pyrrolopyrrol compositions as pyruvate kinase activators (pkr)

专利摘要:
The disclosure relates to the modulation of pyruvate kinase and provides novel chemical compounds of formula (I) useful as pkr activators as well as various uses of these compounds. pkr activating compounds are useful in treating diseases and disorders associated with pkr and / or pkm2, such as pyruvate kinase deficiency (pkd), sickle cell disease (sdc) and thalassemia.
公开号:BR112018075312A2
申请号:R112018075312
申请日:2018-03-20
公开日:2019-10-01
发明作者:Ericsson Anna；Han Bingsong；C Smith Chase；R Lancia David Jr；Richard David；Gustafson Gary；Mitchell Lorna；Green Neal；Shelekhin Tatiana；Zheng Xiaozhang；Wang Zhongguo
申请人:Forma Therapeutics Inc；
IPC主号:

专利说明:

COMPOUND CONCENTRATION, μΜ
1/138
Invention Patent Descriptive Report for PIRROLOPIRROL COMPOSITIONS AS ACTIVATORS OF PLRUVATO KINASE (PKR).
REMISSIVE REFERENCE TO RELATED APPLICATIONS [001] This application claims priority to US provisional patent application No. 62 / 473,751, filed on March 20, 2017, the entire contents of which are incorporated by reference.
TECHNICAL FIELD [002] The present description is directed to the modulation of pyruvate kinase, including innovative compounds useful as activators of PKR.
BACKGROUND [003] Pyruvate kinase (PK) converts phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) into pyruvate and adenosine triphosphate (ATP), respectively, which is the final step in glycolysis. In humans, four isoforms of PK are expressed by two structural genes. The PKLR gene encodes the specific tissue isoforms PKR and PKL expressed in erythroid cells and in the liver, respectively. The PKM gene encodes the PKM1 isoforms, expressed in the brain and skeletal muscle, and PKM2 (pyruvate kinase type M2), expressed in fetal tissues and in most adult tissues, except erythroid cells (Takenaka et al, Eur J Biochem 1991, 198: 101).
[004] Mutations in the PKLR gene can lead to deficiency of pyruvate kinase (PKD), an autosomal recessive disorder, which is the most frequent enzymatic defect of the glycolytic pathway in erythrocytes. More than 200 different mutations have been identified in the structural PKLR gene (Bianchi et al, Blood Cells Mol Dis 2000, 26: 47). In general, most patients with PKD are heterozygous with two different mutant alleles, but homozygous mutations have also been described (Diez et al. Blood 2005, 106: 1851). Clinical symptoms of PKD
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2/138 vary considerably from mild to severe anemia. Mutations can reduce the enzymatic activity of PK or decrease the stability of the PK protein. Pathological manifestations are usually seen when enzyme activity is below 25% of normal PK activity, and severe disease has been associated with a high degree of reticulocytosis (Miwa et al, Am J Hematol 51: 122). Although the global incidence of PKD is unknown, it has been estimated at 51 cases per million in North America (Beutler et al, Blood 2000, 95: 3585).
[005] Currently, there is no definitive treatment for severe PKD (Cazzola, Haematologica 2005, 90: 1). Although splenectomy can be clinically useful in patients with severe disease, in some cases, an allogeneic hematopoietic transplant is necessary (Tanphaichitr et al, Bone Marrow Transplant 2000, 26: 689). In these patients, hematopoietic stem cell (HSC) gene therapy can be a good and more effective treatment. Gene therapy strategies for PKD have been treated in animal models demonstrating that introducing the correct version of the human PKLR gene into hematopoietic stem cells using retroviral vectors relieves the disease (Meza et al, Hum Gene Ther 2007, 18: 502). Although bone marrow transplantation (BMT) or gene therapy strategies are definitive treatments for the disease, important adverse effects are associated with both approaches (Aiuti et al, Gene Ther 2007, 14: 1555).
[006] There is a need for strategies to improve the treatment of diseases related to PKR, such as PKD, including the discovery / development of small molecules that activate PKR. PKR exists in both dimeric and tetrameric states, but works more efficiently as a tetramer. Small molecules have been shown to be able to change the balance of PKR to the tetrameric (more active) form, providing a mechanistic logic for its use as therapy for hemolytic anemia associated with PKD.
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Thus, there is a need for PKR activating compounds, useful for the treatment of diseases and disorders associated with PKR and / or PKM2 modulation.
SUMMARY [007] Compounds that activate PKR are disclosed in the present invention. The PKR activating compounds shown in the present invention can increase the activity of wild and mutant PK enzymes in the biochemical assays disclosed herein (for example, in Example 47). The data for PKR activating compounds described here illustrate the potential of these compounds to restore glycolytic pathway activity in patients with PK deficiency, to provide clinical benefit. The compounds disclosed in the present invention are useful in the treatment of diseases or disorders associated with the function of pyruvate kinase. For example, the PKR activating compounds disclosed may be useful in the treatment of diseases, including, but not limited to, PKD, sickle cell disease (SDC) (eg sickle cell anemia) and thalassemia (eg beta thalassemia). In other embodiments, the compounds may be useful in the treatment of other indications related to the modulation of pyruvate kinase.
[008] One aspect of the present disclosure relates to Formula I compounds (for example, Formula (I) compounds identified as PKR activating compounds, using the Luminescence Assay Protocol of Example 47):
(I), [009] and its pharmaceutically acceptable salts, [0010] where:
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4/138 [0011] Y is a bond, - (CR ⁵ R ⁵ ') t-, -NR ⁵ (CR ⁵ R ⁵ ') t- or -O-;
[0012] each R ¹ , R ¹ ', R ² and R ² ' [and independently -H, -alkyl (CiCe), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs- Cs), (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O ) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O ) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ; [0013] or R ¹ and R ¹ ', or R ² and R ² ', together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs- Cs) or 5- to 8-membered spiroheterocycle;
[0014] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[0015] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[0016] or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring;
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5/138 [0017] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring;
[0018] R ⁴ is -H, -alkyl (C1-C), -alkenyl (C2-C6), -alkynyl (C2Ce), -cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl , heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , in that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , - NO2, -NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S ( O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[0019] each R ⁵ and R ⁵ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O ) 2NR ⁶ R ⁶ ', -S (O) R ⁶ , S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O ) R ⁶ or -C (O) OR ⁶ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁶ , -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', S (O) R ⁶ , -S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ and -C (O) OR ⁶ ; [0020] or two R ⁵ at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form an optionally substituted cycloalkyl ring (Cs-Cs)
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6/138 with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[0021] or two R ⁵ 'at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[0022] each R ⁶ and R ⁶ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O ) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O ) R ⁷ or -C (O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , -S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C (O) OR ⁷ ; [0023] each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), - alkynyl (C2-C6), -cycloalkyl (CsCs), - cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO2, -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S ( O) H, -S (O) NH ₂ , NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents
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7/138 selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH2, -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H , -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
[0024] each R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' is independently, in each occurrence, -H, -alkyl (Ci-Ce), - alkenyl (C ₂ -Ce), alkynyl (C ₂ -Ce), -cycloalkyl (Cs-Cs) or -cycloalkenyl (C4-Cs), where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO ₂ , -NH ₂ , S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H , -S (O) NH ₂ , -NHS (O) ₂ H, -NHS (O) H, C (O) H, oue-C (O) OH, and [0025] te, 1,2 or 3.
[0026] Except where otherwise indicated in the present invention, each occurrence of R ⁷ and R ⁷ 'disclosed in the present invention, for each of R ⁶ , R ⁶ ', R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ , and R ¹¹ , are independently selected from any of the possible cited values of R ⁷ and R ⁷ '. For example, the R ⁷ value may have a different value for each of R ⁶ , R ⁶ ', R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ , and R ¹¹ , except where otherwise indicated in the present invention.
[0027] The present disclosure also provides compounds of Formula (I) and their pharmaceutically acceptable salts, being:
[0028] Y is a link;
[0029] R ¹ is selected from the group consisting of -H, -alkyl (C1Ce), 6-membered aryl and 6-membered heteroaryl;
[0030] R ¹ 'is selected from the group consisting of -H and -alkyl (Ci-C ₆ );
[0031] or R ¹ and R ¹ ', together with the atom to which they are attached, can combine to form a 3- to 8-membered -cycloalkyl (Cs-Cs);
[0032] each R ² and R ² 'is independently selected from the group
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8/138 consisting of -H and -alkyl (Ci-Ce);
[0033] R ³ is -H or -alkyl (C 1 -C);
[0034] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
[0035] R ⁴ is a 6 to 10 membered aryl or 6 to 10 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ or -NR ⁵ R ⁵ ;
[0036] each R ⁵ and R ⁵ 'is independently, in each occurrence, H, -alkyl (Ci-Ce) optionally substituted with one or more among halogen, -OR ⁶ or -NR ⁶ R ⁶ ;
[0037] or two R ⁵ at adjacent atoms of R ⁴ , together with the atoms to which they are attached, optionally form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[0038] each R ⁶ is independently, at each occurrence, -H, alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (C3Cs), - (cycloalkenyl C4- Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ or -C ( O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , -S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C (O) OR ⁷ ; [0039] each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), - alkynyl (C2-C6), -cycloalkyl (C3Cs), - cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO2, -NH2, -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O ) H, -S (O) NH _2j
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NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH2, -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O ) H, -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
[0040] each R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ and R ¹¹ is independently, in each occurrence, -H or -alkyl (Ci-Ce) optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO ₂ , -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , -NHS (O) ₂ H, -NHS (O) H, -C (O) H, or and -C (O) OH. [0041] For example, the present disclosure relates to the compounds of Formula (I) and their pharmaceutically acceptable salts, being:
[0042] Y is a link;
[0043] each R ¹ and R ¹ 'is independently selected from the group consisting of -H, -alkyl (Ci-Ce), aryl and heteroaryl, where each alkyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ e -C (O) OR ⁵ ; [0044] or R ¹ and R ¹ ', together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs-Cs) or 5-spiro-heterocycle to 8 members;
[0045] each R ² and R ² 'is independently selected from the group consisting of -H and -alkyl (Ci-Ce) optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O ) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ',
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C (O) R ⁵ and -C (O) OR ⁵ ;
[0046] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[0047] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
[0048] R ⁴ is a 6 to 10 membered aryl or 6 to 10 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ or -NR ⁵ R ⁵ ;
[0049] each R ⁵ and R ⁵ 'is independently, at each occurrence, H, -alkyl (C 1 -C ₆ ), -OR ⁶ or -NR ⁶ R ⁶ ';
[0050] or any two R ⁵ at adjacent atoms of R ⁴ , together with the atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[0051] each R ⁶ is independently, in each occurrence, -H or alkyl (Ci-Ce); and [0052] each R ⁸ , R ⁸ , R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' is independently, in each occurrence, -H.
[0053] In some PKR activating compounds, R ⁴ is a 6-membered aryl or heteroaryl substituted with two -R ⁵ , selected from the group consisting of OR ⁶ and -NR ⁶ R ⁶ ', in adjacent atoms of R ⁴ ,
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11/138 which together with the atoms to which they are attached, form a heterocycloalkyl ring fused to R ⁴ which is optionally substituted with one or more R ⁶ selected from the group consisting of -H and alkyl (Ci-Ce) .
[0054] In another aspect, the disclosure features pharmaceutical compositions that comprise a compound of Formula I and a pharmaceutically acceptable carrier.
[0055] In another aspect, the disclosure presents methods of treating a disease or disorder associated with the modulation of pyruvate kinase (PKR) which comprises administering to a patient who needs an effective amount of a compound of Formula
I.
[0056] The present disclosure also provides methods of treating a disease associated with decreased PKR activity in an individual who needs it, which comprises administering to the individual an effective amount of a Formula I compound.
[0057] Another aspect of the present disclosure is a method of activating PKR, which comprises bringing PKR into contact with an effective amount of a Formula I compound.
[0058] Additional aspects of the present disclosure include: methods to increase the lifespan of red blood cells; methods of regulating the levels of 2,3-diphosphoglycerate in the blood; and methods of regulating blood ATP levels; each of the aforementioned methods comprising administering to an individual in need of an effective amount of a compound of Formula
I.
[0059] Another aspect of the present invention provides methods of treating hereditary non-spherocytic hemolytic anemia which comprises administering to an individual in need thereof an effective amount of a compound of Formula I.
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12/138 [0060] Also provided in that document are methods of treating a disease or disorder associated with increased levels of 2,3-diphosphoglycerate comprising administering to an individual in need of him an effective amount of a compound of Formula I.
[0061] Another aspect of the disclosure provided herein includes methods of treating a disease or disorder associated with decreased ATP levels which comprise administering to an individual in need of an effective amount of a Formula I compound.
[0062] An additional aspect of the present disclosure includes methods of treating sickle cell anemia comprising administering, to an individual in need thereof, a therapeutically effective amount of any of Formula I.
[0063] An additional aspect of the present disclosure includes methods of treating hemolytic anemia comprising administering, to an individual in need thereof, a therapeutically effective amount of a Formula I compound.
[0064] Another aspect of the present disclosure includes methods of treating beta-thalassemia comprising administering, to an individual in need thereof, a therapeutically effective amount of a Formula I compound.
BRIEF DESCRIPTION OF THE DRAWINGS [0065] FIGURE 1 shows an exemplary dosage response curve for the compounds shown in the present invention. Dosing response curves can be generated using the standard ActivityBase XE Runner four-parameter adjustment algorithm to determine MAX% Fold, MIN% Fold, slope and AC50. MAX% Fold is the biggest% increase sometimes seen in any concentration of the compound, and MIN% Fold is the least% increase sometimes seen in any concentration of the compound. The value of
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ACTION for a compound is the concentration (pm) corresponding to half between the maximum and minimum values of the four parameter logistic curve fit (ie, in which the% increase in times over the four parameter logistic curve fit is half between MAX% Fold and MIN% Fold (midpoint of% times). Another useful parameter for evaluating the compounds of this disclosure is the% times @ 1.54 pM, which is the% times increase in a compound concentration of 1.5 pM (for example, 1.54 pM) The X axis and the Y axis are not necessarily to scale.
DETAILED DESCRIPTION [0066] The present disclosure relates to compounds and compositions that are capable of activating PKR and / or PKM2 activity. The disclosure discloses methods of treating a disease or disorder in which PKR and / or PKM2 plays a role by administering to a patient who requires a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically salt. acceptable value. The methods of the present disclosure can be used to treat a variety of PKR and / or PKM2-dependent diseases and disorders by activating the activity of the PKR and / or PKM2 enzymes. Activation of PKR and PKM2 provides a new approach to the treatment of diseases including, but not limited to, PKD, SCD (eg, sickle cell anemia) and thalassemia (eg, beta-thalassemia). In some embodiments, the PKR activating compounds shown in the present invention may be useful for the treatment of inherited blood disorders related to pyruvate kinase activity, including PKD and SCD.
[0067] In a first aspect of the disclosure, the compounds of Formula (I) are described:
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[0068] and pharmaceutically acceptable salts thereof, where Y, R ¹ , R ¹ ', R ² , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' are as described above in the present invention.
[0069] The details of the disclosure are presented in the attached description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present description, illustrative methods and materials are described below. Other characteristics, objectives and advantages of the disclosure will be evident from the description and the claims. In the specification and in the appended claims, singular forms also include the plural, unless the context clearly determines otherwise. Except where otherwise defined, all technical and scientific terms used in the present invention have the same meaning commonly understood by the person skilled in the art to which this description belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.
Definitions [0070] Articles one and one are used in this description to refer to one or more than one (for example, at least one) of the grammatical object of the article. For example, an element means an element or more than one element.
[0071] The term e / or is used in this description to mean e or or, except where otherwise indicated.
[0072] The optionally substituted term means that a given chemical moiety (for example, an alkyl group) can (but is not
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15/138 required) be linked to other substituents (eg, heteroatoms). For example, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (for example, a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents in place of one or more hydrogen atoms. For example, it can, at any point along the chain, be attached to a halogen atom, to a hydroxyl group, or to any other substituent described here. Therefore, the optionally substituted term means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -Oalkyl (Ci-Ce), alkyl (Ci-Ce), alkoxy (Ci- C6), haloalkyl (Ci-Ce), haloalkoxy (Ci-Ce), -O-alkenyl (C2-C6), -O-alkynyl (C2-C6), alkenyl (C2C ₆ ), alkynyl (C ₂ -C ₆ ), -OP (O) (OH) ₂ , -OC (O) alkyl (C ₁ -C ₆ ), -C (O) alkyl (C 1 -C ₆ ), -OC (O) O-alkyl (C 1 -C) ₆ ), -NH ₂ , -NH-alkyl ((C 1 -C ₆ )), -Nalkyl ((C 1 -C ₆ )) 2, -NHC (O) -alkyl (C ₁ -C ₆ ), -C (O ) NH-alkyl (C 1 -C ₆ ), S (O) ₂ -alkyl (C 1 -C ₆ ), -S (O) NH-alkyl (C 1 -C ₆ ) and S (O) N-alkyl ((C ₁ C ₆ ) ) alkyl) 2. The substituents can themselves be optionally substituted. Optionally substituted, as used here, also refers to substituted or unsubstituted, the meaning of which is described below.
[0073] For use in the present invention, the substituted term means that the specified group or moiety has one or more suitable substituents, the substituents being able to connect to the specified group or moiety in one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that cycloalkyl connects to an atom of the aryl with a bond or merging with the aryl and sharing two or more common atoms.
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16/138 [0074] For use in the present invention, the term unsubstituted means that the specified group has no substituents.
[0075] For use in the present invention, the term partially unsaturated refers to a ring portion that includes at least one double or triple bond. The term partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include portions of aryl or heteroaryl, as defined in the present invention.
[0076] Except where specifically defined otherwise, the term aryl refers to cyclic and aromatic hydrocarbon groups that have 1 to 3 aromatic rings with a total of 5 to 14 ring atoms, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at a single point (for example, biphenyl), or fused (for example, naphthyl). The aryl group can be optionally substituted by one or more substituents, for example, 1 to 5 substituents, at any point of attachment. Examples of substituents include, but are not limited to, -halogen, -Oalkyl (Ci-Ce), alkyl (Ci-Ce), -O-alkenyl (C2-C6), -O-alkynyl (C2Ce), alkenyl (C2 -C6), alkynyl (C2-C6), -OH, -OP (O) (OH) ₂ , OC (O) alkyl (Ci-Ce), -C (O) alkyl (Ci-Ce), -OC ( O) O-alkyl (Ci-Ce), NH ₂ , NH ((Ci-C ₆ alkyl)), N ((Ci-C ₆ alkyl)) ₂ , -S (O) ₂ - (Ci-C ₆ alkyl ), S (O) NH (Ci-Ce alkyl), and -S (O) N ((Ci-Ce) alkyl) 2. The substituents can themselves be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a totally unsaturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzothiophene and the like.
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17/138 [0077] Unless otherwise defined, heteroaryl means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring hetero atoms selected from the group consisting of N, O and S. The aromatic radical is optionally substituted independently with one or more substituents described in that document. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2yl, quinolyl, benzopyranyl, isothiazyl, tazol, zazole, zazole , thieno [3,2-b] thiophene, triazolyl, triazinyl, imidazo [1,2b] pyrazolyl, bore [2,3-c] pyridinyl, imidazo [1,2-a] pyridinyl, indazolyl, pyrrole [2,3 -c] pyridinyl, pyrrolo [3,2-c] pyridinyl, pyrazolo [3,4-c] pyridinyl, thieno [3,2-c] pyridinyl, thieno [2,3-c] pyridinyl, thieno [2,3 -b] pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiocromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanil, quinolinyl, quinolinyl, quinolinyl, isolininyl, quinolinyl, quinolinyl isoquinolinyl, pyrido [4.3b] [1.6] naphthyridinyl, thieno [2,3-b] pyrazinyl, quinazolinyl, tetrazole [1,5-
a] pyridinyl, [1,2,4] triazolo [4,3-a] pyridinyl, isoindolyl, pyrrole [2,3-
b] pyridinyl, pyrrole [3,4-b] pyridinyl, pyrrole [3,2-b] pyridinyl, imidazo [5.4b] pyridinyl, pyrrole [1,2-a] pyrimidinyl, tetrahydropyrrole [1,2- a] pyrimidinyl,
3,4-dihydro-2H-1 À ² -pyrrolo [2,1 -b] pyrimidine, dibenzo [b, d] thiophene, pyridin
2-one, bore [3,2-c] pyridinyl, bore [2,3-c] pyridinyl, 1 H-pyrido [3,4b] [1,4] thiazinyl, benzoxazolyl, benzoisoxazolyl, bore [2,3- b] pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, bore [3,2-b] pyridine, [1,2,4] triazole [1,5-
a] pyridinyl, benzo [1,2,3] triazolyl, imidazo [1,2-a] pyridinyl, [1,2,4] triazolo [4,3-b] pyridazin, benzo [c] [ 1,2,5] thiadiazolyl, benzo [c] [1,2,5] oxadiazole, 1,3-dihydro-2H-benzo [d] imidazol-2-one, 3,4-dihydro-2H-pyrazole [1,5-b] [1,2] oxazinyl, 4,5,6,7-tetrahydropyrazolo [1,5-
a] pyridinyl, thiazol [5,4-d] thiazolyl, imidazo [2,1-b] [1,3,4] thiadiazolyl, tie
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18/138 in [2,3-b] pyrrolyl, 3H-indolyl and derivatives thereof. In addition, when containing two fused rings, the heteroaryl groups defined herein may have an unsaturated or partially saturated ring fused to a totally unsaturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiocromanyl, tetrahydroquinoline, dihydrobenzothiazine, 3,4-dihydro-1 H-isoquinolinyl, 2,3-dihydrobenzofuran , indolinyl, indolyl and dihydrobenzoxanil. [0078] Halogen or halo refers to fluorine, chlorine, bromine or iodine.
[0079] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of an alkyl (Ci-Ce) group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tercbutyl, isopentyl, neopentyl and isohexyl. An alkyl group can be substituted by one or more substituents.
[0080] Aloxy refers to a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms containing an O-terminus in the chain, for example, -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy or pentoxy groups.
[0081] The term alkylene or alkenyl refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be an alkylene by abstraction of a second hydrogen atom of the alkyl. As defined herein, alkylene can also be a C 1 -C alkylene. An alkylene may also be a C1-C4 alkylene Typical alkylene groups include, but are not limited to, -CH2-, -CH (CH ₃ ) -, -C (CH ₃ ) ₂ -, -CH2CH2-, -CH ₂ CH (CH ₃ ) -, CH ₂ C (CH ₃ ) ₂ -, -CH2CH2CH2-, -CH2CH2CH2CH2- and the like.
