WO2023205914A1

WO2023205914A1 - Tricyclic heterocyclic derivatives, compositions and uses thereof

Info

Publication number: WO2023205914A1
Application number: PCT/CN2022/000075
Authority: WO
Inventors: Zhangqi YU; Dan YAN
Original assignee: Danatlas Pharmaceuticals Co., Ltd.
Priority date: 2022-04-28
Filing date: 2022-04-28
Publication date: 2023-11-02

Abstract

The disclosure relates to tricyclic heterocyclic derivatives as shown in Formula (I), to pharmaceutical compositions comprising them, to a process for their preparation, and their use as therapeutic agents.

Description

TRICYCLIC HETEROCYCLIC DERIVATIVES, COMPOSITIONS AND USES THEREOF

TECHNICAL FIELD

The present disclosure relates to tricyclic heterocyclic derivatives as inhibitor of PARG. The present disclosure also relates to methods for preparing the tricyclic heterocyclic derivatives, pharmaceutical compositions, and their uses in the treatment of diseases related to the activity of PARG including, e.g., cancers and other diseases.

BACKGROUND

DNA damage repair (DDR) is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. But once a cancer has formed, DNA repair pathways become a double-edged sword because they promote the repair and survival of cancer cells in response to chemotherapies and radiotherapies. As a result, cancers with compromised DNA repair are susceptible to DNA damage and depend on complementary repair pathways which can be exploited therapeutically.

An aberrant DDR often can sensitize cancer cells to specific types of DNA damage, thus defective DDR can be developed into targeted cancer therapies. Targeting DNA repair deficiencies has become a proven and effective strategy in cancer treatment. For example, the success of poly (ADP-ribose) polymerase (PARP) inhibitors in treating BRCA-deficient breast, ovarian, prostate and pancreatic cancers (Audeh MW et al., 2010) .

Poly (ADP-ribosyl) ation (PARylation) is a unique posttranslational modification for maintaining genome stability through different molecular pathways, especially DNA repair (Kraus WL et al., 2015) . The binding of PARP to the break and the rapid synthesis of poly ADP-ribose (PAR) on PARP itself is one of the earliest events during single strand DNA repair. Current PARP inhibitors primarily suppress PARP1 and PARP2 enzymatic activities, which inhibits PARP1/2-dependent DNA repair. Recently, clinical resistance to PARP inhibitors has been described (Drost and Jonkers, 2014) (Barber LJ et al., 2013) (Tobalina L et al., 2021) and therefore alternative inhibitors targeting the DNA damage repair machinery are required.

PARylation is a transient posttranslational modification and is rapidly degraded by the enzyme PAR glycohydrolase (PARG) (Barkauskaite E et al., 2015) . When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form (Curtin and Szabo, 2013) . Similar to PARPs, PARG also facilitates both DNA double-strand break (DSB) and single-strand break (SSB) repair (Mortusewicz O et al., 2011) . Apart its primary role in DNA repair, PARG impacts PAR signaling in RNA splicing, transcriptional and epigenetic regulation (Ji and Tulin 2009) (Le May N et al., 2012) (Dahl M et al. 2014) (Guastafierro T et al., 2013) (Caiafa P et al., 2009) . Some evidence suggests that PARG depletion inhibits SSB repair and reduces survival of BRCA2-deficient cells (Fathers C et al., 2012) . However, other tumor mutations may give rise to deficiencies in DSB repair mechanisms (so-called "BRCA-ness" ) may also cause sensitizing tumor cells to PARG inhibition.

However, as deficiency in PARG doesn′t sensitize to all agents (e.g. gemcitabine, camptothecin) , it indicates that a specificity for PARG function with certain pathways of DDR and chemo-and radiotherapies (Fujihara H et al., 2009) (Shirai H et al., 2013) (Zhou Y et al., 2011) . In humans, PARG knock-down or depletion can sensitize lung, cervical and pancreatic cancer cells to irradiation or experimental DNA damaging agents (e.g. hydrogen peroxide, Methylmethanesulfonate) (Ame JC et al., 2009) (Nakadate Y et al., 2013) (Shirai H et al., 2013) .

Some studies suggest that PARG inhibition may provide a therapeutic advantage in PARP inhibitor resistant cells (Fisher AE et al., 2007) . Furthermore, depletion of PARG has been reported to lead to a markedly different gene expression pattern to that of PARP in breast cancer cells (Frizzell KM et al., 2009) . Ovarian cancer cells respond differently to PARP inhibitor and PARG inhibitor and sensitivity to the latter is due to persistent fork stalling and replication catastrophe (Pillay N et al., 2019) (Coulson-Gilmer C et al., 2021) .

Recent research has also shown a mechanistic differentiation between PARG and PARP inhibition. Following a genotoxic stimulus depletion of PARG, in contrast to PARP depletion, leads to a drop in NAD levels and causes to lung cancer cell death that may be as a result of energy failure (Erdelyi K et al., 2009) . PARG inhibition can also sequester NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells (Nagashima H et al., 2020) .

Cell permeable PARG inhibitors have been limited to compounds such as Tannic acid or Gallotannin or PDD00017273 which have low specificity for PARG and limited bioavailability (Sun Y et al., 2012) (Fathers C et al., 2012) (Blenn C et al., 2011) (James DI et al., 2016) .

An object of this invention is to provide cell permeable inhibitors of PARG.

SUMMARY

The present disclosure relates to, inter alia, compounds of Formula (I) ,

or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein the variables are as defined below.

In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof and at least one pharmaceutically acceptable carrier.

In another aspect, provided herein is a method of inhibiting PARG comprising:

contacting a PARG with a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof.

In another aspect, provided herein is a method of treating cancers and other diseases comprising administering to a patient a therapeutically effective amount of a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof.

The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

DETAILED DESCRIPTION

The present disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub-combination.

Before the present invention is further described, it is to be understood that the invention is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

The present disclosure provides, inter alia, a compound of formula (I) :

or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof, wherein:

X is O or NR ⁵;

Y ¹ is N or CR ⁶;

Y ² is N, or CR ⁷, and only one of Y ¹ or Y ² is N;

Y ³ is N, or CR ⁸;

n is 0, 1 or 2;

Cy ¹ is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R ⁹;

Cy ² is independently selected from C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 R ¹⁰;

R ¹, R ² and R ³ are each independently selected from H, D, CN, C (O) R ^B, C (O) NR ^CR ^D, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

or R ² and R ³ together with the carbon atom to which they are attached form a C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

or R ² and R ³ together with the carbon atom to which they are attached form -C (=O) -, or -C (=S) -;

R ⁴ is selected from H, D, halo, OH, CN, NO ₂, SF ₅, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, -O-C ₁-C ₃ alkyl, or NR ^CR ^D; wherein, the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl is optionally substituted with halogen or CN;

R ⁵ is selected from H, D, CN, OR ^B, or C ₁-C ₄ alkyl, wherein the C ₁-C ₄ alkyl is optionally substituted with at least one of D, F, Cl, CN, NH ₂, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl;

or R ¹ and R ⁵ together with the atoms to which they are attached is form a 5-7 membered partially saturated heterocycloalkyl, wherein, the 5-7 membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF ₃, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

R ⁶ and R ⁷ are each independently selected from H, D, halogen, OH, CN, NO ₂, C ₁-C ₆ alkyl, C ₁-C ₆ haloalkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) OR ^A, C (O) R ^B, C (O) NR ^CR ^D, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^B, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, NR ^CS (O) ₂R ^B, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, or NR ^CS (O) (=NR ^B) R ^B;

R ⁸ is selected from H, D, CN, halo, OH, C ₁-C ₃ alkyl, C ₁-C ₃ haloalkyl, -O-C ₁-C ₃ alkyl, -OC ₁-C ₃ haloalkyl, C ₁-C ₃ cyanoalkyl, or SF ₅;

each R ⁹ is independently selected H, D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, CN, NO ₂, N ₃, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, or NR ^CS (O) (=NR ^B) R ^B;

each R ¹⁰ is independently selected H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ cyanoalkyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, NR ^CS (O) (=NR ^B) R ^B, Cy ³, C ₁-C ₆ alkyl-Cy ³, OCy ³, or O-C ₁-C ₆ alkyl-Cy ³;

wherein two adjacent R ¹⁰, together with the atoms to which they are attached, optionally form a C ₃-C ₁₀ cycloalkyl or a 4-10 membered heterocycloalkyl, wherein, the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted by l, 2, or 3 substituents independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆-cyanoalkyl, CN, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, OP (O) OR ^eOR ^f, P (O) OR ^eOR ^f, S (O) (=NR ^b) R ^b, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

Cy ³ is independently selected from optionally substituted C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;

wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, or C ₂-C ₆ alkynyl, of any of the R ⁶, R ⁷, R ⁹ and R ¹⁰ can be unsubstituted or substituted with 1, 2, or 3 R ¹¹;

each R ¹¹ is independently selected from H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, OC ₁-C ₆ alkylOH, OC ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1, NR ^c1S (O) ₂NR ^c1R ^d1, NR ^c1S (O) (=NR ^b1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

wherein the C ₃-C ₇ cycloalkyl of R ⁹, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyeloalkyl of Cy ³, can be unsubstituted or substituted with 1, 2, 3 or 4 R ¹²;

each R ¹² is independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkylOH, C ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, NO ₂, N ₃, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, P (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1, NR ^c1 S (O) ₂NR ^c1R ^d1, NR ^c1 S (O) (=NR ^b 1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

R ^A is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C ₁-C ₄ alkyl, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, P (O) R ^eR ^f, P (O) OR ^eOR ^f, OP (O) OR ^eOR ^f, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or NR ^cS (O) (=NR ^b) R ^b;

R ^B is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) ;

R ^C and R ^D are each independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) ;

or R ^C and R ^D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, or C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, or OC ₁-C ₄ haloalkyl;

R ^a and R ^a1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy;

R ^b and R ^b1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;

R ^c and R ^d are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C ₁-4 alkyl, C ₂-4 alkenyl, C ₂-4 alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, and C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl-O-;

or R ^c and R ^d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkoxy-C ₁-C ₄ alkyl, and C ₁-C ₄ alkoxy-C ₁-C ₄ alkoxy;

R ^c1 and R ^d1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy;

or R ^c1 and R ^d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, and C ₁-4 haloalkoxy;

R ^E, R ^e and R ^e1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, (C ₁-C ₄ alkoxy) -C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀cycloalkyl, 3-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl-C ₁-C ₄ alkyl, C ₃-C ₁₀ cycloalkyl-C ₁-C ₄ alkyl, 5-10 membered heteroaryl-C ₁-C ₄ alkyl, or 4-10 membered heterocycloalkyl-C ₁-C ₄alkyl;

R ^F, R ^f and R ^f1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl.

In some embodiments, X is O or NR ⁵. In some embodiments, X is O. In other embodiments, X is NR ⁵.

In some embodiments, Y ¹ is N or CR ⁶. In some embodiments, Y ¹ is N; In other embodiments, Y ¹ is CR ⁶.

In some embodiments, Y ² is N or CR ⁶. In some embodiments, Y ² is N; In other embodiments, Y ² is CR ⁷;

In some embodiments, only one Y ¹ or Y ² is N. In some embodiments, Y ¹ is N, and Y ² is CR ⁷. In other embodiments, Y ¹ is CR ⁶, and Y ² is N. In yet other embodiments, Y ¹ is CR ⁶, and Y ² is CR ⁷.

In some embodiments, Y ³ is N or CR ⁸. In some embodiments, Y ³ is N. In other embodiments, Y ³ is CR ⁸.

In the compounds of Formula I, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, each R ¹, R ² and R ³ is independently selected from H, D, CN, C (O) R ^B, C (O) NR ^CR ^D, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In some embodiments, each R ¹, R ² and R ³ is independently selected from H, D, CN, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, OMe, OCF ₃, OEt.

In embodiments, R ¹ is C (O) R ^B. In embodiments, R ¹ is PrC (O) -. In embodiments, R ¹ is C (O) Et. In embodiments, R ¹ is C (O) Me.

In embodiments, R ¹ is C (O) NR ^CR ^D. In embodiments, R ¹ is C (O) NMe ₂.

In embodiments, R ¹ is independently selected from H, D, CN, CH ₃, CH ₂CH ₃, CH ₂F or CH ₂CH ₂F.

In embodiments, R ¹ is independently selected from CN, CH ₃, CH ₂CH ₃, CH ₂F or CH ₂CH ₂F. In embodiments, R ¹ is CH ₂F. In embodiments, R ¹ is CH ₃. In embodiments, R ¹ is CN.

In embodiments, R ² and R ³ are each independently selected from C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In embodiments, R ² and R ³ together with the carbon atom to which they are attached form a C ₃-C ₆ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In embodiments, R ² and R ³ together with the carbon atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In embodiments, R ² and R ³ together with the carbon atom to which they are attached form a C ₃-C ₆ cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In embodiments, R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl. In embodiments, R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl.

In embodiments, R ² and R ³ together with the carbon atom to which they are attached form -C (=O) -or -C (=S) -. In embodiments, R ² and R ³ together with the carbon atom to which they are attached form -C (=O) -.

In the compounds of Formula I, each R ⁴ is independently selected from H, D, halo, OH, CN, NO ₂, SF ₅, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, -OC ₁-C ₃ alkyl, or NR ^CR ^D; wherein, the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl is optionally substituted with halogen or CN.

In embodiments, each R ⁴ is independently selected from H, D, OH, CN, NO ₂, SF ₅, halo, C ₁-C ₃ alkyl optionally substituted with halogen or CN.

In embodiments, each R ⁴ is independently selected from H, D, halo, C ₁-C ₃ alkyl.

In embodiments, each R ⁴ is independently selected from H, D, halo. In embodiments, each R ⁴ is independently selected from H, D, F, or Cl.

In the compounds of Formula I, each R ⁵ is H, D, CN, OR ^B, or C ₁-C ₄ alkyl, wherein the C ₁-C ₄ alkyl is optionally substituted with at least one of D, F, Cl, CN, NH ₂, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl.

