Pyruvate kinase R

Abstract

The present disclosure provides novel compounds that act as activators of PKR.PKR activating compounds can be used to treat diseases and disorders associated with PKR and / or PKM2 regulation, such as pyruvate kinase deficiency (PKD).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 733,546, filed on September 19, 2018, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to novel chemical compositions for activating pyruvate kinase (PKR). Background of the Invention

[0005] Pyruvate kinase (PK) converts phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and adenosine triphosphate (ATP), respectively, which is the last step of glycolysis. In humans, four PK isoforms are expressed by two structural genes. The PKLR gene encodes the PKR and PKL tissue-specific isoforms expressed in erythroid cells and hepatocytes, respectively. The PKM gene encodes the isoform PKM1 expressed in brain and skeletal muscle and PKM2 (M2-type pyruvate kinase) expressed in fetal and most adult tissues except erythroid cells.

[0006] Mutations in the PKLR gene can lead to pyruvate kinase deficiency (PKD), an autosomal recessive disorder, which is the most common enzyme deficiency in the erythrocyte glycolytic pathway. More than 200 different mutations have been identified on the structural PKLR gene. Typically, most PKD patients are heterozygous with two different mutant alleles, but homozygous mutations have also been described. The clinical symptoms of PKD vary greatly, from mild anemia to severe anemia. Mutations reduce the enzymatic activity of PK or reduce the stability of PK protein. Pathological manifestations are usually observed when the enzyme activity drops below 25% of normal PK activity, and severe disease is associated with high reticulocytosis. Although the global incidence of PKD is unknown, it is estimated to be 51 cases per million in North America.

[0007] Currently, there is no definitive treatment for severe PKD. Although splenectomy may be clinically useful in severely ill patients, in some cases, allogeneic hematopoietic transplantation is required. In these patients, hematopoietic stem cell (HSC) gene therapy may be a better and more effective treatment. Gene therapy strategies for PKD have been addressed in animal models, demonstrating that the introduction of the correct version of the human PKLR gene into hematopoietic stem cells using a retroviral vector can alleviate the disease. Although bone marrow transplantation (BMT) or gene therapy strategies would be definitive treatments for the disease, they have not yet been achieved clinically, and both approaches are associated with important adverse effects.

[0008] Still need to improve the strategy of the treatment of the disease such as PKD relevant with PKR, comprise discovery and development activation PKR small molecule.PKR exists with dimer and tetramer state, but is most effectively used as tetramer.It has been proved that small molecule can convert the balance of PKR into tetramer (highest activity) form, for using it as the therapeutic method of the hemolytic anemia relevant with PKD provides mechanism principle.Therefore, need to be used for the treatment of the disease relevant with the regulation of PKR and / or PKM2 and the PKR activation compound of illness. Summary of the invention

[0009] The present disclosure partly relates to compounds and compositions that can be used for activating PKR, including the development of novel compounds that wild-type (wt) PKR and / or PKR mutant isozyme forms are active. For example, compounds and methods provided herein can be used to activate wild-type PKR isozymes and / or mutant PKR isozymes. Examples of mutant PKR isozymes include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q, I90N and R490W. The present invention is partly based on the discovery of novel compounds, which have demonstrated the activation of G332S and R510Q mutant forms of (wt) PKR and PKR.

[0010] 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) 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, thereby treating PKD in the subject. The method may include or result in activating one or more isozymes of pyruvate kinase. The one or more isozymes of pyruvate kinase may be selected from PKR, PKM2, and PKL; the method may also include or result in activating a mutant PKR isozyme.

[0011] One aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0012]

[0013] in:

[0014] A is phenyl or a monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S,

[0015] wherein each aryl or heteroaryl is optionally substituted with one or more R a ;

[0016] Each R aindependently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0017] wherein each alkyl group is optionally substituted with one or more halogens;

[0018] Z is O, S or NR;

[0019] R 1 and R 2 Each is independently selected from: -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n C4-C 12 Cycloalkenyl, -(CR b R c ) n Heterocyclic group, -(CR b R c ) n C6-C 14 Aryl, -(CR b R c ) n heteroaryl, -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CRb R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 and -(CR b R c ) n SO2OR,

[0020] wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo and -OR, wherein -OR does not form O in the γ-position relative to C(=Z),

[0021] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens,

[0022] wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S, and wherein the heterocyclyl does not contain O in the γ-position relative to C(=Z), and

[0023] wherein each heteroaryl is 5 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S;

[0024] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl or a 3- to 8-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, and

[0025] wherein the heterocyclic group does not contain an O in the γ-position relative to C(=Z), and

[0026] wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo, -OR, and wherein -OR does not form O in the γ-position relative to C(=Z);

[0027] R b and R c Each is independently selected from: -H, halogen and -C1-C6 alkyl;

[0028] Each n is independently 0, 1, 2, 3 or 4;

[0029] B is a monocyclic or bicyclic 3 to 14-membered ring,

[0030] wherein the ring is saturated, fully or partially unsaturated or aromatic,

[0031] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0032] wherein the ring is optionally substituted with (R d ) m ,and

[0033] When the ring is saturated or partially unsaturated, the ring does not contain O in the γ-position relative to C(=Z);

[0034] Each R d independently selected from: halogen, oxo, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0035] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0036] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0037] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0038] wherein each alkyl group is optionally substituted with one or more halogens;

[0039] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0040] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0041] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0042] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0043] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0044] Another aspect of the present invention relates to a compound of formula II or a pharmaceutically acceptable salt thereof:

[0045]

[0046] in:

[0047] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0048] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0049] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0050] wherein the ring is optionally substituted with one or more R a ;

[0051] Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0052] wherein each alkyl group is optionally substituted with one or more halogens;

[0053] Z is O, S or NR;

[0054] R 1 , R 2 and B are each independently -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) nNR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR,

[0055] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens,

[0056] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0057] wherein the heterocyclic group does not contain O in the γ-position relative to C(=Z),

[0058] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR, oxo, -C6 aryl, and -C(O)R', and

[0059] wherein each cycloalkyl or heterocyclyl is optionally fused to a phenyl group or a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S;

[0060] Each R b and R c Independently selected from: -H, -C1-C6 alkyl and halogen;

[0061] Each n is independently 0, 1, 2, 3 or 4;

[0062] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0063] wherein each alkyl group is optionally substituted with one or more halogens;

[0064] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0065] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, -C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0066] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0067] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, -(CR b R c ) n C6-C 14 Aryl, -(CR b R c ) n O(C6-C 14 aryl), and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0068] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2;

[0069] Provided that the compound is not:

[0070]

[0071] Another aspect of the present invention relates to a compound of formula III or a pharmaceutically acceptable salt thereof:

[0072]

[0073] in:

[0074] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0075] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0076] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0077] wherein the ring is optionally substituted with one or more R a ;

[0078] Each R aindependently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0079] wherein each alkyl group is optionally substituted with one or more halogens;

[0080] Z is O, S or NR;

[0081] B is a ring selected from the following: -C6-C 14 aryl and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0082] wherein the ring is optionally substituted with one or more R d ;

[0083] Each R d independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0084] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0085] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0086] wherein each alkyl group is optionally substituted with one or more halogens;

[0087] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0088] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0089] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0090] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0091] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0092] Another aspect of the present invention relates to a compound of formula IV or a pharmaceutically acceptable salt thereof:

[0093]

[0094] in:

[0095] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0096] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0097] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0098] wherein the ring is optionally substituted with one or more R a ;

[0099] Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0100] wherein each alkyl group is optionally substituted with one or more halogens;

[0101] Z is O, S or NR;

[0102] X is O or NR e ;

[0103] R e is -H or -C1-C6 alkyl;

[0104] B is -H or a monocyclic or bicyclic 3 to 14 membered ring,

[0105] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0106] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0107] wherein the ring is optionally substituted with one or more R d ;

[0108] Each R d independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0109] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0110] R 1 and R 2 Each is independently -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n C4-C 12 Cycloalkenyl, -(CR b R c ) n Heterocyclic group, -(CR b R c ) n C6-C 14 Aryl, -(CR b R c ) n Heteroaryl, -(CR b R c ) n OR,-(CR b R c ) n OC(O)R'、-(CR b R c ) n OS(O)2R'、-(CR b R c ) nOS(O)2NR2、-(CR b R c ) n OC(O)NR2、-(CR b R c ) n OC(O)OR、-(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR,

[0111] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR and oxo,

[0112] wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S, and

[0113] wherein each heteroaryl is 5 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S;

[0114] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl, or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0115] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR and oxo;

[0116] or R e and R 1 Combined with the nitrogen to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0117] wherein the heterocyclic group is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo, -OR and -(CR b R c ) n C6-C 14 Aryl;

[0118] or R 2 does not exist, and R 1 and B combine with the carbon to which they are attached to form C6-C 14 aryl or a 5- to 14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S,

[0119] wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0120] Each R b and R c Independently selected from: -H, -C1-C6 alkyl and halogen;

[0121] Each n is independently 0, 1, 2, 3 or 4;

[0122] R 3 , R 4 , R 5 , R 6 , R 7 , R 8, R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0123] wherein each alkyl group is optionally substituted with one or more halogens;

[0124] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0125] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0126] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0127] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0128] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0129] Another aspect of the invention relates to compounds of Formula I, II, III or IV, which are PKR activating compounds. In some embodiments, "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 AC of less than 40 μM; 50 In some embodiments, the PKR activating compound has: (1) an AC of less than 0.1 μM, 0.1-1.0 μM, or 1.01-40 μM. 50 value; (2) 75%-250%, 251-500% or the maximum % multiple of 75%-500%; and / or (3) 75%-250%, 251-500% or the % multiple of 75%-500% @ 1.54 μM. In some embodiments, the PKR activating compound has (1) an AC less than 1.0 μM. 50 value; (2) a maximum % multiple of 75%-500%; and / or (3) a % multiple of 75%-500% @ 1.54 μM. In some embodiments, the luminescence assay protocol of Example 24 is performed using wild-type (wt) PKR, a G332S mutant form of PKR, or a R510Q mutant form of PKR. In some embodiments, the PKR activating compound is a compound of Formula I, II, III, or IV. BRIEF DESCRIPTION OF THE DRAWINGS

[0130] Figure 1 Exemplary dose-response curves for compounds disclosed herein are shown. Dose-response curves can be generated using the standard four-parameter fitting algorithm of ActivityBase XE Runner to determine the maximum % fold, minimum % fold, slope, and AC 50 The maximum % fold is the highest % fold increase observed at any compound concentration, and the minimum % fold is the lowest % fold increase observed at any compound concentration. 50 Values ​​are concentrations (μM) corresponding to the midway between the maximum and minimum values ​​of the four-parameter logistic curve fit (i.e., where the % fold increase along the four-parameter logistic curve fit is halfway between the maximum % fold and the minimum % fold (% fold midpoint). Another useful parameter for evaluating compounds of the present disclosure is % fold @ 1.54 μM, which is the % fold increase at a compound concentration of 1.5 μM (e.g., 1.54 μM). The x-axis and y-axis are not necessarily to scale. Summary of the invention

[0132] One aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0133]

[0134] Among them, 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 herein, individually and in combination in classes and subclasses.

[0135] In some embodiments, a provided compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof:

[0136]

[0137] Among them, A, B, R 1 and R 2 As defined above for Formula I and described herein, individually and in combination in classes and subclasses.

[0138] In some embodiments, a provided compound is a compound of Formula Ib or a pharmaceutically acceptable salt thereof:

[0139]

[0140] Among them, A, B and R 1 As defined above for Formula I and described herein, individually and in combination in classes and subclasses.

[0141] In some embodiments, a provided compound is a compound of Formula Ic or a pharmaceutically acceptable salt thereof:

[0142]

[0143] wherein A is as defined above for Formula I and described herein, individually and in combination in classes and subclasses, and

[0144] Where m is 0, 1, 2, 3, 4 or 5.

[0145] In some embodiments, the compound provided is a compound of Formula Id-1 or a pharmaceutically acceptable salt thereof:

[0146]

[0147] Among them, A, B and R 1 As defined above for Formula I and described herein, individually and in combination in classes and subclasses.

[0148] In some embodiments, the compound provided is a compound of Formula Id-2 or a pharmaceutically acceptable salt thereof:

[0149]

[0150] Among them, A, B and R 1 As defined above for Formula I and described herein, individually and in combination in classes and subclasses.

[0151] In some embodiments, a compound of formula Ia is provided, wherein:

[0152] A is phenyl or a monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S,

[0153] wherein each aryl or heteroaryl is optionally substituted with one or more R a ;

[0154] Each R a independently selected from: halogen, -OR, -NRC(O)R', -CN, -S(O)2NR2 and -C1-C6 alkyl,

[0155] wherein each alkyl group is optionally substituted with one or more halogens;

[0156] R 1 and R 2 Each is independently selected from: -H, halogen, -C1-C6 alkyl and -OR;

[0157] B is a monocyclic or bicyclic 3 to 14-membered ring,

[0158] wherein the ring is partially unsaturated or aromatic, and

[0159] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0160] wherein the ring is optionally substituted with (R d ) m ,

[0161] and when the ring is partially unsaturated, the ring does not contain O in the γ-position relative to C(=Z);

[0162] Each R d independently selected from: halogen, -C1-C6 alkyl and -OR,

[0163] wherein each alkyl group is optionally substituted with one or more halogens;

[0164] m is 0, 1 or 2;

[0165] Each R is independently selected from: -H and -C1-C6 alkyl,

[0166] wherein each alkyl group is optionally substituted with one or more halogens; and

[0167] Each R' is a -C1-C6 alkyl group.

[0168] In some embodiments, a compound of formula Ia is provided, wherein:

[0169] A is phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl,

[0170] wherein each phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl is optionally substituted with one or more R a ;

[0171] Each R a Independently selected from: fluorine, chlorine, methyl, -CF3, -OMe, -OiPr, -OCF3, -OCF2H, -NHC(O)Me, -CN and -SO2NH2;

[0172] R 1 and R 2 Each is independently selected from: -H, fluoro, methyl, ethyl, isopropyl and -OH;

[0173] B is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0174]

[0175] wherein the ring is optionally substituted with (R d ) m ;

[0176] Each R d are independently selected from: fluorine, chlorine, methyl, -CF3 and -OMe; and

[0177] m is 0, 1 or 2.

[0178] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-2, A is phenyl or a monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N, and S, which is optionally substituted with one or more R a In some embodiments, A is optionally substituted with one or more R aIn some embodiments, A is a monocyclic 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S (e.g., pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl), which is optionally substituted with one or more R a In some embodiments, A is phenyl, pyridyl, or thienyl, 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 pyridinyl. In some embodiments, A is unsubstituted.

[0179] In some embodiments of Formulas I, Ia, Ib, Ic, Id-1, and Id-2, each R a is independently selected from: halogen (e.g., fluorine or chlorine), -OR (e.g., -OMe, -OiPr, -OCF3 or -OCF2H), -NRC(O)R' (e.g., -NHC(O)Me), -CN, -S(O)2NR2 (e.g., -SO2NH2), and -C1-C6 alkyl (e.g., methyl or -CF3), wherein each alkyl is optionally substituted with one or more halogens. In some embodiments, each R a In some embodiments, each R a Independently selected from: halogen (eg, fluorine), -C1-C6 alkyl (eg, methyl), and -OR (eg, -OMe or -OCF2H).

[0180] 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., NH2, NOH, or NNH2).

[0181] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, R 1 and R 2 Each is independently selected from: -H, halogen, -C1-C6 alkyl, -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c )n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2 and -(CR b R c ) n NRC(O)OR. In some embodiments, R 1 and R 2 Each is independently selected from: -H, halogen (e.g., fluorine), -C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), and -OR (e.g., -OH). 1 and R 2 Each is independently selected from: -H, halogen (e.g., fluorine), and -OR (e.g., -OH). 1 and R 2 In some embodiments, R 1 is -OH, and R 2 is -H.

[0182] In some embodiments of Formulas I and Ia, R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl or 3 to 8 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, and wherein the heterocyclyl does not contain O in the γ-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, -C1-C6 alkyl, oxo and -OR, wherein -OR does not form O in the γ-position relative to C(=Z). In some embodiments of Formulas I and Ia, R 1 and R 2 Combined with the carbon to which they are attached, they form a C3-C6 cycloalkyl group or a 3- to 6-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S, wherein the heterocyclyl group does not contain O in the γ-position relative to C(=Z), and wherein each cycloalkyl or heterocyclyl group is optionally substituted with one or more substituents selected from the following: halogen, -C1-C6 alkyl, oxo and -OR, wherein -OR does not form O in the γ-position relative to C(=Z).

[0183] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-2, R b and R c Each is -H. In some embodiments, R b and R c Each is independently -H or halogen (eg, fluorine). In some embodiments, R b and R cEach is independently -H or -C1-C6 alkyl (eg methyl).

[0184] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-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.

[0185] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is:

[0186] (i) a monocyclic 3 to 8 membered ring including a C3-C8 cycloalkyl, a 3 to 8 membered heterocyclyl, a phenyl or a 5 to 8 membered heteroaryl ring,

[0187] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S,

[0188] wherein the ring is optionally substituted with (R d ) m ,and

[0189] wherein the ring comprising the 3- to 8-membered heterocyclyl does not contain O in the γ-position relative to C(=Z); or

[0190] (ii) a bicyclic 6 to 14 membered ring comprising a C3-C 10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl or 5- to 11-membered heteroaryl ring,

[0191] wherein the ring is fused to an aromatic saturated or partially saturated 3 to 8 membered carbocyclic ring or an aromatic saturated or partially saturated 3 to 8 membered heterocyclic ring,

[0192] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S,

[0193] wherein the ring is optionally substituted with (R d ) m ,and

[0194] The ring including the 3- to 11-membered heterocyclyl does not contain O in the γ-position relative to C(=Z).

