ACTIVATING PYRUVATE KINASE R - FORMA THERAPEUTICS INC

Title:

ACTIVATING PYRUVATE KINASE R

Document Type and Number:

WIPO Patent Application WO/2020/061255

Kind Code:

Abstract:

The disclosure provides novel chemical compounds useful as activators of PKR. PKR activating compounds are useful in the treatment of disease and disorders associated with modulation of PKR and/or PKM2, such as pyruvate kinase deficiency (PKD).

Inventors:

ZHENG XIAOZHANG (US)
ERICSSON ANNA (US)
GREEN NEAL (US)
GUSTAFSON GARY (US)
LANCIA DAVID (US)
LIN JIAN (US)
MITCHELL LORNA (US)
RICHARD DAVID (US)
SHELEKHIN TATIANA (US)

Application Number:

PCT/US2019/051831

Publication Date:

March 26, 2020

Filing Date:

September 19, 2019

Export Citation:

Click for automatic bibliography generation Help

Assignee:

FORMA THERAPEUTICS INC (US)

International Classes:

A61K39/00; A61K39/12

Domestic Patent References:

WO2016046837A1	2016-03-31
WO2016181408A2	2016-11-17
WO2018175474A1	2018-09-27

Foreign References:

US20180215765A1

2018-08-02

Other References:

See also references of EP 3852791A4

Attorney, Agent or Firm:

SHEREDA, Robert, D. et al. (US)

Download PDF:

View/Download PDF PDF Help

Claims:

CLAIMS

We claim:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl or monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more R^a;

each R^a is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR₂,

-NRC(0)R’, -NRS(0)₂R\ -CN, -N0₂, -SR, -C(0)R\ -C(0)0R, -C(0)NR₂, -S(0)₂R’, -S(0)₂NR₂

-Ci-Cgalkyl, -G-Galkcnyl. -G-Galkynyl. -C3-Ci₂cycloalkyl, -C4-Ci₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, G-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

R¹ and R² are each independently selected from the group consisting of -H, halogen, -Ci-Galkyl, -G-Galkenyl, -C₂-C₆alkynyl, -(CR^bR^c)_nC₃-Ci₂cycloalkyl, -(CR^bR^c)_nC₄-Ci₂cycloalkenyl,

wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-G alkyl, -C₂-Galkenyl, -C₂-Galkynyl, oxo, and -OR, wherein -OR does not result in an O in the g-position relative to

C(=Z),

wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R¹ and R² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cyeloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, and

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and

R^b and R^c are each independently selected from the group consisting of -H, halogen, and -Ci-Cgalkyl; each n is independently 0, 1, 2, 3, or 4;

B is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with (R^d)_m, and

when the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z);

each R^d is independently selected from the group consisting of halogen, oxo, -OR, -OC(0)R’, -NR2, -NRC(0)R’, -NRS(0)₂R\ -CN, -NO2, -SR, -C(0)R\ -C(0)OR, -C(0)NR₂, -S(0)₂R’, -S(0)₂NR₂, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C_t-Cncycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cg alkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, or -OR;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen; or R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰, or combinations thereof, combine with the carbon to which they are attached to form oxo, a Cs-Cscycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(Ci-Cgalkyl), and -N(Ci-Cgalkyl)2, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C4-Ci2Cyeloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cg alkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -O(Ci-Cgalkyl), -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl)₂; and

each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2cycloalkyl, -C4-Ci2cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-C₆alkyl)₂.

2. The compound of claim 1, wherein the compound is of Formula I-a:

(I-a)

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound is of Formula I-b:

(I-b) or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein B is an aromatic monocyclic ring or a bicyclic ring,

wherein at least one of the rings in the bicyclic ring is aromatic,

wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the monocyclic ring or bicyclic ring is optionally substituted with (R^d)_m.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, and -OR, wherein -OR does not result in an O in the g-position relative to C(=Z).

6. The compound of any one of claims 1-3, wherein the compound is of Formula I-c:

(I-c)

or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-5, wherein the compound is of Formula I-d-l:

(I-d-l)

or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl, optionally substituted with one or more R^a.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl.

10. The compound of of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted.

11. The compound of any one of claims 1-10, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-6 and 8, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound is the second eluting enantiomer when separated by the method of Examples 10-1 and 10-2.

14. The compound of any one of claims 1-5 and 8, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1, 2, 4, 5, and 8, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-5, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Description:

ACTIVATING PYRUVATE KINASE R

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of United States Provisional Application No. 62/733,546, filed September 19, 2018, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] This disclosure relates to novel chemical compositions for activating pyruvate kinase (PKR).

BACKGROUND

[0003] Pyruvate Kinase (PK) converts phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and adenosine triphosphate (ATP), respectively, which is the final step in glycolysis. In humans, four PK isoforms are expressed by two structural genes. The PKLR gene encodes PKR and PKL, tissue specific isoforms expressed in erythroid cells and liver cells, respectively. The PKM gene codes for isoforms PKM1, expressed in brain and skeletal muscle, and PKM2 (M2-type pyruvate kinase), expressed in fetal and most adult tissues except erythroid cells.

[0004] Mutations in the PKLR gene can lead to pyruvate kinase deficiency (PKD), an autosomal recessive disorder, which is the most frequent enzymatic defect of the glycolytic pathway in erythrocytes. Over 200 different mutations have been identified on the structural PKLR gene. Generally, most PKD patients are heterozygous with two different mutant alleles, but homozygous mutations have also been described. Clinical symptoms of PKD vary considerably from mild to severe anemia. Mutations can reduce PK enzymatic activity or decrease PK protein stability. Pathological manifestations are usually observed when enzyme activity falls below 25% normal PK activity, and severe disease has been associated with a high degree of reticulocytosis. Although the global incidence of PKD is unknown, it has been estimated at 51 cases per million in North America.

[0005] Currently, there is no definitive treatment for severe PKD. Although splenectomy can be clinically useful in patients with severe disease, in some cases, allogeneic hematopoietic transplantation is required. In these patients, hematopoietic stem cell (HSC) gene therapy might be a good and more effective treatment. Gene therapy strategies for PKD have been addressed in animal models demonstrating that introduction of the correct version of the human PKLR gene into hematopoietic stem cells using retroviral vectors alleviates the disease. Although bone marrow transplant (BMT) or gene therapy strategies would be definitive treatments of the disease, they have yet to be realized clinically, and important adverse effects are associated with both approaches.

[0006] There remains a need for strategies to improve the treatment of diseases related to PKR, such as PKD, including the discovery and development of PKR activating small molecules. PKR exists in both a dimeric and tetrameric state, but functions most efficiently as a tetramer. Small molecules have been shown to be capable of shifting the equilibrium of PKR to the tetrameric (most active) form, providing a mechanistic rationale for their use as therapy for PKD-associated hemolytic anemia. Thus, there is a need for PKR activating compounds, useful for treating diseases and disorders associated with modulation of PKR and/or PKM2.

SUMMARY

[0007] The disclosure relates in part to compounds and compositions useful for activating PKR, including the discvovery of a novel compound active with wild type (wt) PKR and/or mutant isozyme forms of PKR. For example, compounds and methods provided herein can be used for activating wild type PKR isozyme and/or a mutant PKR isozyme. Examples of mutant PKR isozyme include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q, I90N, and R490W. The invention is based in part on the discovery of a novel compound demonstrating activation of (wt) PKR and the G332S and R510Q mutant forms of PKR.

[0008] A method for treating pyruvate kinase deficiency (PKD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of: (a) compound of Formula (I) or a pharmaceutically acceptable salt thereof; (b) a composition comprising a compound of Formula (I) or a salt thereof and a carrier; or (c) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to thereby treat PKD in the subject. The method can include or result in activating one or more isozymes of pyruvate kinase. One or more isozymes of pyruvate kinase can be selected from PKR, PKM2, and PKL; the method can also include or result in activating a mutant PKR isozyme.

[0009] One aspect of this invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl or monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR ₂,

-NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R\ -C(0)0R, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂,

-Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

R ¹ and R ² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-C ₆alkynyl, -(CR ^bR ^c) _nC ₃-Ci ₂cycloalkyl, -(CR ^bR ^c) _nC ₄-Ci ₂cycloalkenyl,

wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cg alkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, oxo, and -OR, wherein -OR does not result in an O in the g-position relative to

C(=Z),

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, wherein each heterocyclyl is 3- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cyeloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, and

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and

R ^b and R ^c are each independently selected from the group consisting of— H, halogen, and -Ci-Cgalkyl; each n is independently 0, 1, 2, 3, or 4;

B is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with (R ^d) _m, and

when the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z);

each R ^d is independently selected from the group consisting of halogen, oxo, -OR, -OC(0)R’, -NR2, -NRC(0)R’, -NRS(0) ₂R’, -CN, -NO2, -SR, -C(0)R\ -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci- Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C _t-Cncycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

or R ³ and R ⁴, R ⁵ and R ⁶, R ⁷ and R ⁸, R ⁹ and R ¹⁰, or combinations thereof, combine with the carbon to which they are attached to form oxo, a Cs-Cscycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(C 1 -Cgalkyl), -N(Ci-C ₆alkyl) ₂, -Ci-C ₆alkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, -C ₃-Ci ₂cycloalkyl, -C _t-Cncycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O(Ci-Cgalkyl), -NH(Ci-Cgalkyl), or -N(Ci-C ₆alkyl) ₂; and

each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-C ₆alkyl) ₂.

[0010] Another aspect of this invention relates to compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R’, -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

R ¹, R ², and B are each independently -H, halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -OR,

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cyeloalkyl, or a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S,

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z),

wherein each cycloalkyl or heterocyclyl is optionally fused with a phenyl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

each R ^b and R ^c is independently selected from the group consisting of -H, -Ci-Cgalkyl, and halogen; each n is independently 0, 1, 2, 3, or 4;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C4-Ci2Cyeloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, -(CR ^bR ^c) _nCg-Ci4aryl, -(CR ^bR ^c) _nO(Cg-C i4aryl), and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

provided that the compound is other than:

[0011] Another aspect of this invention relates to compounds of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR2, -NRC(0)R’, -NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C4-Ci2Cyeloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

B is a ring selected from the group consisting of -C6-Ci4aryl and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)0R, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cg alkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, or -OR;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH ₂, -NH(Ci-Cgalkyl), -N(Ci-C ₆alkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-C ₆alkynyl, -C ₃-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl) ₂; and

S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-C ₆alkyl) ₂.

[0012] Another aspect of this invention relates to compounds of Formula IV :

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

-C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cycloalkyl, -C4-Ci2Cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

X is O or NR ^e;

R ^e is -H or -Ci-Cgalkyl;

B is -H, or a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR2, -NRC(0)R’, -NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)0R, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-C ₆alkyl, -CVC _galkenyl. -CVC _galkynyl. -C3-Ci2cycloalkyl, -C4-Ci2cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, G- Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

R ¹ and R ² are each independently -H, halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl,

wherein each heterocyclyl is 3- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cycloalkyl, or a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -OR, and oxo; or R ^e and R ¹ combine with the nitrogen to which they are attached to form a 3 - to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, oxo, -OR, and -(CR ^bR ^c) _nCg-Ci ₄aryl;

or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form Cg-Ci ₄aryl or 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, or -OR; each R ^b and R ^c is independently selected from the group consisting of -H, -Ci-Cgalkyl, and halogen; each n is independently 0, 1, 2, 3, or 4;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cgalkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(Ci-Cgalkyl), -N(Ci-C ₆alkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-C ₆alkynyl, -C ₃-Ci ₂cycloalkyl, -C _t-Cncycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl) ₂; and

[0013] Another aspect of this invention relates to compounds of Formula I, II, III, or IV that are PKR

Activating Compounds. In some embodiments, a PKR Activating Compound as used herein refers to a compound having one or more of the following characteristics when tested according to the Luminescence Assay Protocol of Example 24 below: (1) an AC50 value of less than 40 mM; (2) a maximum % Fold (MAX%Fold) value of greater than 75%; and/or (3) a % Fold value at 1.54 pM compound concentration (%Fold@l .54 pM) of at least 75%. In some embodiments, the PKR Activating Compound has: (1) an AC50 value of less than 0.1 pM, 0.1-1.0 pM, or 1.01-40 pM; (2) a MAX%Fold of 75%-250%, 251-500%, or 75%-500%; and/or (3) a %Fold@l .54 pM of 75%-250%, 251-500%, or 75%-500%. In some embodiments, a PKR Activating Compound has (1) an AC50 value of less than 1.0 pM; (2) a MAX%Fold of 75%-500%; and/or (3) a %Fold@l .54 pM of 75%-500%. In some embodiments, the Luminescence Assay Protocol of Example 24 is performed with wild type (wt) PKR, G332S mutant form of PKR or R510Q mutant form of PKR. In some embodiments, a PKR Activating Compound is a compound of Formula I, II, III, or IV.

BRIEF DESCRIPTION OF THE DRAWING

[0014] FIG. 1 shows an exemplary dose-response curve for compounds disclosed herein. Dose- response curves may be generated using the standard four parameter fit algorithm of ActivityBase XE Runner to determine MAX%Fold, MIN%Fold, slope and AC50. MAX%Fold is the highest % fold increase observed at any concentration of compound, and MIN%Fold is the lowest % fold increase observed at any concentration of compound. The AC50 value for a compound is the concentration (mM) corresponding to the midway between the maximum and minimum values of the four parameter logistic curve fit (i.e., at which the % fold increase along the four parameter logistic curve fit is halfway between MAX%Fold and MIN%Fold (% Fold Midpoint). Another useful parameter for evaluating compounds of this disclosure is %Fold@l .54 mM, which is the % fold increase at a compound concentration of 1.5 pM (e.g., 1.54 pM). X-axis and y-axis not necessarily to scale.

DETAILED DESCRIPTION

[0015] One aspect of this invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt thereof,

wherein A, B, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, and Z are as defined above for Formula I and

described in classes and subclasses herein, both singly and in combination.

[0016] In some embodiments, compounds are provided that are compounds of Formula I-a:

(I-a)

or a pharmaceutically acceptable salt thereof, wherein A, B, R ¹, and R ² are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0017] In some embodiments, compounds are provided that are compounds of Formula I-b:

(I-b)

or a pharmaceutically acceptable salt thereof,

wherein A, B, and R ¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0018] In some embodiments, compounds are provided that are compounds of Formula I-c:

or a pharmaceutically acceptable salt thereof,

wherein A is as defined above for Formula I and described in classes and subclasses herein, both singly and in combination, and

wherein m is 0, 1, 2, 3, 4, or 5.

[0019] In some embodiments, compounds are provided that are compounds of Formula I-d-l :

(I-d-l)

or a pharmaceutically acceptable salt thereof,

wherein A, B, and R ¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0020] In some embodiments, compounds are provided that are compounds of Formula I-d-2:

(I-d-2)

or a pharmaceutically acceptable salt thereof,

wherein A, B, and R ¹ are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0021] In some embodiments, a compound of Formula I-a is provided wherein:

A is phenyl or a monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -NRC(0)R’, -CN, -S(0) ₂NR ₂, and -Ci-Cgalkyl,

wherein each alkyl is optionally substituted with one or more halogen;

R ¹ and R ² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, and -OR; B is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with (R ^d) _m,

and when the ring is partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z);

each R ^d is independently selected from the group consisting of halogen, -C i-Cgalkyl. and -OR,

wherein each alkyl is optionally substituted with one or more halogen;

m is 0, 1, or 2;

each R is independently selected from the group consisting of -H and -Ci-Cgalkyl,

wherein each alkyl is optionally substituted with one or more halogen; and

each R’ is -Ci-Cgalkyl.

[0022] In some embodiments, a compound of Formula I-a is provided wherein:

A is phenyl, pyridyl, thiophenyl, imidazolyl, isoxazolyl, or pyrazolyl,

wherein each phenyl, pyridyl, thiophenyl, imidazolyl, isoxazolyl, or pyrazolyl is optionally substituted with one or more R ^a; each R ^a is independently selected from the group consisting of fluoro, chloro, methyl, -CF3, -OMe, -OiPr, -0CF3, -OCF ₂H, -NHC(0)Me, -CN, and -S0 ₂NH ₂;

R ¹ and R ² are each independently selected from the group consisting of -H, fluoro, methyl, ethyl, isopropyl, and -OH;

B is a monocyclic or bicyclic 3- to lO-membered ring selected from the group consisting of:

wherein the ring is optionally substituted with (R ^d) _m;

each R ^d is independently selected from the group consisting of fluoro, chloro, methyl, -CF ₃, and -OMe; and m is 0, 1, or 2.

[0023] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, A is a phenyl or monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, optionally substituted with one or more R ^a. In some embodiments, A is phenyl optionally substituted with one or more R ^a. In some embodiments, A is monocyclic 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S (e.g., pyridyl, thiophenyl, imidazolyl, isoxazolyl, or pyrazolyl), optionally substituted with one or more R ^a. In some embodiments, A is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more R ^a. In some embodiments, A is phenyl or pyridyl, each optionally substituted with one or more R ^a. In some embodiments, A is pyridyl. In some embodiments, A is unsubstituted.

[0024] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, each R ^a is independently selected from the group consisting of halogen (e.g., fluoro or chloro), -OR (e.g., -OMe, -OiPr, -OCF3, or -OCF2H), -NRC(0)R’ (e.g., -NHC(O)Me), -CN, -S(0) ₂NR ₂ (e.g., -S0 ₂NH ₂), and -Ci-C ₆alkyl (e.g., methyl or -CF3), wherein each alkyl is optionally substituted with one or more halogen. In some embodiments, each R ^a is independently selected from the group consisting of halogen (e.g., fluoro or chloro), -OR (e.g., - OMe, -OiPr, or -OCF ₂H), -CN, -Ci-Cgalkyl (e.g., methyl or -CF3). In some embodiments, each R ^a is independently selected from the group consisting of halogen (e.g., fluoro), -Ci-Cgalkyl (e.g., methyl), and -OR (e.g., -OMe or -OCF ₂H).

[0025] In some embodiments of Formula I, Z is O or S. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NR (e.g., NH ₂, NOH, or NNH ₂). [0026] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, R ¹ and R ² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, -OR, -OC(0)R’,

) _nNR ₂, -(CR ^bR ^c) _nNRC(0)R’, In some embodiments, R ¹ and R ² are each independently selected from the group consisting of -H, halogen (e.g., fluoro), -Ci-Cgalkyl (e.g., methyl, ethyl, or isopropyl), and -OR (e.g., -OH). In some embodiments, R ¹ and R ² are each independently selected from the group consisting of -H, halogen (e.g., fluoro), and -OR (e.g., -OH). In some embodiments, one of R ¹ and R ² is -H. In some embodiments, R ¹ is -OH and R ² is -H.

[0027] In some embodiments of Formula I and I-a, R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci ₂cycloalkyl, or 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, oxo, and -OR, wherein -OR does not result in an O in the g-position relative to C(=Z). In some embodiments of Formula I and I-a, R ¹ and R ² combine with the carbon to which they are attached to form a C3-Cgcycloalkyl or 3- to 6-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, oxo, and -OR, wherein -OR does not result in an O in the g-position relative to C(=Z).

[0028] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, R ^b and R ^c are each -H. In some embodiments, R ^b and R ^c are each independently -H or halogen (e.g., fluoro). In some embodiments, R ^b and R ^c are each independently -H or -Ci-Cgalkyl (e.g., methyl).

[0029] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, each n is independently 0, 1, or 2. In some embodiments, each n is 0 or 1. In some embodiments, each n is 0. In some embodiments, each n is 1. In some embodiments, each n is 2.

[0030] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is:

(i) a monocyclic 3- to 8-membered ring, comprising a Cs-Cscycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with (R ^d) _m, and

wherein the ring comprising a 3- to 8-membered heterocyclyl does not contain an O in the g-position relative to C(=Z); or (ii) abicyclic 6- to l4-membered ring, comprising a C3-Ciocycloalkyl, 3- to 1 l-membered heterocyclyl, phenyl, or 5- to 1 l-membered heteroaryl ring,

wherein the ring is fused to an aromatic, saturated, or partially saturated 3- to 8-membered carbocyclic or an aromatic, saturated, or partially saturated 3- to 8-membered heterocyclic ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with (R ^d) _m, and

wherein the ring comprising a 3- to 1 l-membered heterocyclyl does not contain an O in the g-position relative to C(=Z).

[0031] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is an aromatic monocyclic ring or a bicyclic ring wherein at least one of the rings is aromatic, and wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the monocyclic ring or bicyclic ring is optionally substituted with (R ^d) _m. In some embodiments, B is phenyl optionally substituted with (R ^d) _m. In some embodiments, B is unsubstituted phenyl. In some embodiments, B is phenyl fused to a saturated or partially saturated 5- to 8-membered heterocyclic ring. In some embodiments, B is a monocyclic or bicyclic heteroaryl ring, wherein the ring contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the ring is optionally substituted with (R ^d) _m.

[0032] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is a monocyclic or bicyclic 3- to lO-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with (R ^d) _m, and

when the ring is partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z).