In embodiments, R ⁵ is H. In embodiments, R ⁵ is D. In embodiments, R ⁵ is CN. In embodiments, R ⁵ is OR ^B. In embodiments, R ⁵ is C ₁-C4 alkyl, wherein said that C ₁-C ₄ alkyl is optionally substituted with at least one of D, F, Cl, CN, NH ₂, OH, OMe, OCF ₃. In embodiments, R ⁵ is optionally substituted C ₃-C ₇ cycloalkyl. In embodiments, R ⁵ is optionally substituted 4-7 membered heterocycloalkyl.

In embodiments, R ¹ and R ⁵ together with the atoms to which they are attached form a 5-to 7-membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF ₃, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl.

In embodiments, R ¹ and R ⁵ together with the atoms to which they are attached form a 5-to 7-membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF ₃, oxo, OH, OMe, OCF ₃, OEt.

In the compounds of Formula I, each R ⁶ and each R ⁷ are independently selected from H, D, F, Cl, Br, OH, CN, NO ₂, C ₁-C ₆ alkyl, C ₁-C ₆ haloalkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) OR ^A, C (O) R ^B, C (O) NR ^CR ^D, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^B, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, NR ^CS (O) ₂R ^B, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, or NR ^CS (O) (=NR ^B) R ^B.

In embodiments, each R ⁶ is independently H, D. F, Cl, OH, CN, NO ₂, or SF ₅. In some embodiments, R ⁶ is F. In some embodiments, R ⁶ is D. In some embodiments, R ⁶ is H. In embodiments, R ⁶ is OR ^A. In embodiments, R ⁶ is SR ^A. In embodiments, R ⁶ is C ₁-C ₆ alkyl, for example, -CH ₃. In embodiments, R ⁶ is C ₁-C ₆ haloalkyl, for example, -CF ₃. In embodiments, R ⁶ is C ₂-C ₆ alkenyl. In embodiments, R ⁶ is C ₂-C ₆ alkynyl. In embodiments, R ⁶ is B (OR ^C) (OR ^D) , for example, B (OH) ₂. In embodiments, R ⁶ is NHOR ^A. In embodiments, R ⁶ is NR ^CR ^D.

In embodiments, each R ⁷ is independently H, D. F, Cl, OH, CN, NO ₂, or SF ₅. In some embodiments, R ⁷ is F. In some embodiments, R ⁷ is D. In some embodiments, R ⁷ is H. In embodiments, R ⁷ is OR ^A. In embodiments, R ⁷ is SR ^A. In embodiments, R ⁷ is C ₁-C ₆ alkyl, for example, -CH ₃. In some embodiments, R ⁷ is C ₁-C ₆ haloalkyl, for example, -CF ₃. In embodiments, R ⁷ is C ₂-C ₆ alkenyl. In embodiments, R ⁷ is C ₂-C ₆ alkynyl. In some embodiments, R ⁷ is B (OR ^C) (OR ^D) , for example, B (OH) ₂. In some embodiments, R ⁷ is NHOR ^A. In some embodiments, R ⁷ is NR ^CR ^D.

In the compounds of Formula I, each R ⁸ is selected from H, D, CN, halo, OH, C ₁-C ₆ alkyl, C ₁-C ₆ haloalkyl -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl, or SF ₅.

In other embodiments, R ⁸ is selected from H, D, F, Cl, OH, CN, CF ₃, OMe, OCF ₃, or SF ₅.

In other embodiments, R ⁸ is selected from C ₁-C ₆ alkyl, C ₁-C ₆ haloalkyl -O-C ₁-C ₆ alkyl, or -OC ₁-C ₆ haloalkyl.

In some embodiments, R ⁸ is H. In some embodiments, R ⁸ is D. In some embodiments, R ⁸ is F. In some embodiments, R ⁸ is Cl. In some embodiments, R ⁸ is OH. In some embodiments, R ⁸ is CN. In some embodiments, R ⁸ is CF ₃. In some embodiments, R ⁸ is OMe. In some embodiments, R ⁸ is OCF ₃. In some embodiments, R ⁸ is SF ₅.

In some embodiments, Cy ¹ is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R ⁹;

In some embodiments, Cy ¹ is 6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹,

In some embodiments, Cy ¹ is 5 membered heteroaryl optionally substituted by 1, 2, or 3 R ⁹, wherein, the 5 membered heteroaryl is independently selected from:

In some embodiments, Cy ¹ is 5 membered heteroaryl optionally substituted by 1 or 2 R ⁹, wherein, the 5 membered heteroaryl is independently selected from:

In some embodiments, Cy ¹ is 5 membered heteroaryl optionally substituted by 1 or 2 R ⁹, wherein, the 5 membered heteroaryl is

In some embodiments, each R ⁹ in Formula I is independently H, D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, CN, NO ₂, N ₃, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, NR ^CS (O) (=NR ^B) R ^B.

In some embodiments, R ⁹ is independently H. In some embodiments, R ⁹ is independently D. In some embodiments, R ⁹ is independently halo. In some embodiments, R ⁹ is independently CN. In some embodiments, R ⁹ is independently NO ₂. In some embodiments, R ⁹ is independently N ₃. In some embodiments, R ⁹ is independently OR ^A. In some embodiments, R ⁹ is independently SR ^A. In some embodiments, R ⁹ is independently SF ₅. In some embodiments, R ⁹ is independently NHOR ^A. In some embodiments, R ⁹ is independently C (O) R ^B. In some embodiments, R ⁹ is independently C (O) NR ^CR ^D. In some embodiments, R ⁹ is independently C (O) OR ^A.

In other embodiments, each R ⁹ is independently OC (O) NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^CC (O) R ^D. In other embodiments, each R ⁹ is independently NR ^CC (O) NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^CC (O) OR ^A. In other embodiments, each R ⁹ is independently B (OR ^C) (OR ^D) . In other embodiments, each R ⁹ is independently C (=NR ^C) NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^DC (=NR ^C) NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^DC (=NR ^C) R ^B. In other embodiments, each R ⁹ is independently P (O) R ^ER ^F. In other embodiments, each R ⁹ is independently P (O) OR ^EOR ^F. In other embodiments, each R ⁹ is independently OP (O) OR ^EOR ^F. In other embodiments, each R ⁹ is independently S (O) (=NR ^B) R ^B. In other embodiments, each R ⁹ is independently S (O) R ^B. In other embodiments, each R ⁹ is independently S (O) NR ^CR ^D. In other embodiments, each R ⁹ is independently S (O) ₂R ^B. In other embodiments, each R ⁹ is independently NR ^CS (O) ₂R ^B. In other embodiments, each R ⁹ is independently S (O) ₂NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^CS (O) ₂NR ^CR ^D. In other embodiments, each R ⁹ is independently NR ^CS (O) (=NR ^B) R ^B.

In yet other embodiments, each R ⁹ is independently C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl. In some embodiments, each R ⁹ is C ₁-C ₆ alkyl. In other embodiments, each R ⁹ is C ₂-C ₆ alkenyl. In yet other embodiments, each R ⁹ is independently C ₂-C ₆ alkynyl. In yet other embodiments, each R ⁹ is independently C ₁-C ₆ haloalkyl.

In yet other embodiments, each R ⁹ is independently optionally substituted C ₃-C ₇ cycloalkyl.

In some embodiments, Cy ² is independently selected from C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.

In some embodiments, Cy ² is C ₆-C ₁₀ aryl optionally substituted by 1, 2, or 3 R ¹⁰.

In some embodiments, Cy ² is 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.

In some embodiments, Cy ² is C ₃-C ₁₀ cycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.

In some embodiments, Cy ² is 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.

In some embodiments, each R ¹⁰ in Formula I is independently selected from H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ cyanoalkyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, C (=NR ^C) NR ^CR ^D, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, NR ^cS (O) (=NR ^B) R ^B, Cy ³, C ₁-C ₆ alkyl-Cy ³, OCy ³, O-C ₁-C ₆ alkyl-Cy ³.

In some embodiments, R ¹⁰ is independently H. In some embodiments, R ¹⁰ is independently D. In some embodiments, R ¹⁰ is independently halo. In some embodiments, R ¹⁰ is independently CN. In some embodiments, R ¹⁰ is independently NO ₂. In some embodiments, R ¹⁰ is independently N ₃. In some embodiments, R10 is independently OR ^A. In some embodiments, R ¹⁰ is independently SR ^A. In some embodiments, R ¹⁰ is independently SF ₅. In some embodiments, R ¹⁰ is independently NHOR ^A. In some embodiments, R ¹⁰ is independently C (O) R ^B. In some embodiments, R ¹⁰ is independently C (O) NR ^CR ^D. In some embodiments, R ¹⁰ is independently C (O) OR ^A. In some embodiments, R ¹⁰ is independently C (=NR ^C) NR ^CR ^D.

In other embodiments, each R ¹⁰ is independently OC (O) R ^B. In other embodiments, each R ¹⁰ is independently OC (O) NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^CC (O) R ^D. In other embodiments, each R ¹⁰ is independently NR ^CC (O) NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^CC (O) OR ^A. In other embodiments, each R ¹⁰ is independently B (OR ^C) (OR ^D) . In other embodiments, each R ¹⁰ is independently NR ^DC (=NR ^C) NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^DC (=NR ^C) R ^B. In other embodiments, each R ¹⁰ is independently P (O) R ^ER ^F. In other embodiments, each R ¹⁰ is independently P (O) OR ^EOR ^F. In other embodiments, each R ¹⁰ is independently OP (O) OR ^EOR ^F. In other embodiments, each R ¹⁰ is independently S (O) (=NR ^B) R ^B. In other embodiments, each R ¹⁰ is independently S (O) R ^B. In other embodiments, each R ¹⁰ is independently S (O) NR ^CR ^D. In other embodiments, each R ¹⁰ is independently S (O) ₂R ^B. In other embodiments, each R ¹⁰ is independently NR ^CS (O) ₂R ^B. In other embodiments, each R ¹⁰ is independently S (O) ₂NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^CS (O) ₂NR ^CR ^D. In other embodiments, each R ¹⁰ is independently NR ^CS (O) (=NR ^B) R ^B.

In yet other embodiments, each R ¹⁰ is independently C ₁-C ₆ alkyl. In yet other embodiments, each R ¹⁰ is independently C ₂-C ₆ alkenyl. In yet other embodiments, each R ¹⁰ is independently C ₂-C ₆ alkynyl. In yet other embodiments, each R ¹⁰ is independently C ₁-C ₆ haloalkyl. In yet other embodiments, each R ¹⁰ is independently C ₁-C ₆ cyanoalkyl. In yet other embodiments, each R ¹⁰ is independently Cy ³. In yet other embodiments, each R ¹⁰ is independently C ₁-C ₆ alkyl-Cy ³. In yet other embodiments, each R ¹⁰ is independently OCy ³. In yet other embodiments, each R ¹⁰ is independently O-C ₁-C ₆ alkyl-Cy ³.

In some embodiments, two adjacent R ¹⁰ together with the atoms to which they are attached form a C ₃-C ₁₀ membered cycloalkyl or a 4-10 membered heterocycloalkyl, wherein, the C ₃-C ₁₀ membered cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆-cyanoalkyl, CN, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, OP (O) OR ^eOR ^f, P (O) OR ^eOR ^f, S (O) (=NR ^b) R ^b, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments, two adjacent R ¹⁰ together with the atoms to which they are attached form a C ₃-C ₁₀ membered cycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆-cyanoalkyl, CN, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, OP (O) OR ^eOR ^f, P (O) OR ^eOR ^f, S (O) (=NR ^b) R ^b, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments, two adjacent R ¹⁰ together with the atoms to which they are attached form a 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆-cyanoalkyl, CN, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, OP (O) OR ^eOR ^f, P (O) OR ^eOR ^f, S (O) (=NR ^b) R ^b, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments, each Cy ³ is independently selected from optionally substituted C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl. In some embodiments, Cy ³ is optionally substituted C ₆-C ₁₀ aryl. In some embodiments, Cy ³ is optionally substituted phenyl. In some embodiments, Cy ³ is optionally substituted 5-10 membered heteroaryl. In some embodiments, Cy ³ is optionally substituted pyrimidinyl. In some embodiments, Cy ³ is optionally substituted pyridazinyl. In some embodiments, Cy ³ is optionally substituted pyrazinyl. In other embodiments, Cy ³ is optionally substituted pyrazolyl.

In other embodiments, Cy ³ is optionally substituted 3-10 membered cycloalkyl. In other embodiments, Cy ³ is optionally substituted cyclohexanyl. In other embodiments, Cy ³ is optionally substituted cyclopentyl. In other embodiments, Cy ³ is optionally substituted cyclobutyl. In other embodiments, Cy ³ is optionally substituted cyclopropyl.

In other embodiments, Cy ³ is optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, Cy ³ is 4-methylpiperazin-1-yl.

In other embodiments, each R ¹¹ is independently selected from H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkylOH, C ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1 S (O) ₂R ^b1, S (O) ₂NR ^c1 R ^d1, NR ^c1 S (O) ₂NR ^c1R ^d1, NR ^c1S (O) (=NR ^b1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl. In some embodiments, each R ¹¹ is independently selected from H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C (O) R ^b1, C (O) NR ^c1R ^d1, S (O) ₂R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments, each R ¹² is independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkylOH, C ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, NO ₂, N ₃, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, P (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1 R ^d1, NR ^c1 S (O) ₂NR ^c1R ^d1, NR ^c1 S (O) (=NR ^b 1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In some embodiments, each R ¹² is independently selected from D, halo, CN, NO ₂, N ₃, OR ^a1, SR ^a1, SF ₅, or NHOR ^a1.

In some embodiments, each R ¹² is independently selected from C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, P (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1, NR ^c1S (O) ₂NR ^c1R ^d1, or NR ^c1S (O) (=NR ^b1) R ^b1.

In other embodiments, each R ¹² is independently selected from C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkylOH, C ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.

In compounds of Formula I, R ^A is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C ₁-C ₄ alkyl, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, P (O) R ^eR ^f, P (O) OR ^eOR ^f, OP (O) OR ^eOR ^f, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b.

In some embodiments, R ^A is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl or C ₂-C ₄ alkynyl, wherein the C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl or C ₂-C ₄ alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C ₁-C ₄ alkyl, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, P (O) R ^eR ^f, P (O) OR ^eOR ^f, OP (O) OR ^eOR ^f, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b.