[0082] Cycloalkyl or carbocyclyl means saturated rings mo
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19/138 nocicyclic or polycyclic containing from 3 to 18 carbon atoms. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo [2.2.2] octanyl or bicyclo [2.2.2] octenyl, and derivatives of themselves. A Cs-Cs cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (for example, decalin) or bridged (for example, norbornane). A cycloalkyl group can be substituted by one or more substituents.
[0083] Heterocyclyl or heterocycloalkyl means monocyclic rings of 5 to 7 members or polycyclic rings of 7 to 10 members containing carbon and hetero atoms among oxygen, nitrogen or sulfur, where such rings are saturated or partially unsaturated. The heterocycloalkyl ring structure can be replaced by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanila, azetadinila, tetrahydrofuran hidrofuranila, tetrahydrofuran hidropiranila, pyrrolidinyl, oxazolinila, oxazolidinila, tiazolinila, tiazolidinila, pyranyl, tiopiranila, tetrahydrofuran hidropiranila, dioxalinila, piperidinyl, morpholinyl, tiomorfolinila, Thiomorpholinyl S-dioxide, Thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl and homotropanil.
[0084] The term hydroxyalkyl means an alkyl group, as defined in that document, where the alkyl group is replaced by one or more OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CH2-CH2- and CH ₃ -CH (OH) -.
[0085] The term haloalkyl, for use in the present invention, refers to an alkyl group, as defined herein, which is replaced by one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloro
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20/138 romethyl, etc.
[0086] The term haloalkoxy, as used in the present invention, refers to an alkoxy group, as defined herein, which is replaced by one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
[0087] The term cyan, for use in the present invention, means a substituent with a carbon atom attached to a nitrogen atom by a triple bond, that is, -ΟξΝ.
[0088] Spirocycloalkyl or spirocyclopentyl means bicyclic carbogenic ring systems with both rings connected through a single atom. The ring can be different in terms of size and nature, or identical in terms of size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spironane or spirodecane. One or both rings on a spirocycle can be fused to another carbocyclic, heterocyclic, aromatic or heteroaromatic ring. A spirocycloalkyl (C5-C12) is a spirocycle containing between 5 and 12 carbon atoms. One or more of the carbon atoms can be replaced by a hetero atom.
[0089] The term spiroheterocycloalkyl or spiroheterocyclyl is understood as a spirocycle, with at least one of the rings being a heterocycle (for example, at least one of the rings is furanyl, morpholinyl or piperadinyl).
[0090] The term isomer refers to compounds that have the same composition and molecular weight, but differ in terms of physical and / or chemical properties. The structural difference may be in the constitution (for example, geometric isomers) or in the ability to rotate a plane of polarized light (stereoisomers). In relation to stereoisomers, the compounds of Formula (I) can have one or more asymmetric carbon atoms and can occur as racemates,
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21/138 racemic mixtures or as individual enantiomers or diastereomers.
[0091] The description also includes pharmaceutical compositions that comprise an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
[0092] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Representative pharmaceutically acceptable salts include, for example, water-soluble and water-insoluble salts, such as acetate salts, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsilate, carbonate, chloride, citrate, clavulariate, dihydrate, edetate, edisylate, stolate, esilate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycolylsanilate, hexafluorosulfate, hexafluorohydrate hydrochloride, hydroxinaftoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-hydroxy-2 , oxalate, palmitate, pamoate (1,1-methylene-bis-2-hydroxy3-naphtoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicyl to, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, trietiodide and valerate. The compounds of formula I can form salts that are also within the scope of this disclosure. Reference to a compound of formula I of the present invention is understood to include reference to salts thereof, except where otherwise indicated.
[0093] A patient or individual is a mammal, for example,
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22/138 a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
[0094] An effective amount, when used in connection with a compound, is an effective amount for treating or preventing a disease in an individual, as described in the present invention.
[0095] The term vehicle, for use in this disclosure, encompasses vehicles, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid material, diluent, excipient, solvent or packaging material, involved in the execution or transportation of a pharmaceutical agent from one organ, or body part, to another organ, or an individual body part.
[0096] The term treat, in relation to an individual, refers to improving at least one symptom of the individual's disorder. Treatment includes healing, amelioration or at least partial amelioration of the disorder. [0097] The term disorder is used in this disclosure to mean, and is used interchangeably with the terms disease, condition or illness, except where otherwise indicated.
[0098] The term administer, administer or administer, as used in this disclosure, refers to directly administering a disclosed compound, a pharmaceutically acceptable salt of a disclosed compound or composition to an individual, a pharmaceutically acceptable salt of a compound or a composition to an individual, which can form an equivalent amount of active compound within the individual's body.
[0099] The term cancer includes, but is not limited to, the following cancers: bladder cancer, breast cancer (for example, ductal carcinoma), cervical cancer (for example, squamous cell carcinoma), colorectal cancer (for example, adenocarcinoma), esophageal cancer (for example, squamous cell carcinoma), gastric cancer (for example,
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23/138 example, adenocarcinoma, medulloblastoma, colon cancer, choriocarcinoma, squamous cell carcinoma), head and neck cancer, hematological cancer (e.g., acute lymphocytic anemia, acute myeloid leukemia, B-cell lymphoblastic leukemia, anaplastic lymphoma of large cell, B cell lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, chronic eosinophilic leukemia / hypereosinophilic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma, acute T-cell lymphoblastic leukemia), cancer of lung (eg, bronchialveolar adenocarcinoma, mesothelioma, mucoepidermoid carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma), liver cancer (eg, hepatocellular carcinoma), lymphoma, cancer neurological (eg gliobastoma, neuroblastoma, neuroglioma), ovarian (eg example, adenocarcinoma), pancreatic cancer (eg, ductal carcinoma), prostate cancer (eg, adenocarcinoma), kidney cancer (eg, renal cell carcinoma, renal clear cell carcinoma), sarcoma (eg, chondrosarcoma, Ewings sarcoma, fibrosarcoma, multipotential sarcoma, osteosarcoma, rhabdomyosarcoma, synovial sarcoma), skin cancer (e.g. melanoma, squamous cell carcinoma, squamous cell carcinoma), thyroid cancer (e.g. medullary carcinoma) and uterine cancer.
[00100] Unless otherwise indicated, PKR activating compound, for use in the present invention, refers to a compound that has one or more of the following characteristics when tested according to the Luminescence Assay Protocol of Example 47 below: (1) an AC50 value less than 40 μΜ; (2) a maximum value% in times (MAX% Fold) greater than 75%; and / or (3) a% times value in the compound concentration of 1.54 μΜ (% Fold @ 1.54 μΜ) of hair
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24/138 minus 75%. In some embodiments, the Luminescence Assay Protocol of Example 47 is performed with wild type PKR (wt "wild type"), the PKR mutant G332S form or the PKR mutant R510Q form. In some embodiments, the PKR activating compound is a compound of Formula (I). In some embodiments, the PKR activating compound has: (1) an AC50 value of less than 0.1 μΜ, 0.1-1.0 μΜ, or 1.01-40 μΜ; (2) a MAX% Fold of 75% -250%, 251500% or 75% -500%; and / or (3) a% Fold @ 1.54 μΜ of 75% -250%, 251-500% or 75% -500%. In some embodiments, a PKR-activating compound has (1) an AC50 value less than 1.0 pm; (2) a MAX% Fold of 75% -500%; and / or (3) a 75%% Fold @ 1.54 μΜ of 75%. In some embodiments, a PKR Activating Compound has (1) an AC50 value less than 1.0 μΜ; (2) a MAX% Fold of 75% 500%; and / or (3) a% Fold @ 1.54 μΜ of 75% -500%, obtained in the Luminescence Test Protocol with any one or more of the wild type PKR (by weight), PKR mutant G332S form or a mutant form R510Q of PKR. In some embodiments, the PKR Activating Compound has (1) an AC50 value less than 1.0 μΜ; (2) a MAX% Fold of 75% -500%; and / or (3) a% Fold @ 1.54 μΜ of 75% 500%, obtained in the Luminescence Test Protocol with the wild type PKR (by weight). In some embodiments, the PKR Activating Compound has (1) an AC50 value less than 1.0 μΜ; (2) a MAX% Fold of 75% -500%; and / or (3) a 75%% Fold @ 1.54 μΜ of 75%, obtained in the Luminescence Assay Protocol with either or both of the PKR mutant G332S form or the PKR mutant R510Q form.
[00101] It should be understood that all stereoisomeric forms are included in this description, including mixtures thereof.
[00102] The compounds of the revelation may contain asymmetric centers
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25/138 knitted or chiral and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the description, such as those that may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers and diastereomeric forms, including racemic mixtures, are part of the present disclosure. The test results may reflect the data collected for the racemic form, the enantiomerically pure form or any other form in terms of stereochemistry. The individual stereoisomers of the compounds of the description can, for example, be substantially free of other isomers, or they can be mixed, for example, as racemates or with all other selected stereoisomers. In some embodiments of the disclosure, the compounds of Formula (I) are enantiomers. In some embodiments, the compounds are the (S) - enantiomer. In some embodiments, the compounds are the (f) - enantiomer. In some embodiments, the compounds of Formula (I) can be enantiomers (+) or (-).
[00103] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical and chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reacting with a suitable optically active compound (eg chiral auxiliary, such as a chiral alcohol or Mosher acid chloride), separating the diastereomers and converting (eg, by hydrolysis) the individual diastereomers in the corresponding pure enantiomers. In addition, some of the compounds in the disclosure may be atropisomers (for example, substituted biaryls) and are considered to be part of this disclosure.
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Enantiomers can also be separated using a chiral HPLC column.
[00104] Furthermore, except where otherwise indicated, the present disclosure covers all geometric and positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, if a disclosure compound incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the disclosure. If the compound contains a double bond, the substituent can be in the E or Z configuration, except where otherwise indicated. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration, except where otherwise indicated.
[00105] The compounds of the disclosure, and the pharmaceutically acceptable salts and stereoisomers thereof, can exist in their tautomeric forms (for example, as an amide or imino ether). In addition, all ketoenolic and imine-enamine forms of the compounds are included in the disclosure. All such tautomeric forms are contemplated in the present invention as part of the present disclosure.
[00106] The use of the terms salt and the like, is applied equally to the salt of enantiomers, stereoisomers, rotamers, tautomers, positional isomers and racemates of the compounds of the invention.
[00107] The present disclosure relates to the compounds or pharmaceutically acceptable salts thereof, capable of activating PKR and / or PKM2, which are useful for the treatment of diseases and disorders associated with the modulation of a PKR and / or PKM2 enzyme . The description further relates to the compounds or their pharmaceutically acceptable salts which are useful for activating PKR and / or PKM2.
Disclosure compounds [00108] In one aspect of the disclosure, the compounds of Formula (I) are provided:
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(I), [00109] and pharmaceutically acceptable salts thereof, where Y, R ¹ , R ¹ ', R ² , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' are defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00110] Except where otherwise indicated in the present invention, each occurrence of R ⁷ and R ⁷ 'disclosed in the present invention, for each of R ⁶ , R ⁶ ', R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ , and R ¹¹ are independently selected from any of the possible cited values of R ⁷ and R ⁷ '. For example, the value R ⁷ may have a different value for each of R ⁶ , R ⁶ ', R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ , and R ¹¹ , except where otherwise indicated in the present invention.
[00111] In some embodiments, compounds of Formula I have an AC50 value of 40 μΜ for PKR activity determined by a luminescence assay (for example, that described in Example 47 below). In some embodiments, compounds of Formula I have an AC50 value <1.0 μΜ for PKR activity determined by a luminescence assay (for example, that described in Example 47 below). In some embodiments, the compounds of Formula I have an AC50 ^ 0.1 μΜ value for PKR activity determined by a luminescence assay (for example, that described in Example 47 below).
[00112] In some embodiments, the compounds of Formula I are those of Formula (Ia):
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(la), [00113] and pharmaceutically acceptable salts thereof, where R ¹ , R ¹ ', R ² , R ² ', R ³ , R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' are defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00114] In some embodiments, the compounds of Formula I are those of Formula (Ib):
[00115] and pharmaceutically acceptable salts thereof, where R ¹ , R ¹ , R ² , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ¹⁰ and R ¹⁰ are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00116] In some embodiments, the compounds of Formula I are those of Formula (Ic):
(lc), [00117] and pharmaceutically acceptable salts thereof, wherein R ¹ , R ¹ , R ² , R ² , R ³ and R ⁴ are as defined above and described in classes and subclasses of the present invention, both individually and as in combination.
[00118] In some embodiments, compounds of formula (lc) are
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29/138 provided, where:
[00119] each R ¹ , R ¹ ', R ² and R ² ' is independently -H, -alkyl (CiCe), aryl or heteroaryl, where each alkyl, aryl or heteroaryl is optionally substituted with one or more of -OR ⁵ ;
[00120] or R ¹ and R ¹ ', together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs);
[00121] R ³ is -H or -alkyl (C 1 -C);
[00122] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl ring;
[00123] R ⁴ is aryl or heteroaryl, with each aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of -R ⁵ and -OR ⁵ ;
[00124] each R ⁵ is, independently, -H or -alkyl (Ci-Ce), each alkyl being optionally substituted with one or more halogens;
[00125] or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ; and [00126] each R ⁶ is -alkyl (Ci-Ce);
[00127] In some embodiments, compounds of formula (Ic) are provided, in which:
[00128] each R ¹ , R ¹ , R ² and R ² is independently -H, phenyl, pyridyl, ethyl or methyl optionally substituted with -OR ⁵ ;
[00129] or R ¹ and R ¹ ', together with the atom to which they are attached, can combine to form a cyclopropyl ring;
[00130] R ³ is -H or methyl;
[00131] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a tetrahydrofuran, tetrahydropyran, 2,3-dihydrobenzofuran or morpholine;
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30/138 [00132] R ⁴ is phenyl, pyridyl, benzothiazolyl, benzofuranyl or beozoxazolyl, each phenyl, pyridyl or benzoxazolyl being optionally substituted with one or two substituents selected from the group consisting of -R ⁵ and -OR ⁵ ;
[00133] each R ⁵ is independently -H or methyl optionally substituted with two or more halogens;
[00134] or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring comprising two hetero atoms selected from the group consisting of O and N, optionally substituted with one or two R ⁶ ; and [00135] each R ⁶ is methyl.
[00136] In some embodiments, the compounds of Formula I are those of Formula (ld-1):
[00137] and pharmaceutically acceptable salts thereof, wherein Y, R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ , and R ¹¹ are as defined above and described in classes and subclasses of the present invention, either individually or in combination; and [00138] R ¹ is -alkyl (Cl-Ce), -alkenyl (C2-C6), -alkynyl (C2-C6), cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , 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 oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ,
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31/138
S (O) ₂ R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00139] each R ² and R ² 'is independently -H, -alkyl (C1-Ce), alkenyl (C ₂ -C6), -alkynyl (C ₂ -C6), -cycloalkyl (Cs-Cs), (cycloalkenyl C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ; [00140] or R ² and R ² ', together with the atom to which they are attached, can combine to form ring -cycloalkyl (Cs-Cs), heterocycle, spirocycle (Cs-Cs) or 5-spiro-heterocycle to 8 members;
[00141] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[00142] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-Ce), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00143] or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring; and
Petition 870180159548, of 12/06/2018, p. 94/201
32/138 [00144] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring.
[00145] In some embodiments, the compounds of Formula (ld-1) are those of Formula (la-1):
(la-1), [00146] and pharmaceutically acceptable salts thereof, where R ¹ , R ² , R ² ', R ³ , R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ , and R ¹¹ ' are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00147] In some embodiments, the compounds of Formula (ld-1) are those of Formula (lb-1):
[00148] and pharmaceutically acceptable salts thereof, where R ¹ , R ² , R ² ', R ³ , R ⁴ ', R ⁸ , R ⁸ ', R ¹⁰ , and R ¹⁰ are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00149] In some embodiments, the compounds of Formula (ld-1) are those of Formula (lc-1):
(lc-1),
Petition 870180159548, of 12/06/2018, p. 95/201
33/138 [00150] and pharmaceutically acceptable salts thereof, wherein R ¹ , R ² , R ² , R ³ and R ⁴ are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00151] In some embodiments, the compounds of Formula I are those of Formula (ld-2):
(ld-2), [00152] and pharmaceutically acceptable salts thereof, where Y, R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ , and R ¹¹ are as defined above and described in classes and subclasses of the present invention, either individually or in combination; and [00153] R ¹ is -alkyl (Ci-Ce), -alkenyl (C2-C6), -alkynyl (C2-C6), cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , 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 oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00154] each R ² and R ² 'is independently -H, -alkyl (Cl-Ce), alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), (cycloalkenyl C4- Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , -S (O) 2NR ⁵ R ⁵ ' , -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or -C (O) OR ⁵ , in
Petition 870180159548, of 12/06/2018, p. 96/201
34/138 that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , - NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ; [00155] or R ² and R ² ', together with the atom to which they are attached, can combine to form ring -cycloalkyl (Cs-Cs), heterocycle, spirocycle (Cs-Cs) or 5-spiro-heterocycle to 8 members;
[00156] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[00157] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-Ce), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00158] or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring; and [00159] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring.
[00160] In some embodiments, the compounds of Formula (ld-2) are those of Formula (la-2):
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(la-2), [00161] and pharmaceutically acceptable salts thereof, where R ¹ , R ² , R ² ', R ³ , R ⁴ , R ⁸ , R ⁸ ', R ⁹ , R ⁹ ', R ¹⁰ , R ¹⁰ ', R ¹¹ , and R ¹¹ ' are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00162] In some embodiments, the compounds of Formula (ld-2) are those of Formula (lb-2):
[00163] and pharmaceutically acceptable salts thereof, where R ¹ , R ² , R ² ', R ³ , R ⁴ ', R ⁸ , R ⁸ ', R ¹⁰ , and R ¹⁰ are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00164] In some embodiments, the compounds of Formula (ld-2) are those of Formula (lc-2):
(lc-2), [00165] and pharmaceutically acceptable salts thereof, where R ¹ , R ² , R ² , R ³ and R ⁴ are as defined above and described in classes and subclasses of the present invention, both individually and in combination.
[00166] In some modalities of Formulas (I), (Ia), (Ib) and (Ic),
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R ¹ and R ¹ 'are each, independently, hydrogen, optionally substituted (C 1 -C) alkyl (e.g., methyl optionally substituted with -OR ⁵ or ethyl), optionally substituted aryl (e.g., phenyl), or heteroaryl optionally substituted (e.g., pyridyl), or R ¹ and R ¹ 'are taken together with the atoms to which they are attached to form an optionally substituted (C3-C4) -cycloalkyl (e.g., cyclopropyl). In some embodiments, R ¹ and R ¹ 'are both hydrogen. In some embodiments, R ¹ and R ¹ 'are both optionally substituted alkyl (Ci-Ce). In some embodiments, one of R ¹ and R ¹ 'is optionally substituted -alkyl (Ci-Ce), optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, one of R ¹ and R ¹ 'is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, one of R ¹ and R ¹ 'is hydrogen. In some embodiments, one of R ¹ and R ¹ 'is optionally substituted -alkyl (Ci-Ce). In some embodiments, one of R ¹ and R ¹ 'is optionally substituted aryl. In some embodiments, one of R ¹ and R ¹ 'is optionally substituted heteroaryl. In some embodiments, R ¹ and R ¹ 'are taken together with the atoms to which they are attached to form an optionally substituted -cycloalkyl (C3-C4).
[00167] In some modalities of Formulas (ld-1), (la-1), (lb-1), (lc-1), (ld-2), (la-2), (lb-2) and (lc-2), R ¹ is optionally substituted -alkyl (C1-Ce) (eg, methyl optionally substituted with -OR ⁵ or ethyl), optionally substituted aryl (eg phenyl) or optionally substituted heteroaryl (eg pyridyl). In some embodiments, R ¹ is optionally substituted -alkyl (Ci-Ce). In some embodiments, R ¹ is optionally substituted aryl. In some embodiments, R ¹ is optionally substituted heteroaryl.
[00168] In some modalities of Formulas (I), (Ia), (Ib), (Ic), (Id-1), (la-1), (lb-1), (lc-1), (Id -2), (la-2), (lb-2) and (lc-2), R ² and R ² are, ca
Petition 870180159548, of 12/06/2018, p. 99/201
37/138 da um, independently hydrogen or optionally substituted (C 1 -C) alkyl (for example, methyl). In some embodiments, R ² and R ² 'are both hydrogen. In some embodiments, R ² and R ² 'are both optionally substituted alkyl (Ci-Ce). In some embodiments, one of R ² and R ² 'is hydrogen. In some embodiments, one of R ² and R ² 'is optionally substituted -alkyl (Ci-Ce).
[00169] In some modalities of Formulas (I), (Ia), (Ib), (Ic), (Id-1), (la-1), (lb-1), (lc-1), (Id -2), (la-2), (lb-2) and (lc-2), R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce) (for example, methyl). In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is optionally substituted -alkyl (Ci-Ce).
[00170] In some modalities of Formula (I), (la), (lb) and (Ic), R ³ and one of R ¹ or R ¹ 'are taken together with the atoms to which they are attached to form a optionally substituted 5- to 6-membered heterocyclic ring, optionally fused to an aryl ring (e.g., tetrahydrofuran, tetrahydropyran, 2,3-dihydrobenzofuran or morpholine). In some embodiments, R ³ and R ¹ combine to form an optionally substituted heterocyclic ring selected from the group consisting of tetrahydrofuran, tetrahydropyran, morpholine, dioxane and 2,3-dihydrobenzofuran.
[00171] In some modalities of Formula (ld-1), (la-1), (lb-1), (lc-1), (Id-2), (la-2), (lb-2) and (lc-2), R ³ and R ¹ are taken together with the atoms to which they are attached to form an optionally substituted 5- to 6-membered heterocyclic ring (eg, tetrahydrofuran, tetrahydropyran, 2,3 -dihydrobenzofuran or morpholine). In some embodiments, R ³ and R ¹ combine to form an optionally substituted heterocyclic ring selected from the group consisting of tetrahydrofuran, tetrahydropyran, morpholine, dioxane and 2,3-dihydrobenzofuran.
[00172] In some modalities of Formulas (I), (Ia), (Ib) and (Ic),
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R ¹ and R ¹ 'are each independently hydrogen or phenyl or optionally substituted pyridyl; R ² and R ² 'are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce). In some embodiments, R ¹ and R ¹ 'are each independently optionally substituted hydrogen or phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is hydrogen. In some embodiments, one of R ¹ and R ¹ 'is hydrogen and the other is optionally substituted phenyl; R ² and R ² 'are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce). In some embodiments, one of R ¹ and R ¹ 'is hydrogen and the other is optionally substituted pyridyl; R ² and R ² 'are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce). In some embodiments, R ¹ and R ¹ 'are each independently optionally substituted hydrogen or phenyl or pyridyl; R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen. In some embodiments, one of R ¹ and R ¹ 'is hydrogen and the other is optionally substituted phenyl; R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen. In some embodiments, one of R ¹ and R ¹ is hydrogen and the other is optionally substituted pyridyl; R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen.
