(11)-C(12)-C(13)-C(14) 1.54(14) C(12)-C(13)-C(14)-C(15) -0.29(13) C(12)-C(13)-C(14)-Cl(2) 179.97(7) C(13)-C(14)-C(15)-C(10) -1.30(13) Cl(2)-C(14)-C(15)-C(10) 178.44(6) C(13)-C(14)-C(15)-C(16) 179.01(9) Cl(2)-C(14)-C(15)-C(16) -1.25(13) C(11)-C(10)-C(15)-C(14) 1.69(13) C(6)-C(10)-C(15)-C(14) -176.13(7) C(11)-C(10)-C(15)-C(16) -178.57(8) C(6)-C(10)-C(15)-C(16) 3.61(10) C(14)-C(15)-C(16)-C(17) -171.09(9) C(10)-C(15)-C(16)-C(17) 9.21(10) C(15)-C(16)-C(17)-C(6) -18.02(9) C(10)-C(6)-C(17)-C(16) 19.91(8) C(7)-C(6)-C(17)-C(16) -97.17(8) C(5)-C(6)-C(17)-C(16) 142.59(7) C(10)-C(6)-C(7)-F(1) -64.60(8) C(5)-C(6)-C(7)-F(1) 172.52(7) C(17)-C(6)-C(7)-F(1) 48.68(9) C(10)-C(6)-C(7)-C(8) 173.54(7) C(5)-C(6)-C(7)-C(8) 50.66(9) C(17)-C(6)-C(7)-C(8) -73.18(9) C(2)-C(3)-C(8)-N(2) -2.15(12) C(4)-C(3)-C(8)-N(2) 178.95(8) C(2)-C(3)-C(8)-C(7) -179.54(7) C(4)-C(3)-C(8)-C(7) 1.56(12) F(1)-C(7)-C(8)-N(2) 39.22(10) C(6)-C(7)-C(8)-N(2) 161.76(7) F(1)-C(7)-C(8)-C(3) -143.21(8) C(6)-C(7)-C(8)-C(3) -20.68(11) N(1)-C(1)-N(2)-C(8) 1.64(13) S(1)-C(1)-N(2)-C(8) -179.32(6) C(3)-C(8)-N(2)-C(1) 0.47(12) C(7)-C(8)-N(2)-C(1) 177.96(7) ______________________________________________________ Symmetry transformations used to generate equivalent atoms.

Claims

CLAIMS We claim: 1. A compound having the structure of Formula I’:

(Formula I’) or a pharmaceutically acceptable salt thereof, wherein: * is the quaternary carbon atom; A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring optionally substituted with one or more R₅, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R5 is C₁-C₃ cyanoalkyl or C₁-C₃ alkyl substituted with C₁-C₃ alkoxy, then a second and independent instance of R₅ must occur that is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO2R3, -CO2N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; or if A is piperazinyl and one instance of R₅ is unsubstituted C₁-C₃ alkyl, then a second and independent instance of R5 must occur that is hydroxy, halogen, substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -CO₂N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; B is a 5 – 6 membered saturated or partially saturated cycloalkyl or heterocyclyl; C is an aryl or heteroaryl optionally substituted with one or more R4; x₁ is C(R₁)(R₂) or C=O; x2 is a bond, C(R₃)₂, C=O, O, N(R3), S, S(O), or S(O)2; x3 is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y1 is *—y_1b—y_1c and y₂ is y_2a; or y₁ is y_1a and y₂ is *—y_2b—y_2c; or y₁ is *—y_1d y_1e and y₂ is y_2a; or y1 is y_1a and y₂ is *—y_2d y₂e; or y1 is *y_1a—y_1b—y_1c and y₂ is a bond; or y₁ is a bond and y₂ is *y_2a—y_2b—y_2c; y_1a and y_2a are each independently a bond, (C(R8)2)n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)2; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R3), S, S(O), or S(O)2; y_1d, y1e, y_2d and y₂e are each independently C(R3) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be a bond; with the proviso that both y_1b and y_2a cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y_2d and y_2c cannot be heteroatoms; with the proviso that both y_1d and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2d cannot be heteroatoms; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that both y_2a and y_2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms; and with the proviso that when y1 is *y_1a—y_1b—y_1c and y₂ is a bond and A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O; and with the proviso that when y₁ is a bond and y₂ is *y_2a—y_2b—y_2c and A is diazabicyclo[3.2.1]octanyl, y_2d cannot be O; R1 and R2 are each independently H or F; R₃ in each occurrence is independently H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R4 in each instance is independently hydroxy, halogen, N(R₃)₂, (W)tC₁-C₃ alkyl, (W)tC₁-C₃ haloalkyl, (W)tC₂-C₄ alkenyl, (W)tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl; W in each occurrence is independently S or O; R5 in each instance is independently oxo, hydroxy, halogen, nitro, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₃ alkenyl, optionally substituted C₂-C₃ alkynyl, propargyl, allyl, cyano, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, C₁-C₃ alkoxy, HC(=O)-, -CO2R3, -SO2R3, -SO(R₃)₂, -OCF3, -OCHF2, -OCH₂F, -SCF3, -SCHF2, -SCH₂F, - SO2N(R₃)₂, -C(O)N(R₃)₂ optionally substituted cycloalkyl, optionally