[0195] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is an aromatic monocyclic or bicyclic ring, wherein at least one ring is aromatic, and wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N, and S, and wherein the monocyclic or bicyclic ring is optionally substituted with (R d ) m In some embodiments, B is optionally substituted with (R d ) mIn some embodiments, B is an unsubstituted phenyl. In some embodiments, B is a 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 O, N, and S, and wherein the ring is optionally substituted with (R d ) m .

[0196] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is a monocyclic or bicyclic 3 to 10 membered ring,

[0197] wherein the ring is partially unsaturated or aromatic, and

[0198] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0199] wherein the ring is optionally substituted with (R d ) m ,and

[0200] When the ring is partially unsaturated, the ring does not contain O in the γ-position relative to C(=Z).

[0201] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0202]

[0203] wherein the ring is optionally substituted with (R d ) m .

[0204] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0205]

[0206] wherein the ring is optionally substituted with (R d ) m .

[0207] In some embodiments of Formula I, Ia, Ib, Id-1, and Id-2, B is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0208]

[0209] wherein the ring is optionally substituted with (R d ) m .

[0210] In some embodiments of Formulas I, Ia, Ib, Ic, Id-1, and Id-2, each R d Independently selected from: halogen, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, heterocyclyl, -OR and -NR2, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. d is independently selected from: halogen (e.g., fluorine or chlorine), -C1-C6 alkyl (e.g., methyl or -CF3), and -OR (e.g., -OMe), wherein each alkyl is optionally substituted with one or more halogens. d Independently selected from: halogen (eg, fluorine), -C1-C6 alkyl (eg, methyl), and -OR (eg, -OMe).

[0211] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-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.

[0212] In some embodiments of Formula I, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is -H. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 One of them is -C1-C6 alkyl (eg, methyl), and the rest are -H.

[0213] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-2, each R is independently selected from: -H, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, and 3 to 14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. In some embodiments, each R is independently selected from: -H and -C1-C6 alkyl (e.g., methyl or isopropyl), wherein each alkyl is optionally substituted with one or more halogens (e.g., fluorine).

[0214] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-2, each R' is independently -C1-C6 alkyl, -C3-C 12 Cycloalkyl or 3 to 14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. In some embodiments, each R' is -C1-C6 alkyl (eg, methyl).

[0215] In some embodiments of Formula I, Ia, Ib, Ic, Id-1, and Id-2, the compound is not:

[0216]

[0217] For example, some embodiments provide a compound of one or more of Formula I, Ia, Ib, Ic, Id-1, and Id-2 that is not a compound of the formula:

[0218]

[0219] Another aspect of the present invention relates to a compound of formula II or a pharmaceutically acceptable salt thereof:

[0220]

[0221] Among them, 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 herein, individually and in combination in classes and subclasses.

[0222] In some embodiments, the compound provided is a compound of Formula II-a or a pharmaceutically acceptable salt thereof:

[0223]

[0224] Among them, A, B, R 1 and R 2 As defined above for Formula II and described herein, individually and in combination in classes and subclasses.

[0225] In some embodiments, the compound provided is a compound of Formula II-b-1 or a pharmaceutically acceptable salt thereof:

[0226]

[0227] wherein A is as defined above for Formula II and described herein, individually and in combination in classes and subclasses,

[0228] Where R 1 is -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl,

[0229] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens, and

[0230] Wherein B is -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR.

[0231] In some embodiments, the compound provided is a compound of Formula II-b-2 or a pharmaceutically acceptable salt thereof:

[0232]

[0233] wherein A is as defined above for Formula II and described herein, individually and in combination in classes and subclasses,

[0234] Where R 1 is -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl,

[0235] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens, and

[0236] Wherein B is -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b Rc ) n SO2NR2 or -(CR b R c ) n SO2OR.

[0237] In some embodiments, a compound of Formula II-a is provided, wherein:

[0238] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0239] wherein the ring is partially unsaturated or aromatic, and

[0240] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0241] wherein the ring is optionally substituted with one or more R a ;

[0242] Each R a Independently selected from: -C1-C6 alkyl and -OR;

[0243] R 1 , R 2 and B are each independently -H, -C1-C6 alkyl, -OR, -(CR b R c ) n NR2, -(CR b R c ) n NRS(O)2R'or-(CR b R c ) n C(O)OR,

[0244] wherein each alkyl group is optionally substituted with one or more halogens;

[0245] or R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0246] wherein the heterocyclic group does not contain O in the γ-position relative to C(═O),

[0247] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from: -C6 aryl and -C(O)R', and

[0248] wherein each cycloalkyl or heterocyclyl is optionally fused with a C6 aryl or a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S;

[0249] Each R b and R c is -H;

[0250] Each n is independently 0 or 1;

[0251] Each R is independently selected from: -H, -C1-C6 alkyl and C6-C 14 Aryl,

[0252] wherein each aryl group is optionally substituted with one or more halogens or -O(C1-C6 alkyl); and

[0253] Each R' is independently selected from: -C1-C6 alkyl, -(CR b R c ) n C6-C 14 Aryl and -(CR b R c ) n O(C6-C 14 aryl),

[0254] wherein each alkyl or aryl group is optionally substituted with one or more -O(C1-C6 alkyl).

[0255] In some embodiments, a compound of formula II-a is provided, wherein:

[0256] A is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0257]

[0258] wherein the ring is optionally substituted with one or more R a ;

[0259] Each R a Independently selected from: methyl and -OCHF2;

[0260] R 1 , R 2 and B are each independently -H, methyl, ethyl, -CH2CHF2, propyl, -OR, -CH2NH2, -CH2NMe2, -NHS(O)2Me or -CH2C(O)OMe,

[0261] wherein each methyl or ethyl group is optionally substituted with one or more halogens;

[0262] or R 1 and R 2 Combined with the carbon to which they are attached, they form a cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl or chromanyl group,

[0263] wherein each cyclopropyl, cyclopentyl, cyclohexyl or pyrrolidinyl group is optionally substituted with one or more substituents selected from: -C6 aryl and -C(O)R', and

[0264] wherein each tetrahydrofuranyl or chromanyl group does not contain an O at the γ-position relative to C(═O);

[0265] Each R is independently selected from: -H, methyl and phenyl,

[0266] wherein each phenyl group is optionally substituted with one or more fluorine or -OMe; and

[0267] Each R' is independently selected from: methyl, phenyl, -CH2phenyl and -CH2O(phenyl),

[0268] wherein each methyl or phenyl group is optionally substituted with one or more -OMe or -OEt.

[0269] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, A is:

[0270] (i) a monocyclic 3 to 8 membered ring including a C3-C8 cycloalkyl, a 3 to 8 membered heterocyclyl, a phenyl or a 5 to 8 membered heteroaryl ring,

[0271] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0272] wherein the ring is optionally substituted with one or more R a ;or

[0273] (ii) a bicyclic 6 to 14 membered ring comprising a C3-C 10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl or 5- to 11-membered heteroaryl ring,

[0274] wherein the ring is fused to an aromatic saturated or partially unsaturated 3 to 8 membered carbocyclic ring or an aromatic saturated or partially unsaturated 3 to 8 membered heterocyclic ring,

[0275] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0276] wherein the ring is optionally substituted with one or more R a .

[0277] In some embodiments of formula II, II-a, II-b-1 and II-b-2, A is an aromatic monocyclic or bicyclic ring, wherein at least one ring is aromatic, and wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N and S, and wherein the monocyclic or bicyclic ring is optionally substituted with one or more R a .

[0278] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, A is a monocyclic or bicyclic 3 to 10 membered ring,

[0279] wherein the ring is partially unsaturated or aromatic, and

[0280] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0281] wherein the ring is optionally substituted with one or more R a .

[0282] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, A is a monocyclic or bicyclic 3 to 10 membered ring selected from:

[0283]

[0284] 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.

[0285] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, each R a Independently selected from: halogen, -C1-C6 alkyl, -C3-C 12 cycloalkyl, 3 to 14 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, -OR and -NR2, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. In some embodiments of Formula II and II-a, each R a Independently selected from: -C1-C6 alkyl (eg methyl) and -OR (eg -OCHF2).

[0286] 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., NH2, NOH, or NNH2).

[0287] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, R 1 , R 2 and B are each independently -H, halogen, -C1-C6 alkyl, -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) nNR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR or -(CR b R c ) n C(O)OR,

[0288] wherein each alkyl group is optionally substituted with one or more halogens;

[0289] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl, or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0290] wherein the heterocyclic group does not contain O in the γ-position relative to C(=Z),

[0291] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -OR, oxo, -C6 aryl and -C(O)R', and

[0292] wherein each cycloalkyl or heterocyclic group is optionally fused with a C6 aryl group or a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S.

[0293] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, R 1 , R 2 and B are each independently -H, -C1-C6 alkyl (e.g., methyl, ethyl, propyl or -CH2CHF2), -OR, -(CR b R c ) n NR2 (e.g. -CH2NH2 or -CH2NMe2), -(CR b R c ) n NRS(O)2R' (e.g. -NHS(O)2Me) or -(CR b R c ) n C(O)OR (e.g. -CH2C(O)OMe);

[0294] or R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or a 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S (e.g. pyrrolidinyl, tetrahydrofuranyl or chromanyl),

[0295] wherein the heterocyclic group (eg tetrahydrofuranyl or chromanyl) does not contain an O in the γ-position relative to C(=Z), and

[0296] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of -C6 aryl and -C(O)R'.

[0297] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, R 1 , R 2 and B are each independently -H, -C1-C6 alkyl (e.g., methyl, ethyl, propyl or -CH2CHF2), -OR, -(CR b R c ) n NR2 (e.g. -CH2NH2 or -CH2NMe2), -(CR b R c ) n NRS(O)2R' (e.g. -NHS(O)2Me) or -(CR b R c ) n C(O)OR (e.g., -CH2C(O)OMe). In some embodiments, R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 Cycloalkyl (e.g. cyclopropyl, cyclopentyl or cyclohexyl) or a 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from N and S (e.g. pyrrolidinyl, tetrahydrofuranyl or chromanyl), wherein the heterocyclyl does not contain O in the γ-position relative to C(=Z), and wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from: -C6 aryl and -C(O)R'.

[0298] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, R b and R c Each is -H. In some embodiments, R b and R c Each is independently -H or halogen (eg, fluorine). In some embodiments, R b and Rc Each is independently -H or -C1-C6 alkyl (eg methyl).

[0299] In some embodiments of Formula II, II-a, II-b-1, 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.

[0300] In some embodiments of Formula II, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is -H. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 One of them is -C1-C6 alkyl (e.g. methyl), and the rest are -H.

[0301] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, each R is independently selected from: -H, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, and C6-C 14 Aryl, wherein each alkyl, cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more halogens or -O(C1-C6 alkyl). In some embodiments, each R is independently selected from: -H, -C1-C6 alkyl (e.g., methyl) and C6-C 14 Aryl (e.g., phenyl or naphthyl or anthracenyl), wherein each alkyl or aryl is optionally substituted with one or more halogens (e.g., fluorine) or -O(C1-C6 alkyl) (e.g., -OMe). In some embodiments, each R is independently -H or methyl. In some embodiments, each R is -H.

[0302] In some embodiments of Formula II, II-a, II-b-1, and II-b-2, each R' is independently selected from: -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, -(CR b R c )n C6-C 14 Aryl or -(CR b R c ) n O(C6-C 14 In some embodiments, each R' is independently selected from: -C1-C6 alkyl (eg, methyl), -(CR b R c ) n Aryl (e.g., phenyl or -CH2phenyl) or -(CR b R c ) n O(aryl) (eg, -CH2O(phenyl)), wherein each methyl or phenyl group is optionally substituted with one or more -OMe or -OEt. In some embodiments, each R' is methyl.

[0303] Another aspect of the present invention relates to a compound of formula III or a pharmaceutically acceptable salt thereof:

[0304]

[0305] Among them, A, B, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As defined above for Formula III and described herein, individually and in combination in classes and subclasses.

[0306] In some embodiments, the compound provided is a compound of formula III-a or a pharmaceutically acceptable salt thereof:

[0307]

[0308] wherein A and B are as defined above for Formula III and described herein, individually and in combination in classes and subclasses.

[0309] In some embodiments, a compound of formula III-a is provided, wherein:

[0310] A is a bicyclic 3 to 14-membered ring,

[0311] wherein the ring is aromatic, and

[0312] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S;

[0313] B is a ring selected from the following: -C6-C 14aryl and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0314] wherein the ring is optionally substituted with one or more R d ;

[0315] Each R d Independently selected from: -C1-C6 alkyl, -OR and -NR2,

[0316] wherein each alkyl group is optionally substituted with one or more halogens; and

[0317] Each R is independently selected from: -H, -C1-C6 alkyl and a 5- to 14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S,

[0318] wherein each alkyl group is optionally substituted with one or more halogens.

[0319] In some embodiments, a compound of formula III-a is provided, wherein:

[0320] A is benzofuranyl;

[0321] B is a ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl and pyrazolyl,

[0322] wherein the ring is optionally substituted with one or more R d ;and

[0323] Each R d Independently selected from: methyl, -CF3, -OH, -OCH2CF3 and -NH(pyridyl).

[0324] In some embodiments of Formula III and III-a, A is:

[0325] (i) a monocyclic 3 to 8 membered ring including a C3-C8 cycloalkyl, a 3 to 8 membered heterocyclyl, a phenyl or a 5 to 8 membered heteroaryl ring,

[0326] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0327] wherein the ring is optionally substituted with one or more R a ;or

[0328] (ii) a bicyclic 6 to 14 membered ring comprising a C3-C 10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl or 5- to 11-membered heteroaryl ring,

[0329] wherein the ring is fused to an aromatic saturated or partially unsaturated 3 to 8 membered carbocyclic ring or an aromatic saturated or partially unsaturated 3 to 8 membered heterocyclic ring,

[0330] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0331] wherein the ring is optionally substituted with one or more R a .

[0332] In some embodiments of formula III and III-a, A is an aromatic monocyclic or bicyclic ring, wherein at least one ring is aromatic, and wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N and S, and wherein the monocyclic or bicyclic ring is optionally substituted with one or more R a In some embodiments, A is a bicyclic ring, wherein at least one ring is aromatic, and wherein the bicyclic ring contains 0-4 heteroatoms independently selected from 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 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.

[0333] In some embodiments of Formula III and III-a, each R a Independently selected from: halogen, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3 to 14 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, -OR and -NR2, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens.

[0334] 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., NH2, NOH, or NNH2).

[0335] In some embodiments of formula III and III-a, B is a ring selected from phenyl and a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S (e.g., pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl or pyrazolyl), wherein the ring is optionally substituted with one or more R d .

[0336] In some embodiments, B is a 5-6 membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl or pyrazolyl), wherein the ring is optionally substituted with one or more R d .

[0337] In some embodiments of Formula III and III-a, each R d Independently selected from: halogen, -C1-C6 alkyl, -C3-C 12 cycloalkyl, 3 to 14 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, -OR and -NR2, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. d Independently selected from: -C1-C6 alkyl (eg, methyl or -CF3), -OR (eg, -OH, -OCH2CF3) and -NR2 (eg, -NH(pyridyl)), wherein each alkyl is optionally substituted with one or more halogens (eg, fluorine).

[0338] In some embodiments of Formula III, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is -H. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 One of them is -C1-C6 alkyl (e.g. methyl), and the rest are -H.

[0339] In some embodiments of Formula III and III-a, each R is independently selected from: -H, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 Aryl (e.g., phenyl, naphthyl, or anthracenyl), and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, wherein each alkyl, cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more halogens. In some embodiments, each R is independently selected from: -H, -C1-C6 alkyl, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N, and S, wherein each alkyl is optionally substituted with one or more halogens. In some embodiments, each R is -H.

[0340] In some embodiments of Formula III and III-a, each R' is independently selected from: -C1-C6 alkyl, -C3-C 12Cycloalkyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, and C6-C 14 Aryl (eg, phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more halogens. In some embodiments, each R' is -C1-C6 alkyl.

[0341] Another aspect of the present invention relates to a compound of formula IV or a pharmaceutically acceptable salt thereof:

[0342]

[0343] Among them, 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 As defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0344] In some embodiments, the compound provided is a compound of formula IV-a or a pharmaceutically acceptable salt thereof:

[0345]

[0346] Among them, A, B, X, R 1 and R 2 As defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0347] In some embodiments, the compound provided is a compound of Formula IV-b or a pharmaceutically acceptable salt thereof:

[0348]

[0349] wherein A, B, and X are as defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0350] In some embodiments, the compound provided is a compound of Formula IV-c or a pharmaceutically acceptable salt thereof:

[0351]

[0352] wherein A and B are as defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0353] In some embodiments, the compound provided is a compound of Formula IV-d or a pharmaceutically acceptable salt thereof:

[0354]

[0355] wherein A and B are as defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0356] In some embodiments, the compound provided is a compound of formula IV-e-1 or a pharmaceutically acceptable salt thereof:

[0357]

[0358] Where A, B, X and R 1 As defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0359] In some embodiments, the compound provided is a compound of formula IV-e-2 or a pharmaceutically acceptable salt thereof:

[0360]

[0361] Where A, B, X and R 1 As defined above for Formula IV and described herein, individually and in combination in classes and subclasses.