[00173] In some modalities of Formulas (ld-1), (la-1), (lb-1), (lc-1), (Id-2), (la-2), (lb-2) and (lc-2), R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² 'are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce). In some embodiments, R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is hydrogen. In some embodiments, R ¹ is optionally phenyl or pyridyl
Petition 870180159548, of 12/06/2018, p. 101/201
39/138 replaced; R ² and R ² 'are each independently hydrogen or alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen. In some embodiments, R ¹ is optionally substituted phenyl; R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen. In some embodiments, R ¹ is optionally substituted pyridyl; R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted; and R ³ is hydrogen.
[00174] In some modalities of Formulas (I), (Ia), (Ib), (Ic), (Id-1), (la-1), (lb-1), (lc-1), (Id -2), (la-2), (lb-2) and (lc-2), R ⁴ is optionally substituted aryl (eg, phenyl) or heteroaryl (eg, pyridyl, benzofuranyl, benzoxazolyl or benzothiazolyl). In some embodiments, the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', - NR ⁵ S (O) R ⁵ ', C (O) R ⁵ and -C (O) OR ⁵ . In some embodiments, the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo-, -CN, -R ⁵ , -OR ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) NR ⁵ R ⁵ 'and -C (O) R ⁵ . In some embodiments, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of -R ⁵ and -OR ⁵ .
[00175] In some embodiments, R ⁴ is aryl or heteroaryl optionally substituted with one or more -R ⁵ or -OR ⁵ , or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, optionally form a heterocycloalkyl ring replaced with one or more R ⁶ groups. In some modalities, R ⁴ , including any substitution thereof, is selected from the group consisting of:
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[00176] In some embodiments, R ⁴ is a 6-membered aryl or heteroaryl substituted with two -R ⁵ , selected from the group consisting of OR ⁶ and -NR ⁶ R ⁶ ', in adjacent atoms of R ⁴ , which together with the atoms to which they are attached, form a heterocycloalkyl ring fused to R ⁴ which is optionally substituted with one or more R ⁶ selected from the group consisting of -H and -alkyl (Ci-Ce).
[00177] In some embodiments, each R ⁵ is independently H, -alkyl (Ci-Ce) (eg, methyl, optionally substituted with one or more halogens), halogen, -CN, -OR ⁶ , -SR ⁶ , - NO2, NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', -S (O) R ⁶ , -S (O) NR ⁶ R ⁶ ', -NR ⁶ S (O) ₂ R ⁶ ', NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ or -C (O) OR ⁶ . In some embodiments, each R ⁵ is independently -H or -alkyl (Ci-Ce) optionally substituted. [00178] In some embodiments, two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form an aryl ring optionally substituted with one or more R ⁶ . In some embodiments, two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ . In some embodiments, two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more Re. In some embodiments, two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ .
[00179] In some embodiments, each R ⁶ is independently H, -alkyl (Ci-Ce) (eg, methyl), halogen, -CN, -OR ⁷ , -SR ⁷ ,
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N0 ₂ , -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , -S (O) NR ⁷ R ⁷ ', NR ⁷ S (O) ₂ R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ or -C (O) OR ⁷ . In some embodiments, R ⁶ is -alkyl (Ci-Ce).
[00180] In some modalities, Y is a link.
[00181] In some embodiments, Y is -CR ⁵ R ⁵ '-.
[00182] In some embodiments, Y is -NR ⁵ (CR ⁵ R ⁵ ') t-.
[00183] In some modalities, Y is -O-.
[00184] Some non-limiting examples of the compounds of the description include:
Example Structure Name 1 o U o- ^s ^ Q j (S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3- hydroxy-2-pheni I propan-1 one 2 HO ^ -Q ^^ v ' ⁿ / q °) (R) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3- hydroxy-2-pheni I propan-1 one 3 ^a OH / ~ ^Q __ ₀ (N = ^N oq (R or S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3- hydroxy-2- (pyridin-2yl) propan-1-one 4 ^a OH (S or R) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3- hydroxy-2- (pyridin-2yl) propan-1-one
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Example Structure Name 5 ^{b 0} ) - ⁰ 0 — V- SN | N— / H _{N =} / h θ (R or S) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetra- hydro-2H-pyran-3yl) methanone 6 ^{b 0} ) - ⁰ / -r-'X O — V y — SN | N — Z ^Z HN = / o 0 (S or R) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetra- hydro-2H-pyran-3yl) methanone 7 ^F_ ('"the FI OH 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 8 zA ^ oπt rOΗΟ ^ Χ, Ν ^ / ^O 1 - (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 9 9'XX V rp ' ^s ' ° 0 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 10 HO. N ''Ί rVu HQx ^ x-X ^ N ^ ZO 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-(hydroxymethyl) -2-methylpropan-1 one 11 vO>O 1 - (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -2,2bis (hydroxymethyl) butan-1-one
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Example Structure Name 12 ° ~ l rOO (R) - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetrahydrofuran-3yl) methanone 13 / ° η rOO (S) - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetrahydrofuran-3yl) methanone 14 o C ° p ^s - X ⁿ í F— '-' 0 0 F (R) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran-3-yl) methanone 15 O' I-Nx, θ ^ / ^ s° Ύ T /> (5- (benzo [d] thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (tetrahydro2H-pyran-3-yl) methanone 16 ^ 0 ^ 0 ° / ^oh C / M “ ⁿ CX / ⁿ ^ F— '-' 0 0 F (S) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran-3-yl) methanone 17 O (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (1 (methoxymethyl) cyclopropyl) methanone 18 Ο, ζΧΟT rO '°O 1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) il) -3-hydroxy-2-phenyl I propan-1
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Example Structure Name 19 O° Ύ T /> 1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2,2-dimethylpropan1-one 20 ο _χΧ C ^ ' ^S W 0 (R) - (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 H) yl) (tetrahydrofuran-3yl) methanone 21 0 ,, ^δ γ% Λ) ° I1F 3-hydroxy-2,2-di methyl-1 - (5 - ((2methylbenzo [d] oxazol-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) il) propan-1-one 22 ROΗΟ ^ ζ ^, Ν ^ /O 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3hydroxypropan-1-one 23 ^ z (a rZjVÕH O (R) -1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -il) -3-hydroxy butan-1-one 24 ^rO ' ^χ γ ^χχ γ' ^Ν '^ OH o (S) -1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -il) -3-hydroxy butan-1-one 25 rO '°Η ° -γ T 1 - (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-3methylbutan-1-one
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Example Structure Name 26 / —X. ⁰ P ^- V- SN | N— / OH F- <^ = ⁷ 0 0 ^F (+/-) (2S, 3Re2R, 3S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylbutan-1-one 27 F o ^F U _o - <y - ^N CX - / oh = / o ^H (+/-) (2R, 3Re2S, 3S) -1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) - 3-hydroxy-2-phenylbutan-1-one 28 p— ('y — sn | n — '1,! F— (o ^^ ⁷ Λ-ΤΟΗ F / = < ^X (S) -1- (5 - ((4-(difluormethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-3methyl-2-phenylbutan-1-one 29 OΗΟ '' '0'ή' .[A Zn 'PL ü, θχ, χ- ^ S '° Ϊ1> (S) -1 - (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2 -phen I propan-1 ona 30 O ' ⁿ / q ^ (R) -1 - (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2 -phen I propan-1 ona 31 Λ θ / 9 o — e y- sn | n — y F- ( = / o) d ^OH (S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 32 o T rO ^{H HO} / d ^N ^ 0 (S) -1- (5 - ((2,2-dimethyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrole [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenyl I propan-1 one
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Example Structure Name 33 ^c nh / j ^_N OC ^N_ i ^H (S or R) - (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1 H) yl) (tetrahydro-2H-pyran-3yl) methanone 34 ^c (R or S) - (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1 H) yl) (tetrahydro-2H-pyran-3yl) methanone 35 “ .XX / ho. rXj ^{0 H} cor (S) -1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenyl I propan-1 one 36 / V xxO (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (1- (methoxymethyl) cyclopropyl) methanone 37 ..Cô X Ψ ' ⁸ “o 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2,2-dimethylpropane-one 38 / W 9. XX) XfV »'y-vJV _Η ° γ j 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-3-methyl butan-1 one
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Example Structure Name 39 ° Λ Xa0 ^O (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetrahydrofuran-3yl) methanone 40 o ho ^ Aa ^ o <N „zP ° ' ^S TA I 3-hydroxy-1- (5 - ((4methoxyphenyl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4-c] pyrrole 2 (1H) -yl) propan-1-one 41 ^{d F} ^ / = ° ΑγΛ O ^οΗ υ ^Η ^ ^Ν νΧ / ^Ν Λ ^ ^Γ Α HO— * N = / (S or R) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-(pi ridi n-2-i l) propan-1-one 42 ^{d F} ^ _ / = °, P O - /> - SN Γ n — z - v VjZ η HO— 'N = / (Rou S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-(pi ridi n-2-i l) propan-1-one 43 THE .° Ύ T /> (5- (benzo [d] thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (2,3-dihydrobenzofuran-3yl) methanone 44 ^{and 0} .— 0 V-7 S-nAA = N o Ό (R or S) - (5- (pyridin-2ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 H) yl) (tetrahydro-2H-pyran-3yl ) methanone 45 ^and o Ç ^o c Άδ- ^Ν ΟΟ ^Ν y ^h = N o O (S or R) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetrahydro-2H-pyran-3yl) methanone
Petition 870180159548, of 12/06/2018, p. 110/201
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Example Structure Name 46 o HO ^XX y ^< 'N''' h <0 3-hydroxy-1- (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole-2 (1 H) yl) -2-phenyl I propan-1-one 47 O^ CO (5 - ((4-methyl-3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole -2 (1 H) yl) (tetrahydrofuran-3yl) methanone 48 OHO '^ V ^ N'X.[A Zn 'PL ü, θχ, χ- ^ S '° Ϊ1> 1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenyl I propan-1 49 _ / V p— ('y— sn n—% Η ^λ = ^λ Ó W 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 50 N = % / P C à— SN II N — y η .. „ _χ / = <OH (2S) -3-hydroxy-2-phenyl I-1 - [5-(pyridine-3-sulfonyl) 1H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrol-2-yl] propan1-one 51 Z * ^- h ^_N JL ⁿ ^ C = / β Υ .., _χ / = <OH (2S) -3-hydroxy-2-phenyl I-1 - [5-(pyridine-2-sulfonyl) 1H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrol-2-yl] propan1-one
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Example Structure Name 52 ^F / ^N = S / F o d ^0H (2S) -3-hydroxy-2-phenyl-1- (5 - {[6-(trifluormethyl) pyridin-3yl] sulfonyl} -1 H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrol-2-yl) propan1-one 53 0'V-Nx 1 3-methoxy-1 - (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole-2 (1 H) yl) propan-1-one 54 O- <! V — SN | N — K ^F_ o F OH 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3hydroxypropan-1-one 55 0ο ΎΎ5 (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran-3-yl) methanone 56 OVA° Υη (5- (benzo [d] thiazol-6-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (morpholin-3yl) methanone 57 0 or ³ X0 1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) il) -3-methoxypropan-1-one 58 0° TT5 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3methoxypropan-1-one
0s ^to compounds 3 and 4 are enantiomers, but absolute stereochemistry is undetermined (*); ^b Compounds 5 and 6 are enantiomers, however the absolute stereochemistry is undetermined (*); Compounds 33
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50/138 and 34 are enantiomers, are enantiomers, however the absolute stereochemistry is undetermined (*); ^d Compounds 41 and 42 are enantiomers, however the absolute stereochemistry is undetermined (*); ® Compounds 44 and 45 are enantiomers, however the absolute stereochemistry is undetermined (*).
Method for synthesizing the compounds [00185] The compounds of the present disclosure can be produced by various methods, including standard chemistry. Suitable synthetic routes are shown in the Schemes provided below. [00186] The compounds of Formula (I) can be prepared by methods known in the art of organic synthesis, as shown in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used, when necessary, according to general chemistry principles. Protective groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and the order of their execution, must be consistent with the preparation of the compounds of Formula (I).
[00187] Those skilled in the art will recognize whether there is a stereocenter in the compounds of Formula (I). When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolving the final product or any convenient intermediary. For example, the enantiomerically pure compounds of Formula (I) can be prepared using enantiomerically pure chiral building blocks. Alternatively, racemic mixtures of the final compounds or a mixture
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51/138 racemic texture of an advanced intermediate can be subjected to chiral purification as described later in this document to provide the desired enantiomerically pure final intermediates or compounds. In cases where an advanced intermediate is purified on its individual enantiomers, each individual enantiomer can be used separately to produce the enantiomerically pure compounds of Formula (I). Resolution of the final product, an intermediate, or a starting material can be carried out by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen and L. N. Mander (Wiley-lnterscience, 1994). The absolute stereochemistry of the compounds obtained by chiral resolution or chiral purification may or may not be determined. The enantiomerically pure compounds with undetermined absolute stereochemistry were designed as a single arbitrarily chosen enantiomer and are marked with an asterisk (*) on the chiral carbon in the present invention.
[00188] The compounds described herein can be produced from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes.
Preparation of compounds [00189] The compounds of the present disclosure can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as understood by those skilled in the art. Preferred methods include, but are not limited to, those methods described in the synthetic examples below
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52/138 xo.
[00190] It should be understood that, in the description and formula shown above, the various groups Y, R ¹ , R ¹ , R ² , R ² , R ³ , R ⁴ , R ⁸ , R ⁸ , R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ , R ¹¹ and the other variables are as defined above, except where otherwise indicated.
Methods of identification and characterization of PKR-activating compounds [00191] In certain embodiments, specific PKR-Activating Compounds (including compounds of Formula (I), as well as additional examples of such compounds) can be identified using the PKR Protocol Luminescence Assay described in Example 47. PKR Activating Compounds can be selected by obtaining and analyzing data from a dosage response curve for a compound according to the Luminescence Assay Protocol. FIGURE 1 shows an exemplary dosage response curve for the compounds shown in the present invention. The AC50 and MAX% Fold values are independent of each other (that is, the value of one does not affect the other). In some embodiments, PKR Activating Compounds can be selected based on the% increase in times at a given concentration of the compound (for example, 1.54 μΜ) in the Luminescence Assay Protocol. The% increase in times at a given concentration is a value that will be affected by both power (AC50) and activity (MAX% Fold).
[00192] In some embodiments, the PKR Activating Compound can be selected as a compound of Formula (I) having a value% at times in the concentration of 1.54 μΜ of the compound (% Fold @ 1.54 μΜ) of at least 75% (for example, 75% -500%, 75% -250% or 250% -500%) in an assay (for example, the Example 47 Luminescence Assay) using a PKR enzyme (for example, a PKR enzyme wild type or a clinicamen mutant PKR
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53/138 te relevant, such as the PKR G332S or PKR R510Q).
[00193] In some embodiments, PKR Activating Compounds have a% Fold @ 1.54 μΜ of at least 75% (for example, 75% -500% or 250% -500%) obtained using the Assay Protocol Luminescence Test of Example 47. PKR activating compounds can be identified according to Example 47 by a method comprising the steps of (a) incubating a mixture of phosphoenolpyruvic acid (PEP) and a PKR enzyme (for example, PKR type wild-type or a clinically relevant mutant PKR enzyme) with a test compound at a concentration of 1.54 μΜ; (b) adding adenosine-5'-diphosphate (ADP) and a luminescent kinase reporter composition (e.g. Gio Plus kinase) to the mixture from step (a) under conditions effective to induce luminescence in the presence of a test compound that is a PKR Activating Compound; (c) measure the luminescence values of the mixture obtained in step (b); (d) determine the value of% Fold @ 1.54 μΜ for the test compound; and (e) identifying the test compound as a PKR Activating Compound when the test compound has a% Fold @ 1.54 μΜ value of at least 75% (e.g., 75-500% or 250-500%).
Methods of using the disclosed compounds [00194] In another aspect, the present disclosure relates to a method of activating PKR, including methods of treating a disease or disorder in a patient by administering a therapeutically effective amount of a PKR Activation Compound presented in this document. For example, the method may comprise administering to a patient in need of a therapeutically effective amount of a compound of Formula (I). In some embodiments, the disease or disorder is selected from the group consisting of PKD, SCD (eg, sickle cell anemia) and thalassemia (eg, beta-thalassemia). A treatment method
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54/138 of a patient diagnosed with a disease, selected from the group consisting of PKD, SCD and thalassemia, comprises administering a therapeutically effective amount of a compound disclosed in the present invention, including a therapeutically effective amount of a Formula PKR Activating Compound (I). A method of treating PKD comprises administering a therapeutically effective amount of a compound disclosed in the present invention, including a PKR Activating Compound of Formula (I). A method of treating SCD comprises administering a therapeutically effective amount of a compound disclosed in the present invention, including a PKR Activating Compound of Formula (I). A method of treating thalassemia comprises administering a therapeutically effective amount of a compound disclosed in the present invention, including a PKR Activating Compound of Formula (I).
[00195] In other embodiments, the method comprises administering a therapeutically effective amount of a compound of Formula (I) for the treatment of a patient diagnosed with a condition selected from the group consisting of: Hereditary non-spherocytic hemolytic anemia, hemolytic anemia (eg example, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (eg, congenital anemias (eg, enzymes) or enzymes anemia of chronic diseases. In some modalities, the disease or disorder is hereditary non-spherocytic hemolytic anemia. In some embodiments, the disease or disorder is SCD (eg, sickle cell anemia) or thalassemia (eg, beta-thalassemia). In some embodiments, the disease or disorder is hemolytic anemia (for example, in a patient diagnosed with PKD). In some modalities, the disease or disorder is beta
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55/138 thalassemia. In some embodiments, the disease or disorder is SCD. [00196] Another aspect of the disclosure concerns the use of a PKR Activating Compound to treat a disease or disorder associated with PKR and / or PKM2 modulation. The present disclosure also relates to the use of a PKR and / or PKM2 activator for the preparation of a drug used to treat a disease or condition, the drug comprising a compound of formula (I). In other embodiments, the present disclosure relates to the use of a PKR and / or PKM2 activator for the preparation of a drug used to treat a disease or condition, the drug comprising a compound of formula (I). The method may comprise administering to a patient in need of treatment for diseases or disorders associated with PKR and / or PKM2 modulation an effective amount of the compositions and / or compounds of Formula (I). The method may comprise the use of a PKR Activating Compound and / or a compound of Formula (I) in the preparation of a medicament for the treatment of diseases or disorders associated with the modulation (e.g., activation) of PKR and / or PKM2 . [00197] In another aspect, the present disclosure relates to the use of a PKR Activating Compound to treat a disease or disorder associated with the activation of PKR and / or PKM2. The use may comprise administering to a patient in need of treatment for diseases or disorders associated with PKR and / or PKM2 modulation an effective amount of the compositions and / or compounds of Formula (I). In some embodiments, the disease or disorder is selected from the group consisting of SCD, sickle cell anemia, thalassemia (eg, beta-thalassemia), hereditary non-spherocytic hemolytic anemia, hemolytic anemia (eg, chronic hemolytic anemia caused by deficiency of phosphoglycerate kinase), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or Bas syndrome
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56/138 sen-Kornzweig), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (eg, congenital anemias (eg, enzyme disease)) or anemia of chronic diseases.
[00198] In another aspect, the present disclosure relates to a method of activating PKR and / or PKM2. The method involves administering to a patient who is in need of an effective amount of a compound of Formula (I).
[00199] In another aspect, the present disclosure relates to a method for increasing the life span of red blood cells in a patient or ex vivo using an effective amount of a PKR activating compound, such as a compound of Formula (I), in preparation of a drug or composition (eg, reagent) to increase the lifespan of red blood cells in a patient or ex vivo using an effective amount of a PKR activating compound, such as Formula (I).
[00200] In another aspect, the present disclosure relates to a method of regulating the levels of 2,3-diphosphoglycerate in the blood in a patient or ex vivo using an effective amount of a PKR activating compound, such as a compound formula (I), in the preparation of a drug or composition (eg, reagent) to regulate the levels of 2,3-diphosphoglycerate in the blood in a patient or ex vivo.
[00201] In another aspect, the present disclosure relates to a method of regulating ATP levels in the blood in a patient or ex vivo using an effective amount of a PKR activating compound, such as a Formula of compound (I), in the preparation of a drug or composition (eg reagent) to regulate blood levels of ATP in a patient or ex vivo.
[00202] In another aspect, the present disclosure relates to a method for treating a disease or disorder associated with decreased activity
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57/138 outflow of PKR and / or PKM2 in an individual who needs it, the method comprising administering to a patient who needs it an effective amount of a compound of Formula (I). In some embodiments, the disease or disorder is selected from the group consisting of PKD, SCD, sickle cell anemia, thalassemia (eg, beta-thalassemia), hereditary non-spherocytic hemolytic anemia, hemolytic anemia (eg, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or BassenKornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (eg, congenital anemia (eg, enzymeopathies)) or anemia of chronic diseases.
[00203] In another embodiment, the present disclosure relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier used for the treatment of SCD, sickle cell anemia, thalassemia (eg beta-thalassemia), hereditary non-spherocytic hemolytic anemia, hemolytic anemia (eg, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or Bassen-Kornzweigox syndrome), nocturnal hemoglobinuria acquired haemolytic anemia (eg, congenital anemias (eg, enzyme disorders)) or anemia of chronic diseases.
[00204] Another aspect of the disclosure relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
[00205] In another aspect, the present disclosure relates to a method of treating cancer. The method comprises administering to a patient in need of cancer treatment an effective amount of a compound of formula (I), or a pharmaceutically salt
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58/138 acceptable.
[00206] In another aspect, the present disclosure relates to a method for the manufacture of a medicament to treat a disease or condition mediated by PKR and / or PKM2, the medicament comprising a compound of Formula (I). The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90% or from about 1% to about 20% of the disclosed compound by weight or volume.
[00207] The pharmaceutically acceptable carrier may also include an excipient, diluent or surfactant. Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, for example, purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters, triglycerides or mixtures thereof, omega3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol , sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for pills, too; c) a binder, for example, magnesium and aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn-based sweeteners, natural and synthetic gums , such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone and if desired; d) a disintegration
Petition 870180159548, of 12/06/2018, p. 121/201
59/138 t, for example, starches, agar, methylcellulose, bentonite, xanthan gum, algic acid or its sodium salt or effervescent mixtures; e) absorbent, color, flavor and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproil 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that improves the absorption of the compound, such as cyclodextrin, hydroxypropylcyclodextrin, PEG400 and PEG200.