[0033] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is a monocyclic or bicyclic 3- to lO-membered ring selected from the group consisting of:

wherein the ring is optionally substituted with (R ^d) _m.

[0034] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is a monocyclic or bicyclic 3- to lO-membered ring selected from the group consisting of: and T N¾ ^y> ,

wherein the ring is optionally substituted with (R ^d) _m.

[0035] In some embodiments of Formula I, I-a, I-b, I-d-l, and I-d-2, B is a monocyclic or bicyclic 3- to lO-membered ring selected from the group consisting of:

wherein the ring is optionally substituted with (R ^d) _m.

[0036] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, each R ^d is independently selected from the group consisting of halogen, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, heterocyclyl, -OR, and -NR ₂, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen. In some embodiments, each R ^d is independently selected from the group consisting of halogen (e.g., fluoro or chloro), -C _|-G,alkyl (e.g., methyl or -CF3), and -OR (e.g., -OMe), wherein each alkyl is optionally substituted with one or more halogen. In some embodiments, each R ^d is independently selected from the group consisting of halogen (e.g., fluoro), -Ci-Cgalkyl (e.g., methyl), and -OR (e.g., -OMe).

[0037] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0038] In some embodiments of Formula I, R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each -H. In some embodiments, one of R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ is -Ci-Cgalkyl (e.g., methyl) and the others are -H.

[0039] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, and 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen. In some embodiments, each R is independently selected from the group consisting of -H and -Ci-Cgalkyl (e.g., methyl or isopropyl), wherein each alkyl is optionally substituted with one or more halogen (e.g., fluoro).

[0040] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, each R’ is independently -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, or 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen. In some embodiments, each R’ is -Ci-Cgalkyl (e.g., methyl).

[0041] In some embodiments of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, the compound is other than:

For example, some embodiments provide a compound of any one or more of Formula I, I-a, I-b, I-c, I-d-l, and I-d-2, other than the compound of the formula:

[0042] Another aspect of this invention relates to compounds of Formula II:

or a pharmaceutically acceptable salt thereof,

wherein A, B, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, and Z are as defined above for Formula II and

described in classes and subclasses herein, both singly and in combination.

[0043] In some embodiments, compounds are provided that are compounds of Formula Il-a:

(II-a)

or a pharmaceutically acceptable salt thereof,

wherein A, B, R ¹, and R ² are as defined above for Formula II and described in classes and subclasses herein, both singly and in combination.

[0044] In some embodiments, compounds are provided that are compounds of Formula II-b-l :

(II-b-l)

or a pharmaceutically acceptable salt thereof,

wherein A is as defined above for Formula II and described in classes and subclasses herein, both singly and in combination,

wherein R ¹ is -H, halogen, -CVC _galkyl. -CVC _galkenyl. or -CVC _galkynyl.

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, and whe

[0045] In some embodiments, compounds are provided that are compounds of Formula II-b-2:

(II-b-2)

or a pharmaceutically acceptable salt thereof,

wherein A is as defined above for Formula II and described in classes and subclasses herein, both singly and in combination,

wherein R ¹ is -H, halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, or -C ₂-Cgalkynyl, wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, and whe

[0046] In some embodiments, a compound of Formula II -a is provided wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of -Ci-Cgalkyl and -OR;

R ¹, R ², and B are each independently -H, -CVC _galkyl. -OR, -(CR ^bR ^c) _nNR ₂, -(CR ^bR ^c) _nNRS(0) ₂R’, or -(CR ^bR ^c) _nC(0)OR,

wherein each alkyl is optionally substituted with one or more halogen;

or R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci ₂cycloalkyl or 3- to 14- membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S,

wherein the heterocyclyl does not contain an O in the g-position relative to C(=0),

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of -Cgaryl, and -C(0)R’, and

wherein each cycloalkyl or heterocyclyl is optionally fused with a Cgaryl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

each R ^b and R ^c is -H;

each n is independently 0 or 1 ;

each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, and Cg-Ci4aryl,

wherein each aryl is optionally substituted with one or more halogen or -O(Ci-Cgalkyl); and each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -(CR ^bR ^c) _nCg-Ci4aryl, and -(CR ^bR ^c)„0(Cg-Ci ₄aryl),

wherein each alkyl or aryl is optionally substituted with one or more -O(Ci-Cgalkyl).

[0047] In some embodiments, a compound of Formula II -a is provided wherein:

A is a monocyclic or bicyclic 3- to lO-membered ring selected from:

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of methyl and -OCHF2;

R ¹, R ², and B are each independently -H, methyl, ethyl, -CH2CHF2, propyl, -OR, -CH2NH2, -CFbNMe2, -NHS(0) ₂Me, or -CH ₂C(0)0Me,

wherein each methyl or ethyl is optionally substituted with one or more halogen;

or R ¹ and R ² combine with the carbon to which they are attached to form a cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, or chromanyl,

wherein each cyclopropyl, cyclopentyl, cyclohexyl, or pyrrolidinyl is optionally substituted with one or more substituents selected from the group consisting of -Cgaryl, and -C(0)R’, and

wherein each tetrahydrofuranyl or chromanyl does not contain an O in the g-position relative to C(=0); each R is independently selected from the group consisting of -H, methyl, and phenyl,

wherein each phenyl is optionally substituted with one or more fluoro or -OMe; and

each R’ is independently selected from the group consisting of methyl, phenyl, -CFhphenyl, and -CH ₂0(phenyl),

wherein each methyl or phenyl is optionally substituted with one or more -OMe or -OEt.

[0048] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, A is:

(i) a monocyclic 3- to 8-membered ring, comprising a CVCxcycloalkyl. 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with one or more R ^a; or

(ii) a bicyclic 6- to l4-membered ring, comprising a C3-Ciocycloalkyl, 3- to l l-membered heterocyclyl, phenyl, or 5- to 1 l-membered heteroaryl ring,

wherein the ring is fused to an aromatic, saturated, or partially unsaturated 3- to 8-membered carbocyclic or an aromatic, saturated, or partially unsaturated 3- to 8-membered heterocyclic ring, wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with one or more R ^a.

[0049] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, A is an aromatic monocyclic ring or a bicyclic ring wherein at least one of the rings is aromatic, and wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the monocyclic ring or bicyclic ring is optionally substituted with one or more R ^a.

[0050] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, A is a monocyclic or bicyclic 3- to lO-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a.

[0051] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, A is a monocyclic or bicyclic 3- to lO-membered ring selected from:

wherein the ring is optionally substituted with one or more R ^a. In some embodiments, A is a bicyclic ring

selected from: wherein the ring is optionally substituted with one or more R ^a. In some embodiments, A is unsubstituted.

[0052] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, each R ^a is independently selected from the group consisting of halogen, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, -OR, and -NR ₂, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen. In some embodiments of Formula II and Il-a, each R ^a is independently selected from the group consisting of -Ci-Cgalkyl (e.g., methyl) and -OR (e.g., -OCHF2).

[0053] In some embodiments of Formula II, Z is O or S. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NR (e.g., NFF, NOH, or NNFF).

[0054] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, R ¹, R ², and B are each independently -H, halogen, -Ci-Cgalkyl, -OR, -OC(0)R’, -OS(0) ₂R’, -0S(0) ₂NR ₂, -OC(0)NR ₂, -OC(0)OR, -(CR ^bR ^c) _nNR ₂, -(CR ^bR ^c) _nNRC(0)R’, -(CR ^bR ^c)nNRS(0) ₂R\ -(CR ^bR ^c) _nNRC(0)NR ₂, -(CR ^bR ^c) _nNRC(0)OR, or -(CR ^bR ^c) _nC(0)OR,

wherein each alkyl is optionally substituted with one or more halogen; or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cycloalkyl, or a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z),

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -OR, oxo, -Cgaryl, and -C(0)R’, and wherein each cycloalkyl or heterocyclyl is optionally fused with a Cgaryl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

[0055] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, R ¹, R ², and B are each independently -H, -Ci-Cgalkyl (e.g., methyl ethyl, propyl, or -CH2CHF2), -OR, -(CR ^bR ^c) _nNR2 (e.g., -CH2NH2 or -CH ₂NMe ₂), -(CR ^bR ^c)nNRS(0) ₂R’ (e.g, -NHS(0) ₂Me), or -(CR ^bR ^c) _nC(0)OR (e.g, -CH ₂C(0)OMe);

or R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci2cycloalkyl (e.g., cyclopropyl, cyclopentyl, or cyclohexyl) or 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S (e.g., pyrrolidinyl, tetrahydrofuranyl, or chromanyl),

wherein the heterocyclyl (e.g., tetrahydrofuranyl or chromanyl) does not contain an O in the g-position relative to C(=Z), and

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of -Cgaryl, and -C(0)R’ .

[0056] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, R ¹, R ², and B are each independently -H, -Ci-Cgalkyl (e.g., methyl ethyl, propyl, or -CH2CHF2), -OR, -(CR ^bR ^c) _nNR2 (e.g., -CH2NH2 or -CH ₂NMe ₂), -(CR ^bR ^c)nNRS(0) ₂R’ (e.g, -NHS(0) ₂Me), or -(CR ^bR ^c) _nC(0)OR (e.g, -CH ₂C(0)OMe). In some embodiments, R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci2Cycloalkyl (e.g., cyclopropyl, cyclopentyl, or cyclohexyl) or 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of N and S (e.g., pyrrolidinyl, tetrahydrofuranyl, or chromanyl), wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of -Cgaryl, and -C(0)R’ .

[0057] In some embodiments of Formula II, II -a, II-b-l, and II-b-2, R ^b and R ^c are each -H. In some embodiments, R ^b and R ^c are each independently -H or halogen (e.g., fluoro). In some embodiments, R ^b and R ^c are each independently -H or -Ci-Cgalkyl (e.g., methyl). [0058] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, each n is independently 0, 1, or 2. In some embodiments, each n is independently 0 or 1. In some embodiments, each n is 0. In some embodiments, each n is 1. In some embodiments, each n is 2.

[0059] In some embodiments of Formula II, R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each -H. In some embodiments, one of R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ is -Ci-Cgalkyl (e.g., methyl) and the others are -H.

[0060] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and Cg-C^aryl, wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogen or -O(Ci-Cgalkyl). In some embodiments, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl (e.g., methyl), and Cg-C^aryl (e.g., phenyl, or naphthyl or anthracenyl), wherein each alkyl or aryl is optionally substituted with one or more halogen (e.g., fluoro) or -O(Ci-Cgalkyl) (e.g., -OMe). In some embodiments, each R is independently -H or methyl. In some embodiments, each R is -H.

[0061] In some embodiments of Formula II, Il-a, II-b-l, and II-b-2, each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C3-Ci2cycloalkyl, 3- to l4-membered heterocyclyl containing 1- 4 heteroatoms independently selected from the group consisting of O, N, and S, -(CR ^bR ^c) _nCg-Ci4aryl, or -(CR ^bR ^c)nO(Cg-C i4aryl), wherein each alkyl, cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more halogen. In some embodiments, each R’ is independently selected from the group consisting of -Ci-Cgalkyl (e.g., methyl), -(CR ^bR ^c) _naryl (e.g., phenyl or -CFhphenyl), or -(CR ^bR ^c) _nO(aryl) (e.g., -CFhCKphenyl)), wherein each methyl or phenyl is optionally substituted with one or more -OMe or -OEt. In some embodiments, each R’ is methyl.

[0062] Another aspect of this invention relates to compounds of Formula III:

or a pharmaceutically acceptable salt thereof,

wherein A, B, Z, R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are as defined above for Formula III and described in classes and subclasses herein, both singly and in combination.

[0063] In some embodiments, compounds are provided that are compounds of Formula III -a:

(Ill-a)

or a pharmaceutically acceptable salt thereof,

wherein A and B are as defined above for Formula III and described in classes and subclasses herein, both singly and in combination.

[0064] In some embodiments, a compound of Formula III-a is provided wherein:

A is a bicyclic 3- to l4-membered ring,

wherein the ring is aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S;

B is a ring selected from the group consisting of -C6-Ci4aryl and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of -Ci-Cgalkyl, -OR, and -NR ₂,

wherein each alkyl is optionally substituted with one or more halogen; and

each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and

wherein each alkyl is optionally substituted with one or more halogen.

[0065] In some embodiments, a compound of Formula III-a is provided wherein:

A is benzofuranyl;

B is a ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl, and pyrazolyl,

wherein the ring is optionally substituted with one or more R ^d; and

each R ^d is independently selected from the group consisting of methyl, -CF3, -OH, -OCH2CF3, and -NH(pyridyl).

[0066] In some embodiments of Formula III and III-a, A is:

(i) a monocyclic 3- to 8-membered ring, comprising a Cs-Cscycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the ring is optionally substituted with one or more R ^a; or

(ii) a bicyclic 6- to l4-membered ring, comprising a C3-Ciocycloalkyl, 3- to l l-membered heterocyclyl, phenyl, or 5- to 1 l-membered heteroaryl ring,

wherein the ring is optionally substituted with one or more R ^a.

[0067] In some embodiments of Formula III and III-a, A is an aromatic monocyclic ring or a bicyclic ring wherein at least one of the rings is aromatic, and wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the monocyclic ring or bicyclic ring is optionally substituted with one or more R ^a. In some embodiments, A is a bicyclic ring wherein at least one of the rings is aromatic, and wherein the bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the bicyclic ring is optionally substituted with one or more R ^a. In some embodiments, A is an aromatic monocyclic ring, wherein the monocyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the monocyclic ring is optionally substituted with one or more R ^a. In some embodiments, A is benzofuranyl. In some embodiments, A is unsubstituted.

[0068] In some embodiments of Formula III and III-a, each R ^a is independently selected from the group consisting of halogen, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, 3- to l4-membered heterocyclyl containing 1- 4 heteroatoms independently selected from the group consisting of O, N, and S, -OR, and -NR2, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen.

[0069] In some embodiments of Formula III, Z is O or S. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NR (e.g., NFh, NOH, or NNFh).

[0070] In some embodiments of Formula III and III-a, B is a ring selected from the group consisting of phenyl and 5- to 6-membered heteroaryl (e.g., pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl, or pyrazolyl) containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is a 5- to 6- membered heteroaryl ring (e.g., pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl, or pyrazolyl) containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R ^d.

[0071] In some embodiments of Formula III and III-a, each R ^d is independently selected from the group consisting of halogen, -CVCgalkyl. -C3-Ci2cycloalkyl, 3- to l4-membered heterocyclyl containing 1- 4 heteroatoms independently selected from the group consisting of O, N, and S, -OR, and -NR2, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen. In some embodiments , each R ^d is independently selected from the group consisting of -Ci-Cgalkyl (e.g., methyl or -CF3), -OR (e.g., -OH, -OCH2CF3), and -NR2 (e.g., -NH(pyridyl)), wherein each alkyl is optionally substituted with one or more halogen (e.g., fluoro).

[0072] In some embodiments of Formula III, R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each -H. In some embodiments, one of R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ is -Ci-Cgalkyl (e.g., methyl) and the others are -H.

[0073] In some embodiments of Formula III and III -a, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, -C3-Ci2Cycloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl (e.g., phenyl, naphthyl, or anthracenyl), and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogen. In some embodiments, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl is optionally substituted with one or more halogen. In some embodiments, each R is -H.

[0074] In some embodiments of Formula III and III-a, each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C3-Ci2Cycloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and Cg-C^aryl (e.g., phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogen. In some embodiments, each R’ is -Ci-Cgalkyl.

[0075] Another aspect of this invention relates to compounds of Formula IV :

or a pharmaceutically acceptable salt thereof,

wherein A, B, X, Z, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0076] In some embodiments, compounds are provided that are compounds of Formula IV-a:

(IV-a)

or a pharmaceutically acceptable salt thereof,

wherein A, B, X, R ¹, and R ² are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0077] In some embodiments, compounds are provided that are compounds of Formula IV-b:

(IV-b)

or a pharmaceutically acceptable salt thereof,

wherein A, B, and X are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0078] In some embodiments, compounds are provided that are compounds of Formula IV-c:

(IV-c)

or a pharmaceutically acceptable salt thereof,

wherein A and B are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0079] In some embodiments, compounds are provided that are compounds of Formula IV-d:

or a pharmaceutically acceptable salt thereof,

wherein A and B are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination. [0080] In some embodiments, compounds are provided that are compounds of Formula IV-e-l:

(IV-e-l)

or a pharmaceutically acceptable salt thereof,

wherein A, B, X, and R ¹ are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0081] In some embodiments, compounds are provided that are compounds of Formula IV-e-2:

(IV-e-2)

or a pharmaceutically acceptable salt thereof,

wherein A, B, X, and R ¹ are as defined above for Formula IV and described in classes and subclasses herein, both singly and in combination.

[0082] In some embodiments, a compound of Formula IV -a is provided wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -CVCgalkyl. and -OR,

wherein each alkyl is optionally substituted with one or more halogen;

X is O or NR ^e;

R ^e is -H;

B is -H or a monocyclic 3- to l4-membered ring,

wherein the ring is saturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of halogen, -Ci-Cgalkyl, and -OR; R ¹ and R ² are each independently -H, -Ci-Cgalkyl, -(CR ^bR ^c) _nC6-Ci4aryl, and -(CR ^bR ^c) _nOR, wherein each aryl is optionally substituted with one or more substituents selected from the group consisting of halogen;

or R ¹ and R ² combine with the carbon to which they are attached to form a 3 - to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ^e and R ¹ combine with the nitrogen to which they are attached to form a 3 - to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is optionally substituted with one or more -OR or -(CR ^bR ^c) _nC6-Ci4aryl; or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form C6-Ci4aryl ring or 5- to l4-membered heteroaryl ring,

wherein each aryl or heteroaryl is optionally substituted with one or more halogen or -Ci-Cgalkyl; each R ^b and R ^c is independently selected from the group consisting of -H;

each n is independently 0, 1, or 2; and

each R is independently selected from the group consisting of -H and -Ci-Cgalkyl,

wherein each alkyl is optionally substituted with one or more halogen.

[0083] In some embodiments, a compound of Formula IV -a is provided wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring selected from:

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of fluoro, methyl, -CF3, -OCHF2, and -OMe; X is O or NR ^e;

R ^e is -H;

B is -H; or a monocyclic 3- to 6-membered ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, pyrazolyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, oxadiazolyl, cyclopropyl, and tetrahydrofuranyl,

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of fluoro, methyl, -OMe, and -OiPr; R ¹ and R ² are each independently -H, methyl, ethyl, isopropyl, -CH ₂(phenyl), -CFFOMc. and -CH ₂CH ₂OMe,

wherein each phenyl is optionally substituted with one or more fluoro;

or R ¹ and R ² combine with the carbon to which they are attached to form a tetrahydrofuranyl;

or R ^e and R ¹ combine with the nitrogen to which they are attached to form a morpholinyl or azetidinyl, wherein the azetidinyl is optionally substituted with one or more -OH or -CH ₂(phenyl);

or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form a phenyl or isoxazolyl,

wherein each phenyl or isoxazolyl is optionally substituted with one or more fluoro or methyl;

each R ^b and R ^c is -H;

each n is independently 0, 1, or 2; and

each R is independently -H, methyl, isopropyl or -CHF ₂.

[0084] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, A is:

(i) a monocyclic 3- to 8-membered ring, comprising a CVCxcycloalkyl. 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with one or more R ^a; or

(ii) a bicyclic 6- to l4-membered ring, comprising a C3-Ciocycloalkyl, 3- to l l-membered heterocyclyl, phenyl, or 5- to 1 l-membered heteroaryl ring,

wherein the ring is fused to an aromatic, saturated, or partially unsaturated 3- to 8-membered carbocyclic or an aromatic, saturated or partially unsaturated 3- to 8-membered heterocyclic ring, wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with one or more R ^a.

[0085] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, A is an aromatic monocyclic ring or a bicyclic ring wherein at least one of the rings is aromatic, and wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the monocyclic ring or bicyclic ring is optionally substituted with one or more R ^a. In some embodiments, A is a monocyclic or bicyclic 5- to lO-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and wherein the ring is optionally substituted with one or more R ^a. [0086] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, A is a ring selected from the group consisting of:

wherein the ring is optionally substituted with one or more R ^a.

[0087] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, A is selected from the group consisting of:

wherein the ring is optionally substituted with one or more R ^a.

[0088] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, A is selected from the group consisting of:

wherein the ring is optionally substituted with one or more R ^a. In some embodiments, A is unsubstituted.

[0089] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, each R ^a is independently selected from the group consisting of halogen, -OR, and -NR ₂, -Ci-Cgalkyl, -C3- Cncycloalkyl, and 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen. In some embodiments, each R ^a is independently selected from the group consisting of halogen (e.g., fluoro), -Ci-Cgalkyl (e.g., methyl or -CF3), and -OR (e.g., -OMe or -OCHF2). In some embodiments, each R ^a is -OCHF2.

[0090] In some embodiments of Formula IV, Z is O or S. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NR (e.g., NFF, NOH, or NNFF).