substituted 4-6 membered heterocyclyl, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R6 in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R₇; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R3, CH₂N(H)C(O)R3, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; R8 in each occurrence is independently H, F, C1, C₁-C₃ alkyl, OCH3, C₁-C₃ hydroxyalkyl, cyano, C₂-C₃ alkenyl or C₂-C₃ alkynyl; or two occurrences of R₈ combine, together with the one or two carbon atoms to which they are bonded, along with any intervening carbon atoms, to form a C₃-C₆ cycloalkyl; R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1.

2. The compound of claim 1, wherein R5 in each instance is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, _HC(=O)-, -CO₂R₃, -CO₂N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; and R₈ in each occurrence is independently H, F, Cl, C₁-C₃ alkyl or OCH₃.

3. The compound of claim 1 having the structure of Formula I’a:

(Formula I’a) wherein: z1, z2, z3 and z4 are each independently C(H), C(R4) or N; R₃ in each occurrence is independently H, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R₄ in each instance is independently hydroxy, halogen, N(R₃)₂, (W)_tC₁-C₃ alkyl, (W)tC₁-C₃ haloalkyl, (W)tC₂-C₄ alkenyl, (W)tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl; W in each occurrence is independently S or O; and t in each occurrence is independently 0 or 1.

4. The compound of claim 3, wherein z₁, z₂, z₃ and z₄ are each independently C(H) or C(R4).

5. The compound of any one of claims 1-4, wherein y₁ is y_1a and y₂ is y_2a, with the proviso that both y_1a and y_2a cannot be heteroatoms, and the further proviso that neither y_1a or y_2a can be a bond when y₁ is y_1a and y₂ is y_2a.

6. The compound of any one of claims 1-4, wherein y₁ is *—y_1b—y_1c and y₂ is y_2a, with the proviso that both y_1b and y_2a cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be bonds, the proviso that both y_1b and y_1c cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be C=O, and the further proviso that both y_1b and y_1c cannot be C=CH₂.

7. The compound of any one of claims 1-4, wherein y1 is y_1a and y₂ is *—y_2d— y_2c, with the proviso that both y_1a and y_2b cannot be heteroatoms, the proviso that both y_2b and y_2c cannot be bonds, the proviso that both y_2b and y_2c cannot be heteroatoms, the proviso that both y_2d and y_2c cannot be C=O, and the further proviso that both y_2d and y_2c cannot be C=CH₂.

8. The compound of any one of claims 1-4, wherein y1 is *—y_1d y_1e and y₂ is y_2a, with the proviso that both y_1d and y_2a cannot be heteroatoms.

9. The compound of any one of claims 1-4, wherein y1 is y_1a and y₂ is *—y_2d y_2e, with the proviso that both y_1a and y_2d cannot be heteroatoms.

10. The compound of any one of claims 1-4, wherein y₁ is *y_1a—y_1b—y_1c and y₂ is a bond, with the proviso that none ofy_1a, y1b and y1c can be a bond, the proviso that both y_1a and y_1b cannot be heteroatoms, the proviso that both y_1b and y_1c cannot be heteroatoms, the proviso that both y_1a and y_1b cannot be C=O, the proviso that both y_1b and y_1c cannot be C=O, the proviso that both y_1a and y1b cannot be C=CH₂, and the further proviso that both y1b and y1c cannot be C=CH₂.

11. The compound of any one of claims 1-4, wherein y1 is a bond and y₂ is * y_2a—y_2d— y_2c, with the proviso that none of y_2a, y_2d and y_2c can be a bond, the proviso that both y_2a and y_2b cannot be heteroatoms, the proviso that both y_2b and y_2c cannot be heteroatoms, the proviso that both y_2a and y_2b cannot be C=O, the proviso that both y_2b and y_2c cannot be C=O, the proviso that both y_2a and y_2d cannot be C=CH₂, and the further proviso that both y_2b and y_2c cannot be C=CH₂.

12. The compound of any one of claims 1-11, wherein A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring substituted with one or more R₅, wherein no instance of R₅ is C₁-C₃ cyanoalkyl.