[0362] In some embodiments, a compound of formula IV-a is provided, wherein:

[0363] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0364] wherein the ring is partially unsaturated or aromatic, and

[0365] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0366] wherein the ring is optionally substituted with one or more R a ;

[0367] Each R a independently selected from: halogen, -C1-C6 alkyl and -OR,

[0368] wherein each alkyl group is optionally substituted with one or more halogens;

[0369] X is O or NR e ;

[0370] R e is -H;

[0371] B is -H or a monocyclic 3 to 14-membered ring,

[0372] wherein the ring is saturated or aromatic, and

[0373] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0374] wherein the ring is optionally substituted with one or more R d ;

[0375] Each R d Independently selected from: halogen, -C1-C6 alkyl and -OR;

[0376] R 1 and R 2 Each is independently -H, -C1-C6 alkyl, -(CR b R c ) n C6-C 14 Aryl and -(CR b R c ) n OR,

[0377] wherein each aryl group is optionally substituted with one or more substituents selected from halogen;

[0378] or R 1 and R 2 Combined with the carbon to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S;

[0379] or R e and R 1 Combined with the nitrogen to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0380] The heterocyclic group is optionally substituted with one or more -OR or -(CR b R c ) n C6-C 14 Aryl;

[0381] or R 2 does not exist, and R 1 and B combine with the carbon to which they are attached to form C6-C 14 an aryl ring or a 5- to 14-membered heteroaryl ring,

[0382] wherein each aryl or heteroaryl is optionally substituted with one or more halogen or -C1-C6 alkyl;

[0383] Each R b and R c Independently selected from: -H;

[0384] each n is independently 0, 1 or 2; and

[0385] Each R is independently selected from: -H and -C1-C6 alkyl,

[0386] wherein each alkyl group is optionally substituted with one or more halogens.

[0387] In some embodiments, a compound of formula IV-a is provided, wherein:

[0388] A is a monocyclic or bicyclic 3 to 14 membered ring selected from:

[0389]

[0390] wherein the ring is optionally substituted with one or more R a ;

[0391] Each R a Independently selected from: fluorine, methyl, -CF3, -OCHF2 and -OMe;

[0392] X is O or NR e ;

[0393] R e is -H;

[0394] B is -H; or a monocyclic 3 to 6 membered ring selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, pyrazolyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, oxadiazolyl, cyclopropyl and tetrahydrofuranyl,

[0395] wherein the ring is optionally substituted with one or more R d ;

[0396] Each R d independently selected from: fluorine, methyl, -OMe and -OiPr;

[0397] R 1 and R 2 are each independently -H, methyl, ethyl, isopropyl, -CH2(phenyl), -CH2OMe and -CH2CH2OMe,

[0398] wherein each phenyl group is optionally substituted with one or more fluorines;

[0399] or R 1 and R 2 Combined with the carbon to which they are attached, they form a tetrahydrofuranyl group;

[0400] or R e and R 1 Combined with the nitrogen to which they are attached to form a morpholinyl or azetidinyl group,

[0401] wherein the azetidinyl group is optionally substituted with one or more -OH or -CH2(phenyl);

[0402] or R 2 does not exist, and R 1 and B, combined with the carbon to which they are attached, form a phenyl or isoxazolyl group,

[0403] wherein each phenyl or isoxazolyl group is optionally substituted with one or more fluorine or methyl groups;

[0404] Each R b and R c is -H;

[0405] each n is independently 0, 1 or 2; and

[0406] Each R is independently -H, methyl, isopropyl or -CHF2.

[0407] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, A is:

[0408] (i) a monocyclic 3 to 8 membered ring including a C3-C8 cycloalkyl, a 3 to 8 membered heterocyclyl, a phenyl or a 5 to 8 membered heteroaryl ring,

[0409] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0410] wherein the ring is optionally substituted with one or more R a ;or

[0411] (ii) a bicyclic 6 to 14 membered ring comprising a C3-C 10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl or 5- to 11-membered heteroaryl ring,

[0412] wherein the ring is fused to an aromatic saturated or partially unsaturated 3 to 8 membered carbocyclic ring or an aromatic saturated or partially unsaturated 3 to 8 membered heterocyclic ring,

[0413] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0414] wherein the ring is optionally substituted with one or more R a .

[0415] In some embodiments of formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, A is an aromatic monocyclic or bicyclic ring, wherein at least one ring is aromatic, and wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N, and S, and wherein the monocyclic or bicyclic ring is optionally substituted with one or more R aIn some embodiments, A is a monocyclic or bicyclic 5- to 10-membered ring, wherein the ring is saturated, fully or partially unsaturated, or aromatic, and wherein the ring contains 0-4 heteroatoms independently selected from O, N, and S; and wherein the ring is optionally substituted with one or more R a .

[0416] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, A is a ring selected from:

[0417]

[0418] wherein the ring is optionally substituted with one or more R a .

[0419] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, A is a ring selected from:

[0420]

[0421] wherein the ring is optionally substituted with one or more R a .

[0422] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, A is selected from:

[0423]

[0424] wherein the ring is optionally substituted with one or more R a In some embodiments, A is unsubstituted.

[0425] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, each R a are independently selected from: halogen, -OR and -NR2, -C1-C6 alkyl, -C3-C 12 cycloalkyl, and 3 to 14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. a In some embodiments, each R a It is -OCHF2.

[0426] 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., NH2, NOH, or NNH2).

[0427] In some embodiments of Formula IV, IV-a, IV-b, IV-e-1, 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.

[0428] In some embodiments of Formula IV, IV-a, IV-b, IV-e-1, and IV-e-2, R e In some embodiments, R e It is -C1-C6 alkyl (e.g. methyl).

[0429] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, B is:

[0430] (i) -H; or

[0431] (ii) a monocyclic 3 to 8 membered ring including a C3-C8 cycloalkyl, a 3 to 8 membered heterocyclyl, a phenyl or a 5 to 8 membered heteroaryl ring,

[0432] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0433] wherein the ring is optionally substituted with one or more R d ;or

[0434] (iii) a bicyclic 6 to 14 membered ring comprising a C3-C 10 cycloalkyl, 3- to 11-membered heterocyclyl, phenyl or 5- to 11-membered heteroaryl ring,

[0435] wherein the ring is fused to an aromatic saturated or partially unsaturated 3 to 8 membered carbocyclic ring or an aromatic saturated or partially unsaturated 3 to 8 membered heterocyclic ring,

[0436] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0437] wherein the ring is optionally substituted with one or more R d .

[0438] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, 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 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 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 O, N and S, and wherein the ring is optionally substituted with one or more R d In some embodiments, B is unsubstituted.

[0439] In some embodiments of formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1 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, thienyl, 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: phenyl and furanyl, wherein the ring is optionally substituted with one or more R d .

[0440] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, each R d Independently selected from: halogen, -OR, -NR2, -C1-C6 alkyl, -C3-C 12 cycloalkyl, and 3 to 14 membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens. d Independently selected from: halogen (eg, fluorine), -C1-C6 alkyl (eg, methyl), and -OR (eg, -OMe or -OiPr).

[0441] In some embodiments of Formula IV and IV-a, R 1 and R2 Each is independently: -H, halogen, -C1-C6 alkyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n Heterocyclic group, -(CR b R c ) n C6-C 14 Aryl, -(CR b R c ) n Heteroaryl or -(CR b R c ) n OR,

[0442] wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -OR and oxo,

[0443] wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S, and

[0444] wherein each heteroaryl is 5 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S;

[0445] or R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0446] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -OR and oxo;

[0447] or R e and R 1 Combined with the nitrogen to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0448] wherein the heterocyclic group is optionally substituted with one or more halogen, -C1-C6 alkyl, oxo, -OR and -(CR b R c ) n C6-C 14 Aryl;

[0449] or R 2 does not exist, and R1 and B combine with the carbon to which they are attached to form C6-C 14 an aryl ring or a 5- to 14-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S,

[0450] wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl or -OR.

[0451] In some embodiments of Formula IV and IV-a, R 1 and R 2 Each is independently -H, halogen, -C1-C6 alkyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n Heterocyclic group, -(CR b R c ) n Aryl, -(CR b R c ) n Heteroaryl or -(CR b R c ) n OR, wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, -C1-C6 alkyl, -OR and oxo, wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms selected from O, N and S, and wherein each heteroaryl is 5 to 14 members and contains 1-4 heteroatoms selected from O, N and S. In some embodiments, R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 Cycloalkyl or 3 to 14 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the following: halogen, -C1-C6 alkyl, -OR and oxo. In some embodiments, R e and R 1 The heterocyclic group is combined with the nitrogen to which they are attached to form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, wherein the heterocyclic group is optionally substituted with one or more halogen, -C1-C6 alkyl, oxo, -OR and -(CR b R c ) n C6-C 14 In some embodiments, R 2 does not exist, and R 1and B combine with the carbon to which they are attached to form C6-C 14 An aryl ring or a 5- to 14-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S, wherein each aryl or heteroaryl group is optionally substituted with one or more halogen, -C1-C6 alkyl or -OR.

[0452] In some embodiments of Formula IV and IV-a, R 1 and R 2 Each independently represents: -H, -C1-C6 alkyl (such as methyl, ethyl or isopropyl), -(CR b R c ) n C6-C 14 Aryl (e.g. -CH2(phenyl)) or -(CR b R c ) n OR (e.g., -CH2OMe or -CH2CH2OMe), wherein each aryl group is optionally substituted with one or more halogens (e.g., fluorine);

[0453] or R 1 and R 2 Combined with the carbon to which they are attached, they form a tetrahydrofuranyl group;

[0454] or R e and R 1 Combined with the nitrogen to which they are attached to form a morpholinyl or azetidinyl group,

[0455] wherein the azetidinyl group is optionally substituted with one or more -OH or -CH2(phenyl);

[0456] or R 2 does not exist, and R 1 and B, combined with the carbon to which they are attached, form a phenyl or isoxazolyl group,

[0457] wherein each phenyl or isoxazolyl group is optionally substituted with one or more fluorine or methyl groups.

[0458] In some embodiments of Formula IV and IV-a, R 1 and R 2 Each is independently -H, -C1-C6 alkyl (such as methyl, ethyl or isopropyl), -(CR b R c ) n C6-C 14 Aryl (e.g. -CH2(phenyl)) or -(CR b R c ) nOR (e.g., -CH2OMe or -CH2CH2OMe), wherein each aryl group is optionally substituted with one or more halogens (e.g., fluorine). 1 and R 2 Each is -H.

[0459] In some embodiments of Formula IV, IV-a, IV-e-1, and IV-e-2, R b and R c Each is -H. In some embodiments, R b and R c Each is independently -H or halogen (eg, fluorine). In some embodiments, R b and R c Each is independently -H or -C1-C6 alkyl (eg methyl).

[0460] In some embodiments of Formula IV, IV-a, IV-e-1, 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.

[0461] In some embodiments of Formula IV, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is -H. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 One of them is -C1-C6 alkyl (e.g. methyl), and the rest are -H.

[0462] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, each R is independently selected from: -H, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, and C6-C 14Aryl (e.g., phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclic radical, or aryl is optionally substituted with one or more halogens. In some embodiments, each R is independently selected from: -H or -C1-C6 alkyl (e.g., methyl, isopropyl, or -CHF2). In some embodiments, R is -H.

[0463] In some embodiments of Formula IV, IV-a, IV-b, IV-c, IV-d, IV-e-1, and IV-e-2, each R' is independently selected from: -C1-C6 alkyl, -C3-C 12 Cycloalkyl, 3- to 14-membered heterocyclyl containing 1-4 heteroatoms independently selected from O, N and S, and C6-C 14 Aryl (eg, phenyl, naphthyl, or anthracenyl), wherein each alkyl, cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more halogens. In some embodiments, each R' is -C1-C6 alkyl.

[0464] In some embodiments, the compounds are provided in Table 1:

[0465] Table 1.

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499] a Compounds 8-2 and 8-3 are enantiomers, but the absolute stereochemistry is not yet determined (*); b Compounds 9-4 and 9-5 are enantiomers, but the absolute stereochemistry is not yet determined (*); c Compounds 10-1 and 10-2 are enantiomers, but the absolute stereochemistry is not yet determined (*); d Compounds 11-1 and 11-2 are enantiomers, but the absolute stereochemistry is not yet determined (*).

[0500] Unless otherwise specified, it will be understood that when "one or more" substituents are recited for a particular variable, this includes one, two, three, four or more substituents as valency permits.

[0501] In some embodiments of any of the formulas disclosed herein, in R 1 , R 2 or the heterocyclic group at position B relative to C(=Z 1 ) or C(═O) does not contain an O at the γ-position. In some embodiments of any of the formulas disclosed herein, 1 , R 2 The heterocyclic group at the B position contains 1-4 heteroatoms independently selected from N and S.

[0502] Unless otherwise indicated, the structures described herein are also intended to include all stereoisomers (e.g., enantiomers or diastereomers) of the structure, as well as all geometric isomers or conformational isomers of the structure; for example, the R and S configurations of each stereocenter. Therefore, single stereochemical isomers of the compounds of the present invention as well as enantiomers, diastereomers, and geometric isomer (or conformational isomer) mixtures are within the scope of the present disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of the compound, and unless otherwise indicated, represents each stereoisomer alone and / or a mixture of each stereoisomer. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0503] In some embodiments, the compound of Formula I, II, III or IV is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2. In some embodiments, the compound is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2, and is the first eluting isomer of the purification method. In some embodiments, the compound is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2, and is the second eluting isomer of the purification method. In some embodiments, the compound is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2 and is the third, fourth, fifth, sixth, seventh or eighth eluting isomer of the purification method.

[0504] In some embodiments, the PKR activating compound is obtained by a process comprising the purification method of Example 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 obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2, and is the first eluting isomer of the purification method. In some embodiments, the PKR activating compound is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2, and is the second eluting isomer of the purification method. In some embodiments, the PKR activating compound is obtained by a process comprising the purification method of Example 8-2, 8-3, 9-4, 9-5, 10-1, 10-2, 11-1 or 11-2 and is the third, fourth, fifth, sixth, seventh or eighth eluting isomer of the purification method.

[0505] In addition, 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 replacement of hydrogen with deuterium or tritium or replacement of hydrogen with an isotopically enriched atom 13 C- or 14 C-substituted carbon) are all within the scope of the present invention.

[0506] The present disclosure also provides compounds of Formula I, II, III, and IV for use, for example, as analytical tools and / or control compounds in biological assays.

[0507] The compounds of formula I, II, III and IV can form salts, which are also within the scope of the present disclosure. Unless otherwise indicated, references to compounds of formula I, II, III and IV herein should be understood to include references to their salts. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0508] The present disclosure also includes pharmaceutical compositions comprising one or more compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions reported herein can be provided in unit dosage forms (e.g., capsules, tablets, etc.). In some embodiments, the pharmaceutical compositions reported herein can be provided in oral dosage forms. In some embodiments, the pharmaceutical composition is orally administered in any orally acceptable dosage form. In some embodiments, the oral dosage form of compounds of formula I, II, III, and IV can be capsules. In some embodiments, the oral dosage form of compounds of formula I, II, III, and IV can be tablets. In some embodiments, the oral dosage form comprises one or more fillers, disintegrants, lubricants, glidants, anti-adhesive agents, and / or antistatic agents. In some embodiments, oral dosage forms are prepared by dry mixing. In some embodiments, the oral dosage form is a tablet and is prepared by dry granulation. In some embodiments, a pharmaceutical composition is provided, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided, which comprises 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.

[0509] The pharmaceutical compositions provided herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules and tablets (e.g., in unit dosage form). In some embodiments, the compounds disclosed herein are formulated to be orally administered to subjects at a dosage of about 10 mg to about 1000 mg (e.g., as capsules or tablets containing about 50 mg to about 100 mg of the compounds disclosed herein and pharmaceutically acceptable carriers and / or excipients). A dosage lower or higher than the above dosage may be required. The specific dosage and treatment regimen of any particular patient will depend on a variety of factors, including the activity, age, body weight, overall health, sex, diet, administration time, excretion rate, drug combination, severity and course of disease, illness or symptom, patient's tendency to disease, illness or symptom, and the judgment of the treating physician. The pharmaceutical composition of the compound disclosed herein may include one or more other excipients and / or carriers, wherein the compound disclosed herein (e.g., Formula I, II, III and / or IV compound) is present at a dosage level of about 1% to 100%, more preferably about 5% to 95%, of the weight of the pharmaceutical composition.

[0510] According to standard nomenclature, the names "α", "β", "γ", "δ", "ε", etc. used herein refer to the position in the molecule relative to the carbonyl group (e.g., C(=Z) or C(=O)). For example, the carbon in the α-position (or α-carbon) is the carbon atom in the position adjacent to the carbonyl group; the oxygen in the β-position (or β-oxygen) is the oxygen atom two atoms away from the carbonyl group. The following scheme illustrates this nomenclature on an exemplary compound:

[0511]

[0512] Disclosed methods of use of compounds

[0513] Another aspect of the present disclosure is the use of Formula I, II, III and IV compounds. Formula I, II, III and IV compounds can be used in medicine. For example, the compounds and compositions described herein are activators of PKR. Therapeutic methods (e.g., by activating PKR and / or PKM2) may include 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 for treating a disease associated with PKR regulation, comprising administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method for treating pyruvate kinase deficiency (PKD), comprising administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method for treating hemolytic anemia associated with PKD, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0514] The method of treatment may include administering a compound disclosed herein (e.g., a compound of Formula I, II, III, and / or IV) in an amount sufficient to provide a reduction in the blood concentration of 2,3-DPG relative to a reference standard by at least 15% (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%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%. In some embodiments, the analysis is performed by sample analysis of a body fluid, such as blood, by, for example, mass spectrometry (e.g., LC-MS).