In other embodiments, R ^A is independently selected from C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl wherein the C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C ₁-C ₄ alkyl, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, P (O) R ^eR ^f, P (O) OR ^eOR ^f, OP (O) OR ^eOR ^f, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b.

In compounds of Formula I, R ^B is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^B is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl or C ₂-C ₆ alkynyl, wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, or C ₂-C ₆ alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^B is C ₂-C ₆ alkynyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^B is C ₂-C ₆ alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^B is C ₁-C ₆ alkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) . In some embodiments, R ^B is C ₁-C ₆ alkyl. In some embodiments, R ^B is isopropyl. In some embodiments, R ^B is isobutyl. In some embodiments, R ^B is tert-butyl.

In some embodiments, R ^B is C ₃-C ₁₀ cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) . In some embodiments, R ^B is C ₃-C ₁₀ cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl. In some embodiments, R ^B is isopropyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl. In some embodiments, R ^B is cyclobutyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl. In some embodiments, R ^B is cycylopentyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl. In some embodiments, R ^B is cycylohexanyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl.

In other embodiments, R ^B is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) . In some embodiments, R ^B is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In other embodiments, R ^B is C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^C and R ^D are each independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^C is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In some embodiments, R ^D is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) .

In other embodiments, R ^C and R ^D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, or OC ₁-C ₄ haloalkyl.

In some embodiments, each R ^E is independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, (C ₁-C ₄ alkoxy) -C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl-C ₁-C ₄ alkyl, C ₃-C ₁₀ cycloalkyl-C ₁-C ₄ alkyl, 5-10 membered heteroaryl-C ₁-C ₄ alkyl, or 4-10 membered heterocycloalkyl-C ₁-C ₄alkyl.

In some embodiments, each R ^F is independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl.

In some embodiments, each R ^a is independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy.

In some embodiments, each R ^b is independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.

In some embodiments, R ^c and R ^d are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, and C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl-O-.

In some embodiments, R ^c and R ^d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkoxy-C ₁-C ₄ alkyl, and C ₁-C ₄ alkoxy-C ₁-C ₄ alkoxy.

In some embodiments, each R ^e is each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, (C ₁-C ₄ alkoxy) -C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl-C ₁-C ₄ alkyl, C ₃-C ₁₀ cycloalkyl-C ₁-C ₄ alkyl, 5-10 membered heteroaryl-C ₁-C ₄ alkyl, or 4-10 membered heterocycloalkyl-C ₁-C ₄alkyl.

In some embodiments, each R ^a1 is independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy.

In some embodiments, each R ^b1 is independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.

In some embodiments, R ^c1 and R ^d1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy.

In some embodiments, R ^c1 and R ^d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, and C _1-4 haloalkoxy.

In some embodiments, each R ^e1 is each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, (C ₁-C ₄ alkoxy) -C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl-C ₁-C ₄ alkyl, C ₃-C ₁₀ cycloalkyl-C ₁-C ₄ alkyl, 5-10 membered heteroaryl-C ₁-C ₄ alkyl, or 4-10 membered heterocycloalkyl-C ₁-C ₄alkyl.

In some embodiments, each R ^f1 is independently selected from H, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl.

In some embodiments, the compounds of Formula (I) are the pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (I) are stereoisomers. In some embodiments, the compounds of Formula (I) are solvates. In some embodiments, the compounds of Formula (I) are N-oxides of the compounds of Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (II) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁴, Cy ¹, Cy ², X, Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IIa) and (IIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁴, R ⁵, Cy ¹, Cy ², Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IIIa) and (IIIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, Cy ¹, Cy ², Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IV) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁸, X, Cy ¹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments, X in Formula (IV) is independently NR ⁵. In some embodiments, X in Formula (IV) is independently O.

In the compounds of Formula (IV) , each R ⁸ is selected from H, D, F, Cl, OH, CN, CF ₃, OMe, OCF ₃, or SF ₅. In some embodiments, R ⁸ is H. In some embodiments, R ⁸ is D. In some embodiments, R ⁸ is F. In some embodiments, R ⁸ is Cl. In some embodiments, R ⁸ is OH. In some embodiments, R ⁸ is CN. In some embodiments, R ⁸ is CF ₃. In some embodiments, R ⁸ is OMe. In some embodiments, R ⁸ is OCF ₃. In some embodiments, R ⁸ is SF ₅.

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IVa) or (IVb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, R ⁸, Cy ¹, Cy ², Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments, Cy ¹ in Formula (IVa) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R ⁹. In some embodiments, Cy ¹ in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy ¹ in independently optionally substituted 5 membered heteroaryl.

In some embodiments, Cy ¹ in Formula (IVb) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R ⁹. In some embodiments, Cy ¹ in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy ¹ in independently optionally substituted 5 membered heteroaryl.

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (Va) , (Vb) , or (Vc) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁶, R ⁷, R ⁸, Cy ¹, and Cy ²are defined with respect to Formula (I) .

In some embodiments, Cy ¹ in Formula (Va) , (Vb) , or (Vc) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R ⁹. In some embodiments, Cy ¹ in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy ¹ in independently optionally substituted 5 membered heteroaryl.

In some embodiments, Cy ¹ is 6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹.

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VI) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof;

wherein, Cy ¹ is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹;

each R ¹, R ², R ³, R ⁹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIa) or (VIb) :

wherein, Cy ¹ is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹; each R ¹, R ², R ³, R ⁵, R ⁹, Cy ², Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VII) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁸, R ⁹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments of Formula (VII) , X is NR ⁵. In some embodiments of Formula (VII) , X is O.

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIa) or (VIIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, R ⁸, R ⁹, Cy ², Y ¹, and Y ² are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , (VIIIb) , or (VIIIc) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁶, R ⁷, R ⁸, R ⁹, and Cy ² are defined with respect to Formula (I) .

In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IXa) , (IXb) , or (IXc) :

Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I.

In some embodiments, the compound of Formula (I) is:

4- (4- (Cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-pivaloylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclobutane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

(R) -N- (1-cyanocyclopropyl) -4- (4- (cyclobutanecarbonyl) -3-methylpiperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N, N-dimethylpiperazine-1-carboxamide;

4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-carboxamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (morpholine-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-methylpiperazine-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-isobutyrylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-fluorobenzoyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-picolinoylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

Isopropyl 4- (7- (N- (1-cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) piperazine-1-carboxylate;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (thiazol-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridazin-3-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-oxa-7-azaspiro [3.5] nonan-7-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

(R) -N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methylmorpholino) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

or a pharmaceutically acceptable salt thereof.

It will be apparent that the compounds of Formula I, including all subgenera described herein, may have multiple stereogenic centers. As a result, there exist multiple stereoisomers (enantiomers and diastereomers) of the compounds of Formula I (and subgenera described herein) . The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein) , as well as mixtures of said stereoisomers.

Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the disclosure.

Isotopic variants of the compounds of Formula I (including all subgenera described herein) are also contemplated by the present disclosure.

The present disclosure further provides compounds described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. The present disclosure further provides uses of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

The present disclosure further provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The PARG inhibitors of the present disclosure may be useful in the treatment of various types of cancer, including but not limited to breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancers.

Routs of administration for the compounds in the present disclosure include, but not limited to oral, injection, topical and inhalation.

The compounds of the present disclosure may be used as single agent or combined with other treatments. Such treatment may include one or more of the following categories of cancer therapies: such as surgery, chemotherapies, radiation therapies, targeted therapy (for example kinase inhibitors, growth factor inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK 1 inhibitor, WEE 1 inhibitor, CDK 1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, Polθ inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PKMYT1 inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.

Definitions

Unless other indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.

As used herein, the singular forms “a” , “an” , and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely” , “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

At various places in the present specification, variables defining divalent linking groups are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR (CR′R") -includes both -NR (CR′R") -and - (CR′R") NR-and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" , unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra-or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term "Cn-Cm" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. For example, the term “C ₁-C ₆ alkyl” is specifically intended to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl. “C ₀ alkyl” refers to a covalent bond.

It is further intended that the compounds of the invention are stable. As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.

As used herein, unless otherwise indicated, the term “alkyl” , by itself or as part of another substituent, is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. Similary, C _1-8, as in C _1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement. Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) , and the like.

As used herein, unless otherwise indicated, “alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

As used herein, unless otherwise indicated, “alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

As used herein, unless otherwise indicated, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include, but are not limited to, CF ₃, C ₂F ₅, CHF ₂, CH ₂F, CCl ₃, CHCl ₂, C ₂Cl ₅, and the like.

As used herein, unless otherwise indicated, “aryl” refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 14 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. Example aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.

As used herein, unless otherwise indicated, “cycloalkyl” refers to an unsubstituted or substituted non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., a bridged bicycloalkyl group) . In some embodiments, cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds. Cycloalkyl groups can be optionally substituted by oxo or sulfido (e.g., -C (O) -or -C (S) -) . Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent. In some embodiments, the cycloalkyl is a C ₃-C ₇ monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C ₄-C ₁₀ spirocycle or bridged cycloalkyl. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatfienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.2] octanyl, spiro [3.3] heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, cycloalkyl are cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 12 carbon atoms ( “C ₃-C ₁₂” ) , preferably from 3 to 6 carbon atoms ( “C ₃-C ₆” ) . Examples of cycloalkyl groups include, for example, cyclopropyl (C ₃; 3-membered) , cyclobutyl (C ₄; 4-membered) , cyclopropylmethyl (C ₄) , cyclopentyl (C ₅) , cyclohexyl (C ₆) , 1-methylcyclopropyl (C ₄) , 2-methylcyclopentyl (C ₄) , adamantanyl (C ₁₀) , and the like.

The term “spirocycloalkyl” when used alone or as part of a substituent group refers to a non-aromatic hydrocarbon group containing two cycloalkyl rings, and wherein the two cycloalyl rings share a single carbon atom in common.

As used herein, unless otherwise indicated, a “heteroaryl” group refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member such as boron, sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety. Examples ofheteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, unless otherwise indicated, "heterocycloalkyl" refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring) , wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C (O) , S (O) , C (S) , or S (O) ₂, etc. ) . Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S and B) . The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members.

Example heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, 1, 3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1, 2, 3, 4- tetrahydroisoquinoline, azabicyclo [3.1.0] hexanyl, diazabicyclo [3.1.0] hexanyl, oxabicyclo [2.1.1] hexanyl, azabicyclo [2.2.1] heptanyl, diazabicyclo [2.2.1] heptanyl, azabicyclo [3.1.1] heptanyl, diazabicyclo [3.1.1] heptanyl, azabicyclo [3.2.1] octanyl, diazabicyclo [3.2.1] octanyl, oxabicyclo [2.2.2] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [2.2.2] octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro [3.3] heptanyl, diazaspiro [3.3] heptanyl, oxa-azaspiro [3.3] heptanyl, azaspiro [3.4] octanyl, diazaspiro [3.4] octanyl, oxa-azaspiro [3.4] octanyl, oxa-azaspiro [3.5] nonanyl, azaspiro [2.5] octanyl, diazaspiro [2.5] octanyl, azaspiro [4.4] nonanyl, diazaspiro [4.4] nonanyl, oxa-azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, diazaspiro [4.5] decanyl, diazaspiro [4.4] nonanyl, oxa-diazaspiro [4.4] nonanyl, octahydropyrrolo [3, 4-c] pyrrolyl and the like.

In some embodiments, heterocycloalkyl refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.

In some embodiments, the term “spiroheterocycloalkyl” when used alone or as part of a substituent group refers to a non-aromatic group containing two rings, at least one of which is a heterocycloalkyl ring, and wherein the two rings share a single carbon atom in common.

As used herein, unless otherwise indicated, “arylcycloalkyl” refers to cycloalkyl group substituted by an aryl group.

As used herein, unless otherwise indicated, “arylheterocycloalkyl” refers to a heterocycloalkyl group substituted by an aryl group.

As used herein, unless otherwise indicated, “arylheteroaryl” refers to a heteroaryl group substituted by an aryl group.

As used herein, unless otherwise indicated, “biaryl” refers to an aryl group substituted by another aryl group.

As used herein, unless otherwise indicated, “heteroarylcycloalkyl” refers to a cycloalkyl group substituted by a heteroaryl group.

As used herein, unless otherwise indicated, “heteroarylheterocycloalkyl” refers to a heterocycloalkyl group substituted by a heteroaryl group.

As used herein, unless otherwise indicated, “heteroarylaryl” refers to an aryl group substituted by a heteroaryl group.

As used herein, unless otherwise indicated, “biheteroaryl” refers to a heteroaryl group substituted by another heteroaryl group.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

As used herein, unless otherwise indicated, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , t-butoxy, and the like.

As used herein, unless otherwise indicated, “hydroxylalkyl” refers to an alkyl group substituted by OH.

As used herein, unless otherwise indicated, “cyanoalkyl” refers to an alkyl group substituted by CN.

As used herein, unless otherwise indicated, “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group.

As used herein, unless otherwise indicated, “alkoxyalkoxy” refers to an alkoxy group substituted by alkoxy.

As used herein, unless otherwise indicated, “haloalkoxy” refers to an -O- (haloalkyl) group.

As used herein, unless otherwise indicated, “arylalkyl” refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.

As used herein, unless otherwise indicated, “heteroarylalkyl” refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.

As used herein, unless otherwise indicated, “oxo” refers to an oxygen substituent that is connected by a double bond (i.e., =O) .

As used herein, unless otherwise indicated, the phrase "optionally substituted" means unsubstituted or substituted.