13. The compound of any one of claims 1-11, wherein A is is

or

each optionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring.

14. The compound of any one of claims 1-11, wherein A is a 7 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring substituted with one or more R5.

15. The compound of any one of claims 1-12, wherein A is an 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic ring substituted with one or two R5.

16. The compound of any one of claims 1-12, wherein A is an 8-membered bridged heterocyclyl. 17. The compound of any one of claims 1-12, A is

or

each optionally substituted with one or more R5, wherein

denotes the point of attachment to the pyrimidine ring.

17. The compound of claim 17, A is or

each optionally

18. The compound of any one of claims 1-17, wherein B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl.

19. The compound of any one of claims 1-17, wherein B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

20. The compound of any one of claims 1-18, wherein x1 is CH₂.

21. The compound of any one of claims 1-19, wherein x2 is O.

22. The compound of any one of claims 1-21, wherein x₃ is C₁-C₆ alkyl substituted with R6, R6 is cycloalkyl, heterocyclyl, aryl, or heteroaryl each of which is optionally substituted with one or more R7.

23. The compound of any one of claims 1-22, wherein x₃ is C₁-C₃ alkyl and R₆ is heterocyclyl.

24. The compound of any one of claims 1-23, wherein p is 1.

25. The compound of any one of claims 123, wherein p is 2.

26. The compound of claim 24 or 25, wherein B is a 5-membered saturated or partially saturated cycloalkyl or heterocyclyl.

27. The compound of claim 24 or 25, wherein B is a 6-membered saturated or partially saturated cycloalkyl or heterocyclyl.

28. The compound of any one of claims 1-27, wherein R₄ in each instance is independently OH, F, Cl, Br, N(R₃)₂, CFH₂, CHF2, CF3, OCFH₂, OCHF2, OCF3, SCFH₂, SCHF2, SCF3, CH3, OCH3, SCH3, (W)tCF2H, CN, propargyl, cyclopropyl or cyclobutyl.

29. The compound of claim 3 having the structure of Formula I’a-1, I’a-2 or I’a-3:

(Formula I’a-1),

(Formula I’a-2), or

(Formula I’a-3), or a pharmaceutically acceptable salt thereof, wherein: y1a and y2a are each independently a bond, (C(R8)2)n, C=CH₂, C=O, O, N(R3), S, S(O), or S(O)₂; y_2b and y_2c are each independently a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)2; y2d and y2e are each independently C(R3) or N; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y1a and y2a cannot be bond; with the proviso that y2a cannot be a heteroatom; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y2b and y2c cannot be heteroatoms; with the proviso that y2a cannot be a heteroatom; with the proviso that both y_1a and y_2d cannot be heteroatoms; with the proviso that y_1a cannot be a heteroatom; and with the proviso that both y2a and y2b cannot be heteroatoms, and the proviso that both y_2b and y_2c cannot be heteroatoms.

30. The compound of claim 3, having the structure of Formula I’a-4 or I’a-5:

(Formula I’a-4), or

(Formula I’a-5), or a pharmaceutically acceptable salt thereof, wherein: y1a is a bond, (C(R8)2)n, C=CH₂, C=O, O, N(R3), S, S(O), or S(O)2; y1b and y1c are each independently a bond, (C(R8)2)n, C=CH₂, C=O, O, N(R3), S, S(O), or S(O)₂; with the proviso that y1a cannot be a heteroatom; with the proviso that y1a cannot be a bond; with the proviso that y_1b cannot be a heteroatom, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that y1a cannot be a heteroatom; with the proviso that y_1a cannot be a heteroatom; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y1b and y1c cannot be heteroatoms; and with the proviso that, in Formula I’a-4, when A is diazabicyclo[3.2.1]octanyl, y_1b cannot be O.

31. The compound of claim 29 or 30, wherein A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅, wherein no instance of R₅ is C₁-C₅ cyanoalkyl.

32. The compound of claim 29 or 30, wherein A is or

each optionally substituted with one or more R₅

, wherein denotes the point of attachment to the pyrimidine ring.

33. The compound of claim 29 or 30, wherein A is a 7 or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R5.

34. The compound of claim 29 or 30, wherein A is a 7-membered bridged heterocyclyl.

35. The compound of claim 29 or 30, wherein A is an 8-membered bridged heterocyclyl.

36. The compound of claim 29 or 30, wherein A is

, each optionally substituted with one or more R5, wherein

denotes the point of attachment to the pyrimidine ring.

37. The compound of claim36, wherein A is each optionally substituted with one or more R₅, wher

ein denotes the point of attachment to the pyrimidine ring.