[0515] The compounds and compositions described herein can be used as activators of PKR mutants with lower activity compared to the wild type. Such mutations in PKR can affect the enzyme activity (catalytic efficiency), regulatory properties (regulated by fructose diphosphate (FBP) / ATP) and / or thermal stability of the enzyme. Examples of such mutations include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q and R490W. The activation activity of the compounds of the present invention to PKR mutants can be tested according to the method described in Example 24. The compounds described herein are also activators of wild-type PKR.

[0516] A method for treating a patient suffering from or susceptible to a disease or condition associated with decreased PKM2 activity or decreased glycolysis may include administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein. The method may include the following steps: administering to a patient in need thereof an effective amount of a compound described herein, thereby treating, preventing or ameliorating the patient's disease or condition. In certain embodiments, the compound described herein is provided in the form of a pharmaceutical composition. In certain embodiments, the method includes the step of identifying or selecting a patient who will benefit from activation of PKM2 prior to treatment. Identifying or selecting such a patient may be based on the level of PKM2 activity in the patient's cells. The compound may be a compound described herein administered at a dose and frequency sufficient to increase lactate production or oxidative phosphorylation. A method for treating a disease or condition associated with increased 2,3-diphosphoglycerate levels may 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.

[0517] The compounds disclosed herein can be added directly to whole blood or packed cells in vitro, or provided to a subject (e.g., a patient). Without being bound by theory, a reduction in the concentration level of 2,3-DPG causes a leftward shift in the oxygen-hemoglobin dissociation curve and shifts the allosteric equilibrium toward the R or oxidized state, thereby increasing oxygen affinity due to 2,3-DPG depletion, thereby producing a therapeutic inhibitory effect on intracellular aggregation (which is the basis of sickling), thereby stabilizing more soluble oxygenated hemoglobin. In another embodiment, in order to regulate 2,3-diphosphoglycerate, the compounds, compositions, or pharmaceutical compositions described herein are added directly to whole blood or packed cells in vitro or provided to a subject (e.g., a patient).

[0518] A method of increasing PKM2 activity and / or glycolysis levels in a patient may include administering a therapeutically effective amount of a compound disclosed herein to a patient in need thereof. The method may include the following steps: administering an effective amount of a compound as described herein to a patient in need thereof, thereby increasing the level of PKM2 activity and / or glycolysis in the patient. In some embodiments, the compounds or compositions described herein are used to maintain PKM2 in its active conformation or to activate pyruvate kinase activity in proliferating cells as a means of converting glucose metabolites into catabolic rather than anabolic processes in the patient.

[0519] Compounds disclosed herein (e.g., Formula I, II, III and / or IV compounds) can activate wild-type PKR and / or mutant PKR. Some examples of mutant PKR include G332S, G364D, T384M, G37E, R479H, R479K, R486W, R532W, R510Q, I90N and R490W. Therefore, it is possible to select patients and / or subjects treated using Formula I, II, III and / or IV compounds by first assessing the patient and / or subject to determine whether the subject carries a PKR mutation (e.g., one of mutations as described herein), and if it is determined that the subject carries a PKR mutation, it is thus necessary to activate the activity of the mutant PKR, then the subject is administered a therapeutically effective amount of Formula I, II, III and / or IV compounds. Using methods known in the art, the subject can be assessed as carrying a PKR mutation. The subject can also be monitored, for example, after administration of Formula I, II, III and / or IV compounds. Patients may be monitored to assess certain PK / PD parameters of a compound of Formula I, II, III, and / or IV, such as the levels of the compound, the levels of 2,3-DPG, or the levels of ATP.

[0520] In one aspect, the present invention provides a method for treating a subject, the method comprising: administering a compound of Formula I, II, III and / or IV to the subject; and obtaining the level of Formula I, II, III and / or IV compound, the level of 2,3-diphosphoglycerate (2,3-DPG), the level of adenosine triphosphate (ATP) or the activity of PKR in the subject, thereby evaluating the subject. The level value of Formula I, II, III and / or IV compound can be obtained by analyzing the plasma concentration of Formula I, II, III and / or IV compound. In some embodiments, the level of 2,3-DPG is obtained by analyzing the blood concentration of 2,3-DPG. The level of ATP can be obtained by analyzing the blood concentration of ATP. The activity of PKR can be obtained by analyzing the blood concentration of ATP. 13 C-labeled blood drug concentration. 13C-labeled glucose is administered to a subject and is incorporated into certain glycolytic intermediates in the blood.

[0521] The method of treatment may include administering a compound disclosed herein (e.g., a compound of Formula I, II, III, and / or IV) in an amount sufficient to provide a reduction in the blood concentration of 2,3-DPG relative to a reference standard by at least 15% (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%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%. In some embodiments, the analysis is performed by sample analysis of a body fluid, such as blood, by, for example, mass spectrometry (e.g., LC-MS).

[0522] Compounds as described herein can activate mutant PKR. Therefore, patients and / or subjects treated with compounds as described herein can be selected by first assessing patients and / or subjects to determine whether the subject carries a PKR mutation, and if it is determined that the subject carries a PKR mutation, it is necessary to activate the activity of the mutant PKR, and the subject is optionally administered compounds as described herein. Using methods known in the art, subjects can be assessed as carrying a PKR mutation.

[0523] Disclosed is a method for synthesizing a compound

[0524] The compounds of the present disclosure can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below. Example

[0525] The following are illustrative but non-limiting examples of certain embodiments of the present disclosure.Synthetic schemes for the synthesis of certain compounds disclosed herein are presented.

[0526] The definitions used in the following schemes and elsewhere in this paper are:

[0527] ACN Acetonitrile

[0528] AcOH Acetic acid

[0529] AlCl3 Aluminum chloride

[0530] Boc2O Di-tert-butyl dicarbonate

[0531] NaBH4 Sodium borohydride

[0532] Brine Saturated sodium chloride solution

[0533] CDCl3 deuterated chloroform

[0534] δ Chemical shift

[0535] DCM Dichloromethane or Methylene Chloride

[0536] DCE Dichloroethane

[0537] DIEA N,N-Diisopropylethylamine

[0538] DMAP N,N-Dimethylaminopyridine

[0539] DMF N,N-Dimethylformamide

[0540] DMSO Dimethyl sulfoxide

[0541] equiv equivalent

[0542] EtOAc Ethyl acetate

[0543] 1 H NMR Proton nuclear magnetic resonance

[0544] HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate

[0545] HBTU O-(Benzotriazole-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate

[0546] HPLC High Pressure Liquid Chromatography

[0547] Hz Hertz

[0548] LCMS Liquid chromatography / mass spectrometry

[0549] (M+1) Mass +1

[0550] MeOH Methanol

[0551] NCS N-Chlorosuccinimide

[0552] NaBH3CN Sodium cyanoborohydride

[0553] NaHCO3 Sodium bicarbonate

[0554] NaOH Sodium hydroxide

[0555] Na2SO4 Sodium sulfate

[0556] s-BuLi sec-butyllithium

[0557] RT Room temperature

[0558] Rt retention time

[0559] TEA Triethylamine

[0560] TFA Trifluoroacetic acid

[0561] TFAA Trifluoroacetic anhydride

[0562] THF Tetrahydrofuran

[0563] TLC Thin layer chromatography

[0564] ZnI2 Zinc iodide

[0565] Material

[0566] Unless otherwise noted, all materials were purchased from commercial suppliers and used without further purification. Anhydrous solvents were purchased from Sigma-Aldrich (Milwaukee, WI) and used as received. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

[0567] LCMS method 1. Instrument: MS, Waters QDa mass spectrometer; HPLC, Waters Acquity Binary Solvent Manager; UV, Waters Acquity PDA. Conditions: Mobile phase A, 95% water / 5% acetonitrile, containing 0.1% formic acid; Mobile phase B, 95% acetonitrile / 5% water, containing 0.09% formic acid. Column: Acquity UPLC BEHC18, 1.7 μm, 2.1 x 50 mm. Column temperature, 35 °C. LC gradient: 5-100% B in 2.0 min, hold 100% to 2.2 min. LC flow rate, 0.6 mL / min. UV wavelengths: 220 nm and 254 nm, Ionization mode: electrospray ionization; positive / negative.

[0568] Intermediate 1: 2-(Benzofuran-5-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride

[0569]

[0570] Step 1. tert-Butyl 5-(Benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0571] To a solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.7 g, 3.33 mmol) in acetonitrile (20 mL) and DIEA (1.70 mL, 9.76 mmol) was added a solution of benzofuran-5-sulfonyl chloride (17.48 ml, 3.50 mmol) in 1,4-dioxane (17 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was worked up with saturated ammonium chloride solution and EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered off, and concentrated under reduced pressure to give tert-butyl 5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.3 g, 3.33 mmol, 100%) as an oil. LCMS: m / z = 413 [M+Na] + .

[0572] Step 2. 2-(Benzofuran-5-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride

[0573] Tert-butyl 5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.3 g, 3.33 mmol) was dissolved in a mixture of 1,4-dioxane (0.500 mL), DCE (0.25 mL) and 4M HCl in 1,4-dioxane (0.125 mL) and the reaction was heated at 50°C for 2 hours. The solvent was evaporated under reduced pressure and the reaction mixture was azeotropically dried with toluene and further dried 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] + .

[0574] Intermediate 2: 1-(6-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one.

[0575]

[0576] Prepared as described for Intermediate 1 using appropriate synthetic precursors. Overall yield 94%. LCMS: m / z=350 [M+H] + .

[0577] Intermediate 3: 2-(4-Fluorophenylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt

[0578]

[0579] Step 1. tert-Butyl 5-(4-fluorophenylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0580] A mixture of 4-fluorobenzene-1-sulfonyl chloride (2.366 g, 12.16 mmol), tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (2.5 g, 10.13 mmol) and triethylamine (4.24 mL, 30.4 mmol) in DCM (50 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed twice with water and dried over sodium sulfate. The crude material was purified by silica gel column chromatography to give tert-butyl 5-(4-fluorophenylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.5 g, 6.79 mmol, 67%). 1H NMR (300MHz, CDCl3) δppm7.73-7.92(m,2H),7.14-7.32(m,2H),3.93-4.19(m,8H),1.40(s,9H).

[0581] Step 2. 2-(4-Fluorophenylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt

[0582] A solution of tert-butyl 5-(4-fluorophenylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.5 g, 6.79 mmol) in DCM / TFA (1:1, 80 mL) was stirred at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was treated with ether, filtered and dried under reduced pressure to give 2-(4-fluorophenylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt (2.48 g, 6.54 mmol, 96%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.57 (br s, 1H), 7.82-8.06 (m, 2H), 7.32-7.52 (m, 2H), 3.69-4.27 (m, 8H).

[0583] Intermediate 4: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt

[0584]

[0585] Prepare as described for Intermediate 3 using appropriate synthetic precursors.

[0586] Step 1. tert-Butyl 5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate.

[0587] Isolated as an orange solid (100 mg). This material was used without further purification. LCMS: m / z = 352 [M+H] + .

[0588] Step 2. 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt was isolated as a white solid (90 mg, 87%). LCMS: m / z = 252 [M+H] + .

[0589] Intermediate 5: 2-(6-(Trifluoromethyl)pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt

[0590]

[0591] Prepare as described for Intermediate 3 using appropriate synthetic precursors.

[0592] Step 1. 5-[6-(Trifluoromethyl)pyridine-2-sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0593] Isolated as a pale yellow solid (25 mg, 25%).

[0594] Step 2. 2-(6-(Trifluoromethyl)pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, TFA salt

[0595] Isolated as brown oil (21 mg, 81%).

[0596] Intermediate 6: 6-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzo[d]thiazole hydrochloride

[0597]

[0598] To a 50 mL round bottom flask was added tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-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[d]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 4M HCl 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-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzo[d]thiazole hydrochloride (0.640 g, 1.865 mmol, 92%) as a brown oil which was used in the next step without further purification. LCMS: m / z = 307.9 [M+H] + .

[0599] Intermediate 7: 2-((4-(difluoromethoxy)phenyl)sulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride

[0600]

[0601] Using appropriate synthetic precursors, the preparation was carried out according to the method of Intermediate 6 to obtain (0.652 g, 1.848 mmol, 91%). LCMS: m / z = 317.1 [M+H] + .

[0602] Intermediate 8: 2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetic acid

[0603]

[0604] Step 1. tert-Butyl 6-formyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate

[0605] A solution of tert-butyl 6-bromo-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (628 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was added to a 50-mL 3-neck round-bottom flask purged and maintained with an inert nitrogen atmosphere. The mixture was stirred at -78 ° C, and a solution of (2-methylpropyl) lithium (1.3 M in hexane, 1.7 mL, 1.10 equiv) in tetrahydrofuran (10 mL) was added dropwise. The reaction mixture was stirred at -78 ° C for 15 minutes, and 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 at room temperature for 2 hours. Water (1 mL) was added, and the volatiles were then removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution (3 x 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica TLC plate eluting with ethyl acetate / petroleum ether (1:3) to give tert-butyl 6-formyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (0.3 g, 57%) as a yellow solid. LCMS: m / z = 305 [M+1+CH3CN] + .

[0606] Step 2. 6-[Cyano(hydroxy)methyl]-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylic acid tert-butyl ester

[0607] In a 50-mL round-bottom flask, a solution of tert-butyl 6-formyl-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1 g, 3.80 mmol) in dichloromethane (20 mL) was stirred at 0°C. Trimethylsilyl cyanide (1.2 g, 12.10 mmol) was added dropwise at 0°C, followed by ZnI2 (120 mg, 0.38 mmol). The reaction solution was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with brine (3 x 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 6-[cyano(hydroxy)methyl]-3,4-dihydro-2H-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+1] + .

[0608] Step 3. Methyl 2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetate

[0609] In a 25 mL round bottom flask, a solution of tert-butyl 6-[cyano(hydroxy)methyl]-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (1 g, 3.44 mmol, 1.00 equiv) in methanol (10 mL) was treated dropwise with saturated HCl in ethyl acetate (15 mL). The reaction mixture was stirred at 50 °C for 1 hour. 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 silica gel column chromatography eluting with ethyl acetate / petroleum ether (1:1) to give methyl 2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetate (320 mg, 42%) as a light brown oil. LCMS: m / z=265 [M+1+CH3CN] + .

[0610] Step 4. tert-Butyl 6-(1-hydroxy-2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate

[0611] In a 25-mL round-bottom flask, a mixture of methyl 2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetate (240 mg, 1.08 mmol, 1.00 equiv), dichloromethane (3 mL), di-tert-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 at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), washed with brine (3×5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with CH3CN:H2O (1:4) to give tert-butyl 6-(1-hydroxy-2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-benzoxazine-4-carboxylate (210 mg, 60%) as a brown oil. LCMS: m / z = 365 [M+1+CH3CN] + .

[0612] Step 5. 2-(3,4-Dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetic acid

[0613] In an 8-mL vial, a mixture of tert-butyl 6-(1-hydroxy-2-methoxy-2-oxoethyl)-3,4-dihydro-2H-1,4-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) was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was diluted with water (5 mL), the pH of the solution was adjusted to 4 with concentrated aqueous HCl, and the volatiles were removed under reduced pressure to give 2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyacetic acid (120 mg) as a light brown solid. The material was used without further purification. LCMS: m / z = 210 [M+1] + .

[0614] Intermediate 9: 2-[2-[(tert-Butyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-2-hydroxyacetic acid

[0615]

[0616] Step 1. 2,2,2-Trifluoro-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one

[0617] In a 50-mL 3-neck round-bottom flask, a mixture of 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.51 mmol), dichloromethane (15 mL) and TEA (1.1 g, 10.87 mmol) was stirred at 0°C for 10 minutes. TFAA (1.9 g, 9.05 mmol) was added. The solution was stirred at 0°C for 10 minutes and then stirred at room temperature for another 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:10) to give 2,2,2-trifluoro-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one (1.49 g, 87%) as a yellow liquid. LCMS: m / z = 271 [M+CH3CN+H] + .

[0618] Step 2. Ethyl 2-oxo-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate

[0619] To a 50-mL 3-neck round-bottom flask purged and maintained with an inert nitrogen atmosphere was added dichloromethane (30 mL) and AlCl3 (7.0 g, 52.6 mmol). The reaction mixture was stirred in a water / ice bath at 0°C for 10 minutes, and then 2,2,2-trifluoro-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-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 at room temperature for another 2 hours. The reaction mixture was cooled to 0°C in a water / ice bath and then quenched by the addition of 2N HCl solution (aqueous solution, 5 mL). The solution was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and eluted with ethyl acetate / petroleum ether (1:10) to give ethyl 2-oxo-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate (4.1 g, 95%) as a yellow oil. LCMS: m / z=330[M+H] + .