As used herein, unless otherwise indicated, the term “substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s) . Typical substituents include, but are not limited to, D, halo, oxo, C ₁-C _-6 alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkyl-NR ^c1R ^d1, - (CH ₂CH ₂O) _oC ₁-C ₆alkyl wherein o is 1-10; C _2-6 alkenyl-NR ^c1R ^d1, C _2-6 alkynyl-NR ^c1R ^d1, OC _2-6 alkyl-NR ^c1R ^d1, CN, NO ₂, N ₃, OR ^a1, SR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, -CH ₂C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, -NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, C (=NR ^g1) NR ^c1R ^d1, NR ^c1C (=NR ^g1) NR ^c1R ^d1, P (R ^f1) ₂, P (OR ^e1) ₂, P (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, S (O) R ^b1, -SO (=NR ^b1) ; S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1; aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted with D, halo, oxo, C ₁-C-6 alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkyl-NR ^c1R ^d1, C _2-6 alkenyl-NR ^c1R ^d1, C _2-6 alkynyl-NR ^c1R ^d1, OC _2-6 alkyl-NR ^c1R ^d1, CN, NO ₂, N ₃, OR ^a1, SR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, -CH ₂C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, -NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, C (=NR ^g1) NR ^c1R ^d1, NR ^c1C (=NR ^g1) NR ^c1R ^d1, P (R ^f1) ₂, P (OR ^e1) ₂, P (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, S (O) R ^b1, S (O) NR ^c1R ^dd1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine -imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

In some cases, the compounds of the present disclosure may exist as rotational isomers. Descriptions of a compound of the invention that do not indicate a particular rotational isomer are intended to encompass any individual rotational isomers, as well as mixtures of rotational isomers in any proportion. Depiction of a particular rotational isomer is meant to refer to the depicted rotational isomer, substantially free of other rotational isomers.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 ^th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) , each of which is incorporated herein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, 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.

A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.

“Subject” includes humans. The terms “human, ” “patient, ” and “subject” are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

“Compounds of the present disclosure, ” and equivalent expressions, are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits.

As used herein, the term “isotopic variant” refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance. For example, an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( ²H or D) , carbon-13 ( ¹³C) , nitrogen-15 ( ¹⁵N) , or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N, and that the presence and placement of such atoms may be determined within the skill of the art.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers. ” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers, ” for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers at each asymmetric center, or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof. Where one chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. Where more than one chiral center exists in a structure, but no specific stereochemistry is shown for the centers, all enantiomers and diastereomers, individually or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

Pharmaceutical Compositions

Also provided are pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof, and a pharmaceutically acceptable carrier.

The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) , for injection use (for example as aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles) , for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions) , for administration by inhalation (for example as a finely divided powder or a liquid aerosol) , for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing) .

The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

An effective amount of a compound of Formula (I) or a pharmaceutically salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0. 1 mg to 1000 mg of Formula (I) or a pharmaceutically salt thereof with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.

Methods of Administration

The compounds of Formula (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) .

Routes of administration include, but are not limited to, oral (e.g., by ingestion) ; buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc. ) ; transmucosal (including, e.g., by a patch, plaster, etc. ) ; intranasal (e.g., by nasal spray) ; ocular (e.g., by eye drops) ; pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose) ; rectal (e.g., by suppository or enema) ; vaginal (e.g., by pessary) ; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subeutieular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

Methods of Use

The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

As used herein, the term "IC ₅₀" refers to the halfmaximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50%IC, or IC ₅₀) .

In some embodiments, the subject methods utilize a PARG inhibitor with an IC ₅₀ value of about or less than a predetermined value, as ascertained in an in vitro assay. In some embodiments, the PARG inhibitor inhibits PARG with an IC ₅₀ value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 lμM or less, 1. 1 μM or less, 1. 2 μM or less, 1. 3 μM or less, 1. 4 μM or less, 1. 5 μM or less, 1. 6 μM or less, 1. 7 μM or less, 1. 8 μM or less, 1. 9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM, or less, (or a number in the range defined by and including any two numbers above) .

The subject methods are useful for treating a disease condition associated with PARG. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PARG can be an intended disease condition.

Different disease conditions associated with PARG have been reported. PARG has been implicated, for example, auto-immune diseases, neurodegeneration (such as Parkinson’s disease) , cardiovascular disease (such as ischaemia stroke and myocardial infarction) , inflammatory diseases (such as septic shock) , diabetes, and cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.

Non-limiting examples of such conditions include but are not limited to breast cancer, Invasive duct. al carcinoma, Invasive lobular carcinoma, Paget′s disease of the breast, Hereditary breast-ovarian cancer syndrome, Medullary breast cancer, Mucinous breast cancer, Inflammatory breast cancer, Ovarian Cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Prostate cancer, Acinar adenocarcinoma of prostate, Prostatic ductal adenocarcinoma, Prostate sarcoma, Small cell prostate cancer, Squamous cell prostate cancer, Pancreatic Cancer, Exocrine pancreatic cancer, Neuroendocrine pancreatic cancer, Uterine cancer, Uterine sarcoma, Uterine corpus sarcoma, Cervical Cancer, Squamous cell cervical cancer, Cervical adenocarcinoma, Cervical adenosquamous carcinoma, Small cell cervical cancer, Cervical mucinous tumor, Clear cell cervical cancer, Cervical lymphoma, Cervical sarcoma, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Lung cancer, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Brain Stem Glioma, Brain cancer, Cerebellar Astrocytoma, Cerebral Astrocytoma, Head and Neck Cancer, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Ganglioglioma, Ganglioneuroma, Paraganglioma, Primitive neuroectodermal tumor, Supratentorial Primitive Neuroectodermal Tumor, Visual Pathway Glioma, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Esthesioneuroblastoma, Extrahepatic Bile Duct Cancer, Bellini duct carcinoma, Cholangiocarcinoma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblasts leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute myelogenous leukemia, Acute promyelocytic leukemia, Adult T-cell leukemia, Aggressive NK-cell leukemia, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Erythroleukemia, Hairy Cell Leukemia, Leukemia, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Mast cell leukemia, Monocytic leukemia, Myeloid leukemia, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell prolymphocytic leukemia, AIDS-related lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell leukemia, B-cell lymphoma, Cutaneous T-cell lymphoma, Diffuse large B cell lymphoma, Enteropathy-associated T-cell lymphoma, Follicular lymphoma, Hepatosplenic T-cell lymphoma, Hodgkin Lymphoma, Hodgkin′s lymphoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma, MALT lymphoma, Mantle cell lymphoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Precursor T-lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Small cell lymphoma, T-cell lymphoma, Terminal lymphatic cancer.

In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, auto-immune diseases, neurodegeneration (such as Parkinson’s disease) , cardiovascular disease (such as ischaemia stroke and myocardial infarction) , inflammatory diseases (such as septic shock) , diabetes, and cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.

In other embodiments, said method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for treating a disease selected from leukemia such as acute myeloid leukemia (AML) , acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML) , mastocytosis, chronic lymphocytic leukemia (CLL) , multiple myeloma (MM) , myelodysplastic syndrome (MDS) or epidermoid cancer.

Compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with a medical therapy. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes) .

In other aspects, compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with one or more other agents.

In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with agonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with antagonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.

Combination Therapies

The compounds of the present invention may be used as a single agent or combined with other treatments. Such treatment may include one or more of the following categories of cancer therapies: such as surgery, chemotherapies, radiation therapies, targeted therapy (for example growth factor inhibitors, kinase inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, WEE1 inhibitor, CDK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, Polθ inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PKMYT1 inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.

For treating cancers and other proliferative diseases, the compounds of the invention can be used in combination with a medical therapy such as surgery, radiotherapy or chemotherapy. Examples of radiotherapies include gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable chemotherapeutic agents include one or more of the following categories of anti-tumor agents: other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas) ; antimetabolites (for example gemcitabine and antifolates such as fluoropyrimi dines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea) ; antitumor antibiotics (for example anthracyclines like bleomycin, doxorubicin, daunomycin, epimbicin, idarubicin, mitomycin-C, dactinomycin and mithramycin) ; antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and antineoplastic drugs like taxol and taxotere and polokinase inhibitors) ; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin) ; cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene) , antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate) , LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin) , progestogens (for example megestrol acetate) , aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase (for example finasteride) ; anti-invasion agents such as c- Src kinase family inhibitors (for example AZD0530, dasatinib and bosutinib) , and metalloproteinase inhibitors (for example marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase) .

For treating cancer and other proliferative diseases, the compounds of the invention can be used in combination with targeted therapies, including inhibitors of growth factor function (for example the anti-erbB2 antibody trastuzumab, the anti-EGFR antibody panitumumab, the anti-erbB antibody cetuximab and any growth factor or growth factor receptor antibodies disclosed by Stem et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, ppl 1-29) ; such inhibitors also include tyrosine kinase inhibitors (for example inhibitors of the EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and Cl 1033) , erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib; inhibitors of serine/threonine kinases (for example Ras/Raf inhibitors such as sorafenib, tipifamib and lonafamib) ; inhibitors of cell proliferation through MEK and/or AKT kinases; c-kit inhibitors; abl kinase inhibitors; PI3 kinase inhibitors; Fit3 kinase inhibitors, CSF-IR kinase inhibitors; aurora kinase inhibitors (for example AZDl152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4/6 inhibitors; antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib, AZD2171 compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO97/32856 and WO98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avβ3 function and angiostatin) ) ; vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434 and WO02/08213; an endothelin receptor antagonist, for example zibotentan or atrasentan; DNA damage repair modulator such as DNA-PK inhibitor (for example LY294002, NU7026, NU7441, IC86621, IC87102, IC87361, OK-1035, SU11752, vanillin, NK314, IC486241, BVAN08, M3814, AZD7648, VX-984, Doxycycline) , ATM inhibitor (for example caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403) , ATR inhibitor (for example schisandrin B, NU6027, NVP-BEZ235, VE-821, VE-822, AZ20, Elimusertib, RP-3500 and AZD6738) , CHK1 inhibitor (for example LY2606368, PF-00477736, SRA737, SCH900776, MK8776, CCT244747 and AZD6738) , WEE1 inhibitor (for example AZD1775, ZN-c3 and PD0166285 ) , CDK1 (for example AZD5438, RO-3306, JNJ-7706621 and MER162) , DNA LIG4 inhibitor (for example SCR7) , HIF-1 inhibitor (for example LW6 and PX-478) , HDAC inhibitor (for example short-chain fatty acids, benzamides, hydroxamic acids, and cyclic tetrapeptides, suberoylanilide hydroxamic acid (SAHA) , trichostatin A) , RAD51 inhibitor (for example CYT-0851, SCR-6992, SAT-93/101, CAM833, JKYN-1 (IBR120-series, B02-iso) ) , Polθinhibitor (for example ART558, and compounds disclosed in International Patent Application WO2020/243459, WO2020/160213, WO2021/028644, WO2020/160134, WO2022/026565 ) , WRN (for example NCGC00029283) , PKMYT1 (for example RP6306) ; antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent′s freezing temperature to the solvent′s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007) ; Robertson, Protecting Group Chemistry, (Oxford University Press, 2000) ; Smith el ah, March′s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007) ; Peturssion et al, "Protecting Groups in Carbohydrate Chemistry, " J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006) .

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature, ” “room temperature, ” and “r.t. ” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ℃ to about 30 ℃.

Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.

General Synthetic Procedures

A series of tricyclic derivatives of formula 1-7 to 1-13 can be prepared by the methods outlined in Scheme 1. Compounds 1-3 where t and s are an integer (e.g., 2, 3, or 4) can be prepared by reactions of compounds 1-1 where W ¹ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with a suitable amine derivative 1-2 in the presence of a base such as Hunig’s base. Buchwald coupling of compounds 1-3 with a suitable 5-6 membered heteroaryl derivatives Cy ¹W 1-4 where W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Buchwald coupling conditions (e.g., in the presence ora palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs ₂CO ₃, or K ₂CO ₃) can provide compounds 1-5. Removal of the Boc group in compounds 1-5 to compounds 1-6 can be achieved by the treatment with acid such as TFA in DCM, HCl in dioxane or other acidic media. In the presence of a base (e.g., hunig’s base or K ₂CO ₃) , reactions of compounds 1-6 with acyl chloride R ^bCOCl can afford the corresponding compounds 1-7, with suitable chloroformate R ^bOCOCl the corresponding compounds 1-8, with isocyanate R ^cN=C=O compounds 1-9, with carbamic chloride R ^cR ^dNCOCl compounds 1-10, with sulfinic chloride R ^bSOCl compounds 1-11, with sulfonyl chloride R ^bSO ₂Cl compounds 1-12, and with sulfamoyl chloride R ^cR ^dNSO ₂Cl compounds 1-13.

Scheme 1

A series of tricyclic derivatives of formula 2-2 to 2-4 can be prepared by the methods outlined in Scheme 2. Tricyclic derivatives 2-2 can be prepared by N-alkylation with a suitable reagent R ¹⁰-W where W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under alkylation conditions (e.g., in the presence of a base, such as Hunig’s base, NaH, t-BuOK, t-BuONa, Cs ₂CO ₃, or K ₂CO ₃) . Alternatively, tricyclic derivatives 2-3 can be obtained by reductive amination with an aldehyde, ketone or cyclic ketone R ^10aC (O) R ^10b, where R ^10a and R ^10b are selected from H or alkyl or R ^10a and R ^10b together with the carbon atom to which they are attached is a C ₃-C ₁₀ eycloalkyl, or 4-10 membered heterocycloalkyl, under standard reductive amination’s conditions (e.g., in the presence of a reductive reagent, such as NaBH (OAc) ₃, or NaBH ₃CN) . Treatment of compounds 2-1 with a suitable aryl or heteroaryl reagent Cy ³-W under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as Cs ₂CO ₃ or K ₃PO ₄) can provide compounds 2-4.

Scheme 2

A series of tricyclic derivatives of formula 3-5 to 3-9 can be prepared by the methods outlined in Scheme 3. Suzuki coupling of compounds 3-1 where W ¹ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with vinyl boronic acid or boronate ester 3-2 where R ^10a and R ^10b are selected from H or alkyl, or R ^10a and R ^10b together with the carbon atom to which they are attached is a C ₃-C ₁₀ cycloalkyl, or 4-10 membered heterocycloalkyl can afford compounds 3-5 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis(diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K ₃PO ₄) . Hydrogenation of compounds 3-5 can produce the corresponding compounds 3-6 in the presence of a palladium catalyst such as Pd/C or Pd (OH) ₂/C.