38. The compound of claim 29, wherein the compound of Formula I’a-1 has the structure of Formula I’a-1a or I’a-1b: (Formula I’a-1a), or (Formula I’a-1b).

39. The compound of claim 29, wherein the compound of Formula I’a-2 has the structure of Formula I’a-2a or I’a-2b:

(Formula I’a-2a), or

(Formula I’a-2b).

40. The compound of claim 29, wherein the compound of Formula I’a-3 has the structure of Formula I’a-3a or I’a-3b: (Formula I’a-3a), or (Formula I’a-3b).

41. The compound of claim 30, wherein the compound of Formula I’a-4 has the structure of Formula I’a-4a or I’a-4b:

(Formula I’a-4a), or (Formula I’a-4b).

42. The compound of claim 31, wherein the compound of Formula I’a-5 has the structure of Formula I’a-5a or I’a-5b: (Formula I’a-5a) or

(Formula I’a-5b).

43. A compound having the structure of Formula I’a-1-1, I’a-2-1, I’a-4-1 or I’a-5-1: (Formula I’a-1-1), (Formula I’a-2-1),

(Formula I’a-4-1), or

(Formula I’a-5-1), or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R4-1 is absent if X is N, or R4-1 is H, NH₂, OH or CH3; R_4-2 is H, Cl, F, CN, cyclopropyl, C(CH), CH₃ or CH₂CH₃; R_4-3 is H, CH₃, Cl or F; R4-4 is H, Cl or F; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

, wherein

denotes the point of attachment)), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl (preferably

wherein denotes the point of attachment), aryl, heteroaryl

(preferably or wherein

denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably and wherein

denotes the point of attachment), heteroarylalkyl (preferably

wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R₇; R7 in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2 or 3.

44. The compound of claim 43 having the structure of Formula I’a-2-1a, I’a-2-1b, I’a-4- 1a, I’a-4-1b, I’a-5-1a or I’a-5-1b: (Formula I’a-2-1a),

(Formula I’a-2-1b), (Formula I’a-4-1a),

(Formula I’a-4-1b), (Formula I’a-5-1a), or

(Formula I’a-5-1b).

45. The compound of claim 43 or 44, wherein R_6-1 is

or , wherein

denotes the point of attachment.

46. The compound of claim 43 or 44, wherein R_6-1 is

or wherein denotes the point of

attachment

47. The compound of claim 43 or 44, wherein R6-1 is

wherein

denotes the point of attachment.

48. The compound of claim 43 or 44, wherein R6-1 is

wherein denotes the point of attachment.

49. The compound of claim 43 or 44, wherein R6-1 is

wherein denotes the point of attachment

50. The compound of claim 43 or 44, wherein R_6-1 is

wherein denotes the point of attachment.

51. The compound of claim 43 or 44, wherein R_6-1 is or

wherein denotes the point of attachment.

52. The compound of claim 43 or 44, wherein R_6-1 is

or , wherein denotes the point of attachment; R7a in each occurrence is independently F, Cl, C₁-C₃ alkyl (preferably CH3 or CH₂CH3), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH₂; when substituted, preferably fluoro-substituted such as - CH=CHF) or C₂-C₃ alkynyl; R7b is C₁-C₃ alkyl (preferably CH3 or CH₂CH3), C₁-C₃ haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro-substituted), optionally substituted C3-C5 cycloalkyl or optionally substituted C₄-C₆ heterocyclyl; and q is 1, 2 or 3.

53. The compound of claim 44, wherein the compound has the structure of Formula I’a- 4-1 (such as I’a-4-1a or I’a-4-1b) or I’a-5-1 (such as I’a-5-1a or I’a-5-1b), or a pharmaceutically acceptable salt thereof, and wherein R_4-2 is Br, Cl, F, or CH₃.

54. The compound of claim 53, wherein R4-2 is Cl.

55. The compound of claim 44, wherein the compound has the structure of Formula I’a- 4-1 (such as I’a-4-1a or I’a-4-1b) or I’a-5-1 (such as I’a-5-1a or I’a-5-1b), or a pharmaceutically acceptable salt thereof, and wherein R_4-1 is H or OH.