[0091] In some embodiments of Formula IV, IV-a, IV-b, IV-e-l, and IV-e-2, X is O or NH. In some embodiments, X is O. In some embodiments, X is NR ^e. In some embodiments, X is NH. [0092] In some embodiments of Formula IV, IV-a, IV-b, IV-e-l, and IV-e-2, R ^e is -H. In some embodiments, R ^e is -Ci-Cgalkyl (e.g., methyl).

[0093] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, B is:

(i) -H; or

(ii) a monocyclic 3- to 8-membered ring, comprising a Cs-Cscycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 8-membered heteroaryl ring,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the ring is optionally substituted with one or more R ^d; or

(iii) a bicyclic 6- to l4-membered ring, comprising a C3-Ciocycloalkyl, 3- to l l-membered heterocyclyl, phenyl, or 5- to 1 l-membered heteroaryl ring,

wherein the ring is optionally substituted with one or more R ^d.

[0094] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, B is -H; or a monocyclic 3- to 8-membered ring, wherein the ring is saturated or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is -H; or a monocyclic 3- to 6- membered ring, wherein the ring is saturated or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is -H. In some embodiments, B is a monocyclic 3- to 6-membered ring, wherein the ring is saturated or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is unsubstituted.

[0095] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, B is -H, or a monocyclic 3- to 6-membered ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, pyrazolyl, thiophenyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, oxadiazolyl, cyclopropyl, and tetrahydrofuranyl, wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is -H, or a monocyclic 3- to 6-membered ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, pyrazolyl, isoxazolyl, thiazolyl, oxazolyl, and tetrahydrofuranyl, wherein the ring is optionally substituted with one or more R ^d. In some embodiments, B is a monocyclic 3- to 6-membered ring selected from the group consisting of phenyl and furanyl, wherein the ring is optionally substituted with one or more R ^d.

[0096] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, each R ^d is independently selected from the group consisting of halogen, -OR,-NR2, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, and 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more halogen. In some embodiments, each R ^d is independently selected from the group consisting of halogen (e.g., fluoro), -Ci-Cgalkyl (e.g., methyl), and -OR (e.g., -OMe or -OiPr).

[0097] In some embodiments of Formula IV and IV-a, R ¹ and R ² are each independently:

-H, halogen, -Ci-Cgalkyl, -(CR ^bR ^c) _nC ₃-Ci2cycloalkyl, -(CR ^bR ^c) _nheterocyclyl, -(CR ^bR ^c) _nCg-Ci ₄aryl,

-(CR ^bR ^c) _nheteroaryl, or -(CR ^bR ^c) _nOR,

wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -OR, and oxo, wherein each heterocyclyl is 3- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci2Cyeloalkyl or 3- to 14- membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -OR, and oxo;

or R ^e and R ¹ combine with the nitrogen to which they are attached to form a 3 - to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is optionally substituted with one or more halogen, -Ci-Cgalkyl, oxo, -OR, and -(CR ^bR ^c) _nCg-Ci ₄aryl;

or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form a Cg-Ci ₄ aryl ring or a 5- to l4-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, or -OR.

[0098] In some embodiments of Formula IV and IV-a, R ¹ and R ² are each independently -H, halogen, -Ci-Cgalkyl, -(CR ^bR ^c) _nC3-Ci2cycloalkyl, -(CR ^bR ^c) _nheterocyclyl, -(CR ^bR ^c) _naryl, -(CR ^bR ^c) _nheteroaryl, or -(CR ^bR ^c) _nOR, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -OR, and oxo, wherein each heterocyclyl is 3- to l4-membered and contains 1-4 heteroatoms selected from the group consisting of O, N, and S, and wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci2Cyeloalkyl or 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -OR, and oxo. In some embodiments, R ^e and R ¹ combine with the nitrogen to which they are attached to form a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the heterocyclyl is optionally substituted with one or more halogen, -Ci-Cgalkyl, oxo, -OR, and -(CR ^bR ^c) _nCg-Ci4aryl. In some embodiments, R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form Cg-Ci ₄ aryl ring or 5- to 14- membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, or -OR.

[0099] In some embodiments of Formula IV and IV-a, R ¹ and R ² are each independently:

-H, -Ci-Cgalkyl (e.g., methyl, ethyl, or isopropyl), -(CR ^bR ^c) _nCg-Ci4aryl (e.g., -CFhiphenyl)), or

-(CR ^bR ^c) _nOR (e.g., -CFbOMe or -CFFCFFOMc). wherein each aryl is optionally substituted with one or more halogen (e.g., fluoro);

or R ¹ and R ² combine with the carbon to which they are attached to form a tetrahydrofuranyl;

or R ^e and R ¹ combine with the nitrogen to which they are attached to form a morpholinyl or azetidinyl, wherein the azetidinyl is optionally substituted with one or more -OH or -CH2(phenyl);

or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form a phenyl or isoxazolyl,

wherein each phenyl or isoxazolyl is optionally substituted with one or more fluoro or methyl.

[00100] In some embodiments of Formula IV and IV-a, R ¹ and R ² are each independently -H, -Ci-Cgalkyl (e.g., methyl, ethyl, or isopropyl), -(CR ^bR ^c) _nCg-Ci4aryl (e.g., -Qrbiphenyl)), or -(CR ^bR ^c) _nOR (e.g., -CH ₂0Me or -GrhGrbOMe), wherein each aryl is optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, R ¹ and R ² are each -H.

[00101] In some embodiments of Formula IV, IV-a, IV-e-l, and IV-e-2, R ^b and R ^c are each -H. In some embodiments, R ^b and R ^c are each independently -H or halogen (e.g., fluoro). In some embodiments, R ^b and R ^c are each independently -H or -Ci-Cgalkyl (e.g., methyl). [00102] In some embodiments of Formula IV, IV-a, IV-e-l, and IV-e-2, each n is independently 0, 1, or 2. In some embodiments, each n is independently 0 or 1. In some embodiments, each n is 0. In some embodiments, each n is 1. In some embodiments, each n is 2.

[00103] In some embodiments of Formula IV, R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each -H. In some embodiments, one of R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ is -Ci-Cgalkyl (e.g., methyl) and the others are -H.

[00104] In some embodiments of Formula IV, IV-a, IV -b, IV-c, IV-d, IV-e-l, and IV-e-2, each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, -C3-Ci2Cyeloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and Cg-C^aryl (e.g., phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogen. In some embodiments, each R is independently selected from the group consisting of -H or -Ci-Cgalkyl (e.g., methyl, isopropyl, or -CHF2). In some embodiments R is -H.

[00105] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-l, and IV-e-2, each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C3-Ci2cycloalkyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and Cg-C^aryl (e.g., phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogen. In some embodiments, each R’ is -Ci-Cgalkyl.

[00106] In some embodiments, compounds are provided in Table 1 :

Table 1.

aCompounds 8-2 and 8-3 are enantiomers, but absolute stereochemistry is undetermined (*); ^bCompounds 9-4 and 9-5 are enantiomers, but absolute stereochemistry is undetermined (*); ^cCompounds 10-1 and 10- 2 are enantiomers, but absolute stereochemistry is undetermined (*); ^dCompounds 11-1 and 11-2 are enantiomers, but absolute stereochemistry is undetermined (*).

[00107] Unless otherwise stated, it will be appreciated that when“one or more” substituents are recited for a particular variable, it includes one, two, three, four, or more substituents as valency permits.

[00108] In some embodiments of any Formula disclosed herein, a heterocyclyl at the R ¹, R ², or B position does not contain an O in the g-position relative to C(=Z ¹) or C(=0). In some embodiments of any Formula disclosed herein, a heterocyclyl at the R ¹, R ², or B position contains 1-4 heteroatoms independently selected from the group consisting of N and S.

[00109] Unless otherwise stated, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure; for example, the R and S configurations for each stereocenter. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. For example, in some cases Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and/or as a mixture. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[00110] In some embodiments, a compound of Formula I, II, III, or IV is obtained by a process comprising a purification method of Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2. In some embodiments, the compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the I ^st eluting isomer of the purification method. In some embodiments, the compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the 2 ^nd eluting isomer of the purification method. In some embodiments, the compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the 3 ^rd, 4 ^th, 5 ^th, 6 ^th, 7 ^th, or 8 ^th eluting isomer of the purification method.

[00111] In some embodiments, a PKR Activating Compound is obtained by a process comprising a purification method of Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2. In some embodiments, the PKR Activating Compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the I ^st eluting isomer of the purification method. In some embodiments, the PKR Activating Compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the 2 ^nd eluting isomer of the purification method. In some embodiments, the PKR Activating Compound is the obtained by a process comprising a purification method Examples 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1, or 11-2 and is the 3 ^rd, 4 ^th, 5 ^th, 6 ^th, 7 ^th, or 8 ^th eluting isomer of the purification method.

[00112] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, compounds having the present structure including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure.

[00113] The disclosure also provides compound of Formulas I, II, III, and IV that are useful, for example, as analytical tools and/or control compounds in biological assays.

[00114] The compound of Formulas I, II, III, and IV may form salts which are also within the scope of this disclosure. Reference to a compound of Formula I, II, III, or IV herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[00115] The disclosure also includes pharmaceutical compositions comprising one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet or the like). In some embodiments, pharmaceutical compositions reported herein can be provided in an oral dosage form. In some embodiments, the pharmaceutical composition is orally administered in any orally acceptable dosage form. In some embodiments, an oral dosage form of a compound of Formula I, II, III, or IV can be a capsule. In some embodiments, an oral dosage form of a compound of Formula I, II, III, or IV is a tablet. In some embodiments, an oral dosage form comprises one or more fillers, disintigrants, lubricants, glidants, anti-adherents and/or anti-statics. In some embodiments, an oral dosage form is prepared via dry blending. In some embodiments, an oral dosage form is a tablet and is prepared via dry granulation. In some embodiments, a pharmaceutical composition is provided comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided comprising a compound of Formula III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided comprising a compound of Formula IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[00116] The pharmaceutical compositions provided herewith may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, and tablets (e.g., in unit dosage forms). In some embodiments, a compound disclosed herein is formulated for oral administering to the subject at a dose of about 10 mg to about 1000 mg, e.g., as a capsule or tablet containing about 50 mg - about 100 mg of a compound disclosed herein and pharmaceutically acceptable carriers and/or excipients. Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician. Pharmaceutical compositions of a compound disclosed herein may comprise one or more additional excipients and/or carriers, with a compound disclosed herein (e.g., a compound of Formulae I, II, III and/or IV) present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% by weight of the pharmaceutical composition.

[00117] The designations“a”,“b”,“g”,“d”,“e”, etc. are used herein to refer to a position in a molecule relative to a carbonyl group (e.g., C(=Z) or C(=0)), in accordance with standard nomenclature. For example, a carbon in the a-position (or an a-carbon) is a carbon atom in the position adjacent to a carbonyl group; and an oxygen in the b-position (or a b-oxygen) is an oxygen atom in the position two atoms away from a carbonyl group. The scheme below illustrates this nomenclature on an exemplary compound: Methods of Using the Disclosed Compounds

[00118] Another aspect of the present disclosure is the use of compounds of Formula I, II, III, and IV. Compounds of Formula I, II, III, and IV are useful in medicine. For example, compounds and compositions described herein are activators of PKR. Methods of treatment (e.g., by activating PKR and/or PKM2) can comprise administering to a subject in need thereof a therapeutically effective amount of (i) a compound disclosed herein, or a pharmaceutically acceptable salt thereof or (ii) a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, a method of treating a disease associated with modulation of PKR comprises administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method of treating pyruvate kinase deficiency (PKD) comprises administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method of treating PKD-associated hemolytic anemia comprises administering a therapeutically effective amount of a compound disclosed herein.

[00119] A method of treatment can comprise administering an amount of a compound disclosed herein (e.g., a compound of Formulae I, II, III and/or IV) sufficient to provide a blood concentration of 2,3-DPG that is reduced by at least 15% relative to the reference standard (e.g. , from about 15% to about 60%). In some embodiments, the blood concentration of 2,3-DPG is reduced by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60%. In some embodiments, the analysis is performed by sample analysis of bodily fluid, such as blood, by e.g., mass spectroscopy, e.g. LC-MS.

[00120] Compounds and compositions described herein are useful as activators of PKR mutants having lower activities compared to the wild type. Such mutations in PKR can affect enzyme activity (catalytic efficiency), regulatory properties (modulation by fructose bisphosphate (FBP)/ATP), and/or thermostability of the emzyme. Examples of such mutations include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q, and R490W. The activating activity of the present compounds against PKR mutants may be tested following a method described in Example 24. Compounds described herein are also activators of wild type PKR.

[00121] A method of treating a patient suffering from or susceptible to a disease or disorder associated with reduced PKM2 activity or reduced glycolysis can include administering a therapeutically effective amount of a compound disclosed herein to a patient in need thereof. The method can include the step of administering an effective amount of a compound described herein to the patient in need thereof, thereby treating, preventing or ameliorating the disease or disorder in the patient. In certain embodiment the compound described herein is provided in a pharmaceutical composition. In certain embodiments, the method includes the step of identifying or selecting a patient who would benefit from activation of PKM2 prior to treatment. Identifying or selecting such a patient can be on the basis of the level of PKM2 activity in a cell of the patient. The compound can be a compound described herein administered at a dosage and frequency sufficient to increase lactate production or oxidative phosphorylation. A method for treating diseases or conditions that are associated with increased 2,3-diphosphoglycerate levels can include administering to a subject in need thereof a therapeutically effective amount of (1) a compound disclosed herein or a pharmaceutically acceptable salt, solvate or hydrate thereof; (2) a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

[00122] The compounds disclosed herein can be added directly to whole blood or packed cells extracorporeally or be provided to the subject (e.g., the patient). Without being bound by theory, a decrease in the level of 2, 3-DPG concentration induces a leftward shift of the oxygen- hemoglobin dissociation curve and shifts the allosteric equilibribrium to the R, or oxygenated state, thus producing a therapeutic inhibition of the intracellular polymerization that underlies sickling by increasing oxygen affinity due to the 2,3- DPG depletion, thereby stabilizing the more soluble oxy-hemoglobin. In another embodiment, to regulate 2,3- diphosphoglycerate, a compound, composition or pharmaceutical composition described herein is added directly to whole blood or packed cells extracorporeally or be provided to the subject (e.g., the patient).

[00123] A method of increasing the level of PKM2 activity and/or glycolysis in a patient can include the administration of a therapeutically effective amount of a compound disclosed herein to a patient in need thereof. The method can comprise the step of administering an effective amount of a compound described herein to the patient in need thereof, thereby increasing the level of PKM2 activity and/or glycolysis in the patient. In some embodiments, a compound or a composition described herein is used to maintain PKM2 in its active conformation or activate pyruvate kinase activity in proliferating cells as a means to divert glucose metabolites into catabolic rather than anabolic processes in the patient. [00124] A compound disclosed herein (e.g., a compound of Formulae I, II, III, and/or IV) can activate wild type PKR and/or mutant PKRs. Some examples of the mutant PKRs include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q, I90N, and R490W. Accordingly, a patient and/or subject can be selected for treatment using a compound of Formulae I, II, III, and/or IV by first evaluating the patient and/or subject to determine whether the subject carries a mutation in PKR (for examples, one of the mutations as described herein), and if the subject is determined to be carrying a mutation in PKR thus is in need of activation of the activity of the mutant PKR, then administering to the subject a therapeutically effective amount of a compound of Formulae I, II, III, and/or IV. A subject can be evaluated as carrying a mutation in PKR using methods known in the art. The subject can also be monitored, for example, subsequent to administration of a compound of Formulae I, II, III, and/or IV. A patient can be monitored for evaluation of certain PK/PD parameters of a compound of Formulae I, II, III, and/or IV such as levels of such compound, levels of 2,3-DPG, or levels of ATP.

[00125] In one aspect, the present invention provides a method of treating a subject, the method comprising: administering to the subject a compound of a compound of Formulae I, II, III, and/or IV; and acquiring a value for the level of a compound of Formulae I, II, III, and/or IV, the level of 2,3- diphosphoglycerate (2,3-DPG), the level of adenosine triphosphate (ATP), or the activity of PKR in the subject, to thereby evaluate the subject. The value for the level of a compound of Formulae I, II, III, and/or IV can be acquired by analyzing the plasma

concentration of a compound of Formulae I, II, III, and/or IV. In some embodiments, the level of 2,3-DPG is acquired by analyzing the blood concentration of 2,3-DPG. The level of ATP can be acquired by analyzing the blood concentration of ATP. The activity of PKR can be acquired by analyzing the blood concentration of a ¹³C-label in the blood. For example, ¹³C-labeled glucose is administered to a subject, and incorporated into certain glycolytic intermediates in the blood.

[00126] A method of treatment can comprise administering an amount of a compound disclosed herein (e.g., a compound of Formulae I, II, III and/or IV) sufficient to provide a blood concentration of 2,3-DPG that is reduced by at least 15% relative to the reference standard (e.g. , from about 15% to about 60%). In some embodiments, the blood concentration of 2,3-DPG is reduced by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60%. In some embodiments, the analysis is performed by sample analysis of bodily fluid, such as blood, by e.g., mass spectroscopy, e.g. LC-MS.

[00127] The compounds described herein can activate mutant PKRs. Accordingly, a patient and/or subject can be selected for treatment using a compound described herein by first evaluating the patient and/or subject to determine whether the subject carries a mutation in PKR, and if the subject is determined to be carrying a mutation in PKR thus is in need of activation of the activity of the mutant PKR, then optionally administering to the subject a compound described herein. A subject can be evaluated as carrying a mutation in PKR using methods known in the art.

Methods of Synthesizing the Disclosed Compounds

[00128] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.

Examples

[00129] The following are illustrative, but non-limiting, examples of certain embodiments of the present disclosure. The synthetic schemes are presented for the synthesis of certain compounds herein disclosed.

Definitions used in the following Schemes and elsewhere herein are:

ACN acetonitrile

AcOH acetic acid

AICI ₃ trichloroaluminum

B0C2O di-toV-butyl dicarbonate

NaBEE sodium borohydride

Brine saturated aqueous sodium chloride solution

CDCI ₃ deuterated chloroform

d chemical shift

DCM dichloromethane or methylene chloride

DCE dichloroethane

DIEA A'.A'-di i sopropylethy lam i ne

DMAP A', A'-d i m c t h y 1 am i n o p y r i d i n c

DMF A'. A'-d i m e th y 1 fo rm amide

DMSO dimethylsulfoxide equiv equivalents

EtOAc ethyl acetate

‘HNMR proton nuclear magnetic resonance

HATU 2-(3//-| 1.2.3 |triazolo|4.5- > |pyridin-3-yl)- 1.1.3.3-tetramethylisouronium

hexafluorophosphate

HBTU 0-( Bcnzotriazol -yl )NNN JV -tetramethyluronium hexafluorophosphate

HPEC high pressure liquid chromatography

Hz hertz

FCMS liquid chromatography/mass spectrometry

(M+l) mass + 1

MeOH methanol

NCS L'-ch 1 o ro s iicci n i m i de

NaBH ₃CN sodium cyanoborohydride

NaHCCF sodium bicarbonate

NaOH sodium hydroxide

Na2SC> ₄ sodium sulfate v-BuLi .veobutvllithium

RT room temperature

Rt retention time

TEA triethylamine

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TFC thin layer chromatography

Znh zinc iodide

Materials

[00130] Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, WI) and used directly. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

[00131] LCMS Method 1. Instruments: MS, Waters QDa Mass Detector; HPLC, Waters Acquity Binary Solvent Manager; UV, Waters Acquity PDA. Conditions: Mobile phase A, 95% water/5 % acetonitrile with 0.1% formic acid; Mobile phase B, 95% acetonitrile/5 % water with 0.09% formic acid. Column: Acquity UPLC BEH Cl 8, 1.7 pm 2.1x50 mm. Column temperature, 35 DC. LC gradient: 5-100% B in 2.0 min, hold 100% to 2.2 min. LC Plow rate, 0.6 mL/min. UV wavelength, 220 nm and 254 nm, Ionization Mode: electrospray Ionization; pos/neg.

[00132] Intermediate 1: 2-(Benzofuran-5-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4 -c]pyrrole hydrochloride

Step 2 Intermediate 1

Step 1. tert-Butyl 5-(benzofuran-5-ylsulfonyl)-3, 4,5, 6-tetrahydropyrrolo[3, 4-c]pyrrole-2(lH)-carboxylate

[00133] To a solution of tert- butyl 3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrolc-2( l//)-carboxylatc (0.7 g, 3.33 mmol) in acetonitrile (20 mL) and DIEA (1.70 mL, 9.76 mmol) was added benzofiiran-5-sulfonyl chloride (17.48 ml, 3.50 mmol) in 1,4 dioxane (17 mL). The resulting mixture was stirred at RT overnight. The reaction mixture was worked up with saturated ammonium chloride solution and EtOAc. The combined organics were washed with brine, dried over NaiSCri. filtered off and concentrated under reduced pressure to give / -butyl 5-(bcnzofuran-5-ylsulfonyl)-3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrolc-2( l //)-carboxylatc (1.3 g, 3.33 mmol, 100%) as an oil. LCMS: m/z = 413 [M+Na] ⁺.