Similarly, compounds 3-1 can be coupled with R ¹⁰-Ar-M (e.g., Ar is aryl or heteroaryl; M is B (OH) ₂, Bpin, BF ₃K, Sn (Me) ₃, Sn (Bu) ₃, or ZnCl ₂) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Xanphos Pd, or [1, 1 ′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K ₃PO ₄) , or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium (0) or [1, 1 ′-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) ) , or standard Stille conditions (e.g., in the presence of a palladium (0) catalyst, such as tetrakis (triphenyl-phosphine) palladium (0) ) to afford compounds 3-7. When R ¹⁰ group in compounds 3-7 is a carbonate ester group, it can be saponified to acid 3-8 under basic conditions in the presence of a base such as LiOH, NaOH or KOH. Coupling of compounds 3-8 with amines R ^cR ^dNH 3-4 under standard amide coupling conditions (e.g., in the presence of a coupling reagent, such as BOP, PyBOP, HATU or HBTU, and a base, such as Et3N or Hunig’s base) can provide compounds 3-9.

Scheme 3

A series of tricyclic intermediates of formula 4-7 can be prepared by the methods outlined in Scheme 4. Sulfonamides 4-3 can be prepared by reaction of the sulfonyl chloride 4-1 with an amine 4-2 in the presence of a base such as Hunig’s base. Coupling of the sulfonamides 4-3 with 2-cyanoacetamide in the presence of a base, such as NaH, t-BuONa, or t-BuOK can afford compounds 4-4 which can be transformed into indole derivatives 4-5 by the nitro group with a reductive reagent such as Zn/FeCl ₃ in acid media or Fe/NH ₄Cl followed the ring closure under the reaction conditions. Treatment of the indole derivatives 4-5 with trialkyl orthoformate 4-6 in the presence of an acid such as p-TsOH, or HCl can form the desired product indole-pyrimidone 4-7 which can be transformed into the intermediates 4-8 where W ¹ is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) either by reaction with a halogenation reagent such as SOCl ₂, POCl ₃ or POBr3 with or without the catalytic of DMF (where W ¹ is Cl or Br) or reaction with TfCl or MsCl (where W ¹ is OTf or OMs) in the presence of a base such as Hunig’s base.

Scheme 4

A series of tricyclic intermediates of formula 5-8 can be prepared by the methods outlined in Scheme 5. Coupling of compounds 5-1 where W ² is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , and W ³ is halogen (e.g., Br, or I) or pseudohalogen (e.g., OTf ) with compounds 5-2 under Buchwald coupling conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs ₂CO ₃, or K ₂CO ₃) , followed by ring closure by intra-molecular Heck reaction under the standard Heck reaction conditions (e.g., in the presence of a palladium catalyst, such as dichlorobis (triphenylphosphine) palladium, palladium diacetate, or tetrakis (triphenylphosphine) palladium and a base, such as Na ₂CO ₃, K ₂CO ₃, or NaOAc) can afford tricyclic compounds 5-3, which can be transformed into the corresponding sulfonyl chloride 5-4 by oxidation reagents, such as N-chlorosuccinimide, sodium hypochlorite or treatment with a suitable reagent such as 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione. Reaction of the sulfonyl chlorides 5-4 with an amine 5-5 in the presence of a base such as Hunig’s base can produce the sulfonamides 5-6 which can be transformed into 5-7 by oxidative reagents such as hydrogen peroxide, oxone, and m-chloroperbenzoic acid. The compound 5-7 can be converted into the intermediates 5-8 where W ¹ is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) by reaction with a halogenation reagent such as SOCl ₂, POCl ₃ or POBr ₃ or reaction with TfCl or MsCl in the presence of a base such as Hunig’s base.

Scheme 5

Alternatively, a series of tricyclic intermediates of formula 6-10 can be prepared by the methods outlined in Scheme 6. Tricyclic compounds 6-3 can be obtained in the similar way as describes in scheme 5 for the tricyclic compounds 5-3 by reaction with a suitable aniline 6-2. The removal of benzyl group in compounds 6-3 to the corresponding OH compounds 6-4 can be achieved by hydrogenation in the presence of a catalyst, such as Pd/C or Pd (OH) ₂/C. Treatment the compounds 6-4 with trifluoromethanesulfonic anhydride afford the compounds 6-5 which can be transformed into 6-6 by reaction with phenylmethanethiol or sodium phenylmethanethiolate in the presence of a base such as Hunig’s base, Cs ₂CO ₃, t-BuOK, t-BuONa. The oxidation of compounds 6-6 with oxidation reagents, such as N-chlorosuccinimide, sodium hypochlorite can form the sulfonyl chloride 6-7 which then can be transformed into the desired intermediates 6-10 by reaction with a suitable amine 6-8 in the presence of a base, such as Hunig’s base, Na ₂CO ₃, or K ₂CO ₃, followed by removal of the protecting group Tf in the products 6-9 under basic conditions such as NaOH, or KOH.

Scheme 6

Alternatively, a series of tricyclic intermediates of formula 7-3 and 7-5 can be prepared by the methods outlined in the scheme 7. The compounds 7-3 and 7-5 can be prepared by Buchwald coupling compounds 7-1 where W ² is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with compounds 7-2 and 7-4, respectively under standard conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs ₂CO ₃, or K ₂CO ₃) , followed by intramolecular ring closure in the presence of a Lewis acid, such as AlCl ₃, ZnCl ₂ or other acidic media such as polyphosphoric acid, POCl ₃.

Scheme 7

In a similar manner, a series of tricyclic intermediates of formula 8-3 and 8-5 can be prepared by the methods outlined in the scheme 8. The compounds 8-3 and 8-5 can be prepared by Buchwald coupling compounds 8-1 where W ³ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with compounds 8-2 and 8-5, respectively under standard conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs ₂CO ₃, or K ₂CO ₃) , followed by ring closure by intramolecular Heck reaction under the standard reaction condition (e.g., in the presence of a palladium catalyst, such as dichlorobis (triphenylphosphine) palladium, palladium diacetate, tetrakis (triphenylphosphine) palladium and a base, such as Na ₂CO ₃, K ₂CO ₃, or NaOAc) .

Scheme 8

A series of tricyclic intermediates of formula 9-7 where A is O or S can be prepared by the methods outlined in the scheme 9. The compounds 9-3 can be prepared by nucleophile alkylation of compound 9-1 where W ² is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with 2-cyanoacetate 9-2 where R is alkyl (e.g., Me, Et or t-Bu) in the presence of a strong base, such as t-BuOK, t-BuONa, NaH) . Reduction of the nitro group in 9-3 can be achieved by treatment with a reductive reagent such as Zn dust, or Fe powder in acidic conditions (such as acetic acid or HCl) , followed by intramolecular ring closure to produce compounds 9-4. Heating the mixture of compounds 9-4 with an acetal 9-5 bearing alfa-H in the presence of a base such as NaOMe or NaOEt can yield tricyclic compounds 9-6. Halogenation of compounds 9-6 can provide the desired intermediates 9-7 (where W ¹ is Cl or Br) with a halogenation reagent such as SOCl ₂, POCl ₃ or POBr3 or 9-7 (where W ¹ is OTf or OMs) with TfCl or MsCl in the presence of a base such as Hunig’s base.

Scheme 9

Examples

Example 1: 4- (4- (Cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

Step 1: 4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

To a solution of 4-chloro-N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (111 mg, 0.330 mmol, Intermediate 2) and cyclopropyl (piperazin-l-yl) methanone (189 mg, 0.992 mmol) in MeCN (15 mL) was added NaHCO ₃ (1.11 g, 13.2 mmol) . The mixture was stirred at 52 ℃overnight. The reaction mixture was diluted with H ₂O (10 mL) and extracted with ethyl acetate (10 mL x 3) . The combined organic layers were washed with brine (20 mL x 2) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (0-5%) to afford 4- (4-(cyclopropanecarbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (100 mg, 66.5%yield) as a white solid. ¹H NMR: (400 MHz, DMSO-d ₆) δ 12.6 (s, 1H) 8.55 (s, 1H) 8.11 (s, 1H) 7.93-7.95 (m, 2H) 7.69-7.72 (m, 1H) 3.72-3.94 (m, 8H) 2.02-2.07 (m, 1H) 1.11 (s, 3H) 0.73-0.81 (m, 4H) 0.59-0.61 (m, 2H) 0.35-0.38 (m, 2H) . LCMS calc. for C ₂₂H ₂₅N ₆O ₃S [M-H] ^-: m/z = 453.2; Found: 453.1.

Step 2: 4- (4- (cyclopropanecarbonyl) piperazin-1 -yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2 -yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

A mixture of 4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (20 mg, 0.044 mmol) , 2-bromo-5- (difluoromethyl) -1, 3, 4-thiadiazole (75.7 mg, 0.352 mmol) , t-Bu ₃P (125 mg, 0.616 mmol) and t-BuONa (123 mg, 1.28 mmol) in xylene (3 mL) was degassed and purged with N ₂ for 3 cycles. Pd ₂ (dba) ₃ (60.4 mg, 0.0 66.0 mmol) was added. The mixture was stirred at 110 ℃ overnight under N ₂ atmosphere. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column with water/ACN (30%-60%with (NH ₃. H ₂O+NH ₄HCO ₃) ) to afford 4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (1.8 mg, 3.47%yield) as a white solid. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.46 (s, 1H) , 8.82 (s, 1H) , 8.36 (s, 1H) , 8.10 (d, J= 8.0 Hz, 1H) , 7.99 (d, J= 8.0 Hz, 1H) , 7.68 (t, J= 25.6 Hz, 1H) , 3.73-4.04 (m, 9H) , 1.44 (d, J= 13.2 Hz, 1H) , 1.12 (s, 3H) , 0.76-0.80 (m, 4H) , 0.64-0.66 (m, 2H) , 0.39-0.42 (m, 2H) . LCMS calc. for C ₂₅H ₂₅F ₂N ₈O ₃S ₂ [M-H] ^-: m/z = 587.2; Found: 587.

Example 2: N- (1-Cyanocyelopropyl) -4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.41 (s, 1H) , 8.84 (s, 1H) , 8.12-8.15 (m, 1H) , 8.02-8.05 (m, 1H) , 7.68 (t, J= 53.2 Hz, 1H) , 3.72-3.95 (m, 8H) , 2.04-2.08 (m, 1H) , 1.43-1.46 (m, 2H) , 1.26-1.29 (m, 2H) , 0.76-0.81 (m, 4H) . LCMS calc. for C ₂₅H ₂₂F ₂N ₉O ₃S ₂ [M-H] ^-: m/z = 598.1; Found: 598.2.

Example 3: N- (1-Cyanoeyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-pivaloylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 2, 2-dimethyl-1- (piperazin-1-yl) propan-1-one in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.41 (s, 1H) , 8.84 (s, 1H) , 8.14 (d, J= 8.8 Hz, 1H) , 8.05 (d, J= 8.4 Hz, 1H) , 7.69 (t, J= 53.6 Hz, 1H) , 3.86 (s, 4H) , 3.82 (s, 4H) , 1.43 (s, 2H) , 1.26 (s, 11H) . LCMS calc. for C ₂₆H ₂₆F ₂N ₉O ₃S ₂ [M-H] ^-: m/z = 614.2; Found: 614.2.

Example 4: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclobutane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

Step 1: tert-butyl 4- (1-methylcyclobutane-1-carbonyl) piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (1.00 g, 4.49 mmol) in DMF (5.00 mL) was added 1-methylcyclobutanecarboxylic acid (0.615 g, 5.39 mmol) and TBTU (1.73 g, 5.39 mmol) and DIPEA (2.90 g, 22.5 mmol) . The mixture was stirred at r.t. overnight. The reaction mixture was diluted with H ₂O (30.0 mL) and extracted with MTBE (50.0 mL x 3) . The combined organic layers were washed with brine (4 mL x 2) , dried over Na ₂SO ₄, filtered and concentrated under reduced pressure, and the crude product (0.5 g) was obtained as a white solid, which was used in the next step without purification. LCMS: [M-56+H] ⁺ = 227.0.

Step 2: (1-methylcyclobutyl) (piperazin-1-yl) methanone

A mixture of tert-butyl 4- (1-methylcyclobutane-1-carbonyl) piperazine-1-carboxylate (0.500 g, 1.77 mmol) and HCl/MeOH (1.2 mL, 4 M) in MeOH (1.0 mL) was stirred at r.t. for 2 hrs. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with EtOAc (1.0 mL) at r.t. for 2 hrs. The solid was collected by filtration to afford the title compound as HCl salt (0.250 g, 64.5%yield) as a white solid. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.14 (s, 2H) , 3.48-3.63 (m, 4H) , 3.05-3.08 (m, 4H) , 2.38-2.50 (m, 3H) , 1.92-1.95 (m, 1H) , 1.80-1.81 (m, 2H) , 1.61-1.63 (m, 1H) , 1.35 (s, 3H) . LCMS calc. for C ₁₀H ₁₉N ₂O [M+H] ⁺: m/z = 183.1; Found: 183.2.

Step 3: N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclobutane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (1-methylcyclobutyl) (piperazin-1-yl) methanone HCl salt in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.51 (s, 1H) , 9.42 (s, 1H) , 8.84 (s, 1H) , 8.13 (d, J= 8.4 Hz, 1H) , 8.06 (d, J= 1.6 Hz, 1H) , 7.69 (t,J= 53.6 Hz, 1H) , 3.86 (s, 4H) , 3.54-3.69 (m, 4H) , 1.83-1.96 (m, 4H) , 1.46-1.65 (m, 2H) , 1.43-1.45 (m, 2H) , 1.30 (s, 3H) , 1.26-1.28 (m, 2H) . LCMS calc. for C ₂₇H ₂₈F ₂N ₉O ₃S ₂ [M+H] ⁺: m/z = 628.2; Found: 628.2.

Example 5: (R) -N- (1-Cyanocyclopropyl) -4- (4- (cyclobutanecarbonyl) -3-methylpiperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

Step 1: (R) -cyclobutyl (2-methylpiperazin-1-yl) methanone

This compound was prepared as HCl salt using procedures analogous to those described for Example 4 step 1-2 using cyclobutanecarboxylic acid and tert-butyl (R) -3-methylpiperazine-1-carboxylate in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 4.70 (s, 1H) , 4.14-4.38 (m, 1H) , 3.65 (d, J=12.4 Hz, 1H) , 3.14 (d, J= 12.8 Hz, 2H) , 2.99 (s, 1H) , 2.82 (s, 1H) , 1.93-2.08 (m, 4H) , 1.86-1.90 (m, 1H) , 1.75 (s, 1H) , 1.11-1.31 (m, 3H) .