[00208] Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in the liquid before injection. Liquid compositions, and particularly injectable ones, can, for example, be prepared by dissolving, dispersing etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form an isotonic injectable solution or suspension. Proteins such as albumin, chylomicron particles and whey proteins can be used to solubilize the compounds shown. The compounds shown can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous drug solution to a lipid layer to encapsulate the drug, as described in US Patent No. 5,262,564 which is incorporated herein by reference in its entirety. The compounds shown
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60/138 can also be formulated as a suppository that can be prepared from emulsions or fatty suspensions; using polyalkylene glycols, like propylene glycol, as the vehicle.
[00209] The compounds shown can also be released by using monoclonal antibodies as individual vehicles, to which the compounds shown are coupled. The compounds shown can also be coupled with soluble polymers, such as target drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylspanamidophenol or polyethyleneoxidepolylysine replaced by palmitoyl residues. In addition, the compounds shown can be coupled to a class of biodegradable polymers useful in obtaining the controlled release of a drug, for example, polylactic acid, polypsilon-caprolactone, polyhydroxybutyric acid, polyiortoesters, polyacetals, polyhydropyranes, polyacrylates and hydrogel copolymers in crosslinked or unsympathetic block. In one embodiment, the compounds shown are not covalently bound to a polymer, for example, to a polycarboxylic acid polymer, or to a polyacrylate.
[00210] The administration of the compounds shown can be carried out by any method of administration for therapeutic agents. These modes include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration.
[00211] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid or liquid form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions , syrups, powders, liquids, suspensions or the like, sometimes in unit dosages and consistent with pharmaceutical practices
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Conventional 61/138. Likewise, they can also be administered in an intravenous (either bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, and using forms well known to those skilled in the pharmaceutical art.
[00212] The compounds of the present disclosure can be administered in amounts effective to treat a disease or disorder in individuals. The dosage regimen using the disclosed compound is selected according to a variety of factors including the patient's type, species, age, weight, sex and medical condition; the severity of the condition to be treated; the route of administration; the patient's kidney or liver function; and the specific compound shown used. A doctor or veterinarian skilled in the art can readily determine and prescribe the effective amount of the drug needed to prevent, contain or halt the progress of the condition.
[00213] The effective dosage amounts of the compounds shown, when used for the indicated effects, range from about 0.5 mg to about 5,000 mg of the disclosed compound, as needed to treat the condition. Compositions for use in vivo or in vitro may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compound, or in a range from one quantity to another quantity in the dose list. In one embodiment, the compositions are in the form of a grooved tablet.
[00214] Although the following modalities listed are not limiting, they exemplify certain aspects of the present disclosure: [00215] 1. A compound of formula I:
Petition 870180159548, of 12/06/2018, p. 124/201
62/138 [00216] or a pharmaceutically acceptable salt thereof, [00217] where:
[00218] Y is a bond, - (CR ⁵ R ⁵ ') t-, -NR ⁵ (CR ⁵ R ⁵ ') t- or -O-;
[00219] each R ¹ , R ¹ ', R ² and R ² ' is independently -H, -alkyl (CiCe), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs ), (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, - R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S ( O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ; [00220] or R ¹ and R ¹ ', or R ² and R ² ', together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs- Cs) or 5- to 8-membered spiroheterocycle;
[00221] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[00222] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00223] or R ² and R ³ , together with the atoms to which they are
Petition 870180159548, of 12/06/2018, p. 125/201
63/138 bonded, can combine to form a 5- to 8-membered heterocyclic ring;
[00224] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
[00225] R ⁴ is -H, -alkyl (C1-C), -alkenyl (C2-C6), -alkynyl (C2Ce), -cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl , heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , in that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , - NO2, -NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S ( O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00226] each R ⁵ and R ⁵ 'is independently, in each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O ) 2NR ⁶ R ⁶ ', -S (O) R ⁶ , S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O ) R ⁶ or -C (O) OR ⁶ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁶ , -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', S (O) R ⁶ , -S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ and -C (O) OR ⁶ ; [00227] or two R ⁵ at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵
Petition 870180159548, of 12/06/2018, p. 126/201
64/138 at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[00228] or two R ⁵ 'at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[00229] each R ⁶ and R ⁶ 'is independently, in each occurrence, H, -alkyl (C1-Ce), -alkenyl (C2-Ce), -alquinyl (C2-Ce), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O ) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O ) R ⁷ or -C (O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) ₂ R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , - S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C (O) OR ⁷ ; [00230] each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C ₂ -C6), - alkynyl (C ₂ -Ce), -cycloalkyl (CsCs) , -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO ₂ , -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, al
Petition 870180159548, of 12/06/2018, p. 127/201
65/138 kenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH ₂ , - S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
[00231] each R ⁸ , R ⁸ , R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' is independently, in each occurrence, -H, -alkyl (Ci-Ce), -alkenyl ( C2-C6), alkynyl (C2-C6), -cycloalkyl (Cs-Cs) or -cycloalkenyl (C4-Cs), where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more substituents selected from group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , -S (O) NR ⁷ R ⁷ ', -NR ⁷ S (O) ₂ R ⁷ ', NR ⁷ S (O) R ⁷ , -C (O) R ⁷ and -C (O) OR ⁷ ;
[00232] and [00233] teO, 1,2 or 3.
[00234] 2. A compound of modality 1, which has Formula (Ia):
(Ia);
[00235] or a pharmaceutically acceptable salt thereof.
[00236] 3. The compound of modality 1 or 2, which has Formula (Ib):
[00237] or a pharmaceutically acceptable salt thereof.
[00238] 4. The compound according to any of the modalities
Petition 870180159548, of 12/06/2018, p. 128/201
66/138 from 1 to 3, which has the formula (lc):
(lc);
[00239] or a pharmaceutically acceptable salt thereof.
[00240] 5. The compound of any one of modalities 1 to 4, wherein R ¹ and R ¹ 'are each independently hydrogen, optionally substituted alkyl (CiCe), optionally substituted aryl or optionally substituted heteroaryl, or where R ¹ and R ¹ ', together with the atoms to which they are attached, form an optionally substituted -cycloalkyl (C3C4).
[00241] 6. The compound of any of the modalities 1 to 5, in which R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted.
[00242] 7. The compound according to any of modalities 1 to 6, where R ³ is hydrogen or -alkyl (Ci-Ce) optionally substituted.
[00243] 8. The compound according to any of modalities 1 to 7, where R ³ is hydrogen.
[00244] 9. The compound according to any one of modalities 1 to 4, in which R ³ and one of R ¹ or R ¹ , taken together with the atoms to which they are attached, form a heterocyclic ring from 5 to 6 members optionally replaced.
[00245] 10. The compound according to any one of modalities 1 to 4, wherein R ¹ and R ¹ 'are each independently hydrogen or phenyl or optionally substituted pyridyl; R ² and R ² 'are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (C1Ce).
[00246] 11.0 composed according to any of the modali
Petition 870180159548, of 12/06/2018, p. 129/201
67/138 activities 1 to 4, wherein R ¹ and R ¹ 'are each independently optionally substituted hydrogen or phenyl or pyridyl; R ² and R ² 'are each independently hydrogen; and R ³ is hydrogen.
[00247] 12. The compound according to any one of modalities 1 to 4, wherein R ⁴ is optionally substituted aryl or heteroaryl.
[00248] 13. The compound according to modality 12, in which the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -S (O) ₂ NR ⁵ R ⁵ ', -S (O) NR ⁵ R ⁵ ' and -C (O) R ⁵ .
[00249] 14. The compound according to modality 12, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form an aryl ring optionally substituted with one or more R ⁶ .
[00250] 15. The compound according to modality 12, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ .
[00251] 16. The compound according to modality 12, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more Re.
[00252] 17. The compound according to modality 12, in which two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ .
[00253] 18. The compound according to modality 1, where Y is -CR ⁵ R ⁵ '-.
[00254] 19. The compound according to modality 1, where Y is -NR ⁵ (CR ⁵ R ⁵ ') t-.
Petition 870180159548, of 12/06/2018, p. 130/201
68/138 [00255] 20. The compound according to modality 1, where Y is -O-.
[00256] 21. The compound according to Formula (Id-1):
[00257] or a pharmaceutically acceptable salt thereof, [00258] where:
[00259] Y is a bond, - (CR ⁵ R ⁵ ') t-, -NR ⁵ (CR ⁵ R ⁵ ') t- or -O-;
[00260] R ¹ is -alkyl (Ci-Ce), -alkenyl (C2-C6), -alkynyl (C2-C6), cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl , halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) ₂ R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , in that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , - NO2, -NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S ( O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00261] each R ² and R ² 'is independently -H, -alkyl (C1-C6), alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), (C4- cycloalkenyl) Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or -C ( O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ;
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69/138 or R ² and R ² ', together with the atom to which they are attached, can combine to form cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs-Cs) or spiroheterocycle from 5 to 8 members;
[00262] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[00263] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-Ce), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00264] or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring;
[00265] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
[00266] R ⁴ is -H, -alkyl (Ci-Ce), -alkenyl (C2-Ce), -alkynyl (C2Ce), -cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl , heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , -S (O) ₂ R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , 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 oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO ₂ , -NR ⁵ R ⁵ , S (O) ₂ R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ',
Petition 870180159548, of 12/06/2018, p. 132/201
70/138
NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00267] each R ⁵ and R ⁵ 'is independently, in each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (C3-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O ) ₂ NR ⁶ R ⁶ ', -S (O) R ⁶ , S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C ( O) R ⁶ or -C (O) OR ⁶ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN , -R ⁶ , -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', S (O) R ⁶ , - S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ and -C (O) OR ⁶ ; [00268] or two R ⁵ at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (C ₃ -Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[00269] or two R ⁵ 'at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ 'in adjacent atoms, together with the atoms to which they are attached, form a
Petition 870180159548, of 12/06/2018, p. 133/201
71/138 heterocycloalkyl ring optionally substituted with one or more R ⁶ ; [00270] each R ⁶ and R ⁶ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O ) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O ) R ⁷ or -C (O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , -S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C (O) OR ⁷ ; [00271] each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), - alkynyl (C2-C6), -cycloalkyl (C3Cs), - cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO2, -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S ( O) H, -S (O) NH ₂ , NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
[00272] each R ⁸ , R ⁸ , R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' is independently, in each occurrence, -H, -alkyl (Ci-Ce), -alkenyl ( C2-C6), alkynyl (C2-C6), -cycloalkyl (Cs-Cs) or -cycloalkenyl (C4-Cs), where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more substituents selected from group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , -S (O) NR ⁷ R ⁷ ', -NR ⁷ S (O) ₂ R ⁷ ', NR ⁷ S (O) R ⁷ , -C (O) R ⁷ and -C (O) OR ⁷ ;
[00273] and
Petition 870180159548, of 12/06/2018, p. 134/201
72/138 [00274] t is 0, 1,2 or 3.
[00275] 22. The compound according to modality 21, which has the
Formula (la-1):
(la-1);
[00276] or a pharmaceutically acceptable salt thereof.
[00277] 23. The compound according to modalities 21 or 22, which has the Formula (lb-1):
[00278] or a pharmaceutically acceptable salt thereof.
[00279] 24. The compound according to any of the modalities 21 to 23, which has the Formula (lc-1):
(lc-1);
[00280] or a pharmaceutically acceptable salt thereof.
[00281] 25. The compound according to any of the modalities 21 to 24, in R ¹ is optionally substituted -alkyl (Ci-Ce), optionally substituted aryl or optionally substituted heteroaryl.
[00282] 26. The compound of any of the modalities 21 to 25, in which R ² and R ² 'are each independently hydrogen or optionally substituted (C 1 -C) alkyl.
[00283] 27. The compound according to any of the modali
Petition 870180159548, of 12/06/2018, p. 135/201
73/138 activities 21 to 26, where R ³ is hydrogen or optionally substituted -alkyl (Ci-Ce).
[00284] 28. The compound according to any of the modalities 21 to 27, where R ³ is hydrogen.
[00285] 29. The compound according to any of the modalities 21 to 24, in which R ³ and R ¹ , taken together with the atoms to which they are attached, form an optionally substituted 5- to 6-membered heterocyclic ring.
[00286] 30. The compound according to any one of embodiments 21 to 24, wherein R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce).
[00287] 31. The compound according to any of the modalities 21 to 24, wherein R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is hydrogen.
[00288] 32. The compound according to any of the modalities 21 to 31, wherein R ⁴ is optionally substituted aryl or heteroaryl.
[00289] 33. The compound according to modality 32, in which the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -S (O) ₂ NR ⁵ R ⁵ ', -S (O) NR ⁵ R ⁵ ' and -C (O) R ⁵ .
[00290] 34. The compound according to modality 32, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form an aryl ring optionally substituted with one or more R ⁶ .
[00291] 35. The compound according to modality 32, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form an optionally substituted heteroaryl ring
Petition 870180159548, of 12/06/2018, p. 136/201
74/138 with one or more R ⁶ .
[00292] 36. The compound according to modality 32, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more Re.
[00293] 37. The compound according to modality 32, in which two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ .
[00294] 38. The compound according to modality 21, where Y is -CR ⁵ R ⁵ '-.
[00295] 39. The compound according to embodiment 21, where Y is -NR ⁵ (CR ⁵ R ⁵ ') t-.
[00296] 40. The compound according to modality 21, where Y is -O-.
[00297] 41. A compound according to Formula (ld-2):
[00298] or a pharmaceutically acceptable salt thereof, [00299] where:
[00300] Y is a bond, - (CR ⁵ R ⁵ ') t-, -NR ⁵ (CR ⁵ R ⁵ ') t- or -O-;
[00301] R ¹ is -alkyl (Ci-Ce), -alkenyl (Cs-Ce), -alquinyl (Cs-Ce), cycloalkyl (Cs-Cs), - (cycloalkenyl C4-Cs), heterocyclyl, aryl, heteroaryl , halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group con
Petition 870180159548, of 12/06/2018, p. 137/201
75/138 working in oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , S (O) ₂ R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and - C (O) OR ⁵ ;
[00302] each R ² and R ² 'is independently -H, -alkyl (C1-C6), alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4 -Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ' , -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', NR ⁵ S (O) ₂ R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', NR ⁵ S (O) ₂ R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ , and -C (O) OR ⁵ ; or R ² and R ² , together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs-Csj or a 5- to 8-membered spiroheterocycle;
[00303] or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
[00304] R ³ is independently -H, -alkyl (Ci-Ce), -alkenyl (C2Ce), -alkynyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or - C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , - OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00305] or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5 to 5-membered heterocyclic ring
Petition 870180159548, of 12/06/2018, p. 138/201
76/138 members;
[00306] or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
[00307] R ⁴ is -H, -alkyl (C1-C), -alkenyl (C2-C6), -alkynyl (C2Ce), -cycloalkyl (Cs-Cs), - (C4-Cs cycloalkenyl), heterocyclyl, aryl , heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , in that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , - NO2, -NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S ( O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
[00308] each R ⁵ and R ⁵ 'is independently, in each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O ) 2NR ⁶ R ⁶ ', -S (O) R ⁶ , S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O ) R ⁶ or -C (O) OR ⁶ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁶ , -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', S (O) R ⁶ , -S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) 2R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ and -C (O) OR ⁶ ; [00309] or two R ⁵ at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ on adjacent atoms, together with the atoms to which they are
Petition 870180159548, of 12/06/2018, p. 139/201
77/138 so attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[00310] or two R ⁵ 'at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
[00311] each R ⁶ and R ⁶ 'is independently, in each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-Ce), -alquinyl (C2-Ce), -cycloalkyl (Cs-Cs) , - (C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O ) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O ) R ⁷ or -C (O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) ₂ R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , - S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) 2R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C (O) OR ⁷ ; [00312] each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C ₂ -C6), - alkynyl (C ₂ -Ce), -cycloalkyl (CsCs) , -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO ₂ , -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or he
Petition 870180159548, of 12/06/2018, p. 140/201
78/138 teroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH2, -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
[00313] each R ⁸ , R ⁸ , R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ ', R ¹¹ and R ¹¹ ' is independently, in each occurrence, -H, -alkyl (Ci-Ce), -alkenyl ( C2-Ce), alkynyl (C2-Ce), -cycloalkyl (Cs-Cs) or -cycloalkenyl (C4-Cs), where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , -S (O) NR ⁷ R ⁷ ', -NR ⁷ S (O) ₂ R ⁷ ', NR ⁷ S (O) R ⁷ , -C (O) R ⁷ and -C (O) OR ⁷ ;
[00314] and [00315] téO, 1,2 or 3.
[00316] 42. The compound according to modality 41, which has the
Formula (la-2):
(la-2);
[00317] or a pharmaceutically acceptable salt thereof.
[00318] 43. The compound according to modalities 41 or 42, which has the Formula (lb-2):
R ⁸ R ¹⁰
(lb-2);
[00319] or a pharmaceutically acceptable salt thereof.
[00320] 44. The compound according to any of the modali
Petition 870180159548, of 12/06/2018, p. 141/201
79/138 activities 41 to 43, which has the Formula (lc-2):
(lc-2);
[00321] or a pharmaceutically acceptable salt thereof.
[00322] 45. The compound according to any one of embodiments 41 to 44, wherein R ¹ is optionally substituted -alkyl (Ci-Ce), optionally substituted aryl or optionally substituted heteroaryl.
[00323] 46. The compound according to any one of modalities 41 to 45, wherein R ² and R ² 'are each independently hydrogen or -alkyl (C 1 -C) optionally substituted.
[00324] 47. The compound according to any one of modalities 41 to 46, in which R ³ is hydrogen or -alkyl (Ci-Ce) optionally substituted.
[00325] 48. The compound according to any of modalities 41 to 47, where R ³ is hydrogen.
[00326] 49. The compound according to any one of modalities 41 to 44, wherein R ³ and R ¹ , taken together with the atoms to which they are attached, form an optionally substituted 5- to 6-membered heterocyclic ring.
[00327] 50. The compound according to any one of embodiments 41 to 44, wherein R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce).
[00328] 51. The compound according to any one of embodiments 41 to 44, wherein R ¹ is optionally substituted phenyl or pyridyl; R ² and R ² are each independently hydrogen; and R ³ is hydrogen.
Petition 870180159548, of 12/06/2018, p. 142/201
80/138 [00329] 52. The compound according to any one of embodiments 41 to 51, wherein R ⁴ is optionally substituted aryl or heteroaryl.
[00330] 53. The compound according to modality 52, wherein the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -S (O) ₂ NR ⁵ R ⁵ ', -S (O) NR ⁵ R ⁵ ' and -C (O) R ⁵ .
[00331] 54. The compound according to modality 52, in which two R ⁵ in adjacent atoms, together with the atoms to which they are attached, form an aryl ring optionally substituted with one or more R ⁶ .
[00332] 55. The compound according to modality 52, in which two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ .
[00333] 56. The compound according to modality 52, in which two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more Re.
[00334] 57. The compound according to modality 52, in which two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ .
[00335] 58. The compound according to modality 41, where Y is -CR ⁵ R ⁵ '-.
[00336] 59. The compound according to modality 41, where Y is -NR ⁵ (CR ⁵ R ⁵ ') t-.
[00337] 60. The compound according to modality 41, where Y is -O-.
[00338] 61. A compound selected from the group consisting of:
Petition 870180159548, of 12/06/2018, p. 143/201
81/138
Example Structure Name 1 o Õll P U ° XYj (S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7-il) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one 2 0O (R) -1 - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7-il) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one 3 o HO ^X '''-Ç'N''' h <N | l P U (R) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy -2- (pyridin-2-yl) propan-1 one 4 HO ' ^X * X ^ N''' _ N il 'X ^ N ^ P U (S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy -2- (pyridin-2-yl) propan-1 one 5 The X ^l ~ V ».P (R) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetra- hydro-2H-pyran-3yl) methanone 6 Xi. ,XO (S) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) (tetra- hydro-2H-pyran-3yl) methanone
Petition 870180159548, of 12/06/2018, p. 144/201
82/138
Example Structure Name 7 F I OH 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 8 χϊ ^ οπt rOΗΟ ^ Χ, Ν ^ / ^O 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 9 and rp '°0 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 10 HO, N%Ί rvHO ^^ N ^ ÚO 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-(hydroxymethyl) -2-methylpropan-1 one 11 vO>O 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -2,2bis (hydroxymethyl) butan-1-one 12 ° ~ l rO ° U _y nJ ^ o (R) - (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrol-2 (1H) -yl) (tetrahydrofuran3-yl) methanone 13 vCO'°O (S) - (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrol-2 (1H) -yl) (tetrahydrofuran3-yl) methanone 14 the G °p rCT / HF— '-' O OF (R) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran3-yl) methanone
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Example Structure Name 15 o ' ^ N _X > 9 ° Ύ T /> (5- (benzo [d] thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro-2Hpyran-3-yl) methanone 16 ^ 0 ^ 0 ° / ^oh C / M “ ⁿ CX / ⁿ ^ F— '-' 0 0 F (S) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran3-yl) methanone 17 zO ^ ccr> / ^ N% gcPO (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (1 - (methoxymethyl) cyclopropyl) methanone 18 Ot rO ΗΟ ^ Χ, Ν ^ / ^ o 1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxy n-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one 19 O° Ύ T /> 1- (5- (benzo [d] thiazol-6-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxy-2,2dimethylpropan- 1-one 20 0/0000 (R) - (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 H) yl) (tetrahydrofuran-3-yl ) methanone 21 O 3-hydroxy-2,2-di methyl-1 - (5 - ((2-methylbenzo [d] oxazol-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) propan-1-one 22 /Egg00O rO '° ΗΟ ^ γΝ0 ^O 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxypropan1-one
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Example Structure Name 23 ÕH 0 (R) -1- (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxybutan1-one 24 ROOh o (S) -1- (5- (benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrol-2 (1H) -yl) -3-hydroxybutan1-one 25 Γ0Η ° -γ T 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-3methylbutan-1-one 26 O .---. O (p — v 7— SN II N- <OH F— (0 ^^ ⁷ O ^F CG (2S, 3Re2R, 3S) -1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) - 3-hydroxy-2-phenylbutan-1-one 27 f 0 = / 0 ^H (+/-) (2R, 3Re2S, 3S) -1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) - 3-hydroxy-2-phenylbutan-1-one 28 p— < ⁷ y — sn 1 n — '1, 1 F— (^ = ⁷ 0 Λ-éoH F / = < ^X (S) -1- (5 - ((4-(difluormethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-3methyl-2-phenylbutan-1-one 29 O HO '^ ^S y ^><N' ^ <rAi Zn 'P L II, θχ, χ- ^ S' ⁰ Ύ X> (S) -1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one 30 O ' ⁿ / q ^ (R) -1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one
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Example Structure Name 31 o — e y- sn | n— ^F_ ( ^{x = /} δ d ^OH (S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 32 o T rO ^{H H0} / 'V ^N V 0 (S) -1- (5 - ((2,2-dimethyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrole [3,4-c] pyrrole-2 (1H) -yl) 3-hydroxy-2-phenylpropan-1-one 33 /GOXX 0 ^ “O (S) - (5 - ((3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro-2Hpiran-3 -il) methanone 34 / VA ARCu ^{8 υ} ΊΧ o (R) - (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro-2Hpyran-3-yl) methanone 35 .χχ ho. rXj ^{0 H} or (S) -1- (5 - ((3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 36 /GO° λ XX X0 (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrol-2 (1 H) -yl) (1 - (methoxymethyl) cyclopropyl) methanone 37 x Ψ ' ^ε ”o 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole- 2 (1H) -yl) -3-hydroxy-2,2dimethylpropan-1-one
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Example Structure Name 38 H 0/0 / ^N '- / ^ ^H ° -T j 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole- 2 (1 H) -yl) -3-hydroxy-3methylbutan-1-one 39 / 0 / °>° Λ XaO (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 ( 1H) -yl) (tetrahydrofuran3-yl) methanone 40 o ho ^ Aa® o ° ' ^S TA ^ O I 3-hydroxy-1- (5 - ((4-methoxyphenyl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) propan-1-one 41 p — e v— s-n Η n—% F- (^ = / ó> 'F N = OHO (S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2 (pyridin-2-yl) propan- 1-year 42 ^F A ó X “ FN = <OH W (R) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2 (pyridin-2-yl) propan- 1-year 43 THE ./ Sy ^ S° Ύ T /> (5- (benzo [d] thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (2,3-dihydrobenzofuran-3-yl) methanone 44 c °'-' o O (R) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro-2Hpyran-3-yl) methanone
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Example Structure Name 45 '-' 0 0 (S) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro-2Hpyran-3-yl) methanone 46 O1 * 11 P 10 ΛΟ0 3-hydroxy-1- (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole-2 (1H) -yl) 2-phenylpropan-1-one 47 O1 (5 - ((4-methyl-3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6-yl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran3-yl) methanone 48 o ΗΟ ' ^Χχ γ ^χΧ ' Ν '^ <[A Zn' P L ü, θχρ- ^ s ^ ° Ϊ1> 1- (5- (benzo [d] thiazol-6-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1 -one 49 _ / V J F / = <OHW 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 50 N = OO <L / d ^0H ífOOH (2S) -3-hydroxy-2-phenyl I-1 - [5 (pyridine-3-sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrol-2-yl] propan-1-one 51 Z ^ NOO Ç ^x ) —SN | N— O / / = <OH (2S) -3-hydroxy-2-phenyl I-1 - [5 (pyridine-2-sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrol-2-yl] propan-1-one 52 ₇ ⁿ = 9 ζ-τρΛ zp F o> ™ d ^0H (2S) -3-hydroxy-2-phenyl-1- (5 - {[6-(trifluormethyl) pyridin-3-yl] sulfonyl} 1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4c] pyrrol-2-yl) propan-1-one
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Example Structure Name 53 0'v-Nx' 9 1 3-methoxy-1 - (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole-2 (1 H) yl) propan-1-one; and 54 F- (οF OH 1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-hydroxypropan-one. 55 O (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydrofuran3-yl) methanone 56 ° Ύ T /> (5- (benzo [d] thiazol-6-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (morpholin-3yl) methanone 57 O^ co 1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxy n-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) 3-methoxypropan-1-one 58 o _o - <xN _x // ° ^z ΥΪ3 1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3-methoxypropan1-one
[00339] 62. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 61 and a pharmaceutically acceptable carrier.