56. The compound of claim 55, wherein R4-1 is OH.

57. The compound of claim 55, wherein R_4-1 is H.

58. A compound having the structure of Formula II’:

(Formula II’) or a pharmaceutically acceptable salt thereof, wherein: * is the quaternary carbon atom; A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R₅; B is a 5 – 6 membered cycloalkyl or heterocyclyl; C is a 6-membered aryl or heteroaryl optionally substituted with one or more R₄; D is a 6-membered aryl or heteroaryl optionally substituted with one or more R₄; x1 is C(R₁)(R₂) or C=O; x2 is a bond, C(R₃)₂, C=O, O, N(R3), S, S(O), or S(O)₂; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C1-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R6; y₁ is y_1a and y₂ is y_2a; or y1 is *—y1b—y1c and y2 is y2a; or y1 is y1a and y2 is *—y2b—y2c; y_1a and y_2a are each independently a bond, (C(R₈)₂)_n, O, N(R₃), S, S(O), or S(O)₂; y_1b, y_1c, y_2b and y_2c are each independently a bond, (C(R₈)₂)_n, O, N(R₃), S, S(O), or S(O)2; with the proviso that both y_1a and y_2a cannot be heteroatoms; with the proviso that both y_1a and y_2a cannot be a bond; with the proviso that both y1b and y2a cannot be heteroatoms, and the proviso that both y1b and y1c cannot be heteroatoms; with the proviso that both y_1a and y_2b cannot be heteroatoms, and the proviso that both y2b and y2c cannot be heteroatoms; with the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that both y_2b and y_2c cannot be heteroatoms; R1 and R2 are each independently H or F; R3 in each occurrence is independently H, C1-C4 alkyl or C1-C4 haloalkyl; R₄ in each instance is independently hydroxy, halogen, N(R₃)₂, (W)_tC₁-C₃ alkyl, (W)tC1-C₃ haloalkyl, (W)tC2-C4 alkenyl, (W)tC2-C4 alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl; W in each occurrence is independently S or O; R5 in each instance is independently hydroxy, halogen, optionally substituted C₁-C₃ alkyl, propargyl, allyl, C₁-C₃ cyanoalkyl, C₁-C₃ hydroxyalkyl, HC(=O)-, -CO2R3, -C(O)N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R6 in each occurrence is independently halogen, hydroxyl, C1-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C₁-C₃ alkyl, C₁-C₆ alkyl, C₁-C₃ alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R7; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH2)nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R3, CH2N(H)C(O)R3, CH2OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; R₈ in each occurrence is independently H, F, C1, C₁-C₃ alkyl or OCH₃; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1.

59. The compound of claim 58, wherein A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R5.

60. The compound of claim 58, wherein A is or

, each optionally substituted with one or more R₅, wherein denotes the point of attachment to the pyrimidine ring.

61. The compound of claim 58, wherein A is a 7- or 8-membered or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅.

62. The compound of claim 61, wherein A is a 7-membered bridged heterocyclyl.

63. The compound of claim 61, wherein A is , each optionally substituted with one or more R₅, wherein

denotes the point of attachment to the pyrimidine ring.

64. The compound of claim 63, wherein A is each optionally substituted with one or more R₅, where

in denotes the point of attachment to the pyrimidine ring.

65. The compound of claim 61, wherein A is an 8-membered bridged heterocyclyl.

66. The compound of claim 58 having the structure of Formula II’a-1, II’a-2 or II’a-3: (Formula II’a-1),

(Formula II’a-2), or

(Formula II’a-3),

wherein: y1a and y2a are each independently (C(R8)2)n, O, N(R3), S, S(O), or S(O)2; y_1b and y_1c are each independently (C(R₈)₂)_n, O, N(R₃), S, S(O), or S(O)₂; with the proviso that both y_1a and y_2a cannot be heteroatoms; and with the proviso that both y1b and y1c cannot be heteroatoms.

67. The compound of claim 66, wherein: y1 is y1a and y2 is y2a, with the proviso that both y1a and y2a cannot be heteroatoms, and the further proviso that both y1a and y2a cannot be bond; or y₁ is *—y_1b—y_1c and y₂ is y_2a, with the proviso that both y_1b and y_2a cannot be heteroatoms, the further proviso that both y_1b and y_1c cannot be heteroatoms, the further proviso that both y1b and y1c cannot be heteroatoms, and the further proviso that both y1b and y_1c cannot be bond.

68. The compound of claim 66, wherein A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R₅.

69. The compound of claim 66, 67, or 68, wherein A is

or each optionally substituted with one or more R₅

, wherein

denotes the point of attachment to the pyrimidine ring.

70. The compound of claim 66, 67, or 68, wherein A is a 7 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R5.

71. The compound of claim 67, wherein A is a 7- or 8-membered bridged heterocyclyl.

72. The compound of claim 71, wherein A is

each optionally substituted with one or more R5

, wherein denotes the point of attachment to the pyrimidine ring.

73. The compound of claim 72, wherein A is

74. The compound of claim 66 having the structure of Formula II’a-1a or II’a-1b:

(Formula II’a-1a), or (Formula II’a-1b).

75. The compound of claim 66 having the structure of Formula II’a-2a or II’a-2b:

(Formula II’a-2a) or (Formula II’a-2b).