Step 2: (R) -N- (1-cyanocyclopropyl) -4- (4- (cyclobutanecarbonyl) -3-methylpiperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (R) -cyclobutyl (2-methylpiperazin-1-yl) methanone HCl salt in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.41 (s, 1H) , 8.81 (s, 1H) , 8.16 (d, J= 8.4 Hz, 1H) , 8.03 (d, J= 8.4 Hz, 1H) , 7.69 (t, J= 52.8 Hz, 1H) , 4.72 (s, 1H) , 4.36 (s, 2H) , 4.20-4.22 (m, 2H) , 3.67-3.75 (m, 2H) , 2.12-2.19 (m, 3H) , 1.76 (s, 1H) , 1.46 (s, 1H) , 1.42-1.46 (m, 2H) , 1.28 (s, 3H) , 1.26-1.28 (m, 2H) , 1.01-1.02 (m, 2H) . LCMS calc. for C ₂₇H ₂₆F ₂N ₉O ₃S2 [M-H] ^-: m/z = 626.2; Found: 626.2.

Example 6: 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indoi-4-yl) -N, N-dimethylpiperazine-1-earboxamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and N, N-dimethylpiperazine-1-carboxamide in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.49 (s, 1H) , 9.41 (s, iH) , 8.82 (s, 1H) , 8.05-8.13 (m, iH) , 8.03-8.04 (m, 1H) , 7.68 (t, J= 53.2 Hz, 1H) , 3.89 (s, 4H) , 3.41 (s, 4H) , 2.81 (s, 6H) , 1.42-1.45 (m, 2H) , 1.25-1.28 (m, 2H) . LCMS calc. for C ₂₄H ₂₃F ₂N ₁₀O ₃S ₂ [M-H] ^-: m/z = 601.1; Found: 601.1.

Example 7: 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-earboxamide

Step 1: tert-butyl 4- (ethyl (methyl) carbamoyl) piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (3.00 g, 13.5 mmol) in DMF (21 mL) was added N-ethyl-N-methyl-carbamoyl chloride (1.97 g, 16.2 mmol) and DIPEA (8.70 g, 67.4 mmol) . The mixture was stirred at r.t. overnight. The reaction mixture was diluted with H ₂O (100 mL) and extracted with MTBE (80 mL x 3) . The combined organic layers were washed with brine, dried over Na ₂SO ₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (2-100%) to afford the title product (1.3 g, 35.5%yield) as a white solid. LCMS calc. for C ₉H ₁₈N ₃O ₃ [M-56+H] ⁺: m/z =216.2; found: 216.1.

Step 2: N-ethyl-N-methylpiperazine-1-carboxamide

This compound was prepared as HCl salt using procedures analogous to those described for Example 4 step 2. ¹H NMR: (400 MHz, DMSO-d ₆) δ 3.49 (s, 1H) , 3.25-3.28 (m, 4H) , 3.11-3.16 (m, 2H) , 3.06 (s, 4H) , 2.76 (s, 3H) , 1.05 (d, J= 7.2 Hz, 3H) . LCMS calc. for C ₈H ₁₈N ₃O [M+H] ⁺: m/z =172.1; found: 171.9.

Step 3: 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-carboxamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1 -cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and N-ethyl-N-methylpiperazine-l-carboxamide HCl salt in step 1. The residue was purified by prep-HPLC on a C18 column eluting with MeCN/H ₂O (25-70%with 0.1%TFA) to afford the title compound as off-white solid. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.40 (s, 1H) , 8.82 (s, 1H) , 8.12 (d, J= 8.4 Hz, 1H) , 8.04 (dd, J = 8.4, 1.6 Hz, 1H) , 7.68 (t, J= 53.2 Hz, 1H) , 3.88 (s, 4H) , 3.48 (s, 4H) , 3.16-3.21 (m, 2H) , 2.81 (s, 3H) , 1.42-1.44 (m, 2H) , 1.25-1.29 (m, 2H) , 1.10 (t, J= 7.2 Hz, 3H) . LCMS calc. for C ₂₅H ₂₅F ₂N ₁₀O ₃S ₂ [M-H] ^-: m/z = 615.16; found: 615.2.

Example 8: N- (1-Cyanocyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (morpholine-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, S-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and morpholino (piperazin-1-yl) methanone in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (d, J=1.6 Hz, 1H) , 9.41 (s, 1H) , 8.83 (s, iH) , 8.11 (d, J= 8.4 Hz, 1H) , 8.03 (dd, J= 8.4, 1.6 Hz, 1H) , 7.69 (t, J= 53.2 Hz, 1H) , 3.88 (s, 4H) , 3.60-3.62 (m, 4H) , 3.44 (s, 4H) , 3.21-3.24 (m, 4H) , 1.43-1.50 (m, 2H) , 3.28-3.38 (m, 2H) . LCMS calc. for C ₂₆H ₂₇F ₂N ₁₀O ₄S ₂ [M+H] ⁺: m/z = 645.15; found: 645.2.

Example 9: N- (1-Cyanoeyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-methylpiperazine-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (4-methylpiperazin-1-yl) (piperazin-1-yl) methanone in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ9.50 (d, J= 1.6 Hz, 1H) , 9.41 (s, 1H) , 8.83 (s, 1H) , 8.12 (d, J= 8.8 Hz, 1H) , 8.05 (dd, J= 8.4, 1.6 Hz, 1H) , 7.69 (t, J = 53.2 Hz, 1H) , 3.88 (s, 4H) , 3.41 (m, 6H) , 3.24 (s, 4H) , 2.34 (s, 3H) , 2.21 (m, 2H) , 1.43-1.52 (m, 2H) , 1.24-1.29 (m, 2H) . LCMS calc. for C ₂₇H ₂₈F ₂N ₁₁O ₃S ₂ [M-H] ^-: m/z = 656.19; found: 656.2.

Example 10: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

Step 1: (1-methylcyclopropyl) (piperazin-1-yl) methanone

This compound was prepared as HCl salt using procedures analogous to those described for Example 4 step 1-2 using 1-methylcyclopropane-1-carboxylic acid and reft-butyl piperazine-1-carboxylate in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.48 (s, 2H) , 5.48 (s, 1H) , 3.75 (s, 4H) , 3.07 (s, 4H) , 1.22 (s, 3H) , 0.82-0.84 (m, 2H) , 0.52-0.55 (m, 2H) .

Step 2: N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1 -yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (1-methylcyclopropyl) (piperazin-1-yl) methanone HCl salt in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (d, J= 1.6 Hz, 1H) , 9.41 (s, 1H) , 8.84 (s, 1H) , 8.10-8.16 (m, 1H) , 8.05 (dd, J= 8.4, 1.2 Hz, 1H) , 7.69 (t, J= 53.2 Hz, 1H) , 3.75-3.94 (m, 8H) , 1.41-1.46 (m, 2H) , 1.29 (s, 3H) , 1.25-1.28 (m, 2H) , 0.84-0.89 (m, 2H) , 0.56-0.61 (m, 2H) . LCMS calc. for C ₂₆H ₂₆F ₂N ₉O ₃S ₂ [M+H] ⁺: m/z = 614.1; found: 614.1.

Example 11: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-isobutyrylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 2-Methyl-1- (piperazin-1-yl) propan-1-one in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.51 (d, J = 1.6 Hz, 1H) , 9.42 (s, 1H) , 8.84 (s, 1H) , 8.10-8.16 (m, 1H) , 8.05 (dd, J= 8.4, 1.2 Hz, 1H) , 7.69 (t, J = 53.2 Hz, 1H) , 3.72-3.92 (m, 8H) , 2.92-3.00 (m, 1H) , 1.42-1.47 (m, 2H) , 1.25-1.30 (m, 2H) , 1.06 (d, J= 6.8 Hz, 6H) . LCMS calc. for C ₂₅H ₂₆F ₂N ₉O ₃S ₂ [M+H] ⁺: m/z = 602.1; found: 602.1.

Example 12: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-ehloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and Piperazin-1-yl (tetrahydro-2H-pyran-4-yl) methanone in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (d, J= 1.6 Hz, 1H) , 9.41 (s, 1H) , 8.84 (s, 1H) , 8.13 (d, J = 8.4 Hz, 1H) , 8.04 (dd, J= 8.4, 2.0 Hz, 1H) , 7.69 (t, J= 53.2 Hz, 1H) , 3.66-3.95 (m, 10H) , 3.37-3.45 (m, 2H) , 2.94-3.00 (m, 1H) , 1.58-1.70 (m, 4H) , 1.41-1.46 (m, 2H) , 1.25-1.30 (m, 2H) . LCMS calc. for C ₂₇H ₂₈F ₂N ₉O ₄S ₂ [M+H] ⁺: m/z =644.2; found: 644.1.

Example 13: N- (1-Cyanoeyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-fluorobenzoyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (4-fluorophenyl) (piperazin-1-yl) methanone in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.49 (d, J= 1.6 Hz, 1H) , 9.36 (br s, 1H) , 8.84 (s, 1H) , 8.06-8.12 (m, 1H) , 8.00-8.05 (m, 1H) , 7.69 (t, J= 53.2 Hz, 1H) , 7.54-7.59 (m, 2H) , 7.32 (t, J= 8.8 Hz, 2H) , 3.58-3.95 (m, 8H) , 1.38-1.44 (m, 2H) , 1.22-1.26 (m, 2H) . LCMS calc. for C ₂₈H ₂₃F ₃N ₉O ₃S ₂ [M+H] ⁺: m/z = 654.1; found: 654.1.

Example 14: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-picolinoylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfontamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and piperazin-1-yl (pyridin-2-yl) methanone in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.49 (d, J=1.6 Hz, 1H) , 9.40 (s, 1H) , 8.85 (s, 1H) , 8.64 (d, J= 4.4 Hz, 1H) , 8.14 (d, J = 8.4 Hz, 1H) , 7.94-8.05 (m, 2H) , 7.64-7.84 (m, 2H) , 7.49-7.55 (m, 1H) , 3.70-4.00 (m, 8H) , 1.40-1.45 (m, 2H) , 1.23-1.28 (m, 2H) . LCMS calc. for C ₂₇H ₂₁F ₂N ₁₀O ₃S ₂ [M-H] ^-: m/z = 635.1; found: 635.2.

Example 15: Isopropyl 4- (7- (N- (1-cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) piperazine-1-carboxylate

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 1-methylethyl 1-piperazinecarboxylate in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (s, 1H) , 9.42 (s, 1H) , 8.84 (s, 1H) , 8.06-8.14 (m, 1H) , 8.04-8.06 (m, 1H) , 7.69 (t, J= 53.6 Hz, 1H) , 4.85 (t, J = 6.0 Hz, 1H) , 3.86 (s, 4H) , 3.63 (s, 4H) , 1.44-1.46 (m, 2H) , 1.29-1.42 (m, 2H) , 1.25 (s, 3H) , 1.24 (s, 3H) . LCMS calc. for C ₂₅H ₂₄F ₂N ₉O ₄S ₂ [M-H] ^-: m/z = 616.1; found: 616.2.

Example 16: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (thiazol-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 1- (2-thiazolyl) piperazine in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.51 (s, 1H) , 9.42 (s, 1H) , 8.87 (s, 1H) , 8.17 (d, J= 8.8 Hz, 1H) , 8.04 (dd, J= 8.4, 1.6 Hz, 1H) , 7.70 (t, J= 53.6 Hz, 1H) , 7.24 (d, J= 3.6 Hz, 1H) , 6.94 (d, J= 3.6 Hz, 1H) , 3.98 (s, 4H) , 3.70 (s, 4H) , 1.43-1.44 (m, 2H) , 1.27-1.29 (m, 2H) . LCMS calc. for C ₂₄H ₁₉F ₂N ₁₀O ₂S ₃ [M-H] ^-: m/z = 613.1; found: 613.2.

Example 17: N- (1-Cyanocyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 1- (2-pyridyl) piperazine in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.52 (d, J= 2.0 Hz, 1H) , 9.42 (s, 1H) , 8.85 (s, 1H) , 8.17-8.19 (m, 2H) , 8.06 (dd, J= 8.4, 1.6 Hz, 1H) , 7.69 (t, J= 53.6 Hz, 1H) , 7.59-7.63 (m, 1H) , 6.95 (d, J= 8.8 Hz, 1H) , 6.70-6.73 (m, 1H) , 3.97-3.98 (m, 4H) , 3.79-3.80 (m, 4H) , 1.43-1.46 (m, 2H) , 1.27-1.30 (m, 2H) . LCMS calc. for C ₂₆H ₂₁F ₂N ₁₀O ₂S ₂ [M-H] ^-: m/z =607.1; found: 607.2.

Example 18: N- (1-Cyanocyclopropyl) -9- (5- (diflu orom ethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 1- (2-pyrimidinyl) piperazine in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.50 (d, J= 1.6 Hz, 1H) , 9.41 (s, 1H) , 8.84 (s, 1H) , 8.44 (d, J= 4.8 Hz, 2H) , 8.16 (d, J= 8.4 Hz, 1H) , 8.05 (dd, J= 8.4, 1.8 Hz, 1H) , 7.69 (t, J= 53.2 Hz, 1H) , 6.71 (t, J= 4.8 Hz, 1H) , 3.92-4.05 (m, 8H) , 1.41-1.46 (m, 2H) , 1.25-1.29 (m, 2H) . LCMS calc. for C ₂₅H ₂₀F ₂N ₁₁O ₂S ₂ [M-H] ^-: m/z = 608.1; found: 608.0.

Example 19: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridazin-3-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and 3-piperazin-1-ylpyridazine in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.52 (d, J= 1.6 Hz, 1H) , 9.42 (s, 1H) , 8.86 (s, 1H) , 8.67 (d, J= 4.4 Hz, 1H) , 8.18 (d, J= 8.4 Hz, 1H) , 8.05 (dd, J = 8.4, 1.6 Hz, 1H) , 7.69 (t, J= 54.0 Hz, 1H) , 7.53-7.60 (m, 2H) , 4.00-4.04 (m, 4H) , 3.90-3.94 (m, 4H) , 1.42-1.46 (m, 2H) , 1.27-1.30 (m, 2H) . LCMS calc. for C ₂₅H ₂₀F ₂N ₁₁O ₂S ₂ [M-H] ^-: m/z = 608.1; found: 608.2.