[00340] 63. Method for treating a disease or disorder associated with the modulation of pyruvate kinase (PKR), which comprises administering to a patient who needs an effective amount of a compound according to any of the modalities 1
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[00341] 64. A method of treating a disease associated with decreased PKR activity in an individual who needs it, which comprises administering to the individual an effective amount of a compound according to any one of modalities 1 to 61 or a composition modality 62.
[00342] 65. A method of activating PKR, which comprises administering to an individual in need of an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00343] 66. A method of increasing the life span of red blood cells which comprises administering to an individual in need of an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00344] 67. A method of regulating the levels of 2,3-diphosphoglycerate in the blood which comprises administering to an individual in need of an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00345] 68. A method of regulating ATP levels in the blood which comprises administering to an individual in need of an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00346] 69. A method of treating hereditary non-spherocytic hemolytic anemia which comprises administering to an individual who needs an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00347] 70. A method for treating a disease or disorder associated with increased levels of 2,3-diphosphoglycerate, which with
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[00348] 71. A method for treating a disease or disorder associated with decreased levels of ATP, which comprises administering to a patient who needs an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00349] 72. The method, according to any of the modalities 63-64 or 70-71, in which the disease or disorder is selected from the group consisting of sickle cell disease, sickle cell anemia, thalassemia (for example, beta- thalassemia), hereditary non-spherocytic hemolytic anemia, hemolytic anemia (for example, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), nocturnal hemolytic anemia for example, congenital anemias (eg, enzymopathies)) and anemia of chronic diseases.
[00350] 73. A method of treating a disease or disorder comprising administering to a patient in need of an effective amount of a compound according to any one of modalities 1 to 61 or a composition of modality 62.
[00351] 74. The method, according to modality 73, in which the disease or disorder is selected from the group consisting of sickle cell disease, sickle cell anemia, thalassemia (for example, beta-thalassemia), hereditary non-spherocytic hemolytic anemia, anemia hemolytic (eg, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency), hereditary spherocytosis, hereditary ellipocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (by
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[00352] 75. The method, according to modality 74, in which the disease or disorder is sickle cell anemia.
[00353] 76. The method, according to modality 74, in which the disease or disorder is hemolytic anemia.
[00354] 77. The method, according to modality 74, in which the disease or disorder is beta-thalassemia.
[00355] 78. A PKR activating compound that has a% Fold @ 1.54 of at least 75%, according to the Luminescence Assay Protocol of Example 47.
[00356] 79. The PKR Activating Compound according to modality 78, which has a% Fold @ 1.54 μΜ of 75 to 500%.
[00357] 80. The PKR Activating Compound according to modality 79, which has a% Fold @ 1.54 μΜ of 250 to 500%.
Examples [00358] The description is further illustrated by the following examples and synthesis schemes, which should not be interpreted as limiting this description in scope or spirit to the specific procedures described here. It should be understood that the examples are provided to illustrate certain modalities and are intended to limit the scope of the description. It should also be understood that the appeal can be had in several other modalities, modifications and equivalents of the same that can be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the attached claims.
[00359] Illustrative but not limiting examples of certain modalities of the present disclosure are shown below. Synthetic schemes are presented for the synthesis of certain compounds disclosed in the present invention.
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92/138 [00360] The definitions used in the following diagrams and other sections of this document are:
ACN acetonitrile AcOH Acetic Acid AIBN azobisisobutyronitrile AlCb trichloraluminium BOC2O di-tert-butyl dicarbonate NaBH ₄ sodium borohydride BOP 4- (3- (pyridin-3-ylmethyl) ureido) ammonium benzenesulfinate Brine Saturated aqueous saturated sodium chloride CDCh deuterated chloroform δ chemical displacement DCM dichloromethane or methylene chloride DCE dichloroethane DIEA Λ /, ΛΖ-diisopropylethylamine DMA A /, A / -dimethylacetamide DMF A /, A / -dimethylformamide DMSO dimethylsulfoxide DMT dimercaptotriazine EDCI A / 1 - ((ethylimino) methylene) hydrochloride -A / 3, A / 3dimethylpropane-1,3-diamine equivEtOAc, EA ethyl acetate equivalents EtOH ethanol H hour HCI hydrochloric acid ¹ H NMR Proton nuclear magnetic resonance HOAc Acetic Acid
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HATU 2- (3 / 7- [1,2,3] triazolo [4,5-ò] pyridin- hexafluorophosphate3-yl) -1,1,3,3-tetramethylisouronium HBTU O- (benzotriazol-yl) hexafluorophosphate A /, A /, ΛΓ, ΛΓtetramethyluronium HOBT 1/7-benzo [d] [1,2,3] triazole-1-ol hydrate HPLC high performance liquid chromatography Hz hertz KOAc potassium acetate LCMS Liquid chromatography / mass spectrometry LDA lithium diisopropylamide (M + 1) m-CPBA mass + 1M-chloroperbenzoic acid MeOH methanol min minute (s) / - BuLi n-butyl-lithium NCS A / -chlorosuccinimide NaH sodium hydride NaHCO ₃ sodium bicarbonate NaOH sodium hydroxide NasSCU sodium sulfate Pd ₂ (dba) ₃ AFC tris (dibenzylideneacetone) dipaladium (0) paraformaldehyde PTLC preparative thin layer chromatography RT room temperature Rt retention time SFC supercritical fluid chromatography SPE solid phase extraction TEA triethylamine TFAA trifluoroacetic anhydride TMSCN trimethylsilyl cyanide
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THF tetrahydrofuran CCF thin layer chromatography Xantphos Znl ₂ Materials 4,5-bis (diphenylphosphino) -9,9-dimethylxanthenezinc iodide
[00361] Except where otherwise specified, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sig ma-Aldrich (Milwaukee, Wl, USA) and used directly. All reactions involving reagents sensitive to air or moisture were carried out under a nitrogen atmosphere.
Intermediate 1: 2- [2 / - /, 3 / - / - [1,41dioxino [2,3-b] pyridine-7-sulfonyl11 / - /, 2 / - /, 3 / - /, 4 / - / , 5 / - /, 6 / - / - oirrolo [3,4-c1oirrol
n-BuLi, n-Bu ₂ Mg, THF
SO ₂ CI ₂ -10 ° C, 2 h step 1
HN T N-Boc
TEA, DCM, 20 ° C, 2 h
S-N jf N-Boc step 2
DCM, TFA ^and C, 1 h step 3
Step 1. 2 / - /, 3 / - / - [1,41dioxino [2,3-b] pyridine-7-sulfonyl chloride [00362] In a 100 ml round-bottom flask purged and maintained in an inert atmosphere of nitrogen was placed a solution of / - BuLi in hexane (2.5 M, 2 ml_, 5.0 mmol, 0.54 equiv) and a solution of / - Bu ₂ Mg in heptanes (1.0 M, 4.8 ml, 4.8 mmol, 0.53 equiv). The resulting solution was stirred for 10 min at room temperature (20 Ό). Then a solution of 7-bromo-2 / - /, 3 / - / - [1,4] dioxin [2,3-b] pyridine (2 g, 9.26 mmol, 1, 00 equivalent) in tetrahydrofuran (16 ml) with stirring at -10 Ό in 10 minutes. The resulting mixture was stirred for 1 h at -10Ό. The reaction mixture was slowly added to a -10Ό solution of thionyl chloride (16 ml). The resulting mixture was stirred for 0.5 ha
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-10 Ό. The reaction was then quenched by the careful addition of 30 ml of 0 0 saturated ammonium chloride solution.
The resulting mixture was extracted with 3 x 50 ml of dichloromethane. The organic layers were combined, 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: 3). This produced 1.3 g (60%) of 2 / 7.3 / 7- [1,4] dioxin [2,3-b] pyridine-7-sulfonyl chloride as a white solid. LCMS m / z: calculated for CyHeCINCUS: 235.64; found: 236 [M + H] ⁺ .
Step __________ 2 .__________ 5- [2 / - /, 3 / - / - (1,41dioxinoí2,3-b] pyridine-7-sulfonyl11 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / Tert-Butyl 7-pyrrole (3,4-c] pyrrole-2-carboxylate
Boc [00363] 2 / 7.3 / 7- (1,4] dioxin [2,3-b] pyridine-7-sulfonyl chloride (1.3 g, 5 , 52 mmol, 1.00 equiv), tert-butyl 1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrolo [3,4-c] pyrrole-2carboxylate ( 1.16 g, 5.52 mmols), dichloromethane (40 ml) and triethylamine (1.39 g, 13.74 mmols, 2.49 equivalents) .The solution was stirred for 2 h at 20 Ό and then diluted with 40 ml of water. The resulting mixture was extracted with 3 x 30 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane / methanol (10: 1). This provided 1.2 g (53%) of 5- (2 / -7.3 / -7- [1,4] dioxin [2,3-b] pyridine- 7-sulfonyl] 1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrole [3.4c] tert-butyl pyrrole-2-carboxylate as a yellow solid. / z calculated for CishhsNsOeS: 409.46; found: 410 [M + H] ⁺ .
Step __________ 3 .__________ 2- (2 / 7.3 / 7- (1,4] dioxin [2,3- £> lpiridine-7-sulfonyl11 / 7.2 / 7.3 / 7.4 / 7.5 / 7, 6/7-pyrrole (3,4-c] pyrrole
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[00364] In a 100 ml round bottom flask, 5- [2H, 3H- [1,4] dioxin [2,3-b] pyridine-7-sulfonyl] -1 H, 2H, 3HAH, 5H were placed, 6 tert-Butyl pyrrole [3,4-c] pyrrole-2-carboxylate (1.2 g, 2.93 mmol, 1.00 equiv), dichloromethane (30 ml) and trifluoroacetic acid (6 ml). The solution was stirred for 1 h at 20 Ό. The resulting mixture was concentrated in vacuo. The residue was dissolved in 10 ml of methanol and the pH was adjusted to 8 with sodium bicarbonate (2 mol / L). The resulting solution was extracted with 3x10 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / methanol (10: 1). This provided 650 mg (72%) of 2- [2 / - /, 3 / - / - [1,4] dioxin [2,3-b] pyridine-7sulfonyl] -1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrole as a yellow solid. LCMS m / z calculated for C13H15N3O4S: 309.34; found: 310 [M + H] ⁺ .
Intermediate 2: 2 - ((2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) sulfonyl) -1, 2, 3, 4, 5,6-hexahydroorolo [3,4- c1-Dírrol
⁰ X ^ H ^_N 3Cy ^NH [00365] It was prepared as described for 0 Intermediate 1 (step 2 and step 3), using the appropriate synthetic precursors. Step __________ 2 __________ 5- (2,3-dihydro-1,4-benzodioxin-6-sulfonyl) 1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-clpyrrol-2-carboxylate tert- butyl [00366] This resulted in 170 mg (98%) of 5- (2,3-dihydro-1,4benzodioxin-6-sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H-pyrrole [3 , 4-c] tert-butyl pyrrole-2-carboxylate as a brown solid. LCMS: m / z = 409 [M + H] ⁺ .
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Step __________ 3: __________ 2- (2,3-dihydro-1,4-benzodioxin-6-sulfonyl) 1H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrole [00367] This resulted in 200 mg (91%) of 2- (2,3-dihydro-1,4benzodioxin-6-sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrole as a brown solid. LCMS: m / z = 309 [M + H] ⁺ .
Intermediates 3 and 4 · (S) -3-Hydroxy-2-phenylpropanoic acid and (f) 3-hydroxy-2-phenylpropanoic acid
O
S enantiomer
O
R-enantiomer
Intermediate 4 [00368] Materials 3-hydroxy-2-phenylpropanoic acid (1 g) was separated by Prep-SFC with the following conditions: Instrument name: SHIMADZU LC-20AD, LC parameters: Pump mode: Binary gradient, concentration Pump B initial: 100.0%, Total flow: 170 mL / min, Phase A, Phase B: MeOH (0.1% HAC), Column name: CHIRALPAK AD-H, Length: 100 mm, internal diameter: 4.6 mm, particle size: 5 pm, column temperature: 20 Ό, PDA model: SPD-M20A, Wavelength: 190 nm to 500 nm. This provided peak 1: (Tr = 5.76 min) 380 mg (S) -3-hydroxy-2-phenylpropanoic acid as a white solid, and peak 2: (Tr = 6.87 min) 370 mg of acid (F ) - 3-hydroxy-2-phenylpropanoic as a white solid.
[00369] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 12.31 (br s, 1H), 7.40-7.20 (m, 5H), 4.94 (br s, 1H) , 3.92 (t, J = 9 Hz, 1H), 3.67-3.54 (m,
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2H). S enantiomer: aJj ^& = -110 (C 0.02, water); [literature: -79] Physical enantiomer: 'rX ^Y = +125 (C 0.02, water).
Intermediate 5: 1- (5 - ((2,3-dihydro- [1,41dioxino [2,3-b] pyridin-7yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3, 4-c] pyrrole-2 (1 / - /) - yl) -2- (pyridin-2yl) ethan-1-one [00370] Prepared according to the reaction conditions described for Example 1 from the appropriate reagents. 1- (5 - ((2,3-dihydro- [1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4- c] pyrrole-2 (1 H) -yl) -2- (pi ridi n-2-yl) ethan-1-one was isolated as a white solid (300 mg, 76%). LC-MS: m / z calculated for C20H20N4O5S: 428.12; found 429.10 [M + H] ⁺ .
Intermediate 6: 1 - (5 - ((4- (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -2- ( pyridin-2-yl) ethan-1-one [00371] Prepared according to the reaction conditions described for Example 7 from the appropriate reagents. The crude material was purified by preparative HPLC: Column: SunFire C18 Prep 5 pm, 19 * 150 mm; mobile phase: water (contains 0.1% TFA) and CH ₃ CN with a gradient of 43% to 73% CH3CN in 7 min; detector UV wavelength: 220 nm. This resulted in 25.6 mg (21%) of 1- (5 ((4- (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H ) -yl) -2- (pyridin-2-yl) ethan-1-one as a white solid.
[00372] ¹ H NMR (300 MHz, DMSO-d ₆ , 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
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99/138 (br, 2H), 3.97-4.14 (br, 6H), 3.90-3.94 (br, 2H). LC-MS m / z: Calculated for C20H19F2N3O4S: 435.11; found: 436 [M + H] ⁺ .
Intermediate 7: 2- (Benzofuran-5-ylsulfonyl) hydrochloride -1,2,3,4,5,6hexa-hydrooirrolo [3,4-clDirrol
4NHCI dioxane / DCE
Step 2
Step 1. 5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4
c] pyrrole-2 (1 / - /) - tert-butyl carboxylate [00373] To a solution of 3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole
2 (1 / - /) - tert-butyl carboxylate (0.7 g, 3.33 mmol) in acetonitrile (20 ml_) and DIEA (1.70 ml_, 9.76 mmol) was added benzofuran-5 chloride -sulfonyl (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 and concentrated under reduced pressure to produce 5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 ( 1 / - /) - tert-butyl carboxylate (1.3 gm, 3.33 mmols, 100%) as an oil. LCMS: m / z = 413 [M + Na] ⁺ .
Step 2. 2- (Benzofuran-5-ylsulfonyl) -1,2,3,4,5,6-hexa hydropyrrolo [3,4-c] pyrrole [00374] 5- (benzofuran-5-ylsulfonyl) hydrochloride - 3,4,5,6-tetrahydropyrrolo [3,4-
c] tert-butyl pyrrole-2 (1 / - /) - carboxylate (1.3 g, 3.33 mmol) was dissolved in a mixture of methanol (3.0 ml), DCE (10.0 ml) and 4 M HCI in 1.4 dioxane (5.0 ml). The reaction was heated to 50 Ό for 2 h. The sun
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100/138 vents were evaporated under reduced pressure and the reaction mixture was subjected to azeotropic drying with toluene and additionally subjected to vacuum drying overnight to produce 2- (benzofuran5-sulfonyl) hydrochloride -1,2,3 , 4,5,6-hydropyrrolo [3,4-c] pyrrole (0.95 mg, 3.33 mmol, 100%). LCMS: m / z = 291 [M + H] ⁺ .
Intermediate 8: 1- (6 (((3,4,5,6-tetrahydropyrrolo [3,4c1oirrol-2 (1 / - /) - yl) sulfonyl) -2,3-dihydro-4 / hydrochloride - / - benzo [b] [1,4] oxazin-4-yl) ethan-1one.
HCI [00375] It was prepared as described for Intermediate 7 using suitable synthetic precursors. 94% of total income. LCMS: m / z = 350 [M + H] ⁺ .
Intermediate 9: 2- (Pyridin-2-ylsulfonyl) hydrochloride salt -1,2,3,4,5,6hexa-hydropyrrolo [3,4-c] pyrrole
Λ — N O
Ç —SN | NH ^{HCI λ} 'O [00376] It was prepared as described for Intermediate 7 using suitable synthetic precursors.
Step 1. 5- (oiridine-2-sulfonyl) -1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c ] tert-butyl pyrrole2-carboxylate.
[00377] Isolated as an orange solid (570 mg, 36%). The material was used without further purification. LCMS: m / z = 352 [M + H] ⁺ .
Step 2. Hydrochloride salt of 2- (pyridin-2-ylsulfonyl) -1,2,3,4,5,6-hexahydropyrrolo [3,4-c] pyrrole [00378] Isolated as a white solid (467 mg, quantitative yield). LCMS: m / z = 252 [M + H] ⁺ .
Intermediate 10: 3-hydroxy-2,2-dimethyl-1- (3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) - yl) propan-1- hydrochloride ona
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2) 4 M HCI / dioxane [00379] To a solution of 3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 / - /) - ierc-butyl carboxylate (50.5 mg , 0.24 mmol) in DCM (1.2 ml_) and DIEA (105 μΙ_, 0.60 mmol) was added 3-hydroxy-2,2-dimethylpropanoic acid (28.4 mg, 0.240 mmol) in 1,4-dioxane (1.2 ml_), followed by a solution of HATU (630 μΙ, 0.252 mmol) in acetonitrile (1.3 ml_). The reaction mixture was stirred at room temperature for 3 hours and 1 N NaOH (aqueous) and EtOAc were added. The resulting material was dissolved in DCM (0.9 ml) and 4 M HCI was added in
1,4-dioxane (0.36 ml). The mixture was stirred at room temperature overnight. The reaction was concentrated, azeotropically dried with toluene and subjected to additional drying under vacuum to produce 3-hydroxy-2,2-dimethyl-1 - (3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole hydrochloride -2 (1 / - /) - yl) propan-1-one (44.4 mg, 0.180 mmol, 75.0% yield).
Intermediate 11: (R) - (tetrahydrofuran-3-yl) hydrochloride salt (3,4,5,6tetrahydroDrolo [3,4-c1oirrol-2 (1 H) -yl) methanone
[00380] It was prepared according to the procedure for Intermediate 10 using the appropriate synthetic precursors
Intermediate 12: 6 - ((3,4,5,6-tetrahydrohydrochloride [3,4-c1oirrol2 (1 / - /) - yl) sulfonyl) benzo [o1thiazole hydrochloride
NH-HCI
1) DlEA / dioxane
2) 4 M HCI in dioxane
[00381] To a 50 ml round bottom flask_ were added
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102/138 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 produce a brown suspension. Benzo [d] thiazol-6-sulfonyl chloride (0.497 g, 2.128 mmol) was added. The reaction was heated to 50 Ό with stirring for 2 hours. The volatile compounds were removed under reduced pressure. The residue was resuspended in dioxane (10 ml) and 4 M HCI in dioxane (5.07 ml, 20.26 mmol) was added. The reaction was heated to 50 ΐ with stirring for 2 hours. The volatile compounds were removed under reduced pressure to produce 6 - ((3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) yl) sulfonyl) benzo [d ] thiazole (0.640 g, 1.865 mmol, 92%) as a brown oil that was used without further purification. LCMS: m / z = 307.9 [M + H] ⁺ .