Step 2. 2-(Benzofuran-5-ylsulfonyl)-J2,3, 4,5, 6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride

[00134] Tert-butyl 5-(bcnzofuran-5-ylsulfonyl)-3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrolc-2( 1 //)- carboxylate (1.3 g, 3.33 mmol) was dissolved in a mixture of l,4-dioxane (0.500 mL), DCE (0.25 mL) and 4 M HC1 in l,4-dioxane (0.125 mL) and the reaction was heated at 50 °C for 2 h. The solvents were evaporated under reduced pressure and the reaction mixture was azeotropically dried with toluene and dried further under vacuum overnight to give 2-(benzofuran-5-ylsulfonyl)- 1,2, 3,4,5, 6-hexahydropyrrolo [3,4- c]pyrrole hydrochloride (0.95 mg, 3.33 mmol, 100%). LCMS: m/z = 291 [M+H] ⁺. [00135] Intermediate 2: l-(6-((3,4,5,6-Tetrahydropyrrolo[3,4-c]pyrrol-2(l/7)-yl)sulf onyl)-2,3- dihydro-4/7-benzo[Z>] [l,4]oxazin-4-yl)ethan-l-one.

Intermediate 2

[00136] Prepared as described for Intermediate 1, using the appropriate synthetic precursors. 94 % overall yield LCMS: m/z = 350 [M+H] ⁺.

[00137] Intermediate 3: 2-(4-Fluorophenylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4- c]pyrrole, TFA salt

Step 1. tert-Butyl 5-(4-fluorophenylsulfonyl)-3, 4, 5, 6-tetrahydropyrrolo [ 3, 4-c]pyrrole-2(lH)-carboxylate

[00138] A mixture of 4-fluorobenzene-l-sulfonyl chloride (2.366 g, 12.16 mmol), tert-butyl 3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride (2.5g, 10.13 mmol) and triethylamine (4.24 mL, 30.4 mmol) in DCM (50 mL) was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, washed with water twice, and dried over sodium sulfate. The crude material was purified on column chromatography on silica gel to afford tert-butyl 5-(4- fluorophenylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol e-2(lH)-carboxylate (2.5 g, 6.79 mmol, 67%). 1H NMR (300 MHz, CDC13) d ppm 7.73 - 7.92 (m, 2 H), 7.14 - 7.32 (m, 2 H), 3.93 - 4.19 (m, 8 H), 1.40 (s, 9H).

Step 2. 2-(4-Fluorophenylsulfonyl)-l ,2, 3, 4,5, 6-hexahydropyrrolo[3, 4-c]pyrrole, TFA salt

[00139] A solution of tert-butyl 5-(4-fluorophenylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]p yrrole- 2(lH)-carboxylate (2.5g, 6.79 mmol) in DCM/TFA (1 : 1, 80 mL) was stirred at RT for 3 days . The volatiles were removed under reduced pressure, the residue was treated with ether, filtered and dried under reduced pressure to give 2-(4-fluorophenylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4- c]pyrrole, TFA salt (2.48g, 6.54 mmol, 96%). 1H NMR (300 MHz, DMSO-d6) d ppm 9.57 (br s, 1 H), 7.82 - 8.06 (m, 2 H), 7.32 - 7.52 (m, 2 H), 3.69 - 4.27 (m, 8 H).

[00140] Intermediate 4: 2-(Pyridin-2-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4-c] pyrrole,

TFA salt

Intermediate 4

[00141] Prepared as described for Intermediate 3, using the appropriate synthetic precursors.

Step 1. tert-Butyl 5-(pyridine-2-sulfonyl)-lH, 2H, 3H 4H, 5H 6H-pyrrolo[ 3, 4-c]pyrrole-2-carboxylate.

[00142] Isolated as an orange solid (100 mg). The material was used without further purification. LCMS: m/z = 352 [M+H] ⁺.

Step 2. 2-(Pyridin-2-ylsulfonyl)-l ,2, 3, 4, 5, 6-hexahydropyrrolo[ 3, 4-c] pyrrole, TFA salt

[00143] Isolated as a white solid (90 mg, 87%). LCMS: m/z = 252 [M+H] ⁺.

[00144] Intermediate 5: 2-(6-(Trifluoromethyl)pyridin-2-ylsulfonyl)-l,2,3,4,5,6- hexahydropyrrolo [3, 4-c] pyrrole, TFA salt

Intermediate 5

[00145] Prepared as described for Intermediate 3, using the appropriate synthetic precursors.

Step 1. tert-Butyl 5-[6-(trifluoromethyl)pyridine-2-sulfonyl]-lH,2H,3H, 4H,5H, 6H-pyrrolo[3,4-c]pyrrole- 2-carboxylate

[00146] Isolated as a light yellow solid (25 mg, 25%).

Step 2. 2-(6-(T rifluoromethyl)pyridin-2-ylsulfonyl)-l,2,3, 4,5, 6-hexahydropyrrolo[3, 4-c]pyrrole, TFA salt [00147] Isolated as a brown oil (21 mg, 81%).

[00148] Intermediate 6: 6-((3,4,5,6-Tetrahydropyrrolo[3,4-c]pyrrol-2(Lff)- yl)sulfonyl)benzo[i/]thiazole hydrochloride

Intermediate 6

[00149] To a 50 mL round-bottomed flask was added tert- butyl 3,4,5,6-tetrahydropyrrolo[3,4- c |pyrrole-2( 1 //)-carboxylate hydrochloride (0.5 g, 2.026 mmol), DIEA (1.059 ml, 6.08 mmol), and dioxane (10 mL) to give a brown suspension. Benzo[ri]thiazole-6-sulfonyl chloride (0.497 g, 2.128 mmol) was added. The reaction was heated at 50 °C with stirring for 2 hours. The volatiles were removed under reduced pressure. The residue was resuspended in dioxane (10 mL) and 4 M HC1 in dioxane (5.07 ml, 20.26 mmol) was added. The reaction was heated at 50 °C with stirring for 2 hours. The volatiles were removed under reduced pressure to give 6-((3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrol-2( l//)-yl)sulfonyl)bcnzo|£/|thiazolc hydrochloride (0.640 g, 1.865 mmol, 92 %) as a brown oil that was used in the next step without further purification. LCMS: m/z = 307.9 [M+H] ⁺.

[00150] Intermediate 7: 2-((4-(Difluoromethoxy)phenyl)sulfonyl)-l,2,3,4,5,6- hexahydropyrr olo [3,4-c] pyrrole hydrochloride

Intermediate 7

[00151] Prepared according to the procedure for Intermediate 6, using the appropriate synthetic precursors. Obtained (0.652 g, 1.848 mmol, 91 %). LCMS: m/z = 317.1 [M+H] ⁺.

[00152] Intermediate 8: 2-(3,4-Dihydro-2/7-l,4-benzoxazin-6-yl)-2-hydroxyacetic acid

Step 4 Step 5 Intermediate 8

Step 1. tert-Butyl 6-formyl-3,4-dihydro-2H-J 4-benzoxazine-4-carboxylate

[00153] To a 50-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of / -butyl 6-bromo-3,4-dihydro-2H-l,4-benzoxazine-4-carboxylate (628 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). The mixture was stirred at -78 °C and a solution of (2-methylpropyl) lithium (1.3 M in hexanes, 1.7 mL, 1.10 equiv) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred for 15 min at -78 °C, then a solution of DMF (292 mg, 4.00 mmol, 2.00 equiv) in THF was added dropwise at -78 °C. The reaction mixture was then stirred for 2 h at RT. Water (1 mL) was added, then the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution (3x5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified on a silica gel TLC plate eluted with ethyl acetate/petroleum ether (1 :3) to provide tert- butyl 6-formyl-3,4- dihydro-2//- 1.4-bcnzoxazinc-4-carboxylatc (0.3 g, 57%) as a yellow solid. LCMS: m/z = 305 [M+1+CH ₃CN] ⁺.

Step 2. tert-Butyl 6-[cyano(hydroxy)methyl]-3,4-dihydro-2H-J4-benzoxazine-4-car boxylate

[00154] A solution of tert- butyl 6-formyl-3,4-dihydro-2H-l,4-benzoxazine-4-carboxylate (1 g, 3.80 mmol) in dichloromethane (20 mL) was stirred at 0 °C in a 50-mL round-bottom flask. Trimethylsilanecarbonitrile (1.2 g, 12.10 mmol) was added dropwise at 0 °C, followed by addition of Znl ₂ (120 mg, 0.38 mmol). The reaction solution was stirred for 16 h at RT and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with brine (3x15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide tert- butyl 6- [cyano(hydroxy)methyl] -3 ,4-dihydro-2 H- 1 ,4-benzoxazine-4-carboxylate ( 1.16 g) as a light brown oil . The material was used without further purification. LCMS: m/z = 291 [M+l] ⁺.

Step 3. Methyl 2-(3,4-dihydro-2H-J 4-benzoxazin-6-yl)-2-hydroxyacetate

[00155] A solution of / -butyl 6-[cyano(hydroxy)methyl]-3,4-dihydro-2H-l,4-benzoxazine-4- carboxylate (1 g, 3.44 mmol, 1.00 equiv) in methanol (10 mL) in a 25 mL round-bottom flask was treated dropwise with a saturated solution of HC1 in ethyl acetate (15 mL). The reaction mixture was stirred for 1 h at 50 °C. The volatiles were removed under reduced pressure and the residue was diluted with water (5 mL). The pH was adjusted to 8 with saturated aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1 : 1) to provide methyl 2-(3,4-dihydro-2/7-l,4-benzoxazin-6-yl)-2-hydroxyacetate (320 mg, 42%) as a light brown oil. LCMS: m/z = 265 [M+1+CH ₃CN] ⁺.

Step 4. tert-Butyl 6-(l-hydroxy-2-methoxy-2-oxoethyl)-3, 4-dihydro-2H-J 4-benzoxazine-4-carboxylate

[00156] A mixture of methyl 2-(3,4-dihydro-2/7-l,4-benzoxazin-6-yl)-2-hydroxyacetate (240 mg, 1.08 mmol, 1.00 equiv), dichloromethane (3 mL), di-fert-butyl dicarbonate (281 mg, 1.29 mmol, 1.20 equiv), TEA (217 mg, 2.14 mmol, 2.00 equiv) and DMAP (13 mg, 0.11 mmol, 0.10 equiv) was stirred for 2 h at RT in a 25-mL round-bottom flask. The volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (30 mL), washed with brine (3x5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with CFLCN FLO (1 :4) to provide tert- butyl 6-(l-hydroxy-2-methoxy-2-oxoethyl)-3,4-dihydro-2/7-l,4- benzoxazine-4-carboxylate (210 mg, 60%) as a brown oil. LCMS: m/z = 365 [M+1+CH ₃CN] ⁺.

Step 5. 2-(3, 4-Dihydro-2H-J 4-benzoxazin-6-yl)-2-hydroxyacetic acid

[00157] A mixture of fert-butyl 6-(l-hydroxy-2-methoxy-2-oxoethyl)-3,4-dihydro-2/7-l,4- benzoxazine-4-carboxylate (110 mg, 0.34 mmol, 1.00 equiv), methanol (1.6 mL), water (0.4 mL) and sodium hydroxide (27 mg, 0.68 mmol, 2.00 equiv) in an 8-mL vial was stirred for 2 h at RT. The volatiles were removed under reduced pressure . The residue was diluted with water (5 mL) and the pH of the solution was adjusted to 4 with concentrated aqueous HC1 solution, then the volatiles were removed under reduced pressure to provide 2-(3.4-dihydro-2//- 1.4-bcnzoxazin-6-yl)-2-hydroxyacctic acid (120 mg) as a light brown solid. The material was used without further purification. LCMS: m/z = 210 [M+l] ⁺.

[00158] Intermediate 9: 2-[2-[(/e/T-Butoxy)carbonyl]- l ,2,3,4-tetrahydroisoquinolin-7-yl]-2- hydroxyacetic acid

Step 4 Intermediate

Step 3

Step 1. 2,2,2-Trifluoro-l-(J2,3,4-tetrahydroisoquinolin-2-yl)ethan-l -one

[00159] A mixture of l,2,3,4-tetrahydroisoquinoline (1.0 g, 7.51 mmol), dichloromethane (15 mL) and TEA (1.1 g, 10.87 mmol) in a 50-mL 3-necked round-bottom flask was stirred for 10 min at 0 °C. TFAA (1.9 g, 9.05 mmol) was added. The solution was stirred for 10 min at 0 °C then an additional 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel and was eluted with ethyl acetate/petroleum ether (1 : 10) to provide 2,2,2-trifluoro-l-(l,2,3,4- tetrahydroisoquinolin-2-yl)ethan-l-one (1.49 g, 87%) as a yellow liquid. LCMS: m/z = 271 [M+CTLCN+Hf.

Step 2. Ethyl 2-oxo-2-[2-(trifluoroacetyl)-J2, 3,4-tetrahydroisoquinolin-7-yl]acetate

[00160] To a 50-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added dichloromethane (30 mL) and AlCL (7.0 g, 52.6 mmol). The reaction mixture was stirred for 10 min at 0 °C in a water/ice bath, then 2,2,2-trifluoro-l-(l,2,3,4-tetrahydroisoquinolin-2- yl)ethan-l-one (3.0 g, 13.09 mmol) and ethyl 2-chloro-2-oxoacetate (2.46 g, 18.02 mmol) were added. The reaction mixture was stirred for an additional 2 h at RT. The reaction mixture was cooled to 0 °C in a water/ice bath, then quenched by the addition of 2 N HC1 solution (aqueous 5 mL). The solution was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1 : 10) to provide ethyl 2-oxo-2-[2-(trifluoroacetyl)-l, 2,3,4- tetrahydroisoquinolin-7-yl]acetate (4.1 g, 95%) as a yellow oil. LCMS: m/z = 330 [M+H] ⁺.

Step 3. Ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-J2,3,4-tetrahydroisoquinoli n-7-yl]acetate

[00161] A mixture of ethyl 2-oxo-2-[2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin-7 -yl]acetate (1.0 g, 3.04 mmol, 1.00 equiv), tetrahydrofuran (5 mL) and water (2.5 mL) in a l0-mL round-bottom flask was treated with NaBH* (56.2 g, 1.49 mol, 0.50 equiv). The reaction mixture was stirred for 30 min at RT, then cooled to 0 °C with a water/ice bath. The reaction was quenched by the addition of water (1 mL) and extracted with ethyl acetate (3x30 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluted with ethyl acetate/petroleum ether (1 :5) to provide ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-l, 2,3,4- tetrahydroisoquinolin-7-yl]acetate (0.93 g, 92%) as a light yellow oil. ‘H NMR (300MHz, CDCh): d ppm 7.31-7.14 (m, 3H), 5.13 (d, J= 6.0 Hz, 1H), 4.79-4.74 (m, 2H), 4.34- 4.06 (m, 2H), 3.90-3.80 (m, 2H), 3.53 (d, J= 6.0 Hz, 1H), 2.97-2.92 (m, 2H), 1.26 (t, J= 3.0 Hz, 3H).

Step 4. 2-[2-[(tert-Butoxy)carbonylJ-J2, 3,4-tetrahydroisoquinolin-7-yl]-2-hydroxyacetic acid

[00162] A solution of ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinol in-7-yl]acetate

(990 mg, 2.99 mmol, 1.00 equiv) in methanol (4 mL) and water (1 mL) in a l0-mL round-bottom flask was treated with sodium hydroxide (240 mg, 6.00 mmol, 2.00 equiv). The reaction mixture was stirred for 30 min at RT, then di-fert-butyl dicarbonate (1.3 g, 5.96 mmol, 2.00 equiv) was added and the reaction mixture was stirred for an additional 30 min at RT. The pH value of the solution was adjusted to 6 with 2 N aqueous HC1 solution. The reaction mixture was extracted with ethyl acetate, and the extract was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (5: 1) to provide 2-[2-[(/ert-butoxy)carbonyl]-l,2,3,4-tetrahydroisoquinolin-7 -yl]-2-hydroxyacetic acid (960 mg) as a white solid. The material was used without further purification.

[00163] Intermediate 10: (i?)-2-hydroxy-2-phenyl-l-(3,4,5,6-tetrahydropyrrolo[3,4-c]p yrrol-

2(LiT)-yl)ethan-l-one, TFA salt

Step 1

Intermediate 10

Step 1. tert-Butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]-lH,2H,3H, 4H,5H, 6H-pyrrolo[3,4-c]pyrrole-2- carboxylate [00164] To an 8-mL vial was added tert- Butyl l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c |pyrrole-2- carboxylate (120 mg, 0.57 mmol, 1.00 equiv), DCM (2.00 mL), (2R)-2-hydroxy-2 -phenylacetic acid (104 mg, 0.68 mmol, 1.20 equiv), DIEA (221 mg, 1.71 mmol, 3.00 equiv) and HATU (238 mg, 0.63 mmol, 1.10 equiv). The solution was stirred for 3 h at RT, then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1 : 1) to provide tert- butyl 5-[(2R)-2 -hydroxy-2 -phenylacetyl]-li7,2i7,3i7,4i7,5i7,6i7-pyrrolo[3,4-c]pyrrole -2-carboxylate (102 mg, 52%) as a light yellow oil. LCMS: m/z = 345 [M+l] ⁺.

Step 2. (R)-2-hydroxy-2-phenyl-l-(3, 4,5, 6-tetrahydropyrrolo[3, 4-c]pyrrol-2(lH)-yl)ethan-l-one, TFA salt

[00165] To an 8-mL vial was added /t' / -butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrole-2-carboxylate (102 mg, 0.30 mmol, 1.00 equiv), DCM (2.00 mL) and TFA (2.00 mL). The solution was stirred for 2 h at RT, then concentrated under vacuum to provide (R)-2 -hydroxy-2 -phenyl- 1 -(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2( l//)-yl)ethan- 1 -one, TFA salt (139 mg) as a brown oil. The material was used without further purification. LCMS: m/z = 245 [M+l] ⁺.

[00166] Intermediate 11: (i?)-2-hydroxy-2-phenyl-l-(3,4,5,6-tetrahydropyrrolo[3,4-c]p yrrol- 2(l 7)-yl)ethan-l-one hydrochloride

Step 1

Intermediate 11

Step 1. tert-Butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]-lH,2H,3H, 4H,5H, 6H-pyrrolo[3,4-c]pyrrole-2- carboxylate

[00167] /m-Butyl l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c |pyrrolc-2-carboxylatc (200 mg, 0.95 mmol, 1.00 equiv), (2R)-2 -hydroxy -2 -phenylacetic acid (144 mg, 0.95 mmol, 1.00 equiv), HATU (532 mg, 1.40 mmol, 1.50 equiv), DIEA (181 mg, 1.40 mmol, 1.50 equiv) and DMF (5.00 mL) were combined in a 25- mL round-bottom flask. The solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 20 mL of water. The solution was extracted with 3x15 mL of ethyl acetate and washed with 15 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1 :2) to provide tert- butyl 5-[(2R)-2 -hydroxy-2 -phenylacetyl]-li7,2i7,3i7,4i7,5i7,6i7-pyrrolo[3,4-c]pyrrole - 2-carboxylate (120 mg, 37%) as a light yellow solid.

Step 2. (R)-2-hydroxy-2-phenyl-l-(3, 4,5, 6-tetrahydropyrrolo[3, 4-c]pyrrol-2(lH)-yl)ethan-l-one hydrochloride [00168] To a 25-mL round-bottom flask was added tert- butyl 5-|(2/Z)-2-hydroxy-2-phcnylacctyl |- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c |pyrrolc-2-carboxylatc (120 mg, 0.35 mmol, 1.00 equiv) and ethyl acetate freshly saturated with hydrogen chloride (15.0 mL). The solution was stirred overnight at RT. The solids were filtered out and dried under vacuum to provide (R)-2-hydroxy-2-phenyl-l-(3, 4,5,6- tctrahydropyrrolo| 3.4-c |pyrrol-2( 1 //)-yl)cthan- 1 -one hydrochloride (85 mg, 87%) as a gray solid.

[00169] Example 1-1: /V-(2-(5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol- 2(l //)-yl)-2-oxoethyl)methanesulfonamide

[00170] To a solution of 2-(benzofuran-5-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4 -c]pyrrole hydrochloride (1.07 g, 3.27 mmol) in acetonitrile with 10% DIEA (22 mL) was added (methylsulfonyl)glycine (56lmg, 3.66 mmol) in l,4-dioxane with 5% DIEA (20 mL), followed by HBTU (1.263 g, 3.33 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at RT overnight. Volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and 1 N aqueous NaOH solution. The combined organic phases were washed with brine, dried over NaaSCE, fdtered, and the volatiles were evaporated under reduced pressure. The residue was purified by prep HPLC to give N-( 2- (5-(bcnzofuran-5-ylsulfonyl)-3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrol-2( l//)-yl)-2- oxoethyl)methane sulfonamide .

[00171] The Examples in Table 2 below were prepared according to the procedure outlined above for Example 1-1, using the appropriate synthetic precursors.

Table 2.