Example 20: N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-oxa-7-azaspiro [3.5] nonan-7-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (4-fluorophenyl) (piperazin-1-yl) methanone (Intermediate 14) in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.49 (s, 1 H) , 9.39 (s, 1 H) , 8.79 (s, 1 H) , 8.03-8.08 (m, 2 H) , 7.68 (t, J= 53.6 Hz, 1 H) , 4.43 (s, 4 H) , 3.77 (s, 4 H) , 2.02 (s, 4 H) , 1.41-1.46 (m, 2 H) , 1.23-1.30 (m, 2 H) . LCMS calc. for C ₂₄H ₂₃F ₂N ₈O ₃S ₂ [M+H] ⁺: m/z = 573.1; found: 573.1.

Example 21: (R) -N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methylmorpholino) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Example 1 using 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (Intermediate 1) and (R) -2-methylmorpholine in step 1. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.49 (s, 1H) , 9.39 (s, 1H) , 8.82 (s, 1H) , 8.04-8.10 (m, 2H) , 7.68 (t, J= 53.2 Hz, 1H) , 4.27 (d, J= 13.2 Hz, 1H) , 4.19 (d, J=13.2 Hz, 1H) , 3.98 (d, J= 12.0 Hz, 1H) , 3.46-3.53 (m, 2H) , 3.10-3.16 (m, 2H) , 1.42-1.45 (m, 2H) , 1.26-1.30 (m, 2H) , 1.17 (d, J= 6.0 Hz, 3H) . LCMS calc. for C ₂₂H ₂₁F ₂N ₈O ₃S ₂ [M+H] ⁺: m/z = 547.1; found: 547.1.

Intermediate 1: 4-Chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

Step 1: 4-chloro-N- (1-cyanocyclopropyl) -3-nitrobenzenesulfonamide

To a mixture of 1-aminocyclopropane-1-carbonitrile hydrochloride (55.6 g, 469 mmol, 1.20 eq) in MeCN (500 mL) was added pyridine (500 mL) , DMAP (19.1 g, 156 mmol, 0.40 eq) at r.t.. To the mixture was added 4-Chloro-3-nitrobenzenesulfonyl chloride (100 g, 391 mmol, 1.00 eq) at 0～5 ℃. The mixture was then stirred at r.t. for 2 hrs. TLC (petroleum ether: ethyl acetate = 1∶ 1, Rf = 0.43) showed the reaction was completed. The reaction mixture was poured into ice-water (500 mL) , and adjusted to pH ～3 with aq. HCl solution (1 N) at 0～5 ℃. The aqueous phase was extracted with ethyl acetate (300 mL x 3) . The combined organic layers were washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with MTBE (100 mL) at 20 ℃ for 2 hrs. The solid formed was collected by filtration and dried in vacuum to afford 4-chloro-N- (1-cyanocyclopropyl) -3-nitrobenzenesulfonamide (75 g, 63.6%yield) as yellow solid. LCMS calc. for C ₁₀H ₇ClN ₃O ₄S [M-H] ^-: m/z = 300.0. Found: 300.0. ¹H NMR: (400 MHz, DMSO-d ₆) δ 9.54 (s, 1H) , 8.51 (s, 1H) , 8.09-8.14 (m, 2H) , 1.47-1.51 (m, 2H) , 1.31-1.35 (m, 2H)

Step 2: 2-cyano-2- (4- (N- (1-cyanocyclopropyl) sulfamoyl) -2-nitrophenyl) acetamide

To a solution of 2-cyanoacetamide (41.8 g, 497 mmol, 2.00 eq) in DMF (750 mL) was added NaH (39.8 g, 994 mmol, 60%purity, 4.00 eq) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 hr. 4-chloro-N- (1-cyanocyclopropyl) -3-nitrobenzenesulfonamide (75.0 g, 249 mmol, 1.00 eq) was added to the above mixture at 0 ℃. The mixture was stirred at 20 ℃ for 1 hr. TLC (petroleum ether: ethyl acetate = 0∶ 1, product Rf = 0.30) showed the reaction was completed. The reaction was poured into ice-water (500 mL) in portions, and adjusted to pH～3 with aq. HCl solution (1 N) at 0～5 ℃. The aqueous phase was extracted with ethyl acetate (300 mL x 3) . The combined organic layers were washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product 2-cyano-2- (4- (N- (1-cyanocyclopropyl) sulfamoyl) -2- nitrophenyl) acetamide (43.2 g) which was directly used in the next step reaction without further purification.

Step 3: 2-amino-6- (N- (1-cyanocyclopropyl) sulfamoyl) -1H-indole-3-carboxamide

To a solution of 2-cyano-2- (4- (N- (1-cyanocyclopropyl) sulfamoyl) -2-nitrophenyl) acetamide (86.5 g, 248 mmol, 1.00 eq) in DMF (750 mL) was added FeCl ₃ (120 g, 744 mmol, 3.00 eq) at 20 ℃. The mixture was heated to 60 ℃, and Zn (162 g, 2.48 mol, 10.0 eq) was added in small portions. The mixture was stirred and heated at 100 ℃ for 2 hrs. LCMS showed the reaction was completed. After cooling, the reaction mixture was filtered on celite. The filtrate was extracted with DCM (500 mL x 6) . The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (1/0 ～ 0/1) to afford 2～amino-6- (N- (1-cyanocyclopropyl) sulfamoyl) -1H-indole-3-carboxamide (30.0 g, 18.9%yield) as yellow foam. LCMS calc. for C ₁₃H ₁₂N ₅O ₃S [M-H] ^-: m/z = 318.07. Found: 318.0.

Step 4: N- (1-cyanocyclopropyl) -4-oxo-4, 9-dihydro-3 H-pyrimido [4, 5-b] indole-7-sulfonamide

To a mixture of 2-amino-6- (N- (1-cyanocyclopropyl) sulfamoyl) -1H-indole-3-carboxamide (28.0 g, 87.7 mmol, 1.00 eq) in trimethoxymethane (560 mL) was added aq. HCl (12 N, 161 mL, 22.0 eq) at 20 ℃. The mixture was stirred at 60 ℃ for 1 hr. LCMS showed the starting material was consumed completely. The reaction mixture was filtered. The filter cake was dried in vacuum to afford N- (1-cyanocyclopropyl) -4-oxo-4, 9-dihydro-3H-pyrimido [4, 5-b] indole-7-sulfonamide (20.0 g, 69.3%yield) as yellow solid. ¹H NMR: (400 MHz, DMSO-d ₆) δ 12.7 (s, 1H) , 12.5 (s, 1H) , 9.07 (s, 1H) , 8.24 (s, 1H) , 8.17 (d, J= 8.0 Hz, 1H) , 7.96 (s, 1H) , 7.71 (d, J= 10.0 Hz, 1H) , 1.37-1.42 (m, 2H) , 1.22-1.27 (m, 2H) . LCMS calc. for C ₁₄H ₀N ₅O ₃S [M-H] ^-: m/z = 328.06; Found: 328.1.

Step 5: 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

A mixture of N- (1-cyanocyclopropyl) -4-oxo-4, 9-dihydro-3H-pyrimido [4, 5-b] indole-7-sulfonamide (18.0 g, 54.7 mmol, 1.00 eq) in POCl ₃ (720 mL) was stirred at 100 ℃ for 16 hrs. LCMS showed the starting material was consumed completely. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with Petroleum ether/Ethyl acetate (1/0 ～ 0/1) to afford 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide (10.0 g, 47.3%yield) as light yellow solid. LCMS calc. for C ₁₄H ₉ClN ₅O ₂S [M-H] ^-: m/z = 346.0; found: 345.9.

Intermediate 2: 4-Chloro-N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide

This compound was prepared using procedures analogous to those described for Intermediate 1 using 1-methylcyclopropan-1-amine to replace 1-aminocyclopropane-1-carbonitrile hydrochloride in step 1. LCMS calc. for C ₁₄H ₁₂ClN ₄O ₂S [M-H] ^-: m/z = 335.0; found: 334.9.

Example A: Biological Assays

PARG enzymatic activity assay

HTRF assay was used to measure the ability of compounds to inhibit the activity of PARG in vitro. C-terminal His6-tag PARG expressed in E. coli was purified and stored at -80℃ in aliquots. Assay measurements were performed with 1 ×buffer comprising 50 mM Tris pH 7.4, 0.1 mg/mL BSA, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 50 mM KCl and 0.01%Tween 20. Compounds dissolved in DMSO were plated into a 384-weil assay plate (PerkinElmer, Catalog #: 6008280) in duplicate using a dispenser (Labcyte, Echo 665) , and tested on a 10-point 4-fold serial dilution. Add 5 μL Enzyme mix [hPARG (C-terminal His6-tag, 4.2 μM) , 65 pM final] to the test wells. The plates were covered and left to incubate for 60 minutes at RT before the addition of 5 μL substrate mix [biotinylated-NAD ribosylated PARP 1 (6.1 μM) , 8 nM final] to initiate reaction. After incubating 10 minutes at RT, add 2.5 μL Streptavidin-Eu cryptate (Cisbio, Catalog #: 610SAKLA) and 2.5 μL Mab anti 6HIS-XL665 (Cisbio, Catalog #: 61HISXLA) to the plate, and incubate for 60 minutes at RT. Read on a multimode plate reader (PerkinElmer, Envision 2015) in time-resolved fluorescence (TRF) mode, with excitation at 337 nm and emission at both 620 nm and 665 nm. Average HTRF signal of high control (Wells with 1%DMSO) was calculated and as Vehicle Control (VC) . Average HTRF signal of low control (no Enzyme) was calculated and as Positive control (PC) . %Inhibition = (Signal _cmpd-Signal _{Ave_VC}) / (Signal _{Ave_PC}-Signal _{Ave_VC}) × 100. IC ₅₀ values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software.

The compounds of the invention were found to be inhibitors of PARG according to the above-described assay. IC ₅₀ data is proved below in Table 1: a “+” denotes an IC ₅₀ value of>1 μM, a “++” denotes an IC ₅₀ value of 0.1 μM< IC ₅₀<=1 μM, and a “+++” denotes an IC ₅₀ value of<0.1 μM.

Table 1. PARG enzymatic activity assay

Cell viability assay

Cell viability studies were conducted in Kuramochi cell line. Cells were maintained in RPMI (Hyclone, Catalog #: SH3080901B) supplemented with 10%v/v FBS (AusGeneX, Catalog #: FBS500-S) , 1%v/v Penicillin Streptomycin (Gibco, Catalog#: 15140122) . Cells were seeded in 96-well plates (PerkinElmer, Catalog #: 6005680) at a density of 400 cells/well. Compounds dissolved in DMSO were plated in duplicate using a multichannel pipette, and tested on a 9-point 3-fold serial dilution. Cells were incubated for 7 days in a 37 ℃ active humidified incubator at 5%CO2. Cell viability was measured using the Cell Titer-Glo reagent (Promega, Catalog#: G7573) as manufacturer's instructions. Luminescence signal was measured with a multimode plate reader (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus) . Average values of DMSO treated wells in a plate was calculated and as high control (HC) . Average values of only medium in a plate was calculated and as low control (LC) . %inhibition = (Signal _{Ave_HC}-Signal _cmpd) / (Signal _{Ave_HC}-Signal _{Ave_LC}) × 100. IC ₅₀ values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software.

Claims

A compound of Formula (I) , or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof,

wherein,

X is O or NR ⁵;

Y ¹ is N or CR ⁶;

Y ² is N, or CR ⁷, and only one of Y ¹ or Y ² is N;

Y ³ is N, or CR ⁸;

n is 0, 1 or 2;

Cy ¹ is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R ⁹;

Cy ² is independently selected from C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 R ¹⁰;

R ¹, R ² and R ³ are each independently selected from H, D, CN, C (O) R ^B, C (O) NR ^CR ^D, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

or R ² and R ³ together with the carbon atom to which they are attached form a C ₃-C ₇ cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

or R ² and R ³ together with the carbon atom to which they are attached form -C (=O) -, or -C (=S) -;

R ⁴ is selected from H, D, halo, OH, CN, NO ₂, SF ₅, C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl, -O-C ₁-C ₃ alkyl, or NR ^CR ^D; wherein, the C ₁-C ₃ alkyl, C ₂-C ₃ alkenyl, C ₂-C ₃ alkynyl is optionally substituted with halogen or CN;

R ⁵ is selected from H, D, CN, OR ^B, or C ₁-C ₄ alkyl, wherein the C ₁-C ₄ alkyl is optionally substituted with at least one of D, F, Cl, CN, NH ₂, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, optionally substituted C ₄-C ₇ heterocycloalkyl;

or R ¹ and R ⁵ together with the atoms to which they are attached is form a 5-7 membered partially saturated heterocycloalkyl, wherein, the 5-7 membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF ₃, NO ₂, oxo, OH, -O-C ₁-C ₆ alkyl, -OC ₁-C ₆ haloalkyl;

R ⁶ and R ⁷ are each independently selected from H, D, halogen, OH, CN, NO ₂, C ₁-C ₆ alkyl, C ₁-C ₆ haloalkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) OR ^A, C (O) R ^B, C (O) NR ^CR ^D, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^B, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, NR ^CS (O) ₂R ^B, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, or NR ^CS (O) (=NR ^B) R ^B;