76. The compound of claim 66 having the structure of Formula II’a-3a or II’a-3b: (Formula II’a-3a), or

(Formula II’a-3b).

77. The compound of claim 66 having the structure of Formula II’a-1-1, Formula II’a-2- 1 or Formula II’a-3-1:

(Formula II’a-1-1), (Formula II’a-2-1), or

(Formula II’a-3-1), wherein C is a 6-membered aryl or heteroaryl; D is a 6-membered aryl or heteroaryl; X1, X3, X4, and X5 are each independently C or N; R_4-1 is absent if X₁ is N, or R_4-1 is H, NH₂, OH or CH₃; R_4-3 is absent if X₃ is N, or R_4-3 is H, CH₃, Cl or F; R4-4 is absent if X4 is N, or R4-4 is H, Cl or F; and R_4-5 is absent if X₅ is N or R_4-5 is H, Cl or F.

78. The compound of claim 77, wherein the compound of Formula II’a-2-1 has the structure of Formula II’a-2-1a:

(Formula II’a-2-1a).

79. The compound claim 77, wherein the compound of Formula II’a-3-1 has the structure of Formula II’a-3-1a:

(Formula II’a-3-1a).

80. The compound of any one of claims 77-79, wherein A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic polycyclic ring substituted with one or more R₅.

81. The compound of any one of claims 77-80, wherein A is

, each optionally substituted with one or more R5,

wherein denotes the point of attachment to the pyrimidine ring.

82. The compound of any one of claims 7780, wherein A is a 7 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring optionally substituted with one or more R5.

83. The compound of claim 82, wherein A is a 7 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or more R5.

84. The compound of claim 83, wherein A is a 7- or 8-membered saturated or partially saturated monocyclic, bridged or spirocyclic heterocyclic ring substituted with one or two R₅.

85. The compound of claim 84, wherein A is

86. The compound of claim 85, wherein A is

87. The compound of claim 86, wherein A is

88. The compound of claim 86, wherein A is

89. The compound of claim 86, wherein A is

90. The compound of claim 86, wherein A is

91. The compound of any one of claims 77-90, wherein X₁, X₃, X₄, and X₅ are each C.

92. The compound of any one of claims 77-91, wherein x2 is O.

93. The compound of any one of claims 77-91, wherein x3 is C1-C3 alkyl substituted with one R6.

94. The compound of any one of claims 77-93, wherein R6 is cycloalkyl, heterocyclyl (preferably or wherein denotes the point of attachment), aryl, or heteroaryl, each of which

is optionally substituted with one or more R₇.

95. The compound of any one of claims 77-94, wherein R4-1, R4-3, R4-4 and R4-5 are each H.

96. The compound of claim 66 having the structure of Formula II’a-2-2 or II’a-3-2:

(Formula II’a-3-2), or

(Formula II’a-2-2), or a pharmaceutically acceptable salt thereof, wherein: X is C or N; R4-1 is absent if X is N, or R4-1 is H, NH2, OH or CH3; R4-3 is H, CH3, Cl or F; R_4-4 is H, Cl or F; R4-5 is H, Cl or F; R_6-1 is C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl (preferably

wherein

wherein denotes the point of attachment), aryl, heteroaryl

(preferably wherein denotes the point of attachment), haloalkyl, heteroalkyl, hydroxyalkyl, heterocyclylalkyl (preferably and

wherein

denotes the point of attachment), heteroarylalkyl (preferably

or

wherein

denotes the point of attachment), wherein each of C₁-C₆ alkyl (such as C₁-C₃ alkyl or aminoalkyl), C₁-C₆ alkoxy (such as C₁-C₃ alkoxy), cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl and heteroarylalkyl may be optionally substituted with one or more R7; R₇ in each occurrence is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R3)2, OC(O)N(R3)2, N(H)C(O)R3, CH2N(H)C(O)R3, CH2OC(O)N(R3)2, cycloalkyl or heterocyclyl; and n in each occurrence is independently 1, 2, or 3.

97. The compound of claim 96 having the structure of Formula II’a-2-2a, II’a-2-2b, II’a-3-2a or II’a-3-2b: (Formula II’a-3-2a),

(Formula II’a-3-2b), (Formula II’a-2-2a), or

(Formula II’a-2-2b).

98. The compound of claim 96 or 97, wherein R_6-1 is or , wherein

denotes the point of attachment.

99. The compound of claim 96 or 97, wherein R_6-1 is

, wherein

denotes the point of

attachment

100. The compound of claim 96 or 97, wherein R6-1 is

wherein denotes the point of attachment.

101. The compound of claim 96 or 97, wherein R6-1 is

wherein denotes the point of attachment.