[00172] Example 2-1: (l-(Aminomethyl)cyclopropyl)(5-(benzofuran-5-ylsulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(l/7)-yl)methanone

MeOH/dioxane Example 2-1

[00173] To a solution of tert- butyl ((l-(5-(benzofuran-5-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrol o[3,4- c]pyrrole-2-carbonyl)cyclopropyl)methyl)carbamate (14.6 mg, 0.03 mmol) in a 3: 1 mixture of DCE/MeOH (0.150 mL) was added 4 M HC1 (75 mΐ, 0.300 mmol) in l,4-dioxane and the reaction was agitated at RT for 2 hours. The reaction was concentrated and the residue partitioned between EtOAc and saturated aqueous NaHCCE. The combined organics were washed with brine and dried over NaaSCE _. The crude material was purified by prep HPLC to yield (l-(aminomethyl)cyclopropyl)(5 -(benzofuran-5 -ylsulfonyl)-3, 4, 5, 6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone. LCMS: m/z 388 [M+H] ⁺.

[00174] Example 3-1: 5-(Benzofuran-5-ylsulfonyl)-/V-((tetrahydrofuran-2-yl)methyl )-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(l )-carboxamide

[00175] To a 0.2 M solution of (tetrahydrofuran-2-yl)methanamine (320 mΐ, 0.064 mmol) in acetonitrile was added di( l//-imidazol- 1 -yl)mcthanonc (15.57 mg, 0.096 mmol). The mixture was agitated at RT for 2 hours, then a 0.2 M solution of 2-(benzofuran-5-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4 -c]pyrrole (330 mΐ, 0.066 mmol) in CH3CN with 10% DIEA was added and the mixture was agitated at 50 °C overnight. The solvent was evaporated and the residue was dissolved in 500 pL DMSO and purified by prep HPLC to yield 5 -(benzofuran-5 -ylsulfonyl)-/V-((tetrahydrofuran-2-yl)methyl)-3,4,5 ,6-tetrahydropyrrolo [3,4- c |pyrrolc-2( I //)-carboxam idc (12 mg, 0.029 mmol, 44.9 % yield). LCMS: m/z 418 [M+H] ⁺.

[00176] The Examples in Table 3 below were prepared according to the procedure outlined above for Example 3-1, using the appropriate synthetic precursors.

Table 3.

[00177] Example 4-1: (2/?)-2-hydroxy-2-phenyl- l -[5-(pyridine-3-sulfonyl)- l 77,277,377,477,577,677- pyrrolo[3,4-c]pyrrol-2-yl]ethan-l-one xamp e -

[00178] To a solution of (R)-2 -hydroxy-2 -phenyl- 1-(3, 4, 5, 6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)ethan-l-one (113 mg, 0.462 mmol) and DIEA (0.242 mL, 1.385 mmol) in dichloromethane (6 mL) was added pyridine -3 -sulfonyl chloride (54.3 mg, 0.462 mmol). The reaction mixture was stirred at room temperature for 4 hours. Dichloromethane was added to the reaction mixture and the organic phase was washed with water, saturated sodium bicarbonate and brine. The organic phase was concentrated and purified silica by flash column chromatography. (2/Z)-2-hydroxy-2-phenyl- 1 -|5-(pyridine-3-sulfonyl)- lT7,2T7,3T7,4T7,5T7,6T7-pyrrolo[3,4-c]pyrrol-2-yl]ethan-l-on e was isolated. ' H NMR (300MHz, CDCh): d ppm 8.96 (d, J = 1.5 Hz, 1H), 8.85 (dd, J\ = 1.8 Hz, J2 = 4.8 Hz, 1H), 8.19-8.23 (m, 1H), 7.63-7.67 (m, 1H), 7.29-7.34 (m, 5H), 5.63 (d, J = 6.3 Hz 1H), 5.16 (d, J = 6.3 Hz, 1H), 3.93-4.09 (m, 8H). LCMS: m/z =386 [M+H] ⁺.

[00179] The Example in Table 4 below were prepared according to the procedure outlined above for Example 4-1, using the appropriate synthetic precursors.

Table 4.

[00180] Example 5-1: 5-(4-Fluorophenylsulfonyl)-/V-(oxazol-5-ylmethyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(Lff)-carboxamide

[00181] In a 25 mL pear flask was added triphosgene (40.7 mg, 0.137 mmol) in DCM (5ml) to give a colorless solution. The solution was cooled to -10 °C and a solution of oxazol-5-ylmethanamine (68.5 mg, 0.698 mmoL) and triethylamine (2.57 mmol) in DCM (10 mL) was added dropwise. The mixture was stirred at RT for 1 hour, then a solution of 2-(4-fhiorophenylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4- c]pyrrole (TFA salt; 267 mg, 0.698 mmol) and triethylamine (2.54 mg, 2.52 mmol) in DCM (5 ml) was added. The mixture was stirred at RT for 5 hours. The reaction was diluted with methylene chloride and washed with aqueous NaOH (1 M), water, and brine. The organic phase was separated, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by prep-HPLC to provide 5-(4-fluorophenylsulfonyl)-A-(oxazol-5-ylmethyl)-3,4,5,6-tet rahydropyrrolo[3,4-c]pyrrole- 2( 177) -carboxamide (8 mg, 0.0204 mmol, 2.92%). ¾ NMR (300 MHz, DMSO-cfe): d ppm 8.39 (br d, J = 1.76 Hz, 1 H), 7.81 - 8.01 (m, 2 H), 7.36 - 7.53 (m, 2 H), 6.93 (br t, J= 5.86 Hz, 1 H), 6.18 - 6.26 (m, 1 H), 4.32 (br d, J= 5.57 Hz, 2 H), 3.90 - 4.12 (m, 8 H). LCMS: m/z = 393.06 [M+H] ⁺.

[00182] Example 5-2: 5-(4-Fluorophenylsulfonyl)-/V-((5-methyl-l,3,4-oxadiazol-2-y l)methyl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(l/7)-carboxamide

[00183] Prepared as described for Example 5-1, using the appropriate sunthetic precursors. (20 mg, 0.050 mmol, 7 %). ¾ NMR (300 MHz, DMSO-cfe): d ppm 7.88 (dd, J = 8.79, 5.28 Hz, 2 H), 7.43 (t, J = 8.79 Hz, 2 H), 6.87 - 7.05 (m, 1 H), 4.34 (br d, J= 5.57 Hz, 2 H), 4.04 (m, 4 H), 3.85 - 3.96 (m, 4 H), 2.40 (s, 3 H). LCMS: m/z = 408.10 [M+H] ⁺.

[00184] Example 6-1: (5-(benzo[d]thiazol-6-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrrol- 2(lH)-yl)(morpholino)methanone

HCI 2)) moororphoolinee., DMF., 2 h., rtt Example 6-1

[00185] To a 8-mL vial purged and maintained with an inert atmosphere of nitrogen was added a mixture of 6-| l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c |pyrrolc-2-sulfonyl |- 1 3-bcnzothiazolc hydrochloride (69 mg, 0.20 mmol, 1.00 equiv), L' L'- d i m c t h y 1 fo rm am i dc (2 mL) and DIEA (77 mg, 0.60 mmol, 3.00 equiv), followed by the addition of ditrichloromethyl carbonate (30 mg, 0.10 mmol, 0.50 equiv). The solution was stirred for 1.0 h at RT under nitrogen atmosphere. Morpholine was added (52 mg, 0.60 mmol, 3.00 equiv) and the reaction mixture was stirred for 2 h at RT. The crude product (200 mg) was purified by prep-HPLC with the following conditions: Column: SunFire Prep C18 5um l9* l50mm; mobile phase: water (buffer of lOmM NH ₄HCO ₃ and 0.05%NH ₃.H ₂0) and CH ₃CN with a gradient of 16% to 34% CH ₃CN in 10 min; detector UV wavelength: 220 nm. This provided (5-(benzo[d]thiazol-6-ylsulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(morpholino)methanon e (21.6 mg, 26%) as a white solid. 'H NMR (300MHz, COCh, ppm): d 9.22 (s, 1H), 8.53 (d, J= 1.5 Hz, 1H), 8.29 (d, J= 7.8 Hz, 1 H), 7.98 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 4.17-4.13 (m, 8H), 3.68-3.65 (m, 4H), 3.27-3.23 (m, 4H). LCMS m/z = 421

[M+H] ⁺.

[00186] Example 7-1: (5-((3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yl)sulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)(tetrahydro-2H-pyran -4-yl)methanone

Example 7-1

Step 1. l-( 6-[ 5-[( Oxan-4-yl) carbonyl /-I H 2H, 3H, 4H, 5H, 6H -pyrrolo[ 3,4-c] pyrrole-2-sulfonyl ]-3, 4- dihydro-2H-J4-benzoxazin-4-yl)ethan-l-one

[00187] To an 8-mL vial purged and maintained with an inert atmosphere of nitrogen was added oxane- 4-carboxylic acid (31 mg, 0.24 mmol, 1.20 equiv), dichloromethane (3 mL), DIEA (77 mg, 0.60 mmol, 3.00 equiv), I -(6-| I //.2//.3//.4//.5//.6//-pyrrolo| 3.4-c |pyrrolc-2-sulfonyl |-3.4-dihydro-2//- 1.4- benzoxazin-4-yl)ethan-l-one hydrochloride (77 mg, 0.20 mmol, 1.00 equiv) and HATU (91 mg, 0.24 mmol, 1.20 equiv). The reaction mixture was stirred for 16 h at RT, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with dichloromethane/methanol (100/1) to provide 1 -(6-| 5-| (oxan-4-yl)carbonyl |- 1 H.2H3HAH.5H.6H- pyrrolo| 3.4-c |pyrrolc-2-sulfonyl |-3.4-dihydro-2//- 1 4-bcnzoxazin-4-yl)cthan- 1 -one (90 mg, 98%) as a white solid. LCMS: m/z = 462.2 [M+H] ⁺.

Step 2. 6-[5-[ ⁽ Oxan-4-yl)carbonyl J-1H 2H, 3H 4H, 5H 6H-pyrrolo[ 3, 4-c]pyrrole-2-sulfonyl J-3, 4-dihydro- 2H- 7, 4-benzoxazine

[00188] To an 8-mL vial was added l-(6-[5-[(oxan-4-yl)carbonyl]-li7,2i7,3i7,4i7,5i7,6i7-pyrrol o[3,4- c|pyrrole-2-sulfonyl |-3.4-dihydro-2//- 1 4-bcnzoxazin-4-yl)cthan- 1 -one (90 mg, 0.20 mmol, 1.00 equiv), methanol (2 mL), water (0.5 mL) and sodium hydroxide (32 mg, 0.80 mmol, 4.00 equiv). The resulting solution was stirred for 6 h at RT. The crude product was purified by prep-HPLC with the following conditions: Column: Waters XBridge RP18 l9* l50mm, 5um; mobile phase: water (it contains

0.05%NH ₃.H ₂0) and CH3CN with a gradient of 28% to 33% CH3CN in 5 min; detector UV wavelength: 220 nm. This provided 6-| 5 -|(Oxan-4-yl (carbonyl |- l//.2//.3//.4//.5//.6//-pyrrolo| 3.4-c |pyrrole-2- sulfonyl]-3,4-dihydro-2i/-l, 4-benzoxazine (32.3 mg , 39%) as a white solid. ' H NMR (300MHz, CDCI3): d ppm 7.14-7.11 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 4.32-4.00 (m, 12H), 3.48-3.42 (m, 4H), 2.56-2.48 (m, 1H), 2.01-1.81 (m, 2H), 1.62-1.58 (m, 2H). LCMS: m/z = 420 [M+H] ⁺. [00189] Example 8-1: l-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-lH,2H,3H,4H,5H,6 H- pyrrolo[3,4-c]pyrrol-2-yl)-2-(pyridin-2-yl)ethan-l-one

[00190] Into a 50-mL round-bottom flask, was placed a mixture of 2-(pyridin-2-yl)acetic acid hydrochloride (48 mg, 0.28 mmol, 1.00 equiv), 2-[[4-(difluoromethoxy)benzene]sulfonyl]- lH,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole hydrochloride (100 mg, 0.28 mmol, 1.00 equiv), DIEA (155 mg, 1.20 mmol, 4.00 equiv), dichloromethane (5 mL) and HATU (114 mg, 0.30 mmol, 1.00 equiv). The reaction mixture was stirred for 4 h at 25 °C. The reaction was then quenched by the addition of 10 mL of water and the aqueous phase was extracted with 3x10 mL of dichloromethane and washed with water and brine. The crude product (80 mg) was purified by Prep-HPLC with the following conditions. Column: SunLire Prep C18 5 mhi 19* 150mm; mobile phase: water (contains 0. l%TLA) and CH3CN with a gradient of 43% to 73% CH3CN in 7 min; detector UV wavelength: 220nm. This resulted in 25.6 mg (21%) of l-(5- [[4-(difluoromethoxy)benzene]sulfonyl]-lH,2H,3H,4H,5H,6H-pyr rolo[3,4-c]pyrrol-2-yl)-2-(pyridin-2- yl)ethan-l-one as a white solid. fll NMR ^OOMHz, DMSO-d6, /?/?«): d 8.50-8.51 (d, J = 4.2Hz, 1H), 7.84- 7.89 (m, 2H), 7.71-7.76 (t, J = 7.5 Hz, 1H), 7.44-7.46 (d, J = 8.1 Hz, 1H), 7.23-7.29 (m, 3H), 6.37-6.85 (t, J = 72.6 Hz, 1H), 4.40 ( br, 2H), 3.97-4.14 (br, 6H), 3.90-3.94 ( br, 2H). LC-MS (ESI) m/z: Calculated for C20H19P2N3O4S: 435.11; found: 436 [M+H] ⁺.

[00191] The Examples in Table 5 below were prepared according to the procedure outlined above for Example 8-1, using the appropriate synthetic precursors.

Table 5.

* Compounds 8-2 and 8-3 are enantiomers, but absolute stereochemistry is undetermined. These compounds were prepared as a racemate, then separated by Chiral-Prep-HPLC (SHIMADZU LC-20AT) with the following conditions: Column, REPAIRED IA; mobile phase: isocratic elution with DCM: IPA (10:90; with 0.1% DEA); flow rate: 20mL/min; detector UV wavelength: 254 nm.

[00192] Example 9-1: l -(5-[[4-(Difluoromethoxy)benzene]sulfonyl]- l //,2//,3//,4//,5//,6//- pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(pyridin-3-yl)ethan-l -one

Example 9-1

[00193] Into a 8-mL vial (1 atm), was placed a mixture of 2-hydroxy-2-(pyridin-3-yl)acetic acid (39.8 mg, 0.26 mmol, 1.30 equiv), N,N-dimethylformamide (1.5 mL), 2-((4-(difluoromethoxy)phenyl)sulfonyl)- l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrolehydrochloride (70.6 mg, 0.20 mmol, 1.00 equiv), DIEA (65 mg, 0.50 mmol, 2.50 equiv) and HATU (91 mg, 0.24 mmol, 1.20 equiv). The resulting solution was stirred for 16 h at room temperature. The reaction solution was diluted with 50 mL of ethyl acetate, washed with 4x10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by prep-TLC. This resulted in l-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c |pyrrol-2-yl)-2-hydroxy-2-(pyridin-3-yl)cthan- 1 -one as an off-white solid. ¾ NMR (300MHz, CDCE): 5 ppm 8.66 (d, J= 4.8 Hz, 1H), 8.65-7.87 (m, 2H), 7.51-7.48 (m, 1H), 7.48-7.31 (m, 5H), 5.01 (s, 1H), 4.32-4.15 (m, 7H), 3.63 (d, J= 12.3 Hz, 1H). LCMS m/z: 452 [M+H] ⁺.

[00194] The Examples in Table 6 below were prepared according to the procedure outlined above for Example 9-1, using the appropriate synthetic precursors.

Table 6.

*Example 9-4 and Example 9-5 are enantiomers, but absolute stereochemistry is undetermined. These compounds were prepared as a racemate, then separated by Chiral-Prep-HPLC (SHIMADZU LC-20AT) with the following conditions: Column: CHIRALPAK IC; mobile phase solvent A: ethanol, solvent B: methanol; detector UV wave length: 220 nm.

[00195] Example 9-2: Synthesis of (2R)-2-Hydroxy-2-phenyl-l-(5-(pyridin-2-ylsulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)ethan-l-one

[00196] Intermediate A: tert- Butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c] pyrrole-2(lH)-carboxylate

[00197] To a suspension oftert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate, HC1 (1.10 g, 4.46 mmol) in dichloromethane (25 mL) at room temperature was added TEA (1.49 mL, 10.7 mmol) followed by pyridine-2-sulfonyl chloride (0.950 g, 5.35 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was taken up in EtOAc (50 mL). The organic mixture was sequentially washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was collected, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0 % EtO Ac/hexane for 5 min then 0-75% EtO Ac/hexane for 30 min) to afford tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyr role-2(lH)-carboxylate (0.57 g, 1.622 mmol, 36.4 % yield). LCMS (m/z, M+H+) 351.9, 1H-NMR (300MHz, CDC13): d ppm 8.69 (m, 1H), 8.00-7.88 (m, 2H), 7.49 (m, 1H), 4.33 (m, 4H), 4.05 (m, 4H), 1.45 (s, 9H).

[00198] Intermediate B: 2-(Pyridin-2-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4-c] pyrrole, HC1

[00199] To a solution of tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyr role- 2(lH)-carboxylate (0.570 g, 1.62 mmol) in dichloromethane (4.96 ml) was added 4 M HCl/dioxane (17.6 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure then triturated with ether. The white solid was filtered off to give 2-(pyridin-2- ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, HC1 (0.547 g, 1.90 mmol, quantitative yield) that was used in the next step without further purification. LCMS (m/z, M+H+) 252.0, 1H-NMR (300MHz, DMSO-d6): 5 ppm 9.99 (br m, 2 H), 8.75 (m, 1H), 8.13 (m, 1H), 7.97 (m, 1H), 7.71 (m 1H), 4.24 (m, 4H), 3.89 (m, 4H).

[00200] (R)-2-Hydroxy-2-phenyl-l-(5-(pyridin-2-ylsulfonyl)-3,4,5,6-t etrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)ethan-l-one itsifeftssriisis B -2

[00201] To a suspension of 2-(pyridin-2-ylsulfonyl)-l,2,3,4,5,6-hexahydropyrrolo[3,4-c] pyrrole, HC1 (0.547 g, 1.90 mmol) in dichloromethane (12.6 mL) was added (R)-2 -hydroxy-2 -phenylacetic acid (0.241 g, 1.58 mmol), BOP (0.771 g, 1.74 mmol) and DIEA (0.830 ml, 4.75 mmol). The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography on (gradient of 0- 10% MeOH/dichloromethane) to afford (R)-2-hydroxy-2-phenyl-l-(5-(pyridin-2-ylsulfonyl)-5,6- dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)ethanone (0.353 g, 0.916 mmol, 57.8 % yield). LCMS (m/z, M+H+) 385.9, 1H-NMR (300MHz, DMSO-d6): d ppm 8.69 (m, 1H), 8.07 (m, 1H), 7.91 (m, 1H), 7.68- 7.64 (m, 1H), 7.33-7.26 (m, 5H), 5.64 (d, J = 6.0 Hz, 1H), 5.14 (d, J = 6.3 Hz, 1H), 4.30-3.88 (m, 8H).

[00202] Examples 10-1 and 10-2: (2i?)-l-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5- dihydropyrrolo[3,4-c]pyrrol-2(l/7,3/7,4/7)-yl)-2-hydroxy-2-( 4-methyl-3,4-dihydro-2/7- benzo[/>] [l,4]oxazin-6-yl)ethanone and (2£)-l-(5-(4-(difluoromethoxy)phenylsulf(myl)-4,5- dihydropyrrolo[3,4-c]pyrrol-2(l/7,3/7,4/7)-yl)-2-hydroxy-2-( 4-methyl-3,4-dihydro-2/7- benzo [/>] [1,4] oxazin-6-yl)ethanone

[00203] 1 -(5-| |4-(Difluoromcthoxy)bcnzcnc |sulfonyl |- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrol-2- yl)-2-(3.4-dihydro-2//- 1.4-bcnzoxazin-6-yl)-2-hydroxycthan- 1 -one (174 mg, 0.34 mmol, 1.00 equiv), methanol (2 mL), formaldehyde (20.6 mg, 2.00 equiv), NaBffX’N (64.8 mg, 1.03 mmol, 3.00 equiv) and acetic acid (2 mg, 0.03 mmol, 0.10 equiv) were added to a lO-mL round-bottom flask. The solution was stirred for 1 h at RT, then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (15: 1) to provide racemic l-(5-[[4- (difluoromethoxy)benzene]sulfonyl]-lH,2H,3H,4H,5H,6H-pyrrolo [3,4-c]pyrrol-2-yl)-2-hydroxy-2-(4- methyl-3 ,4-dihydro-2H-l,4-benzoxazin-6-yl)ethan-l -one (140 mg, 78%) as a white solid. The enantiomers were separated by Chiral-Prep-HPLC (SHIMADZU LC-20AT) with the following conditions: Column, Lux Cellulose-4; mobile phase solvent A: ethanol, solvent B: methanol; detector UV wavelength: 220 nm. This provided:

Example 10-1 (first eluting enantiomer): (2i?)-l-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5- dihydropyrrolo[3,4-c]pyrrol-2(Lff,3/7,4/7)-yl)-2-hydroxy-2-( 4-methyl-3,4-dihydro-2/7- benzo[Z>] [l,4]oxazin-6-yl)ethanone Isolated as a white solid (26.5 mg, 19%). ¾ NMR (300MHz, CDCh): d ppm 7.89 (m, 2H), 7.39 (t, 3H), 6.49-6.65 (m, 3H), 5.32 (d, J= 6.6 Hz, 1H), 4.98 (d, J= 6.3 Hz, 1H), 3.81-4.25 (m, 10H), 3.21 (m, 2H), 2.75(d, 3H). LCMS: m/z = 522 [M+Hf. *Absolute stereochemistry undetermined.

Example 10-2 (second eluting enantiomer): (2A)-l-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5- dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-yl)-2-hydroxy-2-(4-m ethyl-3,4-dihydro-2H- benzo[b] [l,4]oxazin-6-yl)ethanone Isolated as a white solid (22.7 mg, 16 %). ¾ NMR (300MHz, CDCh): d ppm 7.86 (m, 2H), 7.20 (m, 2H), 6.37-6.85 (m, 4H), 4.89 (s, lH), 4.02-4.40 (m, 10H), 3.72 (m, 1H), 3.29 (m, 2H), 2.9l(s, 3H). LCMS: m/z = 522 [M+H] ⁺. *Absolute stereochemistry undetermined.

[00204] Examples 11-1 and 11-2: (2A)-l-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]- l//,2//,3//,4//,5//,6//-pyrrolo[3,4-e]pyrrol-2-yl)-2-hydroxy -2-(l ,2,3,4-tetrahydroisoquinolin-7- yl)ethan-l-one and (2/?)-l-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]-l //,2//,3//,4//,5//,6//- pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(l,2,3,4-tetrahydrois oquinolin-7-yl)ethan-l-one

min

Step 1. tert-Butyl 7-[2-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-lH,2H,3H, 4H,5H, 6H-pyrrolo[3,4- c]pyrrol-2-yl)-l-hydroxy-2-oxoethyl J-l ,2, 3, 4-tetrahydroisoquinoline-2-carboxylate

[00205] 2-| 2-| (/ -Butoxy)carbonyl |- 1.2.3.4-tctrahydroisoquinolin-7-yl |-2-hydroxyacctic acid (184 mg, 0.60 mmol, 1.00 equiv), 2-[[4-(difluoromethoxy)benzene]sulfonyl]-li7,2i7,3i7,4i7,5i7 ,6i7-pyrrolo[3,4- cjpyrrolc hydrochloride (187 mg, 0.53 mmol, 1.00 equiv), dichloromethane (5 mL), DIEA (205 mg, 1.59 mmol, 3.00 equiv) and HATU (242 mg, 0.64 mmol, 1.20 equiv) were added to a 50-mL round-bottom flask. The mixture was stirred for 30 min at RT, then the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (15: 1) to provide tert- butyl 7-|2-(5-| |4-(difluoromcthoxy)bcnzcnc |sulfonyl \- \H.2H3HAH.5H.6H- pyrrolo [3 ,4-c]pyrrol-2-yl)- 1 -hydroxy-2 -oxoethyl] - 1 ,2,3 ,4-tetrahydroisoquinoline-2-carboxylate (318 mg, 88%) as a yellow solid. LCMS :m/z = 606 [M+H] ⁺.

Step 2. (2S)-l-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]-lH,2H,3H,4H ,5H, 6H-pyrrolo[3, 4-c]pyrrol-2- yl)-2-hydroxy-2-(J2,3,4-tetrahydroisoquinolin-7-yl)ethan-l-o ne and (2R)-l-(5-[[4- (Difluoromethoxy)benzene ]sulfonyl]-lH,2H, 3H 4H, 5H 6H-pyrrolo[3, 4-c]pyrrol-2-yl)-2-hydroxy-2- (l, 2, 3, 4-tetrahydroisoquinolin-7-yl)ethan-l-one

[00206] tert- Butyl 7 - [2-(5 -[ [4-(difluoromethoxy)benzene] sulfonyl]- 1 //.2//.3//.4//.5//.6//-pyrrolo [3,4- c]pyrrol-2-yl)-l-hydroxy-2-oxoethyl]-l,2,3,4-tetrahydroisoqu inoline-2-carboxylate (60.5 mg, 0.10 mmol, 1.00 equiv), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added to a l0-mL round-bottom flask. The solution was stirred for 3 h at RT. The pH of the solution was adjusted to 8.0 with 2 N aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3x15 mL), and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane/methanol (10: 1) to provide racemic l-(5-[[4-(difluoromethoxy)benzene]sulfonyl]- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrol-2-yl)-2-hydroxy -2-( 1 2.3.4-tctrahydroisoquinolin-7-yl)cthan- l-one (40 mg, 79%) as a white solid. The enantiomers were separated by Chiral-Prep-HPLC (SHIMADZU LC-20AT) with the following conditions: Column, DAICEL CHIRALPAK IC 20*250mm 5um; mobile phase: solvent A: CH3CN (it contains 0.1% DEA), solvent B: IPA with gradient of 20 to 50% solvent B in 30 min; detector UV wavelength: 230 nm. This provided:

Example 11-1: (2A)-l -(5-[[4-(difluoromethoxy)benzene]sulfonyl]-l //,2//,3//,4//,5//,6//-pyrrolo[3,4- c]pyrrol-2-yl)-2-hydroxy-2-(l,2,3,4-tetrahydroisoquinolin-7- yl)ethan-l-one Isolated as a white solid (13.7 mg, 27 %).‘H NMR (300MHZ, CD ₃OD): d ppm 7.89 (m, 2H), 7.35 (d, J= 9.0 Hz, 2H), 7.24-6.75 (m, 4H), 5.33 (s, 1H), 4.25-4.09 (m, 7H), 3.98 (d, J= 7.5 Hz, 2H), 3.83-3.79 (m, 1H), 3.09 (t, J= 6.3 Hz, 2H), 2.86-2.81 (m, 2H). LCMS: m/z = 506 [M+H] ⁺. *Absolute stereochemistry undetermined.

Example 11-2: (2/?)-l -(5-[[4-(difluoromethoxy)benzene]sulfonyl]-l //,2//,3//,4//,5//,6//-pyrrolo[3,4- c]pyrrol-2-yl)-2-hydroxy-2-(l,2,3,4-tetrahydroisoquinolin-7- yl)ethan-l-one Isolated as a white solid (11.3 mg, 22%). ¾ NMR (300MHz, CD ₃OD): d ppm 7.89 (m, 2H), 7.35 (d, J= 9.0 Hz, 2H), 7.24-6.75 (m, 4H), 5.15 (s, 1H), 4.25-4.09 (m, 7H), 3.98 (d, J= 7.5 Hz, 2H), 3.83-3.78 (m, 1H), 3.09 (t, J= 6.3 Hz, 2H), 2.86-2.81 (m, 2H). LCMS: m/z = 506 [M+H] ⁺. * Absolute stereochemistry undetermined.

[00207] Example 19-1: (3-Benzyl-3-hydroxyazetidin-l-yl)(5-(quinolin-8-ylsulfonyl)- 4,5- dihydropyrrolo[3,4-c]pyrrol-2(l/7,3/7,4/7)-yl)methanone Step 1 Step 2

Step 3 Example 12-1

Step 1. tert-Butyl 5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3, 4-c]pyrrole-2(lH,3H,4H)-carboxylate

[00208] tert- Butyl 4.5-dihydropyrrolo|3.4-c|pyrrolc-2( l//.3//.4//)-carboxylatc (84 mg, 0.40 mmol,

1.00 equiv), DCM (8.00 mL), DIEA (77.3 mg, 0.60 mmol, 1.50 equiv) and quinoline-8-sulfonyl chloride (100 mg, 0.44 mmol, 1.10 equiv) were combined in a 50-mL round-botom flask. The solution was stirred for 16 h at 20 °C, then concentrated under vacuum. The residue was diluted with ethyl acetate (10 mL), washed with water (3x3 mL), dried over anhydrous sodium sulfate, filtered then concentrated to provide tert- butyl 5-(quinolin-8-ylsulfonyl)-4.5-dihydropyrrolo|3.4-c|pyrrolc-2 ( l//.3//.4//)-carboxylatc as a pink solid (140 mg, 87%). LCMS: m/z = 402 [M+H] ⁺.

Step 2. 8-(4,5-Dihydropyrrolo[3,4-c]pyrrol-2(lH,3H,4H)-ylsulfonyl)qu inoline hydrochloride

[00209] Ethyl acetate (5.60 mL), concentrated aqueous hydrogen chloride (38 mg, 3.00 equiv), and tert- butyl 5-(quinolin-8-ylsulfonyl)-4.5-dihydropyrrolo|3.4-c|pyrrolc-2 ( l//.3//.4//)-carboxylatc (140 mg, 0.35 mmol, 1.00 equiv) were combined in a 50-mL round-bottom flask. The solution was stirred for 6 h at 25 °C, then the solids were collected by filtration to provide 8-(4.5-dihydropyrrolo|3.4-c|pyrrol-2( \H3HLH)- ylsulfonyl) quinoline hydrochloride as a pink solid (110 mg, 93%). LCMS: z = 302 | M+Hf.

Step 3. ( 3-Benzyl-3-hydroxyazetidin-l-yl)(5-(quinolin-8-ylsulfonyl)-4 ,5-dihydropyrrolo[3,4-c]pyrrol -

2(1H, 3H, 4H)-yl)methanone

[00210] 8-(4.5-Dihydropyrrolo|3.4-c|pyrrol-2( l//.3//.4//)-ylsulfonyl) quinoline hydrochloride (100 mg, 0.30 mmol, 1.00 equiv), THF (25.0 mL), TEA (179 mg, 1.77 mmol, 6.00 equiv) and ditrichloromethyl carbonate (44 mg, 0.15 mmol, 0.50 equiv) were combined in a 50-mL round-bottom flask. The solution was stirred for 2 h at 25 °C then 3-benzylazetidin-3-ol (97 mg, 0.59 mmol, 2.00 equiv) was added. The solution was stirred for an additional 2 h at 25 °C, then diluted with ethyl acetate (50 mL), washed with water (3x25 mL), and dried over anhydrous sodium sulfate. The solids were filtered off. The filtrate was concentrated under vacuum. The crude material was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 l9* l50mm; mobile phase, water (containing 0. l%TFA) and ACN with a gradient of 39% to 44% of ACN in 6 min; detector UV wavelength, 220nm. This provided (3-benzyl-3- hydroxyazctidin- l-yl)(5-(quinolin-8-ylsulfonyl)-4.5-dihydropyrrolo|3.4-c|pyr rol-2( I//.3//.4//)- yl)methanone as a white solid (44 mg, 30%). 'H NMR (300MHz. CD CL. ppm): d 9.05 (d../ = 9.6 Hz, 1H), 8.56 (d, J= 6.6 Hz, 1H), 8.32 (d, J= 8.1 Hz, 1 1H), 8.07 (d, J= 8.1 Hz, 1H), 7.64 (m, 1H), 7.56 (m, 1H), 7.35 (m, 3H), 7.22 (m, 2H), 4.51 (m, 4H), 4.10 (m, 6H), 3.85 (m, 2H), 3.06 (m, 2H). LCMS: m/z = 491 [M+H] ⁺.

[00211] Example 13-1: (i?)-4-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrr olo[3,4- c]pyrrol-2(l//)-yl)sulfonyl)benzenesulfonamide

p [00212] (R)-2 -hydroxy-2 -phenyl-l-(3, 4, 5, 6-tetrahydropyrrolo[3,4-c]pyrrol-2(li )-yl)ethan-l-one hydrochloride (40 mg, 0.14 mmol, 1.00 equiv), TEA (36 mg, 0.36 mmol, 2.50 equiv) and DCM (4.00 mL) were combined and stirred in a 25-mL round-bottom flask. 4-Sulfamoylbenzene-l-sulfonyl chloride (36.4 mg, 0.14 mmol, 1.00 equiv) was added and the solution was stirred for 2 h at RT. The reaction was then quenched by addition of 4 mL of water, extracted with 3x10 mL of DCM, and washed with 10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from methanol to provide (R)-4-((5-(2-hydroxy-2-phenylacetyl)-3, 4,5,6- tctrahydropyrrolo|3.4-c|pyrrol-2( l//)-yl)sulfonyl)bcnzcncsulfonamidc (24 mg, 36%) as a white solid. 'H NMR (300MHz, DMSO-d 6 ppm): d 8.01 (s, 4H), 7.62 (br. s, 2H), 7.25-7.34 (m, 5H), 5.61-5.64 (d, 1H), 5.14-5.18 (d, 1H), 3.83-4.30 (m, 8H). LCMS: m/z = 464 [M+H] ⁺.

[00213] Example 14-1: (i?)-/V-(2-fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(l/7)-yl)sulfonyl)phenyl)ace tamide

Step 3

Example 14-1

Step 1. tert-Butyl 5-( (3-acetamido-4-fluorophenyl)sulfonyl)-3, 4, 5, 6-tetrahydropyrrolo [ 3, 4-cJpyrrole- 2(lH)-carboxylate

[00214] To a 8-mL vial was added tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (75 mg, 0.36 mmol, 1.00 equiv), triethylamine (54 mg, 0.53 mmol, 1.50 equiv), 3-acetamido- 4-fluorobenzene-l-sulfonyl chloride (90 mg, 0.36 mmol, 1.00 equiv), and DCM (1.00 mL). The solution was stirred for 3 h at RT. The reaction was then quenched by addition of 10 mL of water. The solution was extracted with 3x10 mL of DCM and washed with 10 mL of brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide tert- butyl 5-((3-acetamido- 4-fluorophcnyl)sulfonyl)-3.4.5.6-tctrahydropyrrolo|3.4-c|pyr rolc-2( l//)-carboxylatc (100 mg, 66%) as a white solid. LCMS: m/z = 426 [M+H] ⁺.

Step 2. N-(2-fluoro-5-((3, 4,5, 6-tetrahydropyrrolo[3, 4-c]pyrrol-2(lH)-yl)sulfonyl)phenyl)acetamide hydrochloride

[00215] To a 50-mL round-bottom flask was added tert- butyl 5-((3-acetamido-4- fluorophcnyl)sulfonyl)-3.4.5.6-tctrahydropyrrolo|3.4-c |pyrrolc-2( l//)-carboxylatc (100 mg, 0.24 mmol, 1.00 equiv) and ethyl acetate freshly saturated with hydrogen chloride gas (20 mL). The solution was stirred overnight at RT. The solids were collected by filtration to provide /V-(2-fluoro-5-((3, 4,5,6- tetrahydropyrrolo|3.4-c |pyrrol-2( l//)-yl)sulfonyl (phenyl (acetamide hydrochloride (65 mg, 76%) as a gray solid. LCMS: m/z = 326 [M+H] ⁺.

Step 3. (R)-N-(2-fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3,4,5, 6-tetrahydropyrrolo[3, 4-c]pyrrol-2(lH)- yl)sulfonyl)phenyl)acetamide

[00216] To an 8-mL vial was added A _''-(2-fluoro-5-((3.4.5.6-tctrahydropyrrolo|3.4-c|pyrrol -2( l//(- yl)sulfonyl)phenyl)acetamide hydrochloride (60 mg, 0.17 mmol, 1.00 equiv), (2R)-2 -hydroxy -2- phenylacetic acid (25 mg, 0.16 mmol, 1.00 equiv), HATU (94 mg, 0.25 mmol, 1.50 equiv) and DIEA (53 mg, 0.41 mmol, 2.50 equiv), and DMF (5.00 mL). The solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The solution was extracted with 3x15 mL of ethyl acetate and washed with 15 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue (50 mg) was purified by Prep-HPLC (waters I) with the following conditions: Column, Xbridge Prep RP18 5pm l9* l50mm; mobile phase, water (containing 10 mM NH4HCO3 + 0.05% ammonia) and CH3CN with a gradient of 87% to 92% CH3CN in 7 min; detector UV wavelength, 254nm. This provided (R)-A-(2-fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3, 4,5,6- tetrahydropyrrolo|3.4-c |pyrrol-2( l//)-yl)sulfonyl (phenyl (acetamide (7 mg, 9%) as a white solid. ' H NMR (300MHz, DMSO -fa, ppm): d 10.04 (s, 1H), 8.49-8.52 (d, J = 7.5 Hz, 1H), 7.27-7.53 (m, 7H), 5.61-5.63 (d, J = 7.5 Hz, 1H), 5.14-5.16 (d, J = 7.5 Hz, 1H), 3.89-4.11 (m, 8H), 2.11 (s, 3H). LCMS: m/z = 460 [M+H] ⁺.

[00217] Example 15-1: A-[(2-fluorophenyl)methyl]-5-(6-methylpyridine-2-sulfonyl)- l //,2//,3//,4//,5//,6//-pyrrolo[3,4-c]pyrrole-2-carboxamide

Example 15-1

Step 1. 2-(benzylsulfanyl)-6-methylpyridine

[00218] To a 250-mL round-botom flask was added 2-chloro-6-methylpyridine (5.00 g, 39.19 mmol, 1.00 equiv), DMSO (80 mL), phenylmethanethiol (5.37 g, 43.24 mmol, 1.10 equiv) and potassium carbonate (10.9 g, 78.87 mmol, 2.00 equiv). The solution was stirred for 3 h at 150 °C, then cooled to RT. The solution was diluted with 300 mL of ethyl acetate, washed with 4x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 2-(benzylsulfanyl)-6-methylpyridine (7.60 g) as a light brown oil. The material was used without further purification. LCMS: m/z = 216 [M+H] ⁺. Step 2. 6-Methylpyridine-2-sulfonyl chloride

[00219] To a 50-mL round-botom flask was added 2-(benzylsulfanyl)-6-methylpyridine (580 mg, 2.69 mmol, 1.00 equiv), ACN (20.0 mL), water (0.60 mL) and AcOH (1.30 mL). NCS (1.80 g, 13.48 mmol, 5.00 equiv) was added in portions. The solution was stirred for 2 h at RT, then concentrated under vacuum. The residue was diluted with 5 mL of H ₂0. The pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The solution was extracted with 80 mL of ethyl acetate. The organic phase was washed with 3x10 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1 :5) to provide 6-methylpyridine-2-sulfonyl chloride (80 mg, 15%) as a viscous yellow oil. LCMS: m/z = 192 [M+H] ⁺.

Step 3. tert-Butyl 5-(6-methylpyridine-2-sulfonyl)-lH,2H, 3H,4H,5H, 6H-pyrrolo[3,4-c]pyrrole-2- carboxylate

[00220] To an 8-mL vial was added 6-methylpyridine-2-sulfonyl chloride (70 mg, 0.37 mmol, 1.00 equiv), DCM (1.50 mL), DIEA (118 mg, 0.91 mmol, 2.50 equiv), and tert- butyl 177,277,377,477,577,677- pyrrolo[3,4-c]pyrrole-2-carboxylate (77 mg, 0.37 mmol, 1.00 equiv). The solution was stirred for 0.5 h at RT, then concentrated. The residue was purified by silica gel column chromatography with DCM/EA (2: 1) to provide fert-butyl 5 -(6-mcthyl pyridi nc-2-sulfon yl )- l //.2//.3//.4//.5//.6//-pyrrolo| 3.4-cjpyrrolc-2- carboxylate (100 mg, 75%) as a white solid. LCMS: m/z = 366 [M+H] ⁺.

Step 4. 2-Methyl-6-[lH,2H, 3H,4H,5H, 6H-pyrrolo[3, 4-c]pyrrole-2-sulfonyl]pyridine hydrochloride [00221] To an 8-mL vial was added tert- butyl 5 -(6-methyl pyridi ne-2-sulfonyl )- 1 //,2//,3//, 4/7,577, 6/7- pyrrolo[3,4-c]pyrrole-2-carboxylate (90 mg, 0.25 mmol, 1.00 equiv) and DCM (1.50 mL). The stirred solution was treated dropwise with EA freshly saturated with hydrogen chloride (3.0 mL). The solution was stirred for 1 h at RT. The mixture was concentrated under vacuum to provide 2-methyl-6- | l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrolc-2-sulfonyl |pyridine hydrochloride (110 mg) as a brown oil. The material was used without further purification. LCMS: m/z = 266 [M+H] ⁺.

Step 5. N-[ (2-fluorophenyl)methyl]-5-( 6-methylpyridine-2-sulfonyl)-lH, 2H, 3H 4H, 5H 6H-pyrrolo[ 3, 4- c] pyrrole -2-carboxamide

[00222] To an 8-mL vial was added l-fluoro-2-(isocyanatomethyl)benzene (100 mg, 0.66 mmol, 1.00 equiv), DMF (3.00 mL), DIEA (115 mg, 0.89 mmol, 3.00 equiv) and 2-methyl-6-[l/7,2/7,3/7,4/7,5/7,6/7- pyrrolo[3,4-c]pyrrole-2-sulfonyl]pyridme hydrochloride (49 mg, 0.14 mmol, 0.90 equiv). The solution was stirred for 1 h at RT, then concentrated. The residue was purified by Prep-HPLC (Waters I) with the following conditions: Column, Waters XBridge RP18 l9* l50mm, 5pm: mobile phase, water (containing lOmM NH ₄HCO ₃ + 0.05% ammonia) and ACN with a gradient of 42% to 65% ACN in 7 min; flow rate, 20mL/min; detector UV wavelength, 254 nm. This provided A'-|(2-fluorophcnyl)mcthyl |-5-(6- mcthylpyridinc-2-sulfonyl)- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrolc-2-carboxamidc (54 mg, 20%) as a white solid. ¾ NMR (300MHz, CDCL, ppm): d 7.83-7.76 (m, 2H), 7.44-7.34 (m, 2H), 7.32-7.23 (m, 1H), 7.14-7.02 (m, 1H), 4.60 (d, .7=6.0 Hz, 1H), 4.51 (d, .7=5.7 Hz, 2H), 4.37 (s, 4H), 4.12 (s, 4H), 2.61 (s,

3H). LCMS: m/z = 417 [M+H] ⁺.

[00223] Example 16-1: 2-(Pyridin-3-yl)-l -[5-(pyridine-2-sulfonyl)- l //,2//,3//,4//,5//,6//- pyrrolo[3,4-c]pyrrol-2-yl]ethan-l-one

Example 16-1

Step 1. tert-Butyl 5-[2-(pyridin-4yl)acetyl]-lH,2H, 3H, 4H, 5H, 6H-pyrrolo[3, 4-c]pyrrole-2-carboxylate

[00224] To an 8-mL vial was added 2-(pyridin-3-yl)acetic acid (78.3 mg, 0.57 mmol, 1.20 equiv), DCM (2.00 mL), DIEA (184 mg, 1.42 mmol, 1.00 equiv), tert- butyl l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrolc- 2-carboxylate (100 mg, 0.48 mmol, 1.00 equiv) and HATU (200 mg, 0.53 mmol, 1.10 equiv). The solution was stirred for 2 h at RT, then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM/methanol (50: 1) to provide tert- butyl 5-[2-(pyridin-4yl)acetyl]- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrolc-2-carboxylatc (135 mg) as a brown oil. The material was used without further purification. LCMS: m/z = 330 [M+H] ⁺.

Step 2. 2-(Pyridin-3-yl)-l-[lH,2H, 3H,4H,5H, 6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-l-one hydrochloride

[00225] To an 8-mL vial was added tert- butyl 5-|2-(pyridin-4yl)acctyl \- \H.2H3HLH.5H.6H- pyrrolo[3,4-c]pyrrole-2-carboxylate (135 mg, 0.41 mmol, 1.00 equiv) and DCM (2.00 mL). The stirred solution was treated with ethyl acetate freshly saturated with hydrogen chloride (2.00 mL). The solution was stirred for 2 h at RT, then the solids were collected by filtration to provide 2-(pyridin-3-yl)-l- | l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrol-2-yl |ethan- 1 -one hydrochloride (125 mg) as a light brown solid. The material was used without further purification. LCMS: m/z = 230 [M+H] ⁺.

Step 3. 2-(Pyridin-3-yl)-l-[5-(pyridine-2-sulfonyl)-lH,2H, 3H, 4H, 5H, 6H-pyrrolo[3, 4-c]pyrrol-2- y l]e than- 1 -one

[00226] To an 8-mL vial was added 2-(pyridin-3-yl)- 1 -| I //.2//.3//.4//.5//.6//-pyrrolo| 3.4-c |pyrrol-2- yl]ethan-l-one hydrochloride (115 mg, 0.43 mmol, 1.00 equiv), DMF (4 mL), pyridine-2-sulfonyl chloride (84.1 mg, 0.47 mmol, 1.10 equiv) and DIEA (139 mg, 1.08 mmol, 2.50 equiv). The solution was stirred for 2 h at RT. The mixture was purified by Prep-HPLC (Waters 2767) with the following conditions: Column, X-Bridge RP18, l9* l50mm, 5 pm : mobile phase, water (containing 10 mM NH ₄HC0 ₃+0.05% ammonia) and CLLCN with a gradient of 16% to 36% CLLCN in 8 min; detector UV wavelength, 220 nm. This provided 2-(pyridin-3-yl)- 1 -|5-(pyridinc-2-sulfonyl)- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrol-2- yl]ethan-l-one (25.5 mg, 16%) as a light yellow solid. ¾ NMR (300MHz, OMSO-de, ppm): d 8.75 (d, J= 3.9 Hz, 1H), 8.44-8.41 (m, 2H), 8.16-8.10 (m, 1H), 7.97 (d, 7=7.8 Hz, 1H), 7.72 (dd, 7=4.8 Hz, .7=1.5 Hz, 1H), 7.71-7.69 (m, 1H), 7.32 (dd, 7=7.2 Hz, 7=4.8 Hz, 1H), 4.31-4.26 (m, 6H), 4.03 (s, 2H), 3.68 (s,

2H). LCMS: m/z = 371 [M+H] ⁺.

[00227] Example 17-1: 3-[5-[(2R)-2-hydroxy-2-phenylacetyl]-lH,2H,3H,4H,5H,6H-pyrro lo[3,4- c]pyrrole-2-sulfonyl]benzene-l-sulfonamide

Example 17-1 [00228] Prepared as described for Step 3 of the preparation of Example 16-1 using the appropriate synthetic precursors, but with a two hour reaction time, and using a Prep-HPLC gradient of 20% to 40% ACN in 8 minutes. Isolated as a white solid (48.3 mg, 29%). 'H NMR (300MHz, OMSO-de, ppm): d 8.19 (d, .7=1.5 Hz, 1H), 8.12-8.01 (m, 2H), 7.86-7.83 (m, 1H), 7.59 (s, 2H), 7.34-7.30 (m, 5H), 5.64 (d, .7=6.3 Hz, 1H), 5.16 (d, 7=6.0 Hz, 1H), 4.25-3.87 (m, 8H). LCMS: m/z = 464 [M+H] ⁺.

[00229] Example 18-1: 3-Methyl-l-{5-[(l-methyl-177-pyrazol-3-yl)sulfonyl]- 177,277,377,477,577,677-pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylb utan-l-one

[00230] To a 1.5 mL vial was added a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate hydrochloride (100 pL, 20 pmol) in dioxane and neat DIEA (10 pL, 57 pmol) to give a brown suspension. A 0.2 M solution of l-methyl-lH-pyrazole-3-sulfonyl chloride (105 pL, 20 pmol) in dioxane was added. The reaction was heated at 50 °C with shaking for 2 hours. 4 M HC1 in dioxane (50.0 pL, 0.200 mmol) was then added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 uL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (25 pL, 0.143 mmol) and a 0.2 M solution of 3-methyl-2-phenylbutanoic acid (110 pL, 22 pmol) in dioxane was added to the vial, followed by a 0.2 M solution of HBTU (110 pL, 22 pmol) in ACN. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The volatiles were removed under reduced pressure. The compound was purified using mass-triggered HPLC to give 3-Methyl-l-{5-[(l- methyl- l77-pyrazol-3 -yl)sulfonyl] - l77,277,377,477,577,677-pyrrolo [3 ,4-c]pyrrol-2-yl } -2-phenylbutan- 1 -one . LCMS: m/z =415.1 [M+H]+.

[00231] The Examples in Table 7 below were prepared according to the procedure oulined above for Example 18-1, using the appropriate synthetic precursors. Table 7.

[00232] Example 18-19: l-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-2-(lH-tetrazol-l-yl )ethan-l-one

[00233] A 0.2 M solution of 4-(difluoromethoxy)benzenesulfonyl chloride (158 pL. 31.5 pmol) in dioxane was added to a 1.5 mL vial charged with a 0.2 M solution of tert-butyl 3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride (150 pL, 30 pmol) in a solvent mixture of acetonitrile/DIEA (90: 10). The reaction mixture was heated at 50 °C with shaking for 2 hours. Dioxane (200 pL), methanol (200 pL), and a solution of 4 N HC1 in dioxane (100 pL, 0.200 mmol) was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 uL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (25 pL, 0.143 mmol) and a 0.2 M solution of 2-(lH-tetrazol-l-yl)acetic acid (165 riL, 33 pmol) in dioxane was added to the vial, followed by a 0.2 T solution of HBTU (165 pL, 33 p ol) in ACN. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The organic layer was concentrated under reduced pressure. The compound was purified using mass-triggered HPLC to give l-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-2-(lH-tetrazol-l-yl )ethan-l-one (4.9 mg, 38 % yield). LCMS: m/z = 427.1 [M+H] ⁺, Rt: 1.10 min (LCMS method 1). [00234] Example 18-25: l-(5-((4-(Difluoromethoxy)phenyl)sulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-2,2-difluoro-2-phen ylethan-l-one

[00235] A 0.2 M solution of 4-(difluoromethoxy)benzenesulfonyl chloride (158 pL. 31.5 pmol) in dioxane was added to a 1.5 mL vial charged with a 0.2 M solution of tert-butyl 3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride (150 pL, 30 pmol) in a solvent mixture of acetonitrile/DIEA (90: 10). The reaction mixture was heated at 50 °C with shaking for 2 hours. Dioxane (200 pL), methanol (200 pL), and a solution of 4 N HC1 in dioxane (100 pL, 0.200 mmol) was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 uL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (25 pL, 0.143 mmol) and a 0.2 M solution of 2,2-difluoro-2-phenylacetic acid (165 riL, 33 pmol) in dioxane was added to the vial, followed by a 0.2 T solution of HBTU (165 pL, 33 p ol) in ACN. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The organic layer was concentrated under reduced pressure. The compound was purified using mass-triggered HPLC to give l-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-2,2-difluoro-2-phen ylethan-l-one (1.7 mg, 12 % yield). LCMS: m/z = 471.1 [M+H]+, Rt: 1.58 min (LCMS method 1).

[00236] Example 19-1: (2i?)-l-{5-[(5-chlorothiophen-2-yl)sulfonyl]- l //,2//,3//,4//,5//,6//- pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylpropan-l-one

Example 19-1

[00237] To a 1.5 mL vial was added a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate hydrochloride (100 pL. 20 pmol), a 0.2 M solution of (R)-2-phenylpropanoic acid (110 pL, 22 pmol), and neat DIEA (10 pL, 0.057 mmol) to give abrown suspension. A 0.2 M solution of HBTU (110 pL, 22 pmol) in ACN was added. The reaction was shaken for 2 hours at RT. 4 M HC1 in dioxane (50.0 pL, 0.200 mmol) was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were evaporated under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The volatiles were evaporated under reduced pressure and ACN (200 pM) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue, then neat DIEA (10 pL, 57 pmol) was added to the vial followed by a 0.2 M solution of 5- chlorothiophene-2-sulfonyl chloride (110 pL, 22 pmol) in dioxane. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The volatiles were removed under reduced pressure. The compound was purified using mass-triggered HPLC to provide (2 R)- l-{5-[(5-chlorothiophen-2-yl)sulfonyl]- l//.2//.3//.4//.5//.6//-pyrrolo| 3.4-c| pyrrol -2-yl [ -2-phenylpropan- l-one. LCMS: m/z =423.1 [M+H]+.

[00238] The Examples in Table 8 below were prepared according to the procedure oulined above for Example 19-1, using the appropriate synthetic precursors.

Table 8.

[00239] Example 19-9: 2-(lH-Benzo[d]imidazol-l-yl)-l-(5-((l,2-dimethyl-lH-imidazol -4- yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl )propan-l-one

[00240] A 0.2 M solution of 1, 2-dimethyl- lH-imidazole-4-sulfonyl chloride (158 pL. 31.5 pmol) in dioxane was added to a 1.5 mL vial charged with a 0.2 M solution of tert-butyl 3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride (150 pL, 30 pmol) in a solvent mixture of acetonitrile/DIEA (90: 10). The reaction mixture was heated at 50 °C with shaking for 2 hours. Dioxane (200 pL), methanol (200 pL), and a solution of 4 N HC1 in dioxane (100 pL, 0.200 mmol) was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 uL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (25 pL, 0.143 mmol) and a 0.2 M solution of 3-(lH-benzo[d]imidazol-l-yl)-2- oxobutanoic acid (165 pL, 33 pmol) in dioxane was added to the vial, followed by a 0.2 M solution of HBTU (165 pL, 33 pmol) in ACN. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The organic layer was concentrated under reduced pressure. The compound was purified using mass-triggered HPLC to give 2-(lH-benzo[d]imidazol-l-yl)- l-(5-((l,2-dimethyl-lH-imidazol-4-yl)sulfonyl)-3,4,5,6-tetra hydropyrrolo[3,4-c]pyrrol-2(lH)-yl)propan- l-one (7.5 mg, 55 % yield). LCMS: m/z = 455.2 [M+H] ⁺, Rt: 0.78 min (LCMS method 1).

[00241] Example 20-1: /V-(furan-2-ylmethyl)-5-(pyridin-3-ylsulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(l/7)-carboxamide

Example 20-1

[00242] To a 1.5 mL vial was added a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate hydrochloride (100 pL, 20 pmol) in ACN, a 0.2 M solution of 2- (isocyanatomethyl)furan (110 pL, 22 pmol) in dioxane, and neat DIEA (10 pL, 57 pmol) to give a brown suspension. The reaction was shaken at RT for 2 hours. 4 M HC1 in dioxane (50.0 pL, 0.200 mmol) was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure and ACN (0.2 pL) was added to the vial along with DIEA (25 pL, 0.143 mmol). The vial was shaken for 15 minutes to resuspend the residue, then a 0.2 M solution of pyridine-3 -sulfonyl chloride (110 pL, 22 pmol) in dioxane was added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The volatiles were removed under reduced pressure. The compound was purified using mass-triggered HPLC to yield N-(furan-2-ylmethyl)- 5-(pyridin-3-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyr role-2(lH)-carboxamide (1.9 mg, 5.08 pmol, 25% yield). LCMS: m/z =375.2 [M+H]+.

[00243] The Examples in Table 9 below were prepared according to the procedure outlined above for Example 20-1, using the appropriate synthetic precursors.

Table 9.

[00244] Example 21-1: 5-(Benzo[i/]thiazol-6-ylsulfonyl)-/V-(furan-2-ylmethyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(l/7)-carboxamide

Example 21-1

[00245] To a 1.5 mL vial was added a 0.2 M solution of 6-((5,6-dihydropyrrolo[3,4-c]pyrrol- 2(lH,3H,4H)-yl)sulfonyl)benzo[d]thiazole (150 pL, 0.030 mmol) in ACN, a 0.2 M solution of 2- (isocyanatomethyl)furan (150 pL, 0.030 mmol) in ACN, and DIEA (25 pL, 0.144 mmol) to give a brown suspension. The reaction was shaken at RT for 2 hours. The reaction was dried down under a stream of nitrogen. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with EtOAc (2 x 0.5 mL). The extracts were dried under a stream of nitrogen. The compound was purified using mass-triggered HPLC to yield 5-(benzo[d]thiazol-6-ylsulfonyl)-N-(furan-2-ylmethyl)-3,4,5, 6-tetrahydropyrrolo[3,4-c]pyrrole- 2(lH)-carboxamide (2.1 mg, 4.88 pmol, 16% yield). LCMS: m/z = 431.0 [M+H]+.

[00246] The Examples in Table 10 below were prepared according to the procedure oulined above for Example 21-1, using the appropriate synthetic precursors.

Table 10.

[00247] Example 22-1: Pyridin-3-ylmethyl 5-((4-(difluoromethoxy)phenyl)sulfonyl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(l/7)-carboxylate

Example 22-1

[00248] In a 1.5 mL reaction vial was added a 0.2M solution of 4-nitrophenyl(pyridin-3- ylmethyl)carbonate (180 pL, 0.036 mmol) in ACN, neat DIEA (15 pL, 0.086 mmol) and a 0.2M solution of 2-((4-(difluoromethoxy)phenyl)sulfonyl)- 1 ,2,3 ,4,5 ,6-hexahydropyrrolo [3 ,4-c]pyrrole hydrochloride (150 pL, 0.030 mmol) in ACN containing 5% DIEA to give a brown solution. The reaction was shaken at RT for 2 hours. The volatiles were removed under a stream of nitrogen. The residue was partitioned between 0.5 mL of 1N NaOH and 0.5 mL of EtOAc. The organic layer was removed. The aqueous layer was extracted with 0.5 mL of EtOAc. The organic layers were combined and the volatiles removed under a stream of nitrogen. The residue was purified using mass-triggered HPLC to provide pyridin-3-ylmethyl 5- ((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrr olo[3,4-c]pyrrole-2(lH)-carboxylate (5.6 mg, 12.4 pmol, 41% yield). LCMS: m/z = 452.2 [M+H]+. [00249] The Examples in Table 11 below were prepared according to the procedure oulined above for Example 22-1, using the appropriate synthetic precursors.

Table 11.

[00250] Example 23-1: 2-(Benzofuran-5-ylsulfonyl)-5-(benzoylprolyl)-l,2,3,4,5,6- hexahydropyrr olo [3,4-c] pyrrole

[00251] To a 1.5 mL vial was added a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate hydrochloride (150 pL, 30 pmol) in dioxane and neat DIEA (10 pL, 57 pmol) to give a brown suspension. A 0.2 M solution of benzofuran-5-sulfonyl chloride (158 pL, 31.5 pmol) in dioxane was added. The reaction was heated at 50 °C with shaking for 2 hours. 4 M HC1 in dioxane (75.0 pL, 0.300 mmol) was then added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 pL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (50 pL, 0.285 mmol) and a 0.2 M solution of (tert-butoxycarbonyl)proline (165 pL, 33 pmol) in dioxane was added to the vial, followed by a 0.2 M solution of HBTU (165 pL, 33 pmol) in ACN. The reaction was shaken at room temperature for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The organic layers were combined and the volatiles were removed under reduced pressure. Dioxane (200 pL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. 4 M HC1 in dioxane (75.0 pL, 0.300 mmol) was then added. The reaction was heated at 50 °C with shaking for an additional 2 hours. The volatiles were removed under reduced pressure. ACN (200 pL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Neat DIEA (50 pL, 0.285 mmol) and a 0.2 M solution of benzoic acid (165 pL, 33 pmol) in dioxane was added to the vial, followed by a 0.2 M solution of HBTU (165 pL, 33 pmol) in ACN. The reaction was shaken at room temperature for an additional 2 hours. The volatiles were removed under reduced pressure. The residue was mixed with 1 N NaOH (0.5 mL) and extracted with 3: 1 EtOAc/ACN (2 x 0.5 mL). The organic layers were combined and the volatiles were removed under reduced pressure. The compound was purified using mass-triggered HPLC to give 2-(benzofuran-5-ylsulfonyl)-5-(benzoylprolyl)- l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (2.0 mg, 6.52 pmol, 22% yield). LCMS: m/z =492.3.1 [M+H]+.

[00252] The Examples in Table 12 below were prepared according to the procedure oulined above for Example 23-1, using the appropriate synthetic precursors. Table 12.

[00253] Example 24. Luminescence Biochemical Assay

[00254] In some embodiments, a PKR Activating Compound refers to a compound having one or more characteristics when tested according to the following Luminescence Assay Protocol of Example 24 performed with wild type (wt) PKR and/or any one or more of G332S mutant form of PKR or R510Q mutant form of PKR: (1) an AC50 value of less than 40 mM (e.g., compounds with AC50 values of “+”, “++”, or“+++” in Table 13); (2) a maximum % Fold (MAX%Fold) value of greater than 75%; and/or (3) a % Fold value at 1.54 pM compound concentration (%Fold@l .54 pM) of at least 75%. In some embodiments, a PKR Activating Compound can have: (1) an AC50 value of less than 0.1 pM (e.g., compounds with AC50 values of“+++” in Table 13), 0.1-1.0 pM (e.g., compounds with AC50 values of “++” in Table 13), or 1.01-40 pM (e.g., compounds with AC50 values of“+” in Table 13); (2) a MAX%Fold of 75%-250%, 250-500%, or 75%-500%; and/or (3) a %Fold@l .54 pM of 75%-250%, 250-500%, or 75%- 500%. In some embodiments, a PKR Activating Compound has (1) an AC50 value of less than 1.0 pM; (2) a MAX%Fold of 75%-500%; and/or (3) a %Fold@l .54 pM of 75%-500%.

[00255] The phosphorylation of Adenosine-5 '-diphosphate (ADP) by various mutants of PKR was determined by the Kinase Glo Plus Assay (Promega) in the presence or absence of FBP [D-Fructose-l,6- diphosphate; BOC Sciences, CAS: 81028-91-3] as follows. Unless otherwise indicated, all reagents were purchased from Sigma- Aldrich. All reagents were prepared in buffer containing 50 mM Tris-HCl, 100 mM KC1, 5 mM MgCl ₂, and 0.01% Triton X100, 0.03% BSA, and 1 mM DTT. Enzyme and PEP [Phospho(enol) pyruvic acid] were added at 2x to all wells of an assay-ready plate containing serial dilutions of test compounds or DMSO vehicle. Final enzyme concentrations for PKR(wt), PKR(R5 l0Q), and PKR(G332S) were 0.8 nM, 0.8 nM, and 10 nM respectively. Final PEP concentration was 100 pM. The Enzyme/PEP mixture was incubated with compounds for 30 minutes at RT before the assay was initiated with the addition of 2x ADP [Adenosine-5 '-diphosphate] and KinaseGloPlus. Final concentration of ADP was 100 pM. Final concentration of KinaseGloPlus was 12.5%. For assays containing FBP, that reagent is added at 30 pM upon reaction initiation. Reactions were allowed to progress for 45 minutes at RT until luminescence was recorded by the BMG PHERAstar FS Multilabel Reader. All compounds were tested in triplicate at concentrations ranging from 42.5 pM to 2.2 nM in 0.83% DMSO.

[00256] Luminescence values were converted to % Fold increase by normalizing to the average of the DMSO control and multiplying by 100. Max, min, slope and AC50 were determined by the standard four parameter fit algorithm of ActivityBase XE Runner. Compounds were evaluated with three parameters - AC50, MAX%Fold, and %Fold@l .54 pM (FIG. 1). The AC50 value for a compound is the concentration (pM) corresponding to the midway between the maximum and minimum values of the four parameter logistic curve fit (i.e., at which the % fold increase along the four parameter logistic curve fit is halfway between MAX%Fold and MIN%Fold (% Fold Midpoint)), MAX%Fold is the highest fold increase observed at any concentration of compound, and %Fold@l .54 pM is the fold increase at a compound concentration of 1.54 pM. The parameter %Fold@l .54 pM was selected to capture elements of both the AC50 and MAX%Fold and to provide a ranking based on both potency and effect. The compound concentration of 1.54 mM was chosen as one that can optimally differentiate the set of compounds based on the range of activities observed.

[00257] As set forth in Table 13 below, AC50 values (columns A, D, G) are defined as follows: < 0.1 mM (+++); > 0.1 mM and < 1.0 pM (++); > 1.0 pM and < 40 pM (+); > 40 pM (0). Max%FOLD values (columns B, E, H) are defined as follows: < 75% (+); > 75% and < 250% (++); > 250% and < 500% (+++). %Fold@l .54 mM values (columns C, F, J) are defined as follows: < 75% (+); > 75% and < 250% (++); > 250% and < 500% (+++).

Table 13.

‘A - AC50 LUM KGP FBP AC ₅₀ mM gmean;

B - AC50 LUM KGP FBP MAX%FOLD mean;

C - AC50 LUM KGP FBP %Fold@L54 mM mean

D - AC50 LUM KGP woFBP AC ₅₀ mM gmean;

E - AC50 LUM KGP woFBP MAX%FOLD mean;

F - AC50 LUM KGP woFBP %Fold@L54 mM mean

G - AC50 LUM KGP woFBP AC50 mM gmean;

H - AC50 LUM KGP woFBP MAX%FOLD mean;

J - AC50 LUM KGP woFBP %Fold@L54 mM mean

Table 14. Biological Data of Additional Compound

D - AC50 LUM KGP woFBP AC ₅₀ mM gmean.

G - AC50 LUM KGP woFBP AC ₅₀ mM gmean;

Equivalents

[00258] The present disclosure enables one of skill in the relevant art to make and use the inventions provided herein in accordance with multiple and varied embodiments. Various alterations, modifications, and improvements of the present disclosure that readily occur to those skilled in the art, including certain alterations, modifications, substitutions, and improvements are also part of this disclosure. Accordingly, the foregoing description and drawings are by way of example to illustrate the discoveries provided herein.

[00259] Embodiment ! . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl or monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R\ -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -CVG.alkenyl. -CV alkynyl. -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

R ¹ and R ² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, -C ₂-C ₆alkenyl, -C ₂-Cgalkynyl, -(CR ^bR ^c) _nC ₃-Ci2Cycloalkyl, -(CR ^bR ^c) _nC ₄-Ci2Cycloalkenyl,

wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C i -C _g alkyl, -CVC _galkenyl. -CVC _galkynyl. oxo, and -OR, wherein -OR does not result in an O in the g-position relative to C(=Z),

wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S, and

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z), and

R ^b and R ^c are each independently selected from the group consisting of -H, halogen, and -Ci-Cgalkyl; each n is independently 0, 1, 2, 3, or 4;

B is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with (R ^d) _m, and

when the ring is saturated or partially unsaturated, then the ring does not contain an O in the g-position relative to C(=Z);

each R ^d is independently selected from the group consisting of halogen, oxo, -OR, -0C(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R\ -C(0)0R, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cg alkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, or -OR;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH ₂, -NH(Ci-Cgalkyl), and -N(Ci-Cgalkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cg alkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O(Ci-Cgalkyl), -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl) ₂; and

[00260] Embodiment 2. The compound of embodiment 1, wherein the compound is of Formula I-a:

(I-a)

or a pharmaceutically acceptable salt thereof.

[00261] Embodiment 3. The compound of embodiment 2, wherein the compound is of Formula I-b:

(I-b)

or a pharmaceutically acceptable salt thereof.

[00262] Embodiment 4. The compound of any one of embodiments 1-3, wherein B is an aromatic monocyclic ring or a bicyclic ring,

wherein at least one of the rings in the bicyclic ring is aromatic,

wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the monocyclic ring or bicyclic ring is optionally substituted with (R ^d) _m.

[00263] Embodiment 5. The compound of any one of embodiments 1-4, wherein R ¹ and R ² are each independently selected from the group consisting of -H, halogen, -Ci-Cgalkyl, and -OR, wherein -OR does not result in an O in the g-position relative to C(=Z).

[00264] Embodiment 6. The compound of any one of embodiments 1-3, wherein the compound is of Formula I-c:

(I-c) or a pharmaceutically acceptable salt thereof.

[00265] Embodiment 7. The compound of any one of embodiments 1-5, wherein the compound is of Formula I-d-l:

(I-d-l)

or a pharmaceutically acceptable salt thereof.

[00266] Embodiment 8. The compound of any one of embodiments 1-5, wherein the compound is of Formula I-d-2:

(I-d-2)

or a pharmaceutically acceptable salt thereof,

[00267] Embodiment 9. The compound of any one of embodiments 1-8, wherein A is phenyl or pyridyl, optionally substituted with one or more R ^a.

[00268] Embodiment 10. The compound of any one of embodiments 1-9, wherein each R ^a is selected from the group consisting of halogen, -Ci-Cgalkyl, and -OR.

[00269] Embodiment 11. The compound of any one of embodiments 1-10, wherein A is pyridyl.

[00270] Embodiment 12. The compound of any one of embodiments 1-11, wherein each R ^d is selected from the group consisting of halogen, -Ci-Cgalkyl, and -OR.

[00271] Embodiment 13. The compound of of any one of embodiments 1-12, wherein A is unsubstituted.

[00272] Embodiment 14. The compound of any one of embodiments 1-13, wherein each R is independently selected from the group consisting of -H and -Ci-Cgalkyl.

[00273] Embodiment 15. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR2, -NRC(0)R’,

-NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)0R, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-C ₆alkyl,

-C ₂-Cgalkenyl, -CVC _galkynyl. -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

R ¹, R ², and B are each independently -H, halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -OR,

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen;

or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci ₂cycloalkyl, or a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S,

wherein the heterocyclyl does not contain an O in the g-position relative to C(=Z),

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -OR, oxo, -Cgaryl, and -C(0)R’, and wherein each cycloalkyl or heterocyclyl is optionally fused with a Cgaryl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

each R ^b and R ^c is independently selected from the group consisting of -H, -Ci-Cgalkyl, and halogen; each n is independently 0, 1, 2, 3, or 4;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(Ci- Cgalkyl), -N(Ci-Cgalkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C ₃-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, -Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O(Ci-Cgalkyl), -NH(Ci-Cgalkyl), or -N(Ci-C ₆alkyl) ₂; and

each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, -(CR ^bR ^c) _nCg-Ci4aryl, -(CR ^bR ^c)nO(Cg-C i4aryl), and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -O(Ci-Cgalkyl), -NH(Ci-Cgalkyl), or -N(Ci-C ₆alkyl) ₂;

provided that the compound is other than:

[00274] Embodiment 16. The compound of embodiment 15, wherein the compound is of Formula II- a:

(II-a)

or a pharmaceutically acceptable salt thereof.

[00275] Embodiment 17. The compound of embodiment 15 or 16, wherein the compound is of Formula II-b-l :

(II-b-l)

or a pharmaceutically acceptable salt thereof,

wherein R ¹ is -H, halogen, -CVC _galkyl. -CVC _galkenyl. or -CVC _galkynyl.

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, and whe

[00276] Embodiment 18. The compound of embodiment 15 or 16, wherein the compound is of Formula II-b-2:

(II-b-2)

or a pharmaceutically acceptable salt thereof,

wherein R ¹ is -H, halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, or -C ₂-Cgalkynyl,

wherein each alkyl, alkenyl, or alkynyl is optionally substituted with one or more halogen, and wherein B is -OR, -OC(0)R’, -OS(0) ₂R\ -0S(0) ₂NR ₂, -OC(0)NR ₂, -OC(0)OR, -(CR ^bR ^c) _nNR ₂, -(CR ^bR ^c) _nNRC(0)R’, -(CR ^bR ^c) _nNRS(0) ₂R’, -(CR ^bR ^c) _nNRC(0)NR ₂, -(CR ^bR ^c) _nNRC(0)OR,

[00277] Embodiment 19. The compound of any one of embodiments 15-18, wherein A is amonocyclic or bicyclic 3- to lO-membered ring,

wherein the ring is partially unsaturated or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a.

[00278] Embodiment 20. The compound of any one of embodiments 15-19, wherein R ^a is selected from the group consisting of halogen, -OR, -NR ₂, -Ci-Cgalkyl, -C3-Ci ₂cycloalkyl, and 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more halogen.

[00279] Embodiment 21. The compound of any one of embodiments 15-20, wherein:

R ¹, R ², and B are each independently -H, -CVCgalkyl. -OR, -(CR ^bR ^c) _nNR ₂, -(CR ^bR ^c) _nNRS(0) ₂R’, or -(CR ^bR ^c) _nC(0)OR,

wherein each alkyl is optionally substituted with one or more halogen;

wherein the heterocyclyl does not contain an O in the g-position relative to C(=0),

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of phenyl, and -C(0)R’, and

wherein each heterocyclyl is optionally fused with a phenyl or 5- to 6-membered heteroaryl

containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

[00280] Embodiment 22. The compound of any one of embodiments 15-21, wherein R ¹, R ², and B are each independently -H, -Ci-C ₆alkyl, -OR, -(CR ^bR ^c) _nNR ₂, -(CR ^bR ^c) _nNRS(0) ₂R\ or -(CR ^bR ^c) _nC(0)OR, wherein each alkyl is optionally substituted with one or more halogen.

[00281] Embodiment 23. The compound of any one of embodiments 15-21, wherein:

R ¹ and R ² combine with the carbon to which they are attached to form a C3-Ci ₂cycloalkyl or 3- to 14- membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N and S,

wherein the heterocyclyl does not contain an O in the g-position relative to C(=0),

wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of phenyl, and -C(0)R’, and wherein each heterocyclyl is optionally fused with a phenyl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

[00282] Embodiment 24. The compound of any one of embodiments 15-23, wherein B is -H.

[00283] Embodiment 25. The compound of any one of embodiments 15-24, wherein each R is independently selected from the group consisting of -H, -Ci-Cgalkyl, and C6-Ci4aryl.

[00284] Embodiment 26. The compound of any one of embodiments 15-25, wherein each R’ is -Ci-Cgalkyl.

[00285] Embodiment 27. A compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

A is a monocyclic or bicyclic 3- to l4-membered ring,

wherein the ring is saturated, fully or partially unsaturated, or aromatic, and

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and

wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR2, -NRC(0)R’, -NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)OR, -C(0)NR ₂, -S(0) ₂R\ -S(0) ₂NR ₂, -Ci-Cealkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

B is a ring selected from the group consisting of -C6-Ci4aryl and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R’, -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-C ₆alkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cg alkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(Ci-Cgalkyl), -N(Ci-C ₆alkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C -Cgalkynyl, -Cs-Cucycloalkyl, -C4-Ci2cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl)2; and

each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cycloalkyl, -C4-Ci2Cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and

[00286] Embodiment 28. The compound of embodiment 27, wherein the compound is of Formula III- a:

(Ill-a)

or a pharmaceutically acceptable salt thereof.

[00287] Embodiment 29. The compound of embodiment 27 or 28, wherein A is a 5- to lO-membered aromatic monocyclic ring or a bicyclic ring,

wherein at least one of the rings of the bicyclic ring is aromatic,

wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the monocyclic ring or bicyclic ring is optionally substituted with one or more R ^a.

[00288] Embodiment 30. The compound of any one of embodiments 27-29, wherein A is a bicyclic aromatic ring containing 0-4 heteroatoms independently selected from the group consisting of O, N, and S.

[00289] Embodiment 31. The compound of any one of embodiments 27-30, wherein B is a ring selected from phenyl or 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein the ring is optionally substituted with one or more R ^d.

[00290] Embodiment 32. The compound of any one of embodiments 27-31, wherein each R ^d is independently selected from the group consisting of -OR,-NR2, and -Ci-Cgalkyl optionally substituted with one or more halogen.

[00291] Embodiment 33. The compound of any one of embodiments 27-32, wherein each R is independently selected from the group consisting of -H, -Ci-Cgalkyl optionally substituted with one or more halogen, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S.

[00292] Embodiment 34. A compound of Formula IV:

or a pharmaceutically acceptable salt thereof, whereimA is a monocyclic or bicyclic 3- to l4-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and wherein the ring is optionally substituted with one or more R ^a;

each R ^a is independently selected from the group consisting of halogen, -OR, -0C(0)R’, -NR2, -NRC(0)R’, -NRS(0) ₂R\ -CN, -NO2, -SR, -C(0)R’, -C(0)0R, -C(0)NR ₂, -S(0) ₂R\ -S(0) ₂NR ₂, -Ci-Cgalkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl is optionally substituted with one or more halogen;

Z is O, S, or NR;

X is O or NR ^e;

R ^e is -H or -Ci-Cgalkyl;

B is -H, or a monocyclic or bicyclic 3- to l4-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S; and wherein the ring is optionally substituted with one or more R ^d;

each R ^d is independently selected from the group consisting of halogen, -OR, -OC(0)R’, -NR ₂, -NRC(0)R’, -NRS(0) ₂R\ -CN, -N0 ₂, -SR, -C(0)R’, -C(0)OR, -C(0)NR ₂, -S(0) ₂R’, -S(0) ₂NR ₂, -Ci-Cgalkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, -C3-Ci ₂cycloalkyl, -C4-Ci ₂cycloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, C6-Ci4aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C ₂-C ₆alkenyl, -C ₂-C ₆alkynyl, or -OR;

R ¹ and R ² are each independently -H, halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteorcyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -OR, and oxo, wherein each heterocyclyl is 3- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein each heteroaryl is 5- to l4-membered and contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ¹ and R ² combine with the carbon to which they are attached to form oxo, a C3-Ci2Cyeloalkyl, or a 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

or R ² is absent, and R ¹ and B combine with the carbon to which they are attached to form Cg-Ci4aryl or 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S,

wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, or -OR;

each R ^b and R ^c is independently selected from the group consisting of -H, -Ci-Cgalkyl, and halogen; each n is independently 0, 1, 2, 3, or 4;

R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, and R ¹⁰ are each independently -H or -Ci-Cgalkyl,

wherein each alkyl is optionally substituted with one or more halogen;

each R is independently selected from the group consisting of -H, -OH, -O(Ci-Cgalkyl), -NH2, -NH(Ci-Cgalkyl), -N(Ci-C ₆alkyl) ₂, -Ci-Cgalkyl, -C ₂-Cgalkenyl, -C ₂-Cgalkynyl, -C ₃-Ci2Cycloalkyl, -C4-Ci2Cyeloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -O-Ci-Cgalkyl, -NH(Ci-Cgalkyl), or -N(Ci-Cgalkyl)2; and each R’ is independently selected from the group consisting of -Ci-Cgalkyl, -C2-Cgalkenyl, -C2-Cgalkynyl, -C3-Ci2Cyeloalkyl, -C4-Ci2Cyeloalkenyl, 3- to l4-membered heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S, Cg-C^aryl, and 5- to l4-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and

[00293] Embodiment 35. The compound of embodiment 34, wherein the compound is of Formula IV- a:

(IV-a)

or a pharmaceutically acceptable salt thereof.

[00294] Embodiment 36. The compound of embodiment 34 or 35, wherein the compound is of Formula IV-b:

(IV-b)

or a pharmaceutically acceptable salt thereof.

[00295] Embodiment 37. The compound of any one of embodiments 34-36, wherein the compound is of Formula IV-c:

(IV-c)

or a pharmaceutically acceptable salt thereof.

[00296] Embodiment 38. The compound of any one of embodiments 34-36, wherein the compound is of Formula IV-d:

(IV-d)

or a pharmaceutically acceptable salt thereof.

[00297] Embodiment 39. The compound of any one of embodiments 34-36, wherein the compound is of Formula IV-e-l:

(IV-e-l)

or a pharmaceutically acceptable salt thereof.

[00298] Embodiment 40. The compound of any one of embodiments 34-36, wherein the compound is of Formula IV-e-2:

(IV-e-2)

or a pharmaceutically acceptable salt thereof,

[00299] Embodiment 41. The compound of any one of embodiments 34-40, wherein A is a 5- to 10- membered aromatic monocyclic ring or a bicyclic ring,

wherein at least one of the rings of the bicyclic ring is aromatic,

wherein the monocyclic ring or bicyclic ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and

wherein the monocyclic ring or bicyclic ring is optionally substituted with one or more R ^a.

[00300] Embodiment 42. The compound of any one of embodiments 34-41, wherein each R ^a is independently selected from the group consisting of halogen, -Ci-Cgalkyl, and -OR.

[00301] Embodiment 43. The compound of any one of embodiments 34-42, wherein:

B is a monocyclic 3- to 6-membered ring,

wherein the ring is saturated or aromatic,

wherein the ring contains 0-4 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the ring is optionally substituted with one or more R ^d.

[00302] Embodiment 44. The compound of any one of embodiments 34-43, wherein each R ^d is independenly selected from the group consisting of halogen, -Ci-Cgalkyl, and -OR.

[00303] Embodiment 45. The compound of any one of embodiments 34-44, wherein:

R ¹ and R ² are each independently selected from the group consisting of -H, -Ci-Cgalkyl,

-(CR ^bR ^c) _nCg-Ci4aryl optionally substituted with one or more halogen, and -(CR ^bR ^c) _nOR;

or R ¹ and R ² combine with the carbon to which they are attached to form a 3- to l4-membered

heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S;

or R ^e and R ¹ combine with the nitrogen to which they are attached to form a 3- to l4-membered

heterocyclyl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S and optionally substituted with one or more -OR or -(CR ^bR ^c) _nCg-Ci4aryl.

[00304] Embodiment 46. The compound of any one of embodiments 34-45, wherein R ¹ and R ² are each -H.

[00305] Embodiment 47. The compound of any one of embodiments 34-46, wherein R ^b and R ^c are each -H, and each n is 0, 1, or 2.

[00306] Embodiment 48. The compound of any one of embodiments 34-47, wherein each R is independently -H or -Ci-Cgalkyl optionally substituted with one or more halogen.

[00307] Embodiment 49. A compound selected from Table 1.

[00308] Embodiment 50. The compound of embodiment 49, wherein the compound is (2R)-2-hydroxy- 2-phenyl- 1 -|5-(pyridinc-2-sulfonyl)- l//.2//.3//.4//.5//.6//-pyrrolo|3.4-c|pyrrol-2-yl |ethan- 1 -one.

[00309] Embodiment 51. The compound of any one of embodiments 1-50, wherein the compound is a PKR Activating Compound having an AC50 value < 40 mM in the assay of Example 24.

[00310] Embodiment 52. The compound of any one of embodiments 1-51, wherein the compound is a PKR Activating Compound having an AC50 value < 1.0 pM in the assay of Example 24.

[00311] Embodiment 53. The compound of any one of embodiments 1-52, wherein the compound is a PKR Activating Compound having an AC50 value < 0.1 pM in the assay of Example 24.

[00312] Embodiment 54. A pharmaceutically composition, comprising a compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Previous Patent: BRCA1 MODULATING COMPOUNDS, FORMULATIONS THEREOF, AND USES THEREOF

Next Patent: PROTEIN L FOR ACTIVATION AND EXPANSION OF CHIMERIC ANTIGEN RECEPTOR-MODIFIED IMMUNE CELLS