[0620] Step 3. Ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate

[0621] In a 10-mL round-bottom flask, a mixture of ethyl 2-oxo-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate (1.0 g, 3.04 mmol, 1.00 equiv), tetrahydrofuran (5 mL), and water (2.5 mL) was treated with NaBH4 (56.2 g, 1.49 mol, 0.50 equiv). The reaction mixture was stirred at room temperature for 30 minutes and 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to give ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate (0.93 g, 92%) as a light yellow oil. 1 H NMR (300MHz, CDCl3): δppm 7.31-7.14(m,3H),5.13(d,J=6.0Hz,1H),4.79-4.74(m,2H),4.34-4.06(m,2H),3 .90-3.80(m,2H),3.53(d,J=6.0Hz,1H),2.97-2.92(m,2H),1.26(t,J=3.0Hz,3H).

[0622] Step 4. 2-[2-[(tert-Butyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-2-hydroxyacetic acid

[0623] In a 10-mL round-bottom flask, a solution of ethyl 2-hydroxy-2-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]acetate (990 mg, 2.99 mmol, 1.00 equiv) in methanol (4 mL) and water (1 mL) was treated with sodium hydroxide (240 mg, 6.00 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 30 minutes, then di-tert-butyl dicarbonate (1.3 g, 5.96 mmol, 2.00 equiv) was added and the reaction mixture was stirred at room temperature for an additional 30 minutes. The pH of the solution was adjusted to 6 with 2N aqueous HCl. The reaction mixture was extracted with ethyl acetate, and the extract was concentrated in vacuo. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (5:1) to give 2-[2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-2-hydroxyacetic acid (960 mg) as a white solid. This material was used without further purification.

[0624] Intermediate 10: (R)-2-Hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one, TFA salt

[0625]

[0626] Step 1. 5-[(2R)-2-Hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0627] To an 8-mL vial was added tert-butyl 1H,2H,3H,4H,5H,6H-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 at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1:1) as eluent to give tert-butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate (102 mg, 52%) as a light yellow oil. LCMS: m / z = 345 [M+1]+ .

[0628] Step 2. (R)-2-Hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one, TFA salt

[0629] To an 8-mL vial was added tert-butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-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 at room temperature for 2 hours and then concentrated in vacuo to afford (R)-2-hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one, TFA salt (139 mg) as a brown oil. The material was used without further purification. LCMS: m / z = 245 [M+1] + .

[0630] Intermediate 11: (R)-2-Hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one hydrochloride

[0631]

[0632] Step 1. 5-[(2R)-2-Hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0633] 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (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 mixed in a 25-mL round bottom flask. The solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (1:2) to give 5-[(2R)-2-hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (120 mg, 37%) as a light yellow solid.

[0634] Step 2. (R)-2-Hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one hydrochloride

[0635] To a 25-mL round-bottom flask was added tert-butyl 5-[(2R)-2-hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate (120 mg, 0.35 mmol, 1.00 equiv) and ethyl acetate (15.0 mL) freshly saturated with hydrogen chloride. The solution was stirred at room temperature overnight. The solid was filtered off and dried in vacuo to give (R)-2-hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one hydrochloride (85 mg, 87%) as a gray solid.

[0636] Example 1-1: N-(2-(5-(Benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxoethyl)methanesulfonamide

[0637]

[0638] To a solution of 2-(Benzofuran-5-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride (1.07 g, 3.27 mmol) in acetonitrile (22 mL) containing 10% DIEA was added a solution of (methylsulfonyl)glycine (561 mg, 3.66 mmol) in 1,4-dioxane (20 mL) containing 5% DIEA, followed by a solution of HBTU (1.263 g, 3.33 mmol) in acetonitrile (20 mL). The resulting mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aqueous NaOH. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and the volatiles were evaporated under reduced pressure. The residue was purified by preparative HPLC to give N-(2-(5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-oxoethyl)methanesulfonamide.

[0639] The examples in Table 2 below were prepared according to the methods outlined in Example 1-1 above using the appropriate synthetic precursors.

[0640] Table 2.

[0641]

[0642] Example 2-1: (1-(Aminomethyl)cyclopropyl)(5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0643]

[0644] To a solution of tert-butyl ((1-(5-(benzofuran-5-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[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 4M HCl (75 μl, 0.300 mmol) in 1,4-dioxane and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The combined organics were washed with brine and dried over Na2SO4. The crude material was purified by preparative HPLC to give (1-(aminomethyl)cyclopropyl)(5-(benzofuran-5-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone. LCMS: m / z 388 [M+H] + .

[0645] Example 3-1: 5-(Benzofuran-5-ylsulfonyl)-N-((tetrahydrofuran-2-yl)methyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0646]

[0647] To a 0.2M solution of (tetrahydrofuran-2-yl)methylamine (320 μl, 0.064 mmol) in acetonitrile was added di(1H-imidazol-1-yl)methanone (15.57 mg, 0.096 mmol). The mixture was stirred at room temperature for 2 hours, then a 0.2M solution of 2-(benzofuran-5-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (330 μl, 0.066 mmol) in CH3CN containing 10% DIEA was added, and the mixture was stirred at 50°C overnight. The solvent was evaporated and the residue was dissolved in 500 μL DMSO and purified by preparative HPLC to give 5-(benzofuran-5-ylsulfonyl)-N-((tetrahydrofuran-2-yl)methyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (12 mg, 0.029 mmol, 44.9% yield). LCMS: m / z 418 [M+H] + .

[0648] The examples in Table 3 below were prepared according to the method outlined in Example 3-1 above using the appropriate synthetic precursors.

[0649] Table 3.

[0650]

[0651] Example 4-1: (2R)-2-Hydroxy-2-phenyl-1-[5-(pyridine-3-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one

[0652]

[0653] To a solution of (R)-2-hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-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 by silica gel flash column chromatography. (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-3-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one was isolated. 1 H NMR (300MHz, CDCl3): δppm 8.96(d,J=1.5Hz,1H),8.85(dd,J1=1.8Hz,J2=4.8Hz,1H),8.19-8.23(m,1H),7.63-7.67(m,1H),7.29-7.34(m,5H),5.63(d,J=6.3Hz 1H),5.16(d,J=6.3Hz,1H),3.93-4.09(m,8H).LCMS: m / z=386[M+H] + .

[0654] The examples in Table 4 below were prepared according to the method outlined in Example 4-1 above using the appropriate synthetic precursors.

[0655] Table 4.

[0656]

[0657] Example 5-1: 5-(4-Fluorophenylsulfonyl)-N-(oxazol-5-ylmethyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0658]

[0659] A solution of triphosgene (40.7 mg, 0.137 mmol) in DCM (5 ml) was added to a 25 mL pear-shaped bottle to give a colorless solution. The solution was cooled to -10 ° C, and a solution of oxazol-5-ylmethylamine (68.5 mg, 0.698 mmol) and triethylamine (2.57 mmol) in DCM (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, and then a solution of 2-(4-fluorophenylsulfonyl)-1,2,3,4,5,6-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 room temperature for 5 hours. The reaction was diluted with dichloromethane and washed with aqueous NaOH solution (1 M), water, and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford 5-(4-fluorophenylsulfonyl)-N-(oxazol-5-ylmethyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (8 mg, 0.0204 mmol, 2.92%). 1 H NMR (300MHz, DMSO-d6): δppm 8.39(br d,J=1.76Hz,1H),7.81-8.01(m,2H),7.36-7.53(m,2H),6.93(br t,J=5.86Hz,1H),6.18-6.26(m,1H),4.32(br d,J=5.57Hz,2H),3.90-4.12(m,8H).LCMS: m / z=393.06[M+H] + .

[0660] Example 5-2: 5-(4-Fluorophenylsulfonyl)-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0661]

[0662] Prepared as described in Example 5-1 using appropriate synthetic precursors (20 mg, 0.050 mmol, 7%). 1HNMR (300MHz, DMSO-d6): δppm 7.88 (dd, J=8.79, 5.28Hz, 2H), 7.43 (t, J=8.79Hz, 2H), 6.87-7.05 (m, 1H), 4.34 (br d,J=5.57Hz,2H),4.04(m,4H),3.85-3.96(m,4H),2.40(s,3H).LCMS: m / z=408.10[M+H] + .

[0663] Example 6-1: (5-(Benzo[d]thiazol-6-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(morpholino)methanone

[0664]

[0665] To an 8-mL vial purged and maintained with an inert nitrogen atmosphere was added a mixture of 6-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-1,3-benzothiazole hydrochloride (69 mg, 0.20 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL) and DIEA (77 mg, 0.60 mmol, 3.00 equiv), followed by bis(trichloromethyl)carbonate (30 mg, 0.10 mmol, 0.50 equiv). The solution was stirred at room temperature for 1.0 hour under a nitrogen atmosphere. Morpholine (52 mg, 0.60 mmol, 3.00 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. The crude product (200 mg) was purified by preparative HPLC using the following conditions: column: SunFire Prep C18 5um 19*150mm; mobile phase: water (10mM NH4HCO3 and 0.05% NH3.H2O buffer) and CH3CN, CH3CN gradient from 16% to 34% in 10 minutes; detector UV wavelength: 220nm. This provided (5-(benzo[d]thiazol-6-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(morpholino)methanone (21.6 mg, 26%) as a white solid. 1 H NMR (300MHz, CDCl3, ppm): δ9.22(s,1H),8.53(d,J=1.5Hz,1H),8.29(d,J=7.8Hz,1H),7.98(dd,J= 8.4Hz, J=1.8Hz, 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] +.

[0666] Example 7-1: (5-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0667]

[0668] Step 1. 1-(6-[5-[(oxan-4-yl)carbonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-1-one

[0669] To an 8-mL vial purged and maintained with an inert nitrogen atmosphere 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), 1-(6-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-1-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 at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (100 / 1) to give 1-(6-[5-[(oxan-4-yl)carbonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-1-one (90 mg, 98%) as a white solid. LCMS: m / z = 462.2 [M+H] + .

[0670] Step 2. 6-[5-[(Oxan-4-yl)carbonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazine

[0671] 1-(6-[5-[(oxan-4-yl)carbonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-4-yl)ethan-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) were added to an 8-mL vial. The resulting solution was stirred at room temperature for 6 hours. The crude product was purified by preparative HPLC using the following conditions: column: Waters XBridge RP1819*150 mm, 5 um; mobile phase: water (containing 0.05% NH3.H2O) and CH3CN, CH3CN gradient from 28% to 33% in 5 minutes; detector UV wavelength: 220 nm. This provided 6-[5-[(oxan-4-yl)carbonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]-3,4-dihydro-2H-1,4-benzoxazine (32.3 mg, 39%) as a white solid. 1 H NMR (300MHz, CDCl3): δppm 7.14-7.11(m,2H),6.87(d,J=7.8Hz,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] + .

[0672] Example 8-1: 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-(pyridin-2-yl)ethan-1-one

[0673]

[0674] A 50-mL round-bottom flask was charged with a mixture of 2-(pyridin-2-yl)acetic acid hydrochloride (48 mg, 0.28 mmol, 1.00 equiv), 2-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,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 at 25 ° C for 4 hours. The reaction was then quenched by adding 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 preparative HPLC using the following conditions. Column: SunFire Prep C18 5μm 19*150mm; Mobile phase: water (containing 0.1% TFA) and CH3CN, CH3CN gradient from 43% to 73% in 7 minutes; Detector UV wavelength: 220nm. Thus, 25.6mg (21%) of 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-(pyridin-2-yl)ethan-1-one was obtained as a white solid. 1 H NMR (300 MHz, DMSO-d6, ppm): δ 8.50-8.51 (d, J = 4.2 Hz, 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: C 20 H 19 F2N3O4S: 435.11; Found: 436 [M+H] + .

[0675] The examples in Table 5 below were prepared according to the method outlined in Example 8-1 above using the appropriate synthetic precursors.

[0676] Table 5.

[0677]

[0678] *Compounds 8-2 and 8-3 are enantiomers, but the absolute stereochemistry is not yet determined. These compounds were prepared as racemates and then separated by chiral preparative HPLC (SHIMADZU LC-20AT) under the following conditions: column, REPAIREDIA; mobile phase: isocratic elution with DCM:IPA (10:90; containing 0.1% DEA); flow rate: 20 mL / min; detector UV wavelength: 254 nm.

[0679] Example 9-1: 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(pyridin-3-yl)ethan-1-one

[0680]

[0681] To an 8-mL vial (1 atm) was charged 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)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride (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 at room temperature for 16 hours. The reaction solution was diluted with 50 mL of ethyl acetate, washed with 4x10 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative-TLC. This produced 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(pyridin-3-yl)ethan-1-one as an off-white solid. 1 H NMR (300MHz, CDCl3): δppm 8.66(d,J=4.8Hz,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=12.3Hz,1H).LCMS m / z:452[M+H] + .

[0682] The examples in Table 6 below were prepared according to the method outlined in Example 9-1 above using the appropriate synthetic precursors.

[0683] Table 6.

[0684]

[0685]

[0686] *Example 9-4 and Example 9-5 are enantiomers, but the absolute stereochemistry is not yet determined. These compounds were prepared as racemates and then separated by chiral preparative HPLC (SHIMADZU LC-20AT) under the following conditions: column: CHIRALPAK IC; mobile phase: solvent A: ethanol, solvent B: methanol; detector UV wavelength: 220nm.

[0687] Example 9-2: Synthesis of (2R)-2-hydroxy-2-phenyl-1-(5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one

[0688] Intermediate A: tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0689]

[0690] To a suspension of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, HCl (1.10 g, 4.46 mmol) in dichloromethane (25 mL) was added TEA (1.49 mL, 10.7 mmol) followed by pyridine-2-sulfonyl chloride (0.950 g, 5.35 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL). The organic mixture was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL) in sequence. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0% EtOAc / hexanes, 5 minutes, then 0-75% EtOAc / hexanes, 30 minutes) to give tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.57 g, 1.622 mmol, 36.4% yield). LCMS (m / z, M+H+) 351.9, 1H-NMR (300 MHz, CDCl3): δ 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).

[0691] Intermediate B: 2-(Pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, HCl

[0692]

[0693] To a solution of tert-butyl 5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.570 g, 1.62 mmol) in dichloromethane (4.96 ml) was added 4M HCl / dioxane (17.6 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then triturated with ether. The white solid was filtered off to give 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, HCl (0.547 g, 1.90 mmol, quantitative yield), which was used in the next step without further purification. LCMS(m / z,M+H+)252.0,1H-NMR(300MHz,DMSO-d6): δppm9.99(br m,2H),8.75(m,1H),8.13(m,1H),7.97(m,1H),7.71(m 1H),4.24(m,4H),3.89(m,4H).

[0694] (R)-2-Hydroxy-2-phenyl-1-(5-(pyridin-2-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one

[0695]

[0696] To a suspension of 2-(pyridin-2-ylsulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole, HCl (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 bicarbonate 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 (gradient 0-10% MeOH / dichloromethane) to afford (R)-2-hydroxy-2-phenyl-1-(5-(pyridin-2-ylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrrol-2(1H,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): δppm 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=6.0Hz,1H),5.14(d,J=6.3Hz,1H),4.30-3.88(m,8H).

[0697] Examples 10-1 and 10-2: (2R)-1-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)-2-hydroxy-2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethanone and (2S)-1-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)-2-hydroxy-2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethanone

[0698]

[0699] 1-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-hydroxyethan-1-one (174 mg, 0.34 mmol, 1.00 equiv), methanol (2 mL), formaldehyde (20.6 mg, 2.00 equiv), NaBH3CN (64.8 mg, 1.03 mmol, 3.00 equiv) and acetic acid (2 mg, 0.03 mmol, 0.10 equiv) were added to a 10-mL round-bottom flask. The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (15:1) to give racemic 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)ethan-1-one (140 mg, 78%) as a white solid. The enantiomers were separated by chiral preparative HPLC (SHIMADZU LC-20AT) under the following conditions: column, LuxCellulose-4; mobile phase: solvent A: ethanol, solvent B: methanol; detector UV wavelength: 220 nm. This provided:

[0700] Example 10-1 (first eluting isomer): (2R)-1-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)-2-hydroxy-2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethanone, isolated as a white solid (26.5 mg, 19%). 1 H NMR (300MHz, CDCl3): δppm 7.89(m,2H),7.39(t,3H),6.49-6.65(m,3H),5.32(d,J=6.6Hz,1H),4.98(d,J= 6.3Hz,1H),3.81-4.25(m,10H),3.21(m,2H),2.75(d,3H).LCMS: m / z=522[M+H] + .*Absolute stereochemistry not determined.

[0701] Example 10-2 (second eluting isomer): (2S)-1-(5-(4-(difluoromethoxy)phenylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)-2-hydroxy-2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethanone, isolated as a white solid (22.7 mg, 16%). 1 H NMR (300MHz, CDCl3): δppm 7.86(m,2H),7.20(m,2H),6.37-6.85(m,4H),4.89(s,1H),4.02-4.40(m,10H),3.72(m,1H),3.29(m,2H),2.91(s,3H).LCMS: m / z=522[M+H] + .*Absolute stereochemistry not determined.

[0702] Examples 11-1 and 11-2: (2S)-1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one and (2R)-1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one

[0703]

[0704] Step 1. tert-Butyl 7-[2-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-1-hydroxy-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate

[0705] 2-[2-[(tert-Butyloxy)carbonyl]-1,2,3,4-tetrahydroisoquinolin-7-yl]-2-hydroxyacetic acid (184 mg, 0.60 mmol, 1.00 equiv), 2-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole 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 at room temperature for 30 minutes, and then the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane / methanol (15:1) to give tert-butyl 7-[2-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,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] + .