Intermediate 13: 2 - [[4- (difluoromethoxy) benzene] sulfonyl hydrochloride11 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-oirrolo [3,4-c1oirrol
HN
HCI [00382] It was prepared according to the procedure for Intermediate 12 using the appropriate synthetic precursors 0.652 g (1.848 mmol, 91%) was obtained. LCMS: m / z = 317.1 [M + H] ⁺ .
Intermediate 14: HCI salt of 2 - ((6- (trifluormethyl) oiridin-3-yl) sulfonyl) -
1,2,3,4,5,6-hexahydroorolo [3,4-clDirrol
NH HCI [00383] It was prepared according to the procedure for Intermediate 12 using the appropriate synthetic precursors LCMS: m / z =
319.9 [M + H] ⁺ .
Intermediate 15: 2,2-dimethyl-6- [1 / 7,2 / 7,3 / 7,4 / 7,5 / 7,6 / 7-Dírolo [3,4-c1oirrol2-sulfonyl] -3,4 -dihydro-2 / 7-1,4-benzoxazine, TFA salt
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Step 1 Step 2 _{Step 3}

Step 6
Step 1.2-Bromo-A / - (2-hydroxyphenyl) -2-methylpropanamide [00384] To a 500 ml 3-necked round-bottom flask was added a mixture of 2-aminophenol (5 g, 45.82 mmol, 1 .00 equiv.), THF (150 ml) and TEA (5.1 g, 50.40 mmol). 2bromo-2-methylpropanoyl bromide (11.6 g, 50.46 mmol, 1.10 equiv) was then added by dripping. The solution was stirred for 1 h at 0 Ό. The reaction was then quenched by the addition of water (15 ml). The solution was extracted with ethyl acetate (3 x 200 ml), then the extract was washed with brine (2 x 150 ml) and dried over anhydrous sodium sulfate to produce 2-bromo-A / - (2-hydroxyphenyl) ) -2methylpropanamide (11.0 g, 93%) as a yellow oil. LCMS: m / z = 259 [M + H] ⁺ .
Step 2. 2,2-dimethyl-3,4-dihydro-2 / - / - 1,4-benzoxazin-3-one [00385] To a 250 ml 3-neck round bottom flask were added 2- bromo-N- (2-hydroxyphenyl) -2-methylpropanamide (6 g, 23.25 mmol, 1.00 equiv), CS2CO3 (9.85 g, 30.23 mmol, 1.30 equiv) and DMF (180 ml_ ). The reaction mixture was stirred for 3 h at 60 Ό and then quenched by the addition of water (200 ml). The mixture was extracted with ethyl acetate (3 x 200 ml) and the extract was
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104/138 washed with brine (2 x 150 ml) and dried over anhydrous sodium sulfate to produce 2,2-dimethyl-3,4-dihydro-2 / 7-1,4-benzoxazin-3-one (2 , 2 g, 53%) as a white solid. LCMS: m / z = 178 [M + H] ⁺ .
Step 3 · 2,2-dimethyl-3,4-dihydro-2 / 7-1,4-benzoxazine [00386] A mixture of 2,2-dimethyl-3,4-dihydro-2 / 7- 1,4-benzoxazin3-one (2.76 g, 15.58 mmol, 1.00 equiv) and THF (10 ml) was prepared in a round bottom flask with 3 100 ml bottles. The mixture was cooled to 0 Ό, and then BH ₃ . THF (1 M, 23.4 ml, 1.50 equiv.) Was added by dropping with stirring. The reaction mixture was stirred for 2 h at 70 Ό. The reaction was brusquely quenched by the addition of methanol (4 ml) and then concentrated in vacuo. The pH was adjusted to 6.0 with a 1N aqueous solution of HCl and it was stirred for 30 minutes at room temperature. The mixture was then neutralized with saturated aqueous sodium carbonate solution and the pH was adjusted to 8.0. The solution was extracted with ethyl acetate (50 ml), and then the organic phase was washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to produce 2,2-dimethyl-3, 4-dihydro-2 / 7-1,4-benzoxazine (2.90 g) as a colorless oil. The material was used without further purification. LCMS: m / z = 164 [M + H] ⁺ .
Step 4. 2,2-Dimethyl-3,4-dihydro-2 / 7-1,4-benzoxazino-6sulfonyl chloride [00387] 2,2-dimethyl-3,4-dihydro-2H-1 , 4-benzoxazine (500 mg, 3.06 mmol, 1.00 equiv) was placed in a round bottom flask with 3 100 mL necks and was cooled to 0 O. Sulfurochloridic acid (5 g, 42.91 mmol, 14.01 equiv) was added by drip. The solution was stirred for 2 h at 60 Ό. The reaction was then quenched by the addition of water (50 ml) and extracted with dichloromethane (50 ml). The organic phase was washed with brine (3 x 20 ml), dried with anhydrous sodium sulfate and concentrated in vacuo to produce 2.2 chloride
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105/138 dimethyl-3,4-dihydro-2H-1,4-benzoxazino-6-sulfonyl (0.14 g, 17%) as a yellow oil.
Step 5 · 5- (2,2-dimethyl-3,4-dihydro-2 / 7-1,4-benzoxazino-6-sulfonyl) 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - tert-butyl pyrrole [3,4-clpyrrol-2-carboxylate [00388] In a 25 ml round bottom flask 2,2-dimethyl chloride was added -3,4-dihydro-2 / - / - 1,4-benzoxazino-6-sulfonyl (124 mg, 0.47 mmol, 1.00 equiv.) And dichloromethane (2 ml), followed by the addition of 1 / -7,2 / -7,3H, 4H, 5H, 6/7-pyrrole [3,4-c] tert-butyl pyrrole-2-carboxylate (100 mg, 0.48 mmol, 1.00 equiv) and DIEA (110 mg, 0.85 mmol, 2.00 equiv). The solution was stirred for 2 h at 25 Ό. The reaction was then quenched by the addition of ethyl acetate (20 ml). The mixture was washed with brine (3x10 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane / ethyl acetate (10: 1) to yield 5- (2,2-dimethyl-3,4-dihydro-2H-1,4benzoxazino-6-sulfonyl) -1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrole [3,4-c] tert-butyl pyrrole-2carboxylate (0.102 g, 49%) as an oil light yellow. LCMS: m / z = 436 [M + H] ⁺ .
Step 6 · 2,2-dimethyl-6- [1 / 7,2 / 7,3 / 7,4 / 7,5 / 7,6 / 7-pyrrole [3,4-c] pyrrol-2sulfonyl] -3 , 4-dihydro-2 / 7-1,4-benzoxazine, TFA salt [00389] To a solution of 5- (2,2-dimethyl-3,4-dihydro-2 / 7-1, 4benzoxazino-6-sulfonyl) -1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrolo [3,4-c] tert-butyl pyrrole-2-carboxylate (102 mg, 0.23 mmols, 1.00 equivalent) in dichloromethane (3 ml) TFA (600 mg, 5.31 mmols, 23.00 equivalents) was added. The solution was stirred for 2 h at 25 Ό under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo to produce 2,2-dimethyl-6- [1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrole [3,4-c] pyrrole-2sulfonyl] -3,4-dihydro-2 / 7-1,4-benzoxazine, TFA salt (85 mg) as a light yellow oil. The material was used without further purification. LCMS: m / z = 336 [M + H] ⁺ .
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Intermediates 17 θ 18: (2R, 3S and 2S, 3R) 3-hydroxy-2-phenylbutanoic acid and (2S, 3S and 2R, 3R) 3-hydroxy-2-phenylbutanoic acid
Intermediate 17 Intermediate 18 [00390] To a 250 ml 3-neck round-bottom flask purged and maintained in an inert nitrogen atmosphere were added 2-phenylacetic acid (2 g, 14.69 mmol, 1.00 equiv) and tetrahydrofuran ( 50 ml). LDA (3.00 equiv, 22 ml_, 2 N in THF) was added with stirring at -50 Ό. The reaction mixture was stirred for 1 h at -50 Ό, and then acetaldehyde (1.94 g, 3.00 equiv) was added. The reaction mixture was stirred for 1 h at -50 Ό, and then for 1 h at room temperature. A 3 N aqueous hydrochloric acid solution (3 N, 20 ml) was added and the mixture was extracted with ethyl acetate (2 x 100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane / methanol (10: 1). This provided:
Intermediate 17: A mixture of (2R, 3S and 2S, 3R) -3-hydroxy-2-phenylbutanoic acid (assumed stereochemical configuration) · [00391] 700 mg (3.89 mmol, 26%) was obtained as an oil. LCMS: m / z = 222 [M + 1] ⁺ .
Intermediate 18: A mixture of (2R, 3R and 2S, 3S) -3-hydroxy-2-phenylbutanoic acid (assumed stereochemical configuration) · [00392] 700 mg (3.89 mmol, 26%) was obtained as a white solid. LCMS: m / z = 222 [M + 1] ⁺ .
Examples 1 and 2: (2S) -1- (5- [2 / - /, 3 / - / - [1,41dioxino [2,3-b] pyridine-7-sulfonyl11 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2-phenylpropan-1one (Example 1) and ( 2fí) -1- (5- [2 / - /, 3 / - / - [1,41dioxino [2,3-b] pyridine-7
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107/138 sulfonill-1 H, 2H, 3H, 4H, 5H, 6H-Dírolo [3,4-clDírrol-2-yl) -3-hydroxy-2-phenylorooan-1-one (Example 2)
OH
OH
HO ·
NH
HATU, DIEA, DCM ° C, overnight
Example 1
OH
Step 1
Example 2 [00393] In a 100 ml round bottom flask
2- [2H, 3H- [1,4] dioxin [2,3-b] pyridine-7-sulfonyl]
H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrole (150 mg, 0.48 mmol, 1.00 equiv), 3-hydroxy-2-phenylpropanoic acid (97 mg, 0, 58 mmol, 1.20 equiv), dichloromethane (10 ml), HATU (369 mg, 0.97 mmol, 2.00 equiv) and DIEA (188 mg, 1.46 mmol, 3.00 equiv). The resulting solution was stirred overnight at 20 Ό. The reaction mixture was diluted with 20 ml of water and was then extracted with 3 x 20 ml of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC and eluted with dichloromethane / methanol (20: 1) and further purified by prep. (XBridge C18 prep column, 100 Á, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; gradient: 15% B to 45% B at over 8 min; Flow rate: 20 mL / min; UV detector: 254 nm). Then, the two enantiomers were separated by chiral preparative HPLC (column, Daicel CHIRALPAK® IF, 2.0 cm x 25 cm, 5 pm; mobile phase A: DCM, phase B: MeOH (maintained with 60% MeOH for 15 min); Flow rate: 16 mL / min; Detector, UV 254 & 220 nm). This resulted in peak 1 (Example 2, Tr: 8.47 min) 9.0 mg (4%) of (2R) -1- (5 [2H, 3H- [1,4] dioxin [2,3-b ] pyridine-7-sulfonyl] -1 H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2-phenylpropan-1-one as a solid
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108/138 yellow. And at peak 2 (Example 1, Tr: 11.83 min) 10.6 mg (5%) of (2S) 1 - (5- [2H, 3H- [1,4] dioxy at [2,3-b ] pi ridi na-7-sulfoni I] -1 H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2-phenylpropan-1-one with a yellow solid.
[00394] Example 2 - ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J =
2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.31-7.18 (m, 5H), 4.75 (t, J = 5.2
Hz, 1H), 4.52-4.45 (m, 2H), 4.40-4.36 (m, 1H), 4.34-4.26 (m, 2H), 4.11
3.87 (m, 8H), 3.80-3.78 (m, 1H), 3.44-3.43 (m, 1H). LC-MS (ESI) m / z: calculated for C22H23N3O6S: 457.13; found: 458.0 [M + H] ⁺ .
[00395] Example 1 - ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H) , 7.31-7.20 (m, 5H), 4.75 (t, J = 5.2
Hz, 1H), 4.50-4.47 (m, 2H), 4.40-4.36 (m, 1H), 4.32-4.29 (m, 2H), 4.11
3.87 (m, 8H), 3.80-3.77 (m, 1H), 3.44-3.41 (m, 1H). LC-MS (ESI) m / z:
calculated for C22H23N3O6S: 457.13; found: 458.0 [M + H] ⁺ .
Examples 3 and 4: (2S or 2fí) -1- (5- [2 / - /, 3 / - / - [1,41dioxino [2,3-b] pyridine-7sulfonill-1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrol-2-yl) -3-hydroxy-2 (pyridin-2-yl) propan -1-one (Example 4) and (2fí or 2S) -1- (5- [2 / - /, 3 / - / [1,41dioxino [2,3-b] pyridine-7-sulfonyl1-1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4 clpyrrol-2-yl) -3-hydroxy-2- (pyridin-2- il) propan-1-one (Example 3)

[00396] In a 25 mL round bottom flask were placed
1- (5 - ((2,3-dihydro- [1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4 -c] pyrrole-2 (1 H) -yl) -2- (pyridin-2-yl) ethan-1-one (80 mg, 0.17
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109/138 mmol, 1.00 equiv) and tetrahydrofuran (10 ml). Sodium hydride (60% dispersion in mineral oil, 8 mg, 0.20 mmol, 1.18 equiv.) Was added. The solution was stirred for 10 min at 20 Ό, and then a solution of paraformaldehyde (8.8 mg) in tetrahydrofuran (1 ml) was added dropwise with stirring at -10 ° C. The mixture was stirred for 2 h at 20 Ό and then it was concentrated in vacuo. The residue was purified by preparative HPLC (column: XBridge C18 prep, 100 Á, 5 pm, 19 mm x 250 mm; Mobile Phase A: water (0.05% NH3.H2O), mobile phase B: MeCN; gradient: 20% B to 45% B over 8 min; Flow rate: 20 mL / min; UV detector: 254 nm). The enantiomers were separated by chiral preparative HPLC (column, Daicel CHIRALPAK® IF, 2.0 cm x 25 cm, 5 pm; mobile phase A: MeOH, phase B: DCM (maintained with 30% MeOH for 23 min); Detector , flow rate: 15 ml / minute; Detector, UV 254 & 220 nm) to produce (2S or 2R) -1 - (5- [2 / - /, 3 / - / - [1,4] dioxy in [2, 3-b] pi ridi na-7-sulfoni I] 1H, 2H, 3H, 4H, 5H, 6 / - / - pyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2- ( pyridin-2yl) propan-1-one as a yellow solid (Example 4, Tr: 12.14 min, 19 mg, 24% yield), and (2F or 2S) -1- (5- [2 / - /, 3 / - / - [1,4] dioxin [2,3-
b] pyridine-7-sulfonyl] -1 H, 2H, 3H, 4H, 5H, 6 / - / - pyrrole [3,4-c] pyrrol-2-yl) -3hydroxy-2- (pyridin-2-yl ) propan-1-one as a yellow solid (Example 3, Tr: 18.44 min., 19.3 mg, 25% yield). The absolute stereochemistry has not been determined (*).
[00397] (Example 4): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.45-8.43 (m, 1H), 8.14 (d, J = 2.4 Hz, 1H) , 7.74-7.62 (m, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.30-7.22 (m, 2H), 4.80 (t, J = 5.20 Hz, 1H), 4.50-4.48 (m, 2H), 4.40-4.37 (m, 1H), 4.32-4.30 (m, 2H), 4, 05-3.91 (m, 9H), 3.70-3.65 (m, 1H). LC-MS (ESI) m / z: calculated for C21H22N4O6S: 458.49; found: 459.0 [M + H] ⁺ .
[00398] (Example 3): ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.45-8.43 (m, 1H), 8.14 (d, J = 2.4 Hz, 1H) , 7.74-7.62 (m, 1H), 7.61 (d, J = 2.4
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Hz, 1H), 7.30-7.22 (m, 2H), 4.80 (t, J = 5.2 Hz, 1H), 4.50-4.48 (m, 2H), 4.40 -4.37 (m, 1H), 4.32-4.30 (m, 2H), 4.05-3.91 (m, 9H), 3.70-3.65 (m, 1H). LC-MS (ESI) m / z: calculated for C21H22N4O6S: 458.49; found: 459.0 [M + H] ⁺ .
Examples 5 and 6: (R or S) - (5 - ((2,3-dihydro- [1,41dioxino [2,3-b1oiridin-7il) sulfonyl) -3,4,5,6-tetra- hydropyrrolo [3,4-chlyrrol-2 (1H) -yl) (tetrahydro-2Hpyran-3-yl) methanone (Example 5) and (S or R) - (5 - ((2,3-dihydro [1,41dioxino [2,3-blpiridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4clpyrrol-2 (1 H) -yl) (tetrahydro-2H-pyran -3-yl) methanone (Example 6)
Example 5 chiral separation
Example 6 [00399] (5 - ((2,3-dihydro- [1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -
3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl) (tetrahydro-2 / - / - pyran-3yl) methanone was prepared using the conditions reactions described for example 1 from the appropriate reagents. The residue was purified by chromatography on silica gel and eluted with dichloromethane / methanol (20: 1) and further purified by prep HPLC. (preparative column XBridge BEH C18 OBD, 130 Á, 5 pm, 19 mm x 150 mm; Mobile phase: water (10 mmol NH4HCO3), MeCN (MeCN 1% up to 40% for 8 min); Flow rate: 20 mL / min ; Detector: 254 & 220 nm). The two enantiomers were separated by chiral preparative HPLC (Column Daicel CHIRALPAK® IB, 2.0 cm x 25 cm, 5 pm; mobile phase A: DCM, phase B: ethanol (maintained with 75% DCM for 13 min); Flow rate : 14 mL / min; Detector, UV 254 & 220 nm; retention time: Example 5: 9.22 min, Example 6: 11.57 min to provide (R or S) - (5 - ((2,3- di
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111/138 hydro- [1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) - il) (tetrahydro-2H-pyran-3-yl) methanone as a white solid (5.3 mg, 2%) and (S or R) - (5 - ((2,3-dihydro- [ 1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) (tetrahydro -2H-pyran-3-yl) methanone with a white solid (4.9 mg, 2%). Absolute stereochemistry has not been determined (*) [00400] Example 5 ¹ H NMR (400 MHz, CDCh): δ 8.31 (s, 1H), 7.60 (s, 1H), 4.57-4.50 (m, 2H), 4.36-4.25 (m, 4H), 4.15-4.09 (m, 6H), 3.94-
3.88 (m, 2H), 3.56-3.50 (m, 1H), 3.49-3.33 (m, 1H), 2.63-2.60 (m, 1H), 1, 95-1.78 (m, 2H), 1.67-1.61 (m, 2H). LC-MS (ESI) m / z: calculated for C19H23N3O6S: 421.13; found: 422 [M + H] ⁺ .
[00401] Example 6 ¹ H NMR (400 MHz, CDCl 3): δ 8.30 (s, 1H), 7.61 (s, 1H), 4.54-4.52 (m, 2H), 4.35 -4.27 (m, 4H), 4.15-4.09 (m, 6H), 3,953.90 (m, 2H), 3.56-3.50 (m, 1H), 3.42-3 , 35 (m, 1H), 2.65-2.60 (m, 1H), 1.95-1.78 (m, 2H), 1.67-1.62 (m, 2H). LC-MS (ESI) m / z: calculated for C19H23N3O6S: 421.13; found: 422 [M + H] ⁺ .
Example __________ 7: __________ 1- (5 - [[4- (Difluoromethoxy) benzene] sulfonyl11H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2,2dimethylpropan -1-one
[00402] 2 - [[4- (difluoromethoxy) benzene] sulfonyl] 1H, 2H, 3H, 4H, 5H, 6H-pyrrole [3,4-c] pyrrole hydrochloride (113 mg, 0.32 mmol, 1.00 equiv), dichloromethane (10 mL), 3-hydroxy-2,2-dimethylpropanoic acid (41 mg, 0.35 mmol, 1.10 equiv.), DIEA (123 mg, 0.95 mmol, 3.00 equiv) and HATU (241 mg, 0.63 mmol, 2.00 equiv). The solution was stirred
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112/138 for 2 h at room temperature and then concentrated in vacuo. The crude product was purified by preparative HPLC (Waters I: column: Xbridge Prep C18 18, 5 pm 19 x 150 mm; mobile phase gradient: CH ₃ CN / water (0.05% NH4OH) from 32% to 47% in 7 minutes of analysis; UV detector wavelength: 254 nm) to provide 25.3 mg (19%) of 1- (5 - [[4- (difluoromethoxy) benzene] sulfonyl] 1 / 7.2 / 7 , 3 / 7,4 / 7,5 / 7,6 / 7-pyrrolo [3,4-c] pyrrol-2-yl) -3-hydroxy-2,2-dimethylpropan-1-one as a white solid.
[00403] ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 7.89-7.92 (m, 2H), 7.39-7.42 (d, J = 7.8 Hz, 2H) , 7.17-7.66 (t, J = 73.2 Hz, 1H), 4.68-4.72 (t, J = 5.4 Hz, 1H), 3.90-4.50 (m , 8H), 3.40-3.42 (d, J = 5.4 Hz, 2H), 1.09 (s, 6H). LC-MS (ESI) m / z: Calculated for C18H22F2N2O5S: 416.12; found: 417 [M + H] ⁺ .
[00404] The Examples in Table 1 below were prepared according to the procedures outlined above for Example 7, using suitable synthetic precursors.
Table 1.
Example Structure, Name LCMS ¹ H NMR 8 ^HO > Xj crr ^v '1 - (5- (Benzofuran-5-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-h idroxy- 2phenylpropan-1-one m / z: 4399 O1 - (5- (Benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-hydroxy-2,2dimethylpropan-1-one m / z: 391
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Example Structure, Name LCMS ¹ H NMR 10 ^ηο ί ^rO u 15 0 1 - (5- (Benzofuran-5-ylsulfonyl) - 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3-h idroxy -2 (hydroxymethyl) -2-methylpropan-1-one m / z: 40711 ^ηο ί ^rO u 15 O 1 - (5- (Benzofuran-5-ylsulfonyl) - 3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -2, 2- bis (hydroxymethyl) butan-1-one m / z: 42112 0 ^ 0 / =. ^{0 0} '- 2- (1-Benzofuran-5-sulfonyl) -5 [(3f ) - oxolane-3-carbonyl] - 1 H, 2H, 3H, 4H, 5H, 6H-pyrrole [3,4c] pyrrole m / z:389.113 '- / ft / = X ^N JL / ^N 4X Xo ^{0 0} ' - 2- (1-Benzofuran-5-sulfonyl) -5 [(3S) -oxolane-3-carbonyl] - 1 H, 2H, 3H , 4H, 5H, 6H-pyrrole [3,4-c] pyrrole m / z:389.114 ° Q p— Vs-njXn— ^H F— ( ^{X = /} o OF (f) - (5 - ((4- (difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3, 4c] pyrrole-2 (1 H) -yl) (tetrahydrofuran-3yl) methanone m / z: 415 (300 MHz, DMSO-cfc): δ ppm 7.89-7.94 (m, 2H), 7.40-7.42 (d, 2H), 7.18-7.66 (t, J = 72 Hz, 1 H) 3.83-4.29 (m,9H), 3.62-3.74 (m, 3H), 3.06-3.16 (m, 1H), 1.94-2.07 (m, 2H).