R ⁸ is selected from H, D, CN, halo, OH, C ₁-C ₃ alkyl, C ₁-C ₃ haloalkyl, -O-C ₁-C ₃ alkyl, -OC ₁-C ₃ haloalkyl, C ₁-C ₃ cyanoalkyl, or SF ₅;

each R ⁹ is independently selected H, D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, optionally substituted C ₃-C ₇ cycloalkyl, CN, NO ₂, N ₃, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, or NR ^CS (O) (=NR ^B) R ^B;

each R ¹⁰ is independently selected H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ cyanoalkyl, OR ^A, SR ^A, SF ₅, NHOR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, B (OR ^C) (OR ^D) , C (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) NR ^CR ^D, NR ^DC (=NR ^C) R ^B, P (O) R ^ER ^F, P (O) OR ^EOR ^F, OP (O) OR ^EOR ^F, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, NR ^CS (O) (=NR ^B) R ^B, Cy ³, C ₁-C ₆ alkyl-Cy ³, OCy ³, or O-C ₁-C ₆ alkyl-Cy ³;

wherein two adjacent R ¹⁰, together with the atoms to which they are attached, optionally form a C ₃-C ₁₀ cycloalkyl or a 4-10 membered heterocycloalkyl, wherein, the C ₃-C ₁₀ cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆-cyanoalkyl, CN, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, OP (O) OR ^eOR ^f, P (O) OR ^eOR ^f, S (O) (=NR ^b) R ^b, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, NR ^cS (O) (=NR ^b) R ^b, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

Cy ³ is independently selected from optionally substituted C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;

wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, or C ₂-C ₆ alkynyl, of any of the R ⁶, R ⁷, R ⁹ and R ¹⁰ can be unsubstituted or substituted with 1, 2, or 3 R ¹¹;

each R ¹¹ is independently selected from H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, OC ₁-C ₆ alkylOH, OC ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, p (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1,S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1, NR ^c1S (O) ₂NR ^c1R ^d1, NR ^c1S (O) (=NR ^b1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

wherein the C ₃-C ₇ cycloalkyl of R ⁹, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl of Cy ³, can be unsubstituted or substituted with 1, 2, 3 or 4 R ¹²;

each R ¹² is independently selected from D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, C ₁-C ₆ alkylOH, C ₁-C ₆ alkyl-O-C ₁-C ₆ alkyl, CN, NO ₂, N ₃, OR ^a1, SR ^a1, SF ₅, NHOR ^a1, C (O) R ^b1, C (O) NR ^c1R ^d1, C (O) OR ^a1, OC (O) R ^b1, OC (O) NR ^c1R ^d1, NR ^c1R ^d1, NR ^c1C (O) R ^b1, NR ^c1C (O) NR ^c1R ^d1, NR ^c1C (O) OR ^a1, B (OR ^c1) (OR ^d1) , C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) NR ^c1R ^d1, NR ^d1C (=NR ^c1) R ^b1, p (O) R ^e1R ^f1, P (O) OR ^e1OR ^f1, OP (O) OR ^e1OR ^f1, S (O) (=NR ^b1) R ^b1, S (O) R ^b1, S (O) NR ^c1R ^d1, S (O) ₂R ^b1, NR ^c1S (O) ₂R ^b1, S (O) ₂NR ^c1R ^d1, NR ^c1S (O) ₂NR ^c1R ^d1, NR ^c1S (O) (=NR ^b1) R ^b1, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;

R ^A is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cyeloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocyclalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C ₁-C ₄ alkyl, NO ₂, oxo, OR ^a, SR ^a, SF ₅, NHOR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, B (OR ^c) (OR ^d) , C (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) NR ^cR ^d, NR ^dC (=NR ^c) R ^b, P (O) R ^eR ^f, P (O) OR ^eOR ^f, OP (O) OR ^eOR ^f, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or NR ^cS (O) (=NR ^b) R ^b;

R ^B is independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, C (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) ;

R ^C and R ^D are each independently selected from H, D, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₃-C ₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, OC ₁-C ₄ haloalkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, C ₁-C ₄ alkyl-O-C ₁-C ₄ haloalkyl, SF ₅, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^b, S (O) ₂NR ^cR ^d, NR ^cS (O) ₂NR ^cR ^d, or B (OR ^c) (OR ^d) ;

or R ^C and R ^D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, or C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₁-C ₄ cyanoalkyl, OC ₁-C ₄ alkyl, or OC ₁-C ₄ haloalkyl;

R ^a and R ^a1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy;

R ^b and R ^b1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, phenyl, C ₃-C ₇ cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;

R ^c and R ^d are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl, and C ₁-C ₄ alkyl-O-C ₁-C ₄ alkyl-O-;

or R ^c and R ^d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, C ₁-C ₄ haloalkoxy, C ₁-C ₄ hydroxyalkyl, C ₁-C ₄ cyanoalkyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C (O) OR ^a1, C (O) R ^b1, S (O) ₂R ^b1, C ₁-C ₄ alkoxy-C ₁-C ₄ alkyl, and C ₁-C ₄ alkoxy-C ₁-C ₄ alkoxy;

R ^c1 and R ^d1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, or C ₁-C ₄ haloalkoxy;

or R ^c1 and R ^d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH ₂, -NH (C ₁-C ₄ alkyl) , -N (C ₁-C ₄ alkyl) ₂, halo, C ₁-C ₄ alkyl, C ₁-C ₄ alkoxy, C ₁-C ₄ haloalkyl, and C _1-4 haloalkoxy;

R ^E, R ^e and R ^e1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₁-C ₄ haloalkyl, C ₂-C ₄ alkenyl, (C ₁-C ₄ alkoxy) -C ₁-C ₄ alkyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C ₆-C ₁₀ aryl-C ₁-C ₄ alkyl, C ₃-C ₁₀ cycloalkyl-C ₁-C ₄ alkyl, 5-10 membered heteroaryl-C ₁-C ₄ alkyl, or 4-10 membered heterocycloalkyl-C ₁-C ₄alkyl;

R ^F, R ^f and R ^f1 are each independently selected from H, D, C ₁-C ₄ alkyl, C ₂-C ₄ alkenyl, C ₂-C ₄ alkynyl, C ₆-C ₁₀ aryl, 5-10 membered heteroaryl, C ₃-C ₁₀ cycloalkyl, 4-10 membered heterocycloalkyl.
The compound of claim 1, wherein, n is independently 0.
The compound of claim 1, wherein, n is independently 1.
The compound of claim 1, wherein, n is independently 2.
The compound of anyone of claim 1-4, wherein, X is O.
The compound of anyone of claim 1-4, wherein, X is NR ⁵.
The compound of anyone of claim 1-6, wherein, each R ⁴ is independently selected from H, D, OH, CN, NO ₂, SF ₅, halo, C ₁-C ₃ alkyl.
The compound of claim 7, wherein, each R ⁴ is H.
The compound of anyone of claim 1-8, wherein, Y ³ is N.
The compound of anyone of claim 1-8, wherein, Y ³ is CR ⁸.
The compound of claim 10, wherein, each R ⁸ is selected from H, D, F, Cl, OH, CN, CF ₃, OMe, OCF ₃, or SF ₅.
The compound of anyone of claim 1-11, wherein, Y ¹ is N.
The compound of anyone of claim 1-11, wherein, Y ¹ is CR ⁶.
The compound of claim 13, wherein, R ⁶ is independently H, D. F, Cl, OH, CN, NO ₂, or SF ₅.
The compound of anyone of claim 1-14, wherein, Y ² is N.
The compound of anyone of claim 1-14, wherein, Y ² is CR ⁷.
The compound of anyone of claim 16, wherein, R ⁷ is independently H, D.F, Cl, OH, CN, NO ₂, or SF ₅.
The compound of anyone of claim 1-17, wherein, Cy ¹ is 5 membered heteroaryl optionally substituted by 1, 2, or 3 R ⁹.
The compound of claim 18, wherein, the 5 membered heteroaryl is optionally substituted by 1, 2, or 3 R ⁹, and selected from:
The compound of claim 18 or 19, wherein, the 5 membered heteroaryl is optionally substituted by 1, 2, or 3 R ⁹, and selected from:
The compound of anyone of claim 18-20, wherein, the 5 membered heteroaryl is optionally substituted by 1, 2, or 3 R ⁹, and selected from
The compound of anyone of claim 1-17, wherein, Cy ¹ is 6 membered heteroaryl; wherein, the 6 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R ⁹.
The compound of anyone of claim 18-22, wherein, R ⁹ is H, D, halo, C ₁-C ₆ alkyl, C ₂-C ₆ alkenyl, C ₂-C ₆ alkynyl, C ₁-C ₆ haloalkyl, CN, NO ₂, or N ₃.
The compound of anyone of claim 1-23, wherein, Cy ² is independently selected from C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.
The compound of claim 24, wherein, Cy ² is C ₆-C ₁₀ aryl optionally substituted by 1, 2, or 3 R ¹⁰.
The compound of claim 24, wherein, Cy ² is 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.
The compound of claim 24, wherein, Cy ² is C ₃-C ₁₀ cycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.
The compound of claim 24 or 26, wherein, Cy ² is 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R ¹⁰.
The compound of anyone of claim 24-28, wherein, R ¹⁰ is H, D, halo, CN, NO ₂, N ₃, C ₁-C ₆ alkyl, C ₆-C ₁₀ aryl, C ₃-C ₁₀ cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, OR ^A, SR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^D, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, S (O) (=NR ^B) R ^B, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^B, S (O) ₂NR ^CR ^D, NR ^CS (O) ₂NR ^CR ^D, NR ^CS (O) (=NR ^B) R ^B, OCy ³, or O-C ₁-C ₆ alkyl-Cy ³.
The compound of anyone of claim 1-29, wherein, each R ¹, R ² and R ³ is independently selected from H, D, CN, C (O) R ^B, C (O) NR ^CR ^D, or C ₁-C ₃ alkyl, wherein the C ₁-C ₃ alkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, OMe, OCF ₃, or OEt.
The compound of claim 30, wherein R ¹, R ² and R ³ is H, D, CN, CH ₃, CH ₂CH ₃, CH ₂F, CH ₂CH ₂F.
The compound of anyone of claim 1-29, wherein, R ² and R ³ together with the carbon atom to which they are attached is -C (O) -, or -C (S) -.
The compound of anyone of claim 1-29, wherein, R ² and R ³ together with the carbon atom to which they are attached form a C ₃-C ₆ cycloalkyl, or 4-6 membered heterocycloalkyl, wherein, the C ₃-C ₆ cycloalkyl, or 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO ₂, oxo, OH, OMe, OCF ₃, or OEt.
The compound of claim 1, wherein, the compound is represented by compounds of Formula (II) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁴, Cy ¹, Cy ², X, Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .
The compound of claim 1 or 34, wherein, the compound is represented by compounds of Formula (IIa) or (IIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁴, R ⁵, Cy ¹, Cy ², Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-35, wherein, the compound is represented by compounds of Formula (IIIa) or (IIIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, Cy ¹, Cy ², Y ¹, Y ² and Y ³ are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-36, wherein, the compounds are represented by compounds of Formula (IV) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁸, Cy ¹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-37, wherein, the compounds are represented by compounds of Formula (IVa) or (IVb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, R ⁸, Cy ¹, Cy ², Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-38, wherein, the compounds are represented by compounds of Formula (Va) , (Vb) , or (Vc) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁶, R ⁷, R ⁸, Cy ¹, and Cy ², are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-39, wherein, the compound is represented by compounds of Formula (VI) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof;

wherein, Cy ¹ is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹;

each R ¹, R ², R ³, R ⁹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-40, wherein, the compound is represented by compounds of Formula (VIa) or (VIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof;

wherein, Cy ¹ is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R ⁹;

each R ¹, R ², R ³, R ⁵, R ⁹, Cy ², Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-41, wherein, the compound is represented by compounds of Formula (VII) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁸, R ⁹, Cy ², X, Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-42, wherein, the compound is represented by compounds of Formula (VIIa) or (VIIb) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁵, R ⁸, R ⁹, Cy ₂, Y ¹, and Y ² are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-43, wherein, the compound is represented by compounds of Formula (VIIIa) , (VIIIb) , or (VIIIc) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁶, R ⁷, R ⁸, R ⁹, and Cy ₂ are defined with respect to Formula (I) .
The compound of anyone of claim 1 or 34-44, wherein, the compound is represented by compounds of Formula (IXa) , (IXb) , or (IXc) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof; wherein each R ¹, R ², R ³, R ⁶, R ⁷, R ⁸, R ⁹, and Cy ² are defined with respect to Formula (I) .
The compound of anyone of claim 1, wherein, the compound of Formula (I) is:

4- (4- (Cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-pivaloylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclobutane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

(R) -N- (1-cyanocyclopropyl) -4- (4- (cyclobutanecarbonyl) -3-methylpiperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N, N-dimethylpiperazine-1-carboxamide;

4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-carboxamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (morpholine-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonarnide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-methylpiperazine-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-isobutyrylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-fluorobenzoyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-picolinoylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

Isopropyl 4- (7- (N- (1-cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) piperazine-1-carboxylate;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (thiazol-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridazin-3-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-oxa-7-azaspiro [3.5] nonan-7-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

(R) -N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methylmorpholino) -9H-pyrimido [4, 5-b] indole-7-sulfonamide;

or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound of anyone of claim 1-46, a pharmaceutically acceptable salt, stereoisomer, prodrug, chelate, or non-covalent complex, and at least one pharmaceutically acceptable carrier or excipient.
Use of the compound of anyone of claim 1-46, a pharmaceutically acceptable salt or stereoisomer, prodrug, chelate, or non-covalent complex thereof for the preparation of a medicament.
The use of claim 48, wherein, the medicament is used as an inhibitor of PARG.
The use of claim 48 or 49, wherein, the medicament is used for the treatment of the cancer.
The use of claim 50, wherein, the cancer is breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
A method of inhibiting PARG, wherein, the method comprising: administering to the patient in need the compound of anyone of claim 1-46, a pharmaceutically acceptable salt or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs, or the pharmaceutical composition of claim 47.
A method of treating a disease associated with inhibition of PARG, wherein, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of anyone of claim 1-46, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs.
The method of claim 53, wherein, the disease is a cancer.
The method of claim 50, wherein, the cancer is breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
Use of the compound of anyone of claim 1-46 in combination with surgery, chemotherapies, radiation therapies, targeted therapy, other DDR modulators, immunotherapies, and gene and cell therapy approaches for the treatment of the cancer.
The use of claim 56, wherein, the targeted therapy is a kinase inhibitor, growth factor inhibitor, cyclin dependent kinase inhibitor.
The use of claim 56, wherein, the DDR modulator is DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, WEE1 inhibitor, CDK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, Polθ inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PKMYT1 inhibitor.