101. The compound of claim 96 or 97, wherein R6-1 is

wherein denotes the point of attachment

102. The compound of claim 96 or 97, wherein R_6-1 is wherein denotes the point of attachment. 103. The compound of claim 96 or 97, wherein R6-1 is or , wherein denotes the point of attachment.

103. The compound of claim 96 or 97, wherein R_6-1 is

, wherein

denotes the point of attachment; R7a in each occurrence is independently F, Cl, C1-C3 alkyl (preferably CH3 or CH2CH3), C1-C3 haloalkyl (preferably fluoro-substituted C1-C3 alkyl such as -CH2F, -CHF2 or -CF₃), optionaly substituted C₁-C₃ alkoxy (when substituted, preferably fluoro- substituted), cyano, C₁-C₃ cyanoalkyl (preferably -CH₂CN), optionally substituted C₂-C₃ alkenyl (preferably -CH=CH2; when substituted, preferably fluoro-substituted such as - CH=CHF) or C2-C3 alkynyl; R7b is C1-C3 alkyl (preferably CH3 or CH2CH3), C1-C3 haloalkyl (preferably fluoro-substituted C₁-C₃ alkyl such as -CH₂F, -CHF₂ or -CF₃), optionaly substituted C1-C3 alkoxy (when substituted, preferably fluoro-substituted), optionally substituted C3-C5 cycloalkyl or optionally substituted C4-C6 heterocyclyl; and q is 1, 2 or 3; and with the proviso that R₆ is not

104. The compound of claim 96 or 97, wherein R6-1 is

wherein denotes the point of attachment).

105. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

106. A compound having the structure:

pharmaceutically acceptable salt thereof.

107. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

108. A compound having the structure:

, or a pharmaceutically acceptable salt thereof.

109. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

110. The compound of claim 1 having the structure:

, or a pharmaceutically acceptable salt thereof.

111. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

112. The compound of claim 33 having the structure:

or a pharmaceutically acceptable salt thereof.

113. A compound selected from:

, and or a pharmaceutically acceptable salt thereof.

114. The compound of claim 1, wherein the compound is selected from:

and , or a pharmaceutically acceptable salt thereof.

115. The compound of claim 1, wherein the compound is selected from:

and

or a pharmaceutically acceptable salt thereof.

116. A compound having the structure selected from:

and or a pharmaceutically acceptable salt thereof.

117. A compound having the structure selected from:

118. A compound having the structure of Formula I’a-4 or I’a-5:

(Formula I’a-4),

(Formula I’a-5), or a pharmaceutically acceptable salt thereof, wherein: A is a 6 – 12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring optionally substituted with one or more R5, wherein A cannot be unsubstituted piperazinyl or unsubstituted 2,7-diazaspiro[3.5]nonanyl, or if A is piperazinyl and one instance of R₅ is C_l-C₃ cyanoalkyl, then a second and independent instance of R₅ must occur that is independently hydroxy, halogen, optionally substituted C₁-C3 alkyl, propargyl, allyl, C₁-C3 cyanoalkyl, C₁-C3 hydroxyalkyl, HC(=O)-, -CO2R3, -CO2N(R3)2, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl, or if A is piperazinyl and one instance of R5 is unsubstituted C₁-C3 alkyl, then a second and independent instance of R5 must occur that is hydroxy, halogen, substituted C₁-C3 alkyl, propargyl, allyl, C_l-C₃ cyanoalkyl, C_l-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -CO₂N(R₃)₂, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; x1 is C(R1)(R2) or C=O; x2 is a bond, C(R3)2, C=O, O, N(R3), S, S(O), or S(O)2; x₃ is H, C₁-C₃ alkyl, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl or heteroaryl, wherein each of C1-C3 alkyl, C1-C6 alkyl, cycloalkyl, heterocyclyl, aralkyl, aryl and heteroaryl may be optionally substituted with one or more R₆; y_1a is a bond, (C(R₈)₂)_n, C=CH₂, C=O, O, N(R₃), S, S(O), or S(O)₂; y1b and y1c are each independently a bond, (C(R8)2)n, C=CH2, C=O, O, N(R3), S, S(O), or S(O)2; with the proviso that y_1a cannot be a heteroatom; with the proviso that y1a cannot be a bond; with the proviso that y1b cannot be a heteroatom, and the proviso that both y_1b and y_1c cannot be heteroatoms; with the proviso that y1a; with the proviso that y1a cannot be a heteroatom; with the proviso that both y_1a and y_1b cannot be heteroatoms, and the proviso that both y_1b and y_1c cannot be heteroatoms; and with the proviso that, in Formula I’a-4, when A is diazabicyclo[3.2.1]octanyl, y1b cannot be O;z₁, z₂, z₃ and z₄ are each independently C(H), C(R₄) or N; R₁ and R₂ are each independently H or F; R3 in each occurrence is independently H, C1-C4 alkyl or C1-C4 haloalkyl; R4 in each instance is independently hydroxy, halogen, N(R3)2, (W)tC1-C3 alkyl, (W)_tC₁-C₃ haloalkyl, (W)_tC₂-C₄ alkenyl, (W)_tC₂-C₄ alkynyl, cyano, propargyl, or 3-5 membered cycloalkyl; W in each occurrence is independently S or O; R₅ in each instance is independently hydroxy, halogen, optionally substituted C_l-C₃ alkyl, propargyl, allyl, C_l-C₃ cyanoalkyl, C_l-C₃ hydroxyalkyl, HC(=O)-, -CO₂R₃, -C(O)N(R3)2, optionally substituted aryl or an optionally substituted 5-6 membered heteroaryl; R₆ in each occurrence is independently halogen, hydroxyl, C₁-C₃ alkyl, C₁-C₆ alkyl, C1-C3 alkoxy, C1-C6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkyl, amino, cyano, heteroalkyl or hydroxyalkyl, wherein each of C1-C3 alkyl, C1-C6 alkyl, C1-C3 alkoxy, C₁-C₆ alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with one or more R7; R7 in each occurrence is independently halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cyano, (CH₂)_nN(R₃)₂, N(R₃)₂, C(O)N(R₃)₂, OC(O)N(R₃)₂, N(H)C(O)R₃, CH₂N(H)C(O)R₃, CH₂OC(O)N(R₃)₂, cycloalkyl or heterocyclyl; R₈ in each occurrence is independently H, F, Cl, C₁-C₃ alkyl or OCH₃; n in each occurrence is independently 1, 2 or 3; p is 0, 1 or 2; and t in each occurrence is independently 0 or 1.