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Example Structure, Name LCMS ¹ H NMR 15 rV o ° O0 O(5- (Benzo [w /] thiazol-6-ylsulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) (tetrahydro-2 / - / / piran-3-yl) methanone m / z: 420 (300 MHz, CDCh): δ ppm9.22 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1 H), 7.97 (dd, 9 = 8.7 Hz, J = 1.8 Hz, 1H), 4.24-4.12 (m, 8H), 3.94-3.90 (m, 2H), 3.543.41 (m, 2H), 2.65-2.55 (m, 1H), 1.86-1.81 (m, 2H), 1.671.49 (m, 2H). 16 pe Μ'Ν TH ^H F— ⁷ OO F (S) - (5 - ((4- (difluoromethoxy) phenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 ( 1 H) -yl) (tetrahydrofuran-3yl) methanone m / z: 415 (300 MHz, DMSO-cfc): δ ppm 7.95-7.98 (m, 2H), 7.35-7.42 (m, 2H), 6.79-7.28 (t, J = 72 Hz, 1H) 3.80-4.32 (m, 14H), 3.24-3.40 (m, 1H ), 2.22 (m, 2H). 17 o _xz o rO ^N ' ^S WO (5- (benzofuran-5-ylsulfonyl) -3,4,5,6tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (1 (methoxymethyl) cyclopropyl) methanone m / z: 40318 OH1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -il) -3h idroxy-2-phenylpropan-1 -one m / z: 457
Example _______ 19: _______ 1- (5- (Benzo [o1thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-clpyrrol-2 (1 / - /) - yl) -3-hydroxy-2, 2-dimethylpropan-1-one
HCI
O
DIEA, ACN
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115/138 [00405] To a 0.2 M solution of 3-hydroxy-2,2dimethyl-1 - (3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 hydrochloride (1/7) -yl) propan-1-one (300 μΙ, 0.060 mmol) in CH ₃ CN with 10% DIEA a 0.2 M solution of benzo [d] thiazol-6-sulfonyl chloride was added (300 μΙ, 0.06 mmol) in CH ₃ CN with 3% DIEA. The reaction was stirred at room temperature for 5 hours, and then concentrated and partitioned between ethyl acetate and aqueous NaOH (1 N). The organic phase was concentrated under reduced pressure and the crude material was purified by preparative HPLC to provide 1- (5- (benzo [d] thiazol-6-ylsulfonyl) -
3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1/7) -yl) -3-hydroxy-2,2-dimethylpropan-1-one (2.6 mg, 10% Yield). LCMS: m / z = 408 [M + H] ⁺ .
[00406] The Examples in Table 2 below were prepared according to the procedure outlined above for Example 19, using suitable synthetic precursors.
Table 2 ·
Example Structure, Name LCMS 20 O * / 00(fí) - (5- (benzo [dJthiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1/7) -yl) (tetrahydrofuran-3-yl ) methanone m / z 406 21 o _xz o rOYfb O 3-Hydroxy-2,2-di methyl-1 - (5 - ((2methylbenzo [d] oxazol-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrene [3,4 -c] pyrrol-2 (1/7) -yl) propan-1-one m / z 406
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Example Structure, Name LCMS 22 r <J Ί0301- (5- (Benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl) -3hydroxypropan-1-one m / z: 363 23 γΌ / coOH(f) -1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) - yl) -3-hydroxybutan1- ona m / z 377 24 xCj ⁿ / CO ⁰ OH (S) -1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl ) -3-hydroxybutan1-one m / z 377 25 OH O SN jT I ^ / - ⁷ OO (5- (Benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) -yl) (1 (methoxy methyl) cyclic opropyl) methane in m / z: 391.14
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Example 26: (2S, 3fi and 2 / ⁼ , 3S) -1- (5 - [[4- (difluoromethoxy) benzene] sulfonylT / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-clPyrrol-2-yl) -3-hydroxy-2-phenylbutan-1ona

[00407] To an 8 ml flask were added 2 - ((4 (difluoromethoxy) phenyl) sulfonyl) -1,2,3,4,5,6-hexahydropyrrolo [3,4-c] pyrrole hydrochloride ( 64 mg, 0.18 mmol, 1.00 equiv), DMF (1.50 ml_), DIEA (58 mg, 0.45 mmol, 2.50 equiv), acid (2S, 3R and 2R, 3S) -3 -hydroxy-2-phenylbutanoic (40 mg, 0.22 mmol, 1.20 equiv), and HATU (84 mg, 0.22 mmol, 1.20 equiv). The solution was stirred for 16 h at room temperature. The solution was diluted with 50 ml of ethyl acetate, washed with 4 x 15 ml of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative TLC (DCM / EA = 1/2) to produce (2S, 3F 'and 2F', 3S) -1- (5 - [[4- (difluoromethoxy) benzene] sulfonyl] 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrol-2-yl) -3-hydroxy-2-phenylbutan- 1 ounce as a white solid (41 mg, 47%). ¹ H NMR (300 MHz, CDCh): δ ppm 7.85-7.80 (m, 2H), 7.37-7.23 (m, 7H), 6.59 (t, J = 72.6 Hz , 1 H), 4.45-4.37 (m, 1H), 4.25-3.95 (m, 7H), 3.78-3.74 (m, 1H), 3.39 (d, J =
3.9 Hz, 1H), 1.05 (d, J = 6.3 Hz, 3 H). LCMS: m / z = 479.0 [M + H] ⁺ .
[00408] The Examples in Table 3 below were prepared according to the procedure outlined above for Example 26, using suitable synthetic precursors.
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Table 3 ·
Example Structure, Name LCMS ¹ H NMR 27 fa αλα ΑΧα _X-0H ° O0A H ^H 0 (+/-) (2R, 3R and 2S, 3S) -1- (5 - [[4- (difluoromethoxy) benzene] sulfonyl] - 1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4c] pyrrol-2-yl) -3-hydroxy-2-phenylbutan-1 one m / z: 479 (300 MHz, CDCh): δ ppm 7.84-7.81 (m, 2H), 7,357.26 (m, 7H), 6.59 (t, J = 72.6 Hz, 1 H), 4, 35-3.97 (m, 8H), 3.76-3.71 (m, 1H), 3.36-3.34 (m, 1H), 1.06 (dd, J = 13.2 Hz, J = 6.3 Hz, 3H) 28 ^F_ (ΛΑ z O— < ^z y— SN N— Z — λ - / 11 vA / _ // - ⁰ y - _ / 'OH (2S) -1- (5 - [[4 (difluoromethoxy) benzene] sulfonyl] 1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4c] pyrrol-2-yl) -3-hydroxy-3-methyl-2-phenylbutan-1-one m / z: 493 (300 MHz, CDCh): δ ppm 7.83 (d, J = 3.7 Hz, 2H), 7.36-7.23 (m, 7H), 6.59 (t, J = 72.6 Hz , 1H), 4.28-3.85 (m, 8H), 3.32 (s, 1H), 1.39(s, 3H), 0.92 (s, 3H) 29 n'OF * CC ⁿ a__r 0 ^ J OH (2S) -1 - [5- (1,3-benzothiazol-6sulfonyl) -1 H, 2H, 3H, 4H, 5H, 3Hpyrrole [3,4-c ] pyrrol-2-yl] -3-hydroxy-2-phenylpropan-1-one m / z: 456 (300 MHz, CDCh): δ ppm 9.20 (s, 1H), 8.49 (s, 1H),8.25 (d, J = 6.6 Hz, 1H),7.94 (d, J = 3.7 Hz, 1H), 7.31-7.20 (m, 5H), 4,264.03 (m, 8H), 3.73-3.64 (m, 3H) 30 .—. o ______ _n n-vA ~ ' ⁿ C / C ⁿ ^ 0 ⁼ OH (2/3) -1 - [5- (1,3-benzothiazol-6sulfonyl) -1 H, 2H, 3H, 4H, 5H, 3Hpirrolo [3,4-c] pyrrol-2-yl] -3-hydroxy-2-phenylpropan-1-one m / z: 456 (300 MHz, CDCh): δ ppm9.22 (s, 1H), 8.49 (s, 1H),8.26 (d, J = 8.4 Hz, 1H),7.94 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 7.34-7.20 (m,5H), 4.30-4.03 (m, 8H), 3.75-3.69 (m, 3H)
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Example Structure, Name LCMS ¹ H NMR 31 J O r ~ ^ J „ = / o çOH(2S) -1- (5 - [[4-(difluoromethoxy) benzene] sulfonyl] -1 / 7.2 / 7.3 / 7.4 / 7.5 / 7.6 / 7-pyrrole [3,4-c] pyrrol-2-yl) -3-hydroxy-2-phenylpropan1-one m / z: 465 (300 MHz, DMSO-c / β): δ ppm 7.89-7.85 (m, 2H), 7.64 -7.15 (m, 8H), 4.76 (t, J = 5.1 Hz, 1H), 4.40-4.36 (m, 1H), 4.04-3.82 (m, 8H),3.80-3.77 (m, 1H), 3.483.41 (m, 1H)
Example 32: (2S) -1 - [5- (2,2-dimethyl-3,4-dihydro-2 / 7-1,4-benzoxazino-6sulfonyl) -1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c1pyrrol-2-yl1-3-hydroxy-2-phenylpropan-1-one

[00409] To a 25 ml round bottom flask, 2,2-dimethyl-6- [1 / -7,2 / -7,3 / 7,4 / 7,5 / 7,5H, 6 / TFA salt was added 7-pyrrolo [3,4-c] pyrrole-2sulfonyl] -3,4-dihydro-2 / 7-1,4-benzoxazine (112 mg, 0.25 mmol, 1.00 equiv), acid (2S ) -3-hydroxy-2-phenylpropanoic (42 mg, 0.25 mmol, 1.00 equiv), HATU (80 mg, 0.21 mmol, 0.84 equiv), DCM (2.00 ml) and DIEA ( 58 mg, 0.45 mmol, 2.00 equiv). The solution was stirred for 2 h at 25 Ό and then extracted with 20 ml of ethyl acetate. The organic phase was washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane / methanol (20/1) to produce (2S) -1- [5- (2,2-dimethyl-3,4-dihydro-2 / 7-1,4benzoxazino-6-sulfonyl) -1 / 7,2 / 7,3 / 7,4 / 7,5 / 7,6 / 7-pyrrolo [3,4-c] pyrrol-2-yl] - 3-hydroxy-2-phenylpropan-1-one as a white solid (18.7 mg, 15%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 7.29-7.28 (m, 5H), 7.04 (s, 1H), 6.90-6.85 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 4.85-4.70 (m, 1H), 4.50-4.30 (m, 1H) , 3.97 -3.93 (m, 8H), 3.90-3.80 (m, 1H), 3.35
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3.50 (m, 1H), 3.02 (d, J = 2.1 Hz, 2H), 1.24 (s, 6H). LCMS: m / z = 484.0 [M + H] ⁺ .
Examples 33 and 34: 6- (5 - [[(3S or 3fí) -oxan-3-illcarbonill1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / -pyrrole [3,4-c1pyrrole-2-sulfonyl) -3,4-dihydro-2 / - / - 1,4benzoxazine (Example 33) and 6- (54 ((3 / = / or 3S) - oxan-3-yl] carbonyl11H, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c1pyrrol-2-sulfonyl) -3,4- dihydro-2 / - / - 1,4benzoxazine (Example 34)
Example 33
Chiral separation
Example 34
Step 1. 1- (6- [5 - [(Oxan-3-yl) carbonyl1- 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / -pi rolo [3,4clpyrrol-2-sulfonill-3,4-dihydro-2 / - / - 1,4-benzoxazin-4-yl) ethan-1-one [00410] To an 8 ml bottle purged and maintained with an inert nitrogen atmosphere, oxane-3-carboxylic acid (62.4 mg, 0.48 mmol, 1.20 equivalent), DIEA (154.8 mg, 1.20 mmol, 3.00 equiv. ), 1- (6 - ((3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) - l) sulfonyl) -2,3-dihydro hydrochloride salt -4 / - / - benzo [ò] [1,4] oxazin-4-yl) ethan-1-one (154.4 mg, 0.40 mmol, 1.00 equiv), HATU (167.2 mg, 0.44 mmol, 1.10
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121/138 equiv) and dichloromethane (4 ml). The solution was stirred for 4 h at room temperature and then concentrated in vacuo. The crude product was purified by preparative TLC (DCM / MeOH = 15/1) to provide 100 mg (54%) of 1- (6- [5 - [(oxan-3-yl) carbonyl] - 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / pyrrole [3,4-c] pyrrole-2-sulfonyl] -3,4-dihydro-2 / - / -1,4-benzoxazin-4-yl) ethan1-one as a white solid. LCMS (ESI) m / z Calculated for C22H27N3O6S: 461.16; found: 462.0 [M + H] ⁺ .
Step 2. 6- [5 - [(oxan-3-yl) carbonyl1-1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [ 3,4clpyrrol-2-sulfonyl1-3,4-dihydro-2 / - / - 1,4-benzoxazine [00411] In an 8 mL bottle, 1- (6- [5 - [(oxan-3il ) carbonyl] - 1H, 2H, 3H, 6 / - / - pyrrole [3,4-c] pyrrole-2-sulfonyl] -3,4-dihydro-2 / - / - 1,4-benzoxazin-4-yl ) ethan-1-one (92 mg, 0.20 mmol, 1.00 equivalent) and a solution of sodium hydroxide (32 mg, 0.80 mmol, 4.00 equivalent) in methanol (2 ml) and water ( 0.5 ml). The solution was stirred for 4 h at room temperature and then the pH was adjusted to 9 with hydrochloric acid (2 mol / L). The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (50/1). The crude product (100 mg) was further purified by preparative HPLC (column: Xbridge Prep C18, 5 pm, 19x150 mm; mobile phase: water (contains 0.05% ΝΗ ₃ · Η ₂ Ο) and CH3CN with a gradient of 16% to 34% CH3CN in 10 minutes; UV detector wavelength 220 & 254 nm) to produce 80 mg (96%) of 6- [5 - [(oxan-3-yl) carbonyl] 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrole-2-sulfonyl] -3,4-dihydro -2 / - / - 1,4benzoxazine as a white solid. LCMS (ESI) m / z Calculated for C20H25N3O5S: 419.15; found: 420 [M + H] ⁺ .
Step 3 · Examples 33 and 34: 6- (5 - [[(3S or Sfij-oxan-S-ilIcarbonilI
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122/138 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - Dirrolo [3,4-c1oirrol-2-sulfonyl) -3,4-di -hydro-2 / - / - 1,4benzoxazine θ 6- (54 ((3 / = / or 3S) -oxan-3-yl] carbonyl11 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - Dirrolo [3,4-c1oirrol-2-sulfonyl) -3,4-dihydro-2 / - / - 1,4benzoxazine

Example 34 [00412] Chiral separation of 6- [5 - [(oxan-3-yl) carbonyl] 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrole-2-sulfonyl] -3,4-dihydro-2 / - / - 1,4benzoxazine racemic (80 mg) was performed by chiral prep HPLC (SHIMADZU LC- 20AT: CHIRALPAK IC column; mobile phase, A: Ethanol [containing 0.1% DEA], Phase B: Methanol; detector UV wavelength: 220 nm) to provide 22.3 mg (28%) of 6- (5 - [[(3S or 3 / = ) - oxan-3-yl] carbonyl] -1 H, 2H, 3H, 6 / - / - pyrrole [3,4-c] pyrrole-2sulfonyl) -3, 4-dihydro-2 / - / - 1,4-benzoxazine (Example 33) as a white solid, and 18.9 mg (24%) of 6- (5 - [[(3S or 3 / = ) -oxan-3-yl] carbonyl] 1 / - /, 2 / - /, 3 / - /, 4 / - /, 5 / - /, 6 / - / - pyrrole [3,4-c] pyrrole-2 -sulfonyl) -3,4-dihydro-2 / - / - 1,4benzoxazine (Example 34) as a white solid. The absolute stereochemistry has not been determined (*).
[00413] Example 33. Preparative chiral HPLC, Tr = 24.2 min. ¹ H NMR (300 MHz, CDCh): δ ppm 7.24-7.19 (m, 2H), 6.89 (d, J = 6.6 Hz,
1H), 4.44-4.34 (d, 2H), 4.25-4.18 (m, 2H), 4.12 (s, 6H), 3.95-3.91 (m, 2H) , 3.56-3.37 (m, 4H), 2.66-2.62 (m, 1H), 1.89-1.68 (m, 4H). LC-MS (ESI) m / z: Calculated for C20H25N3O5S: 419.15; found: 420 [M + H] ⁺ .
[00414] Example 34 Preparative chiral HPLC, Tr = 30.4 minutes. ¹ H NMR (300 MHz, CDCl 3): δ ppm 7.17-7.11 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 4.33-4.25 (m , 4H), 4.12 (s, 6H), 3.95-3.91 (m, 2H), 3.56-3.37 (m, 4H), 2.67-2.57 (m, 1H ), 1.89-1.66 (m, 4H). LC-MS (ESI) m / z: Cal
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123/138 for C20H25N3O5S: 419.15; found: 420 [M + H] ⁺ .
[00415] The Examples in Table 4 below were prepared according to the procedure outlined above for Examples 33 and 34, steps 1 and 2, using suitable synthetic precursors.
Table 4.
Example Structure, Name LCMS 35 ^h °. τΆυ ° ^H 00 (S) -1 - (5 - ((3,4-dihydro-2 / - / - benzo [b] [1,4] oxazin-6-yl) sulfonyl) -3,4, 5,6-tetrahydropyrrolo [3,4- c] pyrrole-2 (1 / - /) - yl) -3-hydroxy-2-phenyl I propan-1-one m / z: 456 36 The <. 'P hV Φ XQO(5 - ((3,4-Dihydro-2 / - / - benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4- c] pyrrole2 (1 H) -yl) (1 - (methoxymethyl) cyclopropyl) methanone m / z: 420 37 The <. 'P h.00O1 - (5 - ((3,4-Dihydro-2 / - / - benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3, 4-c] pyrrole2 (1 / - /) - yl) -3-hydroxy-2,2-phenyl I propan-1-one m / z: 408 38 The <. / P HrO ouI o1 - (5 - ((3,4-Dihydro-2 / - / - benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3, 4-c] pyrrole2 (1 / - /) - yl) -3-hydroxy-3-methyl butan-1-one m / z: 408
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Example Structure, Name LCMS 39 O * / ° HO(fi) - (5 - ((3,4-dihydro-2/7-benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole-2 (1/7) -yl) (tetrahydrofuran-3-yl) methanone m / z: 406 Examples 41 and 42: (I am fi -) - 1- (5- (4- (Difluoromethoxy) phenylsu fonil) -4,5-di-
hydropyrrolo [3,4-c] pyrrole-2 (1 / 7,3 / 7,4 / 7) -yl) -3-hydroxy-2- (pyridin-2-yl) propan1-one (Example 41) and ( fiou S) -1- (5- (4- (difluoromethoxy) phenylsulfonyl) -4,5dihydropyrrolo [3,4-c] pyrrole-2 (1 / 7,3 / 7,4 / 7) -yl) - 3-hydroxy-2- (pyridin-2yl) propan-1-one (Example 42)
Example 41 Example 42 [00416] A 1- (5 - [[4 (difluoromethoxy) benzene] sulfonyl] -1 / 7.2 / 7.3 hydrochloride salt with 3 necks of 100 ml / 7.4 / 7.5 / 7.6 / 7-pyrrolo [3.4c] pyrrol-2-yl) -2- (pyridin-2-yl) ethan-1-one (80 mg, 0.18 mmol , 1.00 equivalent) and sodium hydride (60% oil dispersion, 4.4 mg, 0.18 mmol, 1.00 equivalent) in tetrahydrofuran (10 ml). The reaction mixture was cooled to -10 Ό and formaldehyde (5.5 mg, 0.18 mmol, 1.00 equiv, 0.2 ml in THF) was added by dropping. The mixture was stirred for 4 h at 25 Ό and then quenched by the addition of water (20 ml). The solution was extracted with dichloromethane (3 x 20 ml). The combined organic layers were evaporated under
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125/138 reduced pressure and the crude material was purified by preparative HPLC with the following conditions: Column, X-bridge, RP18, 5 pm, 19x150 mm; mobile phase: water (contains 0.03% ammonia) and CH ₃ CN with a gradient of 45% to 60% CH ₃ CN in 5 min; flow rate: 20 mL / min; detector UV wavelength: 254 nm. This provided 1 - (5- (4- (difluoromethoxy) phenylsulfonyl) -4,5-dihydropyrrolo [3,4-c] pyrrol2 (1 / -7,3 / -7,4 / - /) - yl) -3-hydroxy-2- (pyridin-2-yl) propan-1-one (76 mg, 89%) as a white solid. The enantiomers were separated by chiral preparatory HPLC (SHIMADZU LC-20AD) with the following conditions: Chiral column DAICEL PAK OD-H, 20 x 250 mm, 5 pm; mobile phase: Phase A: ethanol, Phase B: methanol (containing 0.1% DEA) with isocratic elution of 60% ethanol; flow rate: 15 mL / min; detector wavelength: 220 nm. The absolute stereochemistry has not been determined (*). This provided:
[00417] Example 41: (S or / ⁼ ) - 1- (5- (4- (Difluoromethoxy) phenylsulfonyl) -
4,5-dihydroxypyrrolo [3,4-chlyrrol-2 (1 / 7,3 / 7,4 / 7) -yl) -3-hydroxy-2- (pyridin-2yl) propan-1-one Isolated as a yellow solid (11.3 mg, 15%). ¹ H NMR (300 MHz, DMSO-ok): δ ppm 8.45-8.47 (m, 1H), 7.90-7.87 (m, 2H), 7.70-7.75 (m, 1H), 7.37 (t, J = 73.2 Hz, 1H), 7.23-7.37 (m, 4H), 4.704.85 (m, 1H), 4.37-4.42 (m , 1H), 4.03-4.06 (m, 9H), 3.70-3.72 (m, 1H). LCMS: m / z = 466 [M + H] ⁺ .