[0706] Step 2. (2S)-1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one and (2R)-1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one

[0707] tert-Butyl 7-[2-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-1-hydroxy-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (60.5 mg, 0.10 mmol, 1.00 equiv), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added to a 10-mL round-bottom flask. The solution was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 8.0 with 2N aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×15 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, eluting with dichloromethane / methanol (10:1) to give racemic 1-(5-[[4-(difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one (40 mg, 79%) as a white solid. The enantiomers were separated by chiral preparative HPLC (SHIMADZU LC-20AT) under the following conditions: column, DAICEL CHIRALPAK IC 20*250mm 5um; mobile phase: solvent A: CH3CN (which contained 0.1% DEA), solvent B: IPA, solvent B gradient from 20% to 50% in 30 minutes; detector UV wavelength: 230nm. This provided:

[0708] Example 11-1: (2S)-1-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one, isolated as a white solid (13.7 mg, 27%). 1 H NMR (300MHz, CD3OD): δppm 7.89(m,2H),7.35(d,J=9.0Hz,2H),7.24-6.75(m,4H),5.33(s,1H),4.25-4.09(m,7H),3.98(d, J=7.5Hz,2H),3.83-3.79(m,1H),3.09(t,J=6.3Hz,2H),2.86-2.81(m,2H).LCMS: m / z=506[M+H] + .*Absolute stereochemistry not determined.

[0709] Example 11-2: (2R)-1-(5-[[4-(Difluoromethoxy)benzene]sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl)-2-hydroxy-2-(1,2,3,4-tetrahydroisoquinolin-7-yl)ethan-1-one, isolated as a white solid (11.3 mg, 22%). 1 H NMR (300MHz, CD3OD): δppm 7.89(m,2H),7.35(d,J=9.0Hz,2H),7.24-6.75(m,4H),5.15(s,1H),4.25-4.09(m,7H),3.98(d, J=7.5Hz,2H),3.83-3.78(m,1H),3.09(t,J=6.3Hz,2H),2.86-2.81(m,2H).LCMS: m / z=506[M+H] + .*Absolute stereochemistry not determined.

[0710] Example 19-1: (3-Benzyl-3-hydroxyazetidin-1-yl)(5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)methanone

[0711]

[0712] Step 1. tert-Butyl 5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate

[0713] tert-Butyl 4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate (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 bottom flask. The solution was stirred at 20 °C for 16 hours and then concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL), washed with water (3 x 3 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate as a pink solid (140 mg, 87%). LCMS: m / z=402 [M+H] + .

[0714] Step 2. 8-(4,5-Dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-ylsulfonyl)quinoline hydrochloride

[0715] Ethyl acetate (5.60 mL), concentrated aqueous hydrogen chloride solution (38 mg, 3.00 equiv) and tert-butyl 5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-carboxylate (140 mg, 0.35 mmol, 1.00 equiv) were mixed in a 50-mL round bottom flask. The solution was stirred at 25 °C for 6 hours, and then the solid was collected by filtration to give 8-(4,5-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-ylsulfonyl)quinoline hydrochloride as a pink solid (110 mg, 93%). LCMS: m / z = 302 [M+H] + .

[0716] Step 3. (3-Benzyl-3-hydroxyazetidin-1-yl)(5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)methanone

[0717] 8-(4,5-Dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-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 bis(trichloromethyl)carbonate (44 mg, 0.15 mmol, 0.50 equiv) were mixed in a 50-mL round bottom flask. The solution was stirred at 25 °C for 2 hours, then 3-benzylazetidin-3-ol (97 mg, 0.59 mmol, 2.00 equiv) was added. The solution was stirred at 25 °C for another 2 hours, then diluted with ethyl acetate (50 mL), washed with water (3x25 mL), and dried over anhydrous sodium sulfate. The solid was filtered off. The filtrate was concentrated in vacuo. The crude material was purified by preparative HPLC under the following conditions: column, SunFire Prep C18 19*150mm; mobile phase, water (containing 0.1% TFA) and ACN, ACN gradient from 39% to 44% in 6 minutes; detector UV wavelength, 220nm. This provided (3-benzyl-3-hydroxyazetidin-1-yl)(5-(quinolin-8-ylsulfonyl)-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H,3H,4H)-yl)methanone as a white solid (44 mg, 30%). 1H NMR (300MHz, CDCl3, ppm): δ9.05(d,J=9.6Hz,1H),8.56(d,J=6.6Hz,1H),8.32(d,J=8.1Hz,1 1H),8.07(d,J=8.1Hz,1H),7.64(m,1H),7.56(m,1H),7.35(m,3H),7.22(m,2 H),4.51(m,4H),4.10(m,6H),3.85(m,2H),3.06(m,2H).LCMS: m / z=491[M+H] + .

[0718] Example 13-1: (R)-4-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzenesulfonamide

[0719]

[0720] (R)-2-Hydroxy-2-phenyl-1-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)ethan-1-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 mixed and stirred in a 25-mL round bottom flask. 4-Sulfamoylbenzene-1-sulfonyl chloride (36.4 mg, 0.14 mmol, 1.00 equiv) was added and the solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 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 in vacuo. The crude product was recrystallized from methanol to give (R)-4-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)benzenesulfonamide (24 mg, 36%) as a white solid. 1 H NMR (300MHz, DMSO-d6, ppm): δ8.01(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] + .

[0721] Example 14-1: (R)-N-(2-fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)phenyl)acetamide

[0722]

[0723] Step 1. tert-Butyl 5-((3-acetamido-4-fluorophenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0724] To an 8-mL vial was added tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (75 mg, 0.36 mmol, 1.00 equiv), triethylamine (54 mg, 0.53 mmol, 1.50 equiv), 3-acetamido-4-fluorobenzene-1-sulfonyl chloride (90 mg, 0.36 mmol, 1.00 equiv) and DCM (1.00 mL). The solution was stirred at room temperature for 3 hours. The reaction was then quenched by adding 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 in vacuo to give tert-butyl 5-((3-acetamido-4-fluorophenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg, 66%) as a white solid. LCMS: m / z = 426 [M+H] + .

[0725] Step 2. N-(2-Fluoro-5-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)phenyl)acetamide hydrochloride

[0726] To a 50-mL round-bottom flask was added tert-butyl 5-((3-acetamido-4-fluorophenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg, 0.24 mmol, 1.00 equiv) and ethyl acetate (20 mL) freshly saturated with hydrogen chloride gas. The solution was stirred at room temperature overnight. The solid was collected by filtration to give N-(2-fluoro-5-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)phenyl)acetamide hydrochloride (65 mg, 76%) as a gray solid. LCMS: m / z = 326 [M+H] + .

[0727] Step 3. (R)-N-(2-Fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)phenyl)acetamide

[0728] To an 8-mL vial was added N-(2-fluoro-5-((3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-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 at room temperature for 2 hours. 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 in vacuo. The residue (50 mg) was purified by preparative HPLC (waters I) under the following conditions: column, Xbridge Prep RP18 5 μm 19*150 mm; mobile phase, water (containing 10 mM NH4HCO3 + 0.05% ammonia) and CH3CN, CH3CN gradient from 87% to 92% in 7 minutes; detector UV wavelength, 254 nm. This provided (R)-N-(2-fluoro-5-((5-(2-hydroxy-2-phenylacetyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)sulfonyl)phenyl)acetamide (7 mg, 9%) as a white solid. 1 H NMR (300MHz, DMSO-d6, ppm): δ10.04 (s, 1H), 8.49-8.52 (d, J = 7.5Hz, 1H), 7.27-7.53 (m, 7H), 5.61-5. 63(d,J=7.5Hz,1H),5.14-5.16(d,J=7.5Hz,1H),3.89-4.11(m,8H),2.11(s,3H).LCMS: m / z=460[M+H] + .

[0729] Example 15-1: N-[(2-fluorophenyl)methyl]-5-(6-methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxamide

[0730]

[0731] Step 1. 2-(Benzylthio)-6-methylpyridine

[0732] To a 250-mL round bottom flask was added 2-chloro-6-methylpyridine (5.00 g, 39.19 mmol, 1.00 equiv), DMSO (80 mL), phenylmethyl mercaptan (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 at 150 °C for 3 hours and then cooled to room temperature. The solution was diluted with 300 mL of ethyl acetate, washed with 4x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2-(benzylthio)-6-methylpyridine (7.60 g) as a light brown oil. The material was used without further purification. LCMS: m / z=216 [M+H] + .

[0733] Step 2. 6-Methylpyridine-2-sulfonyl chloride

[0734] To a 50-mL round-bottom flask was added 2-(benzylthio)-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 at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with 5 mL of H2O. The pH 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 in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (1:5) to give 6-methylpyridine-2-sulfonyl chloride (80 mg, 15%) as a viscous yellow oil. LCMS: m / z=192[M+H] + .

[0735] Step 3. 5-(6-Methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0736] 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 1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (77 mg, 0.37 mmol, 1.00 equiv). The solution was stirred at room temperature for 0.5 h and then concentrated. The residue was purified by silica gel column chromatography using DCM / EA (2:1) to give 5-(6-methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (100 mg, 75%) as a white solid. LCMS: m / z = 366 [M+H] + .

[0737] Step 4. 2-Methyl-6-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]pyridine hydrochloride

[0738] To an 8-mL vial was added tert-butyl 5-(6-methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-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 (3.0 mL) freshly saturated with hydrogen chloride. The solution was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give 2-methyl-6-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]pyridine hydrochloride (110 mg) as a brown oil. The material was used without further purification. LCMS: m / z = 266 [M+H] + .

[0739] Step 5. N-[(2-Fluorophenyl)methyl]-5-(6-methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxamide

[0740] To an 8-mL vial was added 1-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-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]pyridine hydrochloride (49 mg, 0.14 mmol, 0.90 equiv). The solution was stirred at room temperature for 1 hour and then concentrated. The residue was purified by preparative HPLC (Waters I) using the following conditions: column, Waters XBridge RP18 19*150 mm, 5 μm; mobile phase, water (containing 10 mM NH4HCO3 + 0.05% ammonia) and ACN, ACN gradient from 42% to 65% in 7 minutes; flow rate, 20 mL / min; detector UV wavelength, 254 nm. This provided N-[(2-fluorophenyl)methyl]-5-(6-methylpyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxamide (54 mg, 20%) as a white solid. 1 H NMR (300MHz, CDCl3, ppm): δ7.83-7.76(m,2H),7.44-7.34(m,2H),7.32-7.23(m,1H),7.14-7.02(m,1H), 4.60(d,J=6.0Hz,1H),4.51(d,J=5.7Hz,2H),4.37(s,4H),4.12(s,4H),2.61(s,3H).LCMS: m / z=417[M+H] + .

[0741] Example 16-1: 2-(Pyridin-3-yl)-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one

[0742]

[0743] Step 1. 5-[2-(Pyridin-4-yl)acetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester

[0744] 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), 1H,2H,3H,4H,5H,6H-tert-butyl pyrrolo[3,4-c]pyrrole-2-carboxylate (100 mg, 0.48 mmol, 1.00 equiv) and HATU (200 mg, 0.53 mmol, 1.10 equiv). The solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / methanol (50:1) to give tert-butyl 5-[2-(pyridin-4-yl)acetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-carboxylate (135 mg) as a brown oil. This material was used without further purification. LCMS: m / z = 330 [M+H] + .

[0745] Step 2. 2-(Pyridin-3-yl)-1-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one hydrochloride

[0746] To an 8-mL vial was added tert-butyl 5-[2-(pyridin-4-yl)acetyl]-1H,2H,3H,4H,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 (2.00 mL) freshly saturated with hydrogen chloride. The solution was stirred at room temperature for 2 hours, and then the solid was collected by filtration to give 2-(pyridin-3-yl)-1-[1H,2H,3H,4H,5H,6H-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] + .

[0747] Step 3. 2-(Pyridin-3-yl)-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one

[0748] To an 8-mL vial was added 2-(pyridin-3-yl)-1-[1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-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 at room temperature for 2 hours. The mixture was purified by preparative HPLC (Waters 2767) using the following conditions: column, X-Bridge RP18, 19*150mm, 5μm; mobile phase, water (containing 10mM NH4HCO3+0.05% ammonia) and CH3CN, CH3CN gradient from 16% to 36% in 8 minutes; detector UV wavelength, 220nm. This provided 2-(pyridin-3-yl)-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one (25.5mg, 16%) as a light yellow solid. 1 HNMR (300MHz, DMSO-d6, ppm): δ8.75(d,J=3.9Hz,1H),8.44-8.41(m,2H),8.16-8.10(m,1H),7.97(d,J=7.8Hz,1H),7.72(dd,J=4.8Hz ,J=1.5Hz,1H),7.71-7.69(m,1H),7.32(dd,J=7.2Hz,J=4.8Hz,1H),4.31-4.26(m,6H),4.03(s,2H),3.68(s,2H).LCMS: m / z=371[M+H] + .

[0749] Example 17-1: 3-[5-[(2R)-2-hydroxy-2-phenylacetyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrole-2-sulfonyl]benzene-1-sulfonamide

[0750]

[0751] Prepared as described in step 3 of the preparation of Example 16-1, using appropriate synthetic precursors, but with a reaction time of 2 hours and Prep-HPLC using a gradient from 20% to 40% ACN over 8 minutes. Isolated as a white solid (48.3 mg, 29%). 1H NMR (300MHz, DMSO-d6, ppm): δ8.19 (d, J=1.5Hz, 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,J=6.3Hz,1H),5.16(d,J=6.0Hz,1H),4.25-3.87(m,8H).LCMS: m / z=464[M+H] + .

[0752] Example 18-1: 3-methyl-1-{5-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylbutan-1-one

[0753]

[0754] A 0.2M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (100 μL, 20 μmol) in dioxane and neat DIEA (10 μL, 57 μmol) were added to a 1.5 mL vial to give a brown suspension. A 0.2M solution of 1-methyl-1H-pyrazole-3-sulfonyl chloride (105 μL, 20 μmol) in dioxane was added. The reaction was heated at 50°C with shaking for 2 hours. A 4M solution of HCl in dioxane (50.0 μL, 0.200 mmol) was then added. The reaction was heated at 50°C with shaking for another 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 μL, 0.143 mmol) and 0.2M 3-methyl-2-phenylbutyric acid (110 μL, 22 μmol) in dioxane were added to the vial, followed by 0.2M HBTU (110 μL, 22 μmol) in ACN. The reaction was heated at 50°C for another 2 hours under shaking. The volatiles were removed under reduced pressure. The residue was mixed with 1N 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 by mass-triggered HPLC to give 3-methyl-1-{5-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylbutan-1-one. LCMS: m / z=415.1 [M+H]+.

[0755] The examples in Table 7 below were prepared according to the method outlined in Example 18-1 above using the appropriate synthetic precursors.

[0756] Table 7.

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770] Examples 18-19: 1-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(1H-tetrazolyl-1-yl)ethan-1-one

[0771]

[0772] A 0.2 M solution of 4-(difluoromethoxy)benzenesulfonyl chloride (158 μL, 31.5 μmol) in dioxane was added to a 1.5 mL vial containing a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (150 μL, 30 μmol) in a solvent mixture of acetonitrile / DIEA (90:10). The reaction mixture was heated at 50°C with shaking for 2 hours. Dioxane (200 μL), methanol (200 μL) and 4N HCl in dioxane (100 μL, 0.200 mmol) were added. The reaction was heated at 50°C with shaking for another 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 μL, 0.143 mmol) and 0.2 M 2-(1H-tetrazolyl-1-yl)acetic acid (165 μL, 33 μmol) in dioxane were added to the vial, followed by 0.2 M HBTU (165 μL, 33 μmol) in ACN. The reaction was heated at 50° C. for another 2 hours with shaking. Volatiles were removed under reduced pressure. The residue was mixed with 1N NaOH (0.5 mL) and extracted with 3:1 EtOAc / ACN (2× 0.5 mL). The organic layer was concentrated under reduced pressure. The compound was purified using mass spectrometry triggered HPLC to give 1-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (4.9 mg, 38% yield). LCMS: m / z=427.1 [M+H] + , Rt: 1.10 min (LCMS method 1).

[0773] Example 18-25: 1-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,2-difluoro-2-phenylethan-1-one

[0774]

[0775] A 0.2 M solution of 4-(difluoromethoxy)benzenesulfonyl chloride (158 μL, 31.5 μmol) in dioxane was added to a 1.5 mL vial containing a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (150 μL, 30 μmol) in a solvent mixture of acetonitrile / DIEA (90:10). The reaction mixture was heated at 50°C with shaking for 2 hours. Dioxane (200 μL), methanol (200 μL) and 4N HCl in dioxane (100 μL, 0.200 mmol) were added. The reaction was heated at 50°C with shaking for another 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 μL, 0.143 mmol) and 0.2 M 2,2-difluoro-2-phenylacetic acid (165 μL, 33 μmol) in dioxane were added to the vial, followed by 0.2 M HBTU (165 μL, 33 μmol) in ACN. The reaction was heated at 50°C for another 2 hours with shaking. 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 1-(5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2,2-difluoro-2-phenylethan-1-one (1.7 mg, 12% yield). LCMS: m / z=471.1 [M+H]+, Rt: 1.58 min (LCMS method 1).