119. The compound of claim 118, wherein the compound of of Formula I’a-4 has the structure of Formula I’a-4a or I’a-4b: (Formula I’a-4a), or (Formula I’a-4b).

120. The compound of claim 118, wherein the compound of of Formula I’a-5 has the structure of Formula I’a-5a or I’a-5b:

(Formula I’a-5a) or (Formula I’a-5b).

121. The compound of claim 118 having the structure:

or a pharmaceutically acceptable salt thereof.

122. The compound of claim 118 having the structure:

or a pharmaceutically

acceptable salt thereof.

123. The compound of any of claims 1, 29, 30, 38-44, 58, 66, 74-79, 96-97 and 118-120, wherein the compound has an IC50 of about 100 nM or less for inhibiting GTP by KRAS^G12D binding.

124. The compound of any of claims 118-120, wherein the compound has a KD of about 100 nM or less for inhibiting binding of GTP by KRAS^G12D protein.

125. The compound of any of claims 1, 29, 30, 38-44, 58, 66, 74-79, 96-97 and 118-120, wherein the compound has an average IC50 of about 500 nM or less for inhibiting cell growth of A427, ASPC-1, NCI-H596, HPAC, HPAF-2, LS174T, LS513, PANC 02.03, PANC 04.03, PANC 05.04, PANC-1, PANC 10.05, PL45, SK-BR-3, SNU-C2B and SU.86.86 cell lines.

126. The compound of any of claims 1, 29, 30, 38-44, 58, 66, 74-79, 96-97 and 118-120, wherein the compound has an IC50 of about 100 nM or less for inhibiting cellular pERK.

127. The compound of any of claims 1, 29, 30, 38-44, 58, 66, 74-79, 96-97 and 118-120, wherein the compound has an average IC50 of about 500 nM or less for inhibiting cell growth of cell lines AsPC-1 and AGS

128. A pharmaceutical composition comprising the compound of any one of claims 1- 127 and a pharmaceutically acceptable diluent or excipient.

129. A method of treating a disease or disorder mediated by KRAS G12D in a subject afflicted therewith, comprising administering to the subject a compound of any one of claims 1-127 or a pharmaceutical composition of claim 128.

130. The method of claim 129, wherein the disease mediated by KRAS G12D is a cancer selected from pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, gall bladder cancer, and bile duct cancer.

131. The method of claim 130, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma, and small cell lung carcinoma.

132. A method of treating a cancer in a subject afflicted therewith, comprising administering to the subject a compound of any one of claims 1-127 or a pharmaceutical composition of claim 128.

133. The method of claim 132, wherein the disease mediated by KRAS G12D is a cancer selected from pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, gall bladder cancer, and bile duct cancer.

134. The method of claim 133, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma, and small cell lung carcinoma.