[00418] Example 42: (ph or S) -1- (5- (4- (Difluoromethoxy) phenylsulfonyl) -
4,5-dihydroxypyrrolo [3,4-chlyrrol-2 (1 / 7,3 / 7,4 / 7) -yl) -3-hydroxy-2- (pyridin-2yl) propan-1-one Isolated as a yellow solid (14.2 mg, 19%). ¹ H NMR (300 MHz, DMSO-de): δ ppm 8.45-8.47 (m, 1H), 7.90-7.87 (m, 2H), 7.70-7.75 (m, 1H), 7.31 (t, J = 73.2 Hz, 1H), 7.23-7.31 (m, 4H), 4.704.85 (m, 1H), 4.38-4.42 (m , 1H), 4.03-4.06 (m, 9H), 3.69-3.72 (m, 1H). LCMS: m / z = 466 [M + H] ⁺ .
Example ________ 43: ________ (5- (Benzo [o1thiazol-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-clpyrrol-2 (1 / - /) - 11) (2,3-dihydrobenzofuran -3-yl) methanone
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Example 43 [00419] To an 8 ml_ flask, purged and maintained with an inert nitrogen atmosphere, 6 - ((3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 ( 1 / - /) - yl) sulfonyl) benzo [w /] thiazole (50 mg, 0.15 mmol, 1.00 equiv), 2,3-dihydro-1-benzofuran-3-carboxylic acid (29 mg , 0.18 mmol, 1.20 equiv.), DIEA (68 mg, 0.53 mmol, 3.50 equiv), HATU (65 mg, 0.17 mmol, 1.20 equiv) and DMF (1.00 ml_). The solution was stirred for 16 h at room temperature. Water (2 ml) was added by dripping. The solids were collected by filtration. The filter cake was washed with H2O (0.5 ml_) and MeOH (1.0 ml_), and the filtrate was collected and dried under vacuum to produce (5- (benzo [d] thiazol-6-ylsulfonyl) -
3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl) (2,3-dihydrobenzofuran-3yl) methanone (30 mg, 45%) as an off-white solid. ¹ H NMR (300 MHz, DMSO-ok): δ ppm 9.66 (s, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.99 (dd, J1 = 8.7 Hz, J2 = 1.8 Hz, 1H), 7,147.09 (m, 2H), 6.80-6.75 (m, 2H), 4.67-4.38 (m, 5H), 4.18 (s, 4H), 4.01 (m, 2H). LCMS: m / z = 454 [M + H] ⁺ .
Examples 44 and 45: (ph or S) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) - yl) (tetrahydro-2 / - / - pyran-3-yl) methanone (Example 44) and (S or / ⁼ ) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl) (tetrahydro-2 / - / - pyran-3-yl) methanone (Example 45)
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HATU, DIEA, DCM 20 ° C. overnight
Example 45 [00420] To a 50 ml round bottom flask, 2- (pyridin-2-ylsulfonyl) -1,2,3,4,5,6-hexahydropyrrolo [3,4-c] pyrrole was added (100 mg, 0.40 mmol, 1.00 equiv), oxane-3-carboxylic acid (52 mg, 0.40 mmol, 1.00 equiv), HATU (302 mg, 0.79 mmol, 1.97 equiv ), DCM (10 ml) and DIEA (154 mg, 1.19 mmol, 2.99 equiv). The solution was stirred overnight at 20 Ό. The mixture was diluted with 20 ml of DCM, washed with 2 x 20 ml of water, 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 (10/1). The enantiomers were separated by preparative chiral HPLC with the following conditions: column, Daicel CHIRALPAK® IA 21.2 x 250 mm, 5 pm; mobile phase, A = hexane, phase B = EtOH (maintained at 50.0% EtOH for 42 min); flow rate, 20 mL / min; Detector, UV 254 & 220 nm. The absolute stereochemistry has not been determined (*). This provided:
Example 44 · (ph or S) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol-2 (1 / - /) - yl) (tetra -hydro-2 / - / - pyran-3-yl) methanone (assumed stereochemical configuration) · [00421] Isolated as a white solid (12.1 mg, 8%). Preparative chiral HPLC, Tr = 24.472 min, ¹ H NMR (400 MHz, CDCh): δ 8.73-8.69 (m, 1H), 8.03-7.88 (m, 2H), 7.56- 7.42 (m, 1H), 4.43-4.26 (m, 6H), 4.16 (d, J = 3.6 Hz, 2H), 3.98-3.87 (m, 2H) , 3.54 (t, J = 12.0 Hz, 1H), 3.50
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3.34 (m, 1H), 2.68-2.49 (m, 1H), 1.96-1.76 (m, 2H), 1.69-1.48 (m, 2H). LCMS: m / z = 364.0 [M + H] ⁺ .
Example 45 · (S or ph) - (5- (Dyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - yl) (tetra -hydro-2 / - / - pyran-3-yl) methanone (assumed stereochemical configuration) · [00422] Isolated as a white solid (7.3 mg, 5%). Preparative chiral HPLC, Tr = 33.498 min. ¹ H NMR (400 MHz, CDCh): δ 8.75-8.67 (m, 1H), 8.04-7.88 (m, 2H), 7.58-7.39 (m, 1H), 4.43-4.26 (m, 6H), 4,184.16 (m, 2H), 4.00-3.89 (m, 2H), 3.54 (t, J = 12.0 Hz, 1H) , 3.48-3.29 (m, 1H), 2.69-2.48 (m, 1H), 1.95-1.76 (m, 2H), 1.72-1.58 (m, 2H).
LCMS: m / z = 364.2 [M + H] ⁺ .
Example
46:
3-Hydroxy-1- (5 - ((4-methyl-3,4-dihydro-2 / - / benzo [b] [1,41oxazin-6-yl) sulfonyl) -3,4,5,6 -tetrahydropyrrolo [3,4-c] pyrrole2 (1H) -yl) -2-phenylpropan-1-one

M
HCI / dioxane

[00423] To a 1.5 ml flask was added a 0.2 M solution of 3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 / - /) - tert-butyl carboxylate (100 pL, 20 pmol) in dioxane and pure DIEA (10 pL, 57 pmol) to produce a brown suspension. A 0.2 M solution of 4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazino-6-sulfonyl chloride (105 µL, 20 pmol) in dioxane was added. The reaction was heated to 50 ° with stirring for 2 hours. 4 M HCI in dioxane (50.0 pL, 0.200 mmol) was then added. The reaction was heated to 50 ΐ with stirring
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129/138 tion for an additional 2 hours. The volatile compounds were removed under reduced pressure. ACN (200 μΙ_) was added to the vial. The flask was shaken for 15 minutes to resuspend the residue. Pure DIEA (25 μΙ_, 0.143 mmol) and a 0.2 M solution of 3-hydroxy-2-phenylpropanoic acid (110 μΙ_, 22 μπιοΙ) in dioxane was added to the flask, followed by a 0.2 M solution of HBTU (110 μΙ_, 22 μπιοΙ) in ACN. The reaction was heated to 50 Ό with stirring for an additional 2 hours. The volatile compounds 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 volatile compounds were removed under reduced pressure. The compound was purified using mass-activated HPLC to produce 3-hydroxy1- (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazi n-6 -yl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -2-phenylpropan-1-one. LCMS: m / z = 470.2 [M + H] ⁺ .
[00424] The Examples in Table 5 below were prepared according to the procedure outlined above for Example 46, using suitable synthetic precursors.
Table 5 ·
Example Name Structure LCMS 40 3-hydroxy-1- (5 - ((4methoxyphenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4c] pyrrol-2 (1H) yl) propan-1-one 0ο ΎI47 4-Methyl-6 - {[5 (oxolane-3-carbonyl) 1 H, 2H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl] sulfonyl} -3,4-di-hydro-2 / - / - 1,4benzoxazine 0 r-ACp _N ⁰ m / z 420.2
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Example Name Structure LCMS 48 1- [5- (1,3-Benzothiazole-6sulfonyl) -1 H, 2.H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl] -3-hydroxy-2-phenylpropan-1-one 0 1) --- O q ^H ° X) m / z 456.1 49 1- {5- [4 (Difluoromethoxy) benzenesulfonyl] -1 H, 2.H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl} -3-hydroxy-2-phenylpropan-1-one .o — AA ^- ® ^-n AiA ^F— <o _) - y F / = <OH m / z 465.1 50 (2S) -3-hydroxy-2-phenyl-1 - [5- (pyridine-3sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl] propan-1-one N = OO ãJh- ⁿ CXm - o d ^OH m / z: 400.3 51 (2S) -3-hydroxy-2-phenyl-1 - [5- (pyridine-2sulfonyl) -1 H, 2H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl] propan-1-one Ah ^_n jl ⁿ X = / £ Y .., _x / = <OH m / z: 400.3 52 (2S) -3-hydroxy-2-phenyl-1- (5 - {[6 (trifluormethyl) pyridin3-yl] sulfonyl} -1 H, 2.H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl) propan-1-one ₇ ⁿ = / -r / ⁵ F o d ^0H m / z: 468.2
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Example Name Structure LCMS 53 3-Methoxy-1- {5 - [(4methyl-3,4-dihydro2 / - / - 1,4-benzoxazin-6-yl) sulfonyl] -1 H, 2.H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrol2-yl} propan-1-one N— -O m / z 408.2 54 1- {5- [4 (Difluoromethoxy)benzenesulfonyl] -1 H, 2.H, 3H, 4H, 5H, 6H -pyrrole [3,4-c] pyrrole-2- il} -3-hydroxypropan-1-one 0- ( ^{7 x} > —SN | N — X F- (^ = ⁷ 0 F OH m / z 391.1 55 (5- (benzofuran-5ilsulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrol-2 (1H) yl) (tetrahydrofuran-3yl) methanone 0,P^^ 056 ^to (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrol-2 (1H) yl) (morpholin-3yl) methanone ° Ύ T />57 1 - (5 - ((2,3-dihydrobenzo [b] [1,4] dioxin-6il) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3methoxypropan -1-one 0
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Example Name Structure LCMS 58 1- (5- (benzofuran-5ilsulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1H) -yl) -3methoxypropan-1-one 0Oο Ίθ0
^a The morpholine portion was protected with a Boc group in nitrogen throughout the synthesis of this molecule. The final step in the synthesis was the deprotection of the Boc Group (see step 2 in Example 46).
Example 47: PKR (with / without FBP), PKR (G332S / with FBP), PKR (R510Q / without FBP)
Luminescence Test Protocol [00425] In some embodiments, a PKR Activating Compound refers to a compound that has one or more characteristics when it is tested in accordance with the Luminescence Test Protocol following Example 47 performed with PKR type wild type (WT) and / or any one or more of the PKR G332S mutant form or the PKR R510Q mutant form: (1) an AC50 value less than 40 μΜ (for example compounds with AC50 values equal to +, ++ or +++ in Table 6); (2) a maximum% Fold value (MAX% Fold) greater than 75%; and / or (3) a% Fold value in the compound concentration of 1.54 μΜ (% Fold @ 1.54 μΜ) of at least 75%. In some embodiments, a PKR Activating Compound may have: (1) an AC50 value less than 0.1 μΜ (for example, compounds with AC50 equal to +++ in the Table
6), from 0.1 to 1.0 μΜ (for example, compounds with AC50 values equal to ++ in Table 6), or from 1.01 to 40 μΜ (for example, compounds with AC50 values equal to + in Table 6); (2) a MAX% Fold of 75% to 250%, 250 to 500% or 75% to 500%; and / or (3) a% Fold @ 1.54 μΜ of 75% to 250%, 250 to 500% or 75% to 500%. In some embodiments, a PKR Activating Compound has an AC50 value less than 1.0 μΜ; (2) a MAX% Fold of 75% -500%; and / or (3)
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133/138 a% Fold @ 1.54 μΜ of 75% -500%, obtained in the Luminescence Assay Protocol with any one or more of the wild type PKR (by weight), PKR mutant G332S form or mutant R510Q form of PKR. In some embodiments, the PKR Activating Compound has an AC50 value less than 1.0 μΜ; (2) a MAX% Fold of 75% -500%; and / or (3) a% Fold @ 1.54 μΜ of 75% -500%, obtained in the Luminescence Test Protocol with the wild type PKR (by weight). In some embodiments, the PKR Activating Compound has an AC50 value of less than 1.0 μΜ; (2) a MAX% Fold of 75% -500%; and / or (3) a 75% -500%% Fold @ 1.54 μΜ, obtained in the Luminescence Assay Protocol with either or both of the PKR mutant G332S form or the PKR mutant R510Q form.
[00426] Phosphorylation of Adenosine-5'-diphosphate (ADP) by various PKR mutants was determined by the Gio Plus kinase assay (Promega) in the presence or absence of FBP [D-fructose-1,6-diphosphate; BOC Sciences, CAS: 81028-91-3] as follows. Except where otherwise noted, all reagents were purchased from Sigma Aldrich. All reagents were prepared in buffer containing 50 mM Tris-HCI, 100 mM KCI, 5 mM MgCL and 0.01% Triton X100, 0.03% BSA and 1 mM DTT. Enzyme and PEP [hospho (enol) pyruvic acid] were added in 2x to all wells of a test-ready plate containing serial dilutions of the 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 concentration of PEP was equal to 100 μΜ. The Enzyme / PEP mixture was incubated with compounds for 30 minutes at room temperature before the assay was started with the addition of 2x ADP [Adenosine 5'-diphosphate] and KinaseGloPlus. The final concentration of ADP was equal to 100 μΜ. The final concentration of KinaseGloPlus was equal to 12.5%. For tests containing FBP, this reagent is added
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134/138 at 30 μΜ after the start of the reaction. The reactions progressed for 45 minutes at room temperature, until luminescence was recorded with a BMG PHERAstar FS multi-marker reader. All compounds were tested in triplicate at concentrations ranging from 42.5 μΜ to 2.2 nM at 0.83% DMSO.
[00427] The luminescence values were converted into% increase in times by normalizing the average of the DMSO control and multiplying by 100. Max, min, slope and AC50 were determined by the standard four parameter adjustment algorithm ActivityBase XE Runner. The compounds were evaluated with three parameters: AC50, MAX% Fold and% Fold @ 1.54 μΜ (FIGURE 1). The AC50 value for a compound is the concentration (pm) corresponding to half between the maximum and minimum values of the four-parameter logistic curve fit (ie, in which 0% increase in times over the four-logistic curve fit) parameters is half between MAX% Fold and MIN% Fold (midpoint of% times) MAX% Fold is the highest times increase observed at any concentration of the compound, and% Fold @ 1.54 μΜ is 0 times increase at a compound concentration of 1.54 μΜ. The% Fold @ 1.54 μΜ parameter was selected to capture both AC50 and MAX% Fold elements and to provide a rating based on both power and effect. 1.54 μΜ was chosen as one that can ideally differentiate the set of compounds based on the observed activity range.
[00428] As defined in Tables 6 and 7 below, the AC50 values (columns A, D and G) are defined as follows: <0.1 μΜ (+++); > 0.1 μΜ and <1.0 μΜ (++); > 1.0 μΜ and <40 μΜ (+); > 40 μΜ (0). Max% FOLD values (columns B, E H) are defined as follows: <75% (+); > 75% and <250% (++); > 250% and <500% (+++). The values of% Fold @ 1.54 μΜ (Columns C, F and I) are defined as follows:
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Table 6 - Biological data
Example PKRG332S PKRR510Q WILD TYPEConditions ¹ Conditions ¹ Conditions ¹ THE B ç D AND F G H I 1 ++ ++ ++ +++ +++ +++ +++ ++ ++ 2 + ++ ++ + +++ ++ + ++ ++ 3 ^a + ++ ++ ++ +++ ++ +++ ++ ++ 4 ^a + ++ ++ + ++ ++ 5 ^b + ++ ++ + +++ ++ ++ ++ ++ 6 ^b 0 0 + ++ ++ 7 +++ ++ ++ ++ ++ 8 +++ +++ +++ 9 +++ ++ ++ 10 +++ +++ ++ 11 ++ +++ ++ 12 ++ +++ +++ 13 ++ +++ ++ 14 ++ ++ ++ + +++ ++ ++ +++ +++ 15 0 ++ ++ + +++ ++ ++ ++ ++ 16 ++ ++ ++ + +++ ++ ++ +++ ++ 17 ++ ++ ++ 18 0 ++ ++ +++ ++ ++ 19 0 ++ ++ ++ +++ ++ ++ ++ ++ 20 ++ ++ ++ + +++ ++ ++ +++ ++ 21 + ++ ++ 22 ++ +++ +++ 23 ++ +++ +++ 24 ++ +++ ++ 25 ++ +++ ++ 26 +++ ++ ++ +++ +++ +++ +++ +++ +++ 27 +++ ++ ++ ++ +++ +++ +++ +++ +++
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Example PKRG332S PKRR510Q WILD TYPEConditions ¹ Conditions ¹ Conditions ¹ THE B ç D AND F G H I 28 +++ ++ ++ + +++ ++ ++ +++ ++ 29 +++ ++ ++ +++ +++ +++ +++ +++ +++ 30 ++ ++ ++ ++ +++ +++ ++ +++ +++ 31 +++ ++ ++ +++ +++ +++ +++ +++ +++ 32 0 ++ ++ +++ ++ ++ +++ ++ ++ 33 ^c 0 ++ ++ + +++ ++ + ++ ++ 34 ^c ++ ++ ++ +++ +++ +++ +++ ++ ++ 35 +++ ++ ++ +++ +++ +++ +++ ++ ++ 36 0 ++ ++ + ++ ++ ++ ++ ++ 37 0 ++ ++ +++ +++ +++ ++ ++ ++ 3839 +++ ++ ++ ++ +++ +++ ++ +++ +++ 40 + +++ ++ 41 ^d +++ ++ ++ +++ +++ +++ +++ +++ +++ 42 ^d +++ ++ ++ +++ +++ +++ +++ +++ +++ 43 ++ ++ ++ + +++ +++ ++ +++ +++ 44θ + ++ ++ 0 ++ ++ + ++ ++ 45θ ++ ++ ++ + +++ ++ ++ +++ ++ 46 0 ++ ++ 0 ++ ++ +++ ++ ++ 47 0 ++ ++ + +++ ++ ++ ++ ++ 48 +++ ++ ++ +++ +++ +++ +++ +++ +++ 49 +++ ++ ++ +++ +++ +++ +++ +++ +++ 50 ++ ++ ++ ++ +++ +++ ++ +++ ++ 51 ++ ++ ++ +++ +++ +++ +++ +++ +++ 52 ++ ++ ++ + +++ ++ ++ ++ ++ 53 0 ++ ++ + ++ ++ ++ ++ ++ 54 + +++ ++ + +++ ++ 5556 0 ++ ++ + ++ ++ 57 +++ ++ ++ ++ ++ ++
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Example PKRG332S PKRR510Q WILD TYPEConditions ¹ Conditions ¹ Conditions ¹ THE B ç D AND F G H I 58 +++ ++ ++ ++ +++ ++
0s ^to compounds 3 and 4 are enantiomers, but absolute stereochemistry is undetermined; ^b Compounds 5 and 6 are enantiomers, however the absolute stereochemistry is undetermined; Compounds 33 and 34 are enantiomers, are enantiomers, however the absolute stereochemistry is undetermined; ^d Compounds 41 and 42 are enantiomers, however the absolute stereochemistry is undetermined; ® Compounds 44 and 45 are enantiomers, however the absolute stereochemistry is undetermined. ¹ A - AC50 of LUM KGP FBP AC50 in μΜ of gmean;
B - AC50 of the MAX% FOLD average of LUM KGP FBP;
C - AC50 of the average μΜ of% Fold @ 1.54 μΜ of LUM KGP FBP
D - AC50 of LUM KGP woFBP AC50 in μΜ of gmean; E - AC50 of LUM KGP woFBP, average of MAX% FOLD;
F - AC50 of LUM KGP woFBP, average of% Fold @ 1.54 μΜ G - AC50 of LUM KGP woFBP, AC50 in μΜ of gmean; H - AC50 of LUM KGP woFBP, average of MAX% FOLD;
I - AC50 of LUM KGP woFBP, average of% Fold @ 1.54 μΜ
Table 7 - Biological data for additional compounds.
Example Structure PKRG332S PKRR510Q Conditions ¹ THE D 59 OH HO ^Z 0 0 60 c ° o fr 0 0
¹ A - AC50 of LUM KGP FBP AC50 in μΜ of gmean; D - AC50 of LUM KGP woFBP AC50 in μΜ of gmean.
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Equivalents [00429] Those skilled in the art will recognize, or be able to verify, using no more than routine experimentation, several equivalents to the specific modalities described here. Such equivalents are covered by the scope of the following claims.

权利要求:
Claims (27)
[1]
1. Compound characterized by the fact that it presents Formula I:
R ³ -0 R ¹ R ¹ ' ^r8 r ⁹ ' r ¹⁰ 'R ¹¹ ' (I), or a pharmaceutically acceptable salt thereof, where:
Y is a bond, - (CR ⁵ R ⁵ ') t-, -NR ⁵ (CR ⁵ R ⁵ ') t- or -O-;
each R ¹ , R ¹ ', R ² and R ² ' is independently -H, -alkyl (CiCe), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs), ( C4-Cs cycloalkenyl), heterocyclyl, aryl, heteroaryl, halogen, -CN, OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', S (O) R ⁵ , -S (O) NR ⁵ R ⁵ , -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', -C (O) R ⁵ and -C (O) OR ⁵ ;
or R ¹ and R ¹ ', or R ² and R ² ', together with the atom to which they are attached, can combine to form a cycloalkyl ring (Cs-Cs), heterocycle, spirocycle (Cs-Cs) or 5- to 8-membered spiroheterocycle;
or R ¹ and R ² , together with the atoms to which they are attached, can combine to form a -cycloalkyl (Cs-Cs) or a 3- to 8-membered heterocycle;
R ³ is independently -H, -Alkyl (Ci-Ce), -alkenyl (C2Ce), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl , -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , Petition 870180159548, of 12/06/2018, p. 44/201
[2]
2/20
S (O) NR ⁵ R ⁵ ', -C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, NR ⁵ R ⁵ ', -S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
or R ² and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring;
or R ¹ and R ³ , together with the atoms to which they are attached, can combine to form a 5- to 8-membered heterocyclic ring, optionally fused to an aryl or heteroaryl ring;
R ⁴ is -H, -Alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2Ce), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁵ , -SR ⁵ , -NO2, -NR ⁵ R ⁵ , -S (O) 2R ⁵ , S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) 2R ⁵ ', -NR ⁵ S (O) R ⁵ ', C (O) R ⁵ or -C (O) OR ⁵ , where each alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -R ⁵ , -OR ⁵ , -SR ⁵ , -NO2, - NR ⁵ R ⁵ , S (O) 2R ⁵ , -S (O) 2NR ⁵ R ⁵ ', -S (O) R ⁵ , -S (O) NR ⁵ R ⁵