[0776] Example 19-1: (2R)-1-{5-[(5-chlorothiophen-2-yl)sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylpropan-1-one

[0777]

[0778] To a 1.5 mL vial was added 0.2 M tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (100 μL, 20 μmol), 0.2 M (R)-2-phenylpropionic acid solution (110 μL, 22 μmol) and neat DIEA (10 μL, 0.057 mmol) to give a brown suspension. A 0.2 M solution of HBTU (110 μL, 22 μmol) in ACN was added. The reaction was shaken at room temperature for 2 hours. A 4 M solution of HCl in dioxane (50.0 μL, 0.200 mmol) was added. The reaction was heated at 50° C. with shaking for another 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 μM) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue, and then neat DIEA (10 μL, 57 μmol) was added to the vial, followed by a 0.2 M solution of 5-chlorothiophene-2-sulfonyl chloride (110 μL, 22 μmol) in dioxane. The reaction was heated at 50 °C for another 2 hours under shaking. The volatiles were removed under reduced pressure. The residue was mixed with 1N NaOH (0.5 mL) and extracted with 3:1 EtOAc / ACN (2x0.5 mL). The volatiles were removed under reduced pressure. The compound was purified using mass-triggered HPLC to give (2R)-1-{5-[(5-chlorothien-2-yl)sulfonyl]-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl}-2-phenylpropan-1-one. LCMS: m / z = 423.1 [M+H]+.

[0779] The examples in Table 8 below were prepared according to the method outlined in Example 19-1 above using the appropriate synthetic precursors.

[0780] Table 8.

[0781]

[0782]

[0783]

[0784]

[0785] Example 19-9: 2-(1H-benzo[d]imidazol-1-yl)-1-(5-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)propan-1-one

[0786]

[0787] A 0.2 M solution of 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (158 μL, 31.5 μmol) in dioxane was added to a 1.5 mL vial containing a 0.2 M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (150 μL, 30 μmol) in a solvent mixture of acetonitrile / DIEA (90:10). The reaction mixture was heated at 50°C with shaking for 2 hours. Dioxane (200 μL), methanol (200 μL) and 4N HCl in dioxane (100 μL, 0.200 mmol) were added. The reaction was heated at 50°C with shaking for another 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 μL, 0.143 mmol) and 0.2 M dioxane solution of 3-(1H-benzo[d]imidazol-1-yl)-2-oxobutanoic acid (165 μL, 33 μmol) were added to the vial, followed by 0.2 M HBTU (165 μL, 33 μmol) in ACN. The reaction was heated at 50°C for another 2 hours with shaking. Volatiles were removed under reduced pressure. The residue was mixed with 1N 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-(1H-benzo[d]imidazol-1-yl)-1-(5-((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)propan-1-one (7.5 mg, 55% yield). LCMS: m / z=455.2 [M+H] + , Rt: 0.78 min (LCMS method 1).

[0788] Example 20-1: N-(Furan-2-ylmethyl)-5-(pyridin-3-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0789]

[0790] To a 1.5 mL vial was added 0.2 M of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (100 μL, 20 μmol) in ACN, 0.2 M of 2-(isocyanatomethyl)furan (110 μL, 22 μmol) in dioxane, and neat DIEA (10 μL, 57 μmol) to give a brown suspension. The reaction was shaken at room temperature for 2 hours. 4 M HCl in dioxane (50.0 μL, 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 μL) was added to the vial along with DIEA (25 μL, 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 μL, 22 μmol) in dioxane was added. The reaction was heated at 50°C for another 2 hours with shaking. The volatiles were removed under reduced pressure. The residue was mixed with 1N 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 N-(furan-2-ylmethyl)-5-(pyridin-3-ylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (1.9 mg, 5.08 μmol, 25% yield). LCMS: m / z = 375.2 [M+H]+.

[0791] The examples in Table 9 below were prepared according to the method outlined in Example 20-1 above using the appropriate synthetic precursors.

[0792] Table 9.

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801] Example 21-1: 5-(Benzo[d]thiazol-6-ylsulfonyl)-N-(furan-2-ylmethyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

[0802]

[0803] A 0.2M solution of 6-((5,6-dihydropyrrolo[3,4-c]pyrrole-2(1H,3H,4H)-yl)sulfonyl)benzo[d]thiazole (150 μL, 0.030 mmol) in ACN, a 0.2M solution of 2-(isocyanatomethyl)furan (150 μL, 0.030 mmol) in ACN and DIEA (25 μL, 0.144 mmol) were added to a 1.5 mL vial to give a brown suspension. The reaction was shaken at room temperature for 2 hours. The reaction was dried under a stream of nitrogen. The residue was mixed with 1N NaOH (0.5 mL) and extracted with EtOAc (2 x 0.5 mL). The extract was dried under a stream of nitrogen. The compound was purified using mass spectrometry triggered HPLC to give 5-(benzo[d]thiazol-6-ylsulfonyl)-N-(furan-2-ylmethyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide (2.1 mg, 4.88 μmol, 16% yield). LCMS: m / z=431.0 [M+H]+.

[0804] The examples in Table 10 below were prepared according to the method outlined in Example 21-1 above using the appropriate synthetic precursors.

[0805] Table 10.

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813] Example 22-1: 5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid pyridin-3-ylmethyl ester

[0814]

[0815] A 0.2 M solution of 4-nitrophenyl(pyridin-3-ylmethyl)carbonate (180 μL, 0.036 mmol) in ACN, neat DIEA (15 μL, 0.086 mmol) and a 0.2 M solution of 2-((4-(difluoromethoxy)phenyl)sulfonyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole hydrochloride (150 μL, 0.030 mmol) in ACN (containing 5% DIEA) were added to a 1.5 mL reaction vial to give a brown solution. The reaction was shaken at room temperature for 2 hours. The volatiles were removed under a stream of nitrogen. The residue was partitioned between 0.5 mL of 1 N 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 were removed under a stream of nitrogen. The residue was purified using mass-triggered HPLC to give pyridin-3-ylmethyl 5-((4-(difluoromethoxy)phenyl)sulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5.6 mg, 12.4 μmol, 41% yield). LCMS: m / z = 452.2 [M+H]+.

[0816] The examples in Table 11 below were prepared according to the method outlined in Example 22-1 above using the appropriate synthetic precursors.

[0817] Table 11.

[0818]

[0819] Example 23-1: 2-(Benzofuran-5-ylsulfonyl)-5-(benzoylprolyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole

[0820]

[0821] A 0.2M solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (150 μL, 30 μmol) in dioxane and neat DIEA (10 μL, 57 μmol) were added to a 1.5 mL vial to give a brown suspension. A 0.2M solution of benzofuran-5-sulfonyl chloride (158 μL, 31.5 μmol) in dioxane was added. The reaction was heated at 50°C with shaking for 2 hours. A 4M HCl solution in dioxane (75.0 μL, 0.300 mmol) was then added. The reaction was heated at 50°C with shaking for another 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 (50 μL, 0.285 mmol) and 0.2 M (tert-butoxycarbonyl)proline (165 μL, 33 μmol) in dioxane were added to the vial, followed by 0.2 M HBTU (165 μL, 33 μmol) in ACN. The reaction was shaken for another 2 hours at room temperature. 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 μL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Then 4 M HCl in dioxane (75.0 μL, 0.300 mmol) was added. The reaction was heated at 50° C. with shaking for another 2 hours. The volatiles were removed under reduced pressure. ACN (200 μL) was added to the vial. The vial was shaken for 15 minutes to resuspend the residue. Pure DIEA (50 μL, 0.285 mmol) and 0.2M benzoic acid (165 μL, 33 μmol) in dioxane were added to the vial, followed by 0.2M HBTU (165 μL, 33 μmol) in ACN. The reaction was shaken for another 2 hours at room temperature. Volatiles were removed under reduced pressure. The residue was mixed with 1N NaOH (0.5 mL) and extracted with 3:1 EtOAc / ACN (2x 0.5 mL). The organic layers were combined and the volatiles were removed under reduced pressure. The compound was purified using mass spectrometry triggered HPLC to give 2-(benzofuran-5-ylsulfonyl)-5-(benzoylprolyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (2.0 mg, 6.52 μmol, 22% yield). LCMS: m / z = 492.3.1 [M+H]+.

[0822] The examples in Table 12 below were prepared according to the method outlined in Example 23-1 above using the appropriate synthetic precursors.

[0823] Table 12.

[0824]

[0825] Example 24. Luminescent biochemical assay

[0826] In some embodiments, a PKR activating compound is a compound having one or more of the following characteristics when tested according to the following luminescence assay protocol of Example 24 using any one or more of wild-type (wt) PKR and / or the G332S mutant form of PKR or the R510Q mutant form of PKR: (1) an AC of less than 40 μM; 50 Values ​​(e.g., in Table 13, AC 50 In some embodiments, the PKR activating compound may have: (1) an AC of less than 0.1 μM. 50 Values ​​(e.g., in Table 13, AC 50 Value "+++" compound), 0.1-1.0 μM (for example, in Table 13 with AC 50 Value "++" compound), or 1.01-40 μM (for example, in Table 13 with AC 50 value "+"); (2) a maximum % multiple of 75%-250%, 250-500%, or 75%-500%; and / or (3) a % multiple of 75%-250%, 250-500%, or 75%-500% @ 1.54 μM. In some embodiments, the PKR activating compound has (1) an AC less than 1.0 μM. 50 value; (2) a maximum % multiple of 75%-500%; and / or (3) a % multiple of 75%-500% @ 1.54 μM.

[0827] Phosphorylation of adenosine-5′-diphosphate (ADP) by various mutants of PKR was determined by Kinase Glo Plus Assay (Promega) in the presence or absence of FBP [D-fructose-1,6-diphosphate; BOC Sciences, CAS: 81028-91-3] as shown below. All reagents were purchased from Sigma-Aldrich unless otherwise indicated. All reagents were prepared in a buffer containing 50 mM Tris-HCl, 100 mM KCl, 5 mM MgCl2, and 0.01% Triton X100, 0.03% BSA, and 1 mM DTT. Enzyme and PEP [phospho(enol)pyruvate] were added 2x to all wells of the prepared assay plates containing serially diluted test compounds or DMSO vehicle. The final enzyme concentrations for PKR (wt), PKR (R510Q), and PKR (G332S) were 0.8 nM, 0.8 nM, and 10 nM, respectively. The final PEP concentration was 100 μM. The enzyme / PEP mixture was incubated with the compound for 30 minutes at room temperature before adding 2×ADP [adenosine-5′-diphosphate] and KinaseGloPlus to start the assay. The final concentration of ADP was 100 μM. The final concentration of KinaseGloPlus was 12.5%. For assays containing FBP, the reagent was added at 30 μM at the beginning of the reaction. The reaction was allowed to proceed at room temperature for 45 minutes until luminescence was recorded by a BMG PHERAstar FS multi-label reader. All compounds were tested in triplicate at concentrations ranging from 42.5 μM to 2.2 nM in 0.83% DMSO.

[0828] Luminescence values ​​were converted to % fold increase by normalizing to the mean of DMSO controls and multiplying by 100. Maximum, minimum, slope, and AC were determined by the standard four-parameter fitting algorithm of ActivityBase XE Runner. 50 . Using three parameters - AC 50 , Max %fold and %fold@1.54 μM to evaluate compounds ( Figure 1 ). AC of the compound 50 The value is the concentration (μM) corresponding to the midway between the maximum and minimum values ​​of the four-parameter logistic curve fit (i.e., where the % fold increase along the four-parameter logistic curve fit is halfway between the maximum % fold and the minimum % fold (% fold midpoint)), the maximum % fold is the highest fold increase observed at any concentration of compound, and the % fold @ 1.54 μM is the fold increase at a compound concentration of 1.54 μM. The parameter % fold @ 1.54 μM was selected to obtain AC 50and maximum % multiple elements, and provide rankings based on both potency and efficacy. A compound concentration of 1.54 μM was selected as the concentration that best distinguished a group of compounds based on the range of activities observed.

[0829] As shown in Table 13 below, AC 50 Values ​​(columns A, D, G) are defined as follows: ≤0.1 μM (+++); >0.1 μM and ≤1.0 μM (++); >1.0 μM and ≤40 μM (+); >40 μM (0). Maximum % multiple values ​​(columns B, E, H) are defined as follows: ≤75% (+); >75% and ≤250% (++); >250% and ≤500% (+++). % multiple @ 1.54 μM values ​​(columns C, F, J) are defined as follows: ≤75% (+); >75% and ≤250% (++); >250% and ≤500% (+++).

[0830] Table 13.

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842] 1 A-AC 50 LUM KGP FBP AC 50 μM geometric mean;

[0843] B-AC 50 LUM KGP FBP Maximum % Multiple Average;

[0844] C-AC 50 LUM KGP FBP %Fold@1.54μM Mean

[0845] D-AC 50 LUM KGP woFBP AC 50 μM geometric mean;

[0846] E-AC 50 LUM KGP woFBP max % multiple average;

[0847] F-AC 50 LUM KGP woFBP%fold@1.54μM mean

[0848] G-AC 50 LUM KGP woFBP AC 50 μM geometric mean;

[0849] H-AC 50 LUM KGP woFBP max % multiple average;

[0850] J-AC 50 LUM KGP woFBP%fold@1.54μM mean

[0851] Table 14. Biological data of additional compounds

[0852]

[0853]

[0854]

[0855] 1 A-AC 50 LUM KGP FBP AC 50 μM geometric mean;

[0856] D-AC 50 LUM KGP woFBP AC 50 μM geometric mean.

[0857] G-AC 50 LUM KGP woFBP AC 50 μM geometric mean;

[0858] Equivalent

[0859] The present disclosure enables those skilled in the art to realize and use the invention provided herein according to multiple and varied embodiments. Various changes, modifications and improvements (including certain changes, modifications, substitutions and improvements) of the present disclosure that are easily conceivable by those skilled in the art are also a part of the present disclosure. Therefore, the preceding description and accompanying drawings are used as examples to illustrate the discovery provided herein.

[0860] Embodiment 1. Compound of formula I or a pharmaceutically acceptable salt thereof:

[0861]

[0862] in:

[0863] A is phenyl or a monocyclic 5- to 6-membered heteroaryl ring containing 1-4 heteroatoms independently selected from O, N and S,

[0864] wherein each aryl or heteroaryl is optionally substituted with one or more R a ;

[0865] Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0866] wherein each alkyl group is optionally substituted with one or more halogens;

[0867] Z is O, S or NR;

[0868] R 1 and R 2 Each is independently selected from: -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n C4-C 12 Cycloalkenyl, -(CR b Rc ) n heterocyclic group, -(CR b R c ) n C6-C 14 aryl, -(CR b R c ) n heteroaryl, -OR, -OC(O)R’, -OS(O)2R’, -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R’, -(CR b R c ) n NRS(O)2R’, -(CR b R c ) n NRC(O)NR2, -(CR b R c ) n NRC(O)OR, -(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R’, -(CR b R c ) n C(O)OR, -(CR b R c ) n C(O)NR2, -(CR b R c ) n SO2R’, -(CR b R c ) n SO2NR2 and -(CR b R c ) n SO2OR,

[0869] wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo and -OR, wherein -OR does not form O in the γ-position relative to C(=Z),

[0870] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens,

[0871] wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S, and wherein the heterocyclyl does not contain O in the γ-position relative to C(=Z), and

[0872] wherein each heteroaryl group is 5 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S;

[0873] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl or a 3- to 8-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, and

[0874] wherein the heterocyclic group does not contain an O in the γ-position relative to C(=Z), and

[0875] wherein each cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo, and -OR, wherein -OR does not form O in the γ-position relative to C(=Z);

[0876] R b and R c Each is independently selected from: -H, halogen and -C1-C6 alkyl;

[0877] Each n is independently 0, 1, 2, 3 or 4;

[0878] B is a monocyclic or bicyclic 3 to 14-membered ring,

[0879] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0880] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S,

[0881] wherein the ring is optionally substituted with (R d ) m ,and

[0882] When the ring is saturated or partially unsaturated, the ring does not contain O in the γ-position relative to C(=Z);

[0883] Each R d independently selected from: halogen, oxo, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0884] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0885] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0886] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0887] wherein each alkyl group is optionally substituted with one or more halogens;

[0888] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0889] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl) and -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0890] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0891] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0892] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0893] Embodiment 2. The compound of Embodiment 1, wherein the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof:

[0894]

[0895] Embodiment 3. The compound of Embodiment 2, wherein the compound is a compound of Formula Ib or a pharmaceutically acceptable salt thereof:

[0896]

[0897] Embodiment 4. The compound of any one of Embodiments 1-3, wherein B is an aromatic monocyclic or bicyclic ring,

[0898] wherein at least one ring of the bicyclic ring is aromatic,

[0899] wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N and S, and

[0900] wherein the monocyclic or bicyclic ring is optionally substituted with (R d ) m .

[0901] Embodiment 5. The compound of any one of Embodiments 1-4, wherein R 1 and R 2 Each is independently selected from: -H, halogen, -C1-C6 alkyl and -OR, wherein -OR does not form O in the γ-position relative to C(=Z).

[0902] Embodiment 6. The compound of any one of Embodiments 1-3, wherein the compound is a compound of Formula Ic or a pharmaceutically acceptable salt thereof:

[0903]

[0904] Embodiment 7. The compound of any one of Embodiments 1-5, wherein the compound is a compound of Formula Id-1 or a pharmaceutically acceptable salt thereof:

[0905]

[0906] Embodiment 8. The compound of any one of Embodiments 1-5, wherein the compound is a compound of Formula Id-2 or a pharmaceutically acceptable salt thereof:

[0907]

[0908] Embodiment 9. The compound of any one of Embodiments 1-8, wherein A is phenyl or pyridinyl, which is optionally substituted with one or more R a .

[0909] Embodiment 10. The compound of any one of Embodiments 1-9, wherein each R a Selected from: halogen, -C1-C6 alkyl and -OR.

[0910] Embodiment 11. The compound of any one of Embodiments 1-10, wherein A is pyridinyl.

[0911] Embodiment 12. The compound of any one of Embodiments 1-11, wherein each R d Selected from: halogen, -C1-C6 alkyl and -OR.

[0912] Embodiment 13. The compound of any one of Embodiments 1-12, wherein A is unsubstituted.

[0913] Embodiment 14. The compound of any one of Embodiments 1-13, wherein each R is independently selected from: -H and -C1-C6 alkyl.

[0914] Embodiment 15. Compound of formula II or a pharmaceutically acceptable salt thereof:

[0915]

[0916] in:

[0917] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0918] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0919] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0920] wherein the ring is optionally substituted with one or more R a ;

[0921] Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0922] wherein each alkyl group is optionally substituted with one or more halogens;

[0923] Z is O, S or NR;

[0924] R 1 , R 2 and B are each independently -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b Rc ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR,

[0925] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens,

[0926] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0927] wherein the heterocyclic group does not contain O in the γ-position relative to C(=Z),

[0928] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR, oxo, -C6 aryl, and -C(O)R', and

[0929] wherein each cycloalkyl or heterocyclyl is optionally fused with a C6 aryl or a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S;

[0930] Each R b and R c Independently selected from: -H, -C1-C6 alkyl and halogen;

[0931] Each n is independently 0, 1, 2, 3 or 4;

[0932] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0933] wherein each alkyl group is optionally substituted with one or more halogens;

[0934] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0935] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, -C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0936] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0937] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, -(CR b R c ) nC6-C 14 Aryl, -(CR b R c ) n O(C6-C 14 aryl), and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0938] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2;

[0939] Provided that the compound is not:

[0940]

[0941] Embodiment 16. The compound of Embodiment 15, wherein the compound is a compound of Formula II-a or a pharmaceutically acceptable salt thereof:

[0942]

[0943] Embodiment 17. The compound of Embodiment 15 or 16, wherein the compound is a compound of formula II-b-1 or a pharmaceutically acceptable salt thereof:

[0944]

[0945] Where R 1 is -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl,

[0946] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens, and

[0947] Wherein B is -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CR b Rc ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR.

[0948] Embodiment 18. The compound of Embodiment 15 or 16, wherein the compound is a compound of Formula II-b-2 or a pharmaceutically acceptable salt thereof:

[0949]

[0950] Where R 1 is -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl,

[0951] wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more halogens, and

[0952] Wherein B is -OR, -OC(O)R', -OS(O)2R', -OS(O)2NR2, -OC(O)NR2, -OC(O)OR, -(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b Rc ) n NRC(O)NR2、-(CR b R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR.

[0953] Embodiment 19. The compound of any one of Embodiments 15-18, wherein A is a monocyclic or bicyclic 3 to 10 membered ring,

[0954] wherein the ring is partially unsaturated or aromatic, and

[0955] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0956] wherein the ring is optionally substituted with one or more R a .

[0957] Embodiment 20. The compound of any one of Embodiments 15-19, wherein R a Selected from: halogen, -OR, -NR2, -C1-C6 alkyl, -C3-C 12 Cycloalkyl, and 3 to 14 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from O, N and S, wherein each alkyl, cycloalkyl or heterocyclyl is optionally substituted with one or more halogens.

[0958] Embodiment 21. The compound of any one of Embodiments 15-20, wherein:

[0959] R 1 , R 2 and B are each independently -H, -C1-C6 alkyl, -OR, -(CR b R c ) n NR2, -(CR b R c ) n NRS(O)2R'or-(CR b R c ) n C(O)OR,

[0960] wherein each alkyl group is optionally substituted with one or more halogens;

[0961] or R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12 Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0962] wherein the heterocyclic group does not contain O in the γ-position relative to C(═O),

[0963] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of phenyl and -C(O)R', and

[0964] wherein each heterocyclic group is optionally fused to a phenyl group or a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S.

[0965] Embodiment 22. The compound of any one of Embodiments 15-21, wherein R 1 , R 2 and B are each independently -H, -C1-C6 alkyl, -OR, -(CR b R c ) n NR2, -(CR b R c ) n NRS(O)2R'or-(CR b R c ) n C(O)OR, wherein each alkyl is optionally substituted with one or more halogens.

[0966] Embodiment 23. The compound of any one of Embodiments 15-21, wherein:

[0967] R 1 and R 2 Combine with the carbon to which they are attached to form C3-C 12Cycloalkyl or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[0968] wherein the heterocyclic group does not contain O in the γ-position relative to C(═O),

[0969] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of phenyl and -C(O)R', and

[0970] wherein each heterocyclic group is optionally fused to a phenyl group or a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S.

[0971] Embodiment 24. The compound of any one of Embodiments 15-23, wherein B is -H.

[0972] Embodiment 25. The compound of any one of Embodiments 15-24, wherein each R is independently selected from: -H, -C1-C6 alkyl and C6-C 14 Aryl.

[0973] Embodiment 26. The compound of any one of Embodiments 15-25, wherein each R' is -C1-C6 alkyl.

[0974] Embodiment 27. Compound of formula III or a pharmaceutically acceptable salt thereof:

[0975]

[0976]

[0977] in:

[0978] A is a monocyclic or bicyclic 3 to 14-membered ring,

[0979] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[0980] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[0981] wherein the ring is optionally substituted with one or more R a ;

[0982] Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0983] wherein each alkyl group is optionally substituted with one or more halogens;

[0984] Z is O, S or NR;

[0985] B is a ring selected from the following: -C6-C 14 aryl and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S,

[0986] wherein the ring is optionally substituted with one or more R d ;

[0987] Each R d independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0988] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[0989] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[0990] wherein each alkyl group is optionally substituted with one or more halogens;

[0991] or R 3 and R 4 , R 5and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[0992] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0993] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[0994] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[0995] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0996] Embodiment 28. The compound of embodiment 27, wherein the compound is a compound of formula III-a or a pharmaceutically acceptable salt thereof:

[0997]

[0998] Embodiment 29. The compound of embodiment 27 or 28, wherein A is a 5- to 10-membered aromatic monocyclic or bicyclic ring,

[0999] wherein at least one ring of the bicyclic ring is aromatic,

[1000] wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N and S, and

[1001] Wherein the monocyclic or bicyclic ring is optionally substituted with one or more R a .

[1002] 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 O, N and S.

[1003] Embodiment 31. The compound of any one of Embodiments 27-30, wherein B is a ring selected from phenyl or a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S, wherein the ring is optionally substituted with one or more R d .

[1004] Embodiment 32. The compound of any one of Embodiments 27-31, wherein each R d Independently selected from: -OR, -NR2 and -C1-C6 alkyl, optionally substituted with one or more halogens.

[1005] Embodiment 33. The compound of any one of Embodiments 27-32, wherein each R is independently selected from: -H, -C1-C6 alkyl optionally substituted with one or more halogens, and 5 to 14 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, N and S.

[1006] Embodiment 34. A compound of formula IV or a pharmaceutically acceptable salt thereof:

[1007]

[1008] in:

[1009] A is a monocyclic or bicyclic 3 to 14-membered ring,

[1010] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[1011] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[1012] wherein the ring is optionally substituted with one or more R a ;

[1013] Each R aindependently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[1014] wherein each alkyl group is optionally substituted with one or more halogens;

[1015] Z is O, S or NR;

[1016] X is O or NR e ;

[1017] R e is -H or -C1-C6 alkyl;

[1018] B is -H or a monocyclic or bicyclic 3 to 14 membered ring,

[1019] wherein the ring is saturated, fully or partially unsaturated or aromatic, and

[1020] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S; and

[1021] wherein the ring is optionally substituted with one or more R d ;

[1022] Each R d independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[1023] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[1024] R 1 and R 2 Each is independently -H, halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(CR b R c ) n C3-C 12 Cycloalkyl, -(CR b R c ) n C4-C 12 Cycloalkenyl, -(CR b R c ) n Heterocyclic group, -(CR b R c ) n C6-C 14 Aryl, -(CR b R c ) n Heteroaryl, -(CR b R c ) n OR,-(CR b R c ) n OC(O)R'、-(CR b R c ) n OS(O)2R'、-(CR b R c ) n OS(O)2NR2、-(CR b R c ) n OC(O)NR2、-(CR b R c ) n OC(O)OR、-(CR b R c ) n NR2, -(CR b R c ) n NRC(O)R'、-(CR b R c ) n NRS(O)2R'、-(CR b R c ) n NRC(O)NR2、-(CRb R c ) n NRC(O)OR、-(CR b R c ) n CN, -(CR b R c ) n NO2, -(CR b R c ) n SR, -(CR b R c ) n C(O)R'、-(CR b R c ) n C(O)OR、-(CR b R c ) n C(O)NR2、-(CR b R c ) n SO2R',-(CR b R c ) n SO2NR2 or -(CR b R c ) n SO2OR,

[1025] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR and oxo,

[1026] wherein each heterocyclyl is 3 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S, and

[1027] wherein each heteroaryl group is 5 to 14 members and contains 1-4 heteroatoms independently selected from O, N and S;

[1028] or R 1 and R 2 Combine with the carbon to which they are attached to form oxo groups, C3-C 12 cycloalkyl, or a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[1029] wherein each cycloalkyl or heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OR and oxo;

[1030] or R eand R 1 Combined with the nitrogen to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S,

[1031] wherein the heterocyclic group is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, oxo, -OR and -(CR b R c ) n C6-C 14 Aryl;

[1032] or R 2 does not exist, and R 1 and B combine with the carbon to which they are attached to form C6-C 14 aryl or a 5- to 14-membered heteroaryl group containing 1-4 heteroatoms independently selected from O, N and S,

[1033] wherein each aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -OR;

[1034] Each R b and R c Independently selected from: -H, -C1-C6 alkyl and halogen;

[1035] Each n is independently 0, 1, 2, 3 or 4;

[1036] R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently -H or -C1-C6 alkyl,

[1037] wherein each alkyl group is optionally substituted with one or more halogens;

[1038] or R 3 and R 4 , R 5 and R 6 , R 7 and R 8 , R 9 and R 10 or a combination thereof combined with the carbon to which they are attached to form an oxo group, a C3-C8 cycloalkyl group, or a 3- to 8-membered heterocyclyl group containing 1-4 heteroatoms independently selected from O, N and S;

[1039] Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[1040] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and

[1041] Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl, 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, C6-C 14 aryl, and 5- to 14-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N and S,

[1042] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[1043] Embodiment 35. The compound of Embodiment 34, wherein the compound is a compound of formula IV-a or a pharmaceutically acceptable salt thereof:

[1044]

[1045]

[1046] Embodiment 36. The compound of Embodiment 34 or 35, wherein the compound is a compound of formula IV-b or a pharmaceutically acceptable salt thereof:

[1047]

[1048] Embodiment 37. The compound of any one of Embodiments 34-36, wherein the compound is a compound of formula IV-c or a pharmaceutically acceptable salt thereof:

[1049]

[1050] Embodiment 38. The compound of any one of Embodiments 34-36, wherein the compound is a compound of formula IV-d or a pharmaceutically acceptable salt thereof:

[1051]

[1052] Embodiment 39. The compound of any one of Embodiments 34-36, wherein the compound is a compound of formula IV-e-1 or a pharmaceutically acceptable salt thereof:

[1053]

[1054] Embodiment 40. The compound of any one of Embodiments 34-36, wherein the compound is a compound of formula IV-e-2 or a pharmaceutically acceptable salt thereof:

[1055]

[1056] Embodiment 41. The compound of any one of Embodiments 34-40, wherein A is a 5- to 10-membered aromatic monocyclic or bicyclic ring,

[1057] wherein at least one ring of the bicyclic ring is aromatic,

[1058] wherein the monocyclic or bicyclic ring contains 0-4 heteroatoms independently selected from O, N and S, and

[1059] Wherein the monocyclic or bicyclic ring is optionally substituted with one or more R a .

[1060] Embodiment 42. The compound of any one of Embodiments 34-41, wherein each R a Independently selected from: halogen, -C1-C6 alkyl and -OR.

[1061] Embodiment 43. The compound of any one of Embodiments 34-42, wherein:

[1062] B is a monocyclic 3 to 6-membered ring,

[1063] wherein the ring is saturated or aromatic,

[1064] wherein the ring contains 0-4 heteroatoms independently selected from O, N and S, and

[1065] wherein the ring is optionally substituted with one or more R d .

[1066] Embodiment 44. The compound of any one of Embodiments 34-43, wherein each R d Independently selected from: halogen, -C1-C6 alkyl and -OR.

[1067] Embodiment 45. The compound of any one of Embodiments 34-44, wherein:

[1068] R 1 and R 2 Each is independently selected from: -H, -C1-C6 alkyl, -(CR b R c ) n C6-C 14 Aryl and -(CR b R c ) n OR;

[1069] or R 1 and R 2 Combined with the carbon to which they are attached, they form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S;

[1070] or R e and R 1 The heterocyclic group is combined with the nitrogen to which they are attached to form a 3- to 14-membered heterocyclic group containing 1-4 heteroatoms independently selected from O, N and S, and the heterocyclic group is optionally substituted with one or more -OR or -(CR b R c ) n C6-C 14 Aryl.

[1071] Embodiment 46. The compound of any one of Embodiments 34-45, wherein R 1 and R 2 Each is -H.

[1072] Embodiment 47. The compound of any one of Embodiments 34-46, wherein R b and R c Each is -H, and each n is 0, 1 or 2.

[1073] Embodiment 48. The compound of any one of Embodiments 34-47, wherein each R is independently -H or -C1-C6 alkyl optionally substituted with one or more halogens.

[1074] Embodiment 49. A compound selected from Table 1.

[1075] Embodiment 50. The compound of Embodiment 49, wherein the compound is (2R)-2-hydroxy-2-phenyl-1-[5-(pyridine-2-sulfonyl)-1H,2H,3H,4H,5H,6H-pyrrolo[3,4-c]pyrrol-2-yl]ethan-1-one.

[1076] Embodiment 51. The compound of any one of Embodiments 1-50, wherein the compound is a compound having AC 50 PKR activating compounds with values ​​≤40 μM.

[1077] Embodiment 52. The compound of any one of Embodiments 1-51, wherein the compound is a compound having AC 50 PKR activating compounds with values ​​≤ 1.0 μM.

[1078] Embodiment 53. The compound of any one of Embodiments 1-52, wherein the compound is a compound having AC 50 PKR activating compounds with values ​​≤ 0.1 μM.

[1079] Embodiment 54. A pharmaceutical composition comprising a compound according to any one of embodiments 1-53 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: A is phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl, wherein each phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl is optionally substituted with one or more R a ; Each R a independently selected from: halogen, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl and C6-C 14 Aryl, wherein each alkyl group is optionally substituted with one or more halogens; Z is O, S or NR; R 1 and R 2 are each independently selected from: -H, halogen, -C1-C6 alkyl and -OR, Where -OR does not form O in the γ-position relative to C(=Z), wherein each alkyl group is optionally substituted with one or more halogens, B is selected from: wherein the monocyclic or bicyclic ring is optionally substituted with (R d ) m ; Each R d independently selected from: halogen, oxo, -OR, -OC(O)R', -NR2, -NRC(O)R', -NRS(O)2R', -CN, -NO2, -SR, -C(O)R', -C(O)OR, -C(O)NR2, -S(O)2R', -S(O)2NR2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl and C6-C 14 Aryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl 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 Each is independently -H or -C1-C6 alkyl; Each R is independently selected from: -H, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl) and -N(C1-C6 alkyl)2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl and C6-C 14 Aryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2; and Each R' is independently selected from: -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C 12 Cycloalkyl, -C4-C 12 Cycloalkenyl and C6-C 14 Aryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl is optionally substituted with one or more halogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ia:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl, wherein each phenyl, pyridyl, thienyl, imidazolyl, isoxazolyl or pyrazolyl is optionally substituted with one or more R a ; Each R a Independently selected from: fluorine, chlorine, methyl, -CF3, -Ome, -OiPr, -OCF3, -OCF2H, -NHC(O)Me, -CN and -SO2NH2; R 1 and R 2 Each is independently selected from: -H, fluoro, methyl, ethyl, isopropyl and -OH; B is selected from: wherein the ring is optionally substituted with (R d ) m ; Each R d are independently selected from: fluorine, chlorine, methyl, -CF3 and -OMe; and m is 0, 1 or 2.

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ib:

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ic:

6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Id-1:

7. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl, which is optionally substituted with one or more R a .

8. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl.

9. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is:

11. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is:

12. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is:

13. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is:

14. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the compound is:

15. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 14 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

16. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for preparing a drug for treating a disease associated with pyruvate kinase R, wherein 1) The disease is selected from pyruvate kinase deficiency PKD and PKD-related hemolytic anemia; or 2) The disease has a pyruvate kinase R mutation, and the mutation is selected from G332S and R510Q.

17. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a disease or condition associated with decreased PKM2 activity or decreased glycolysis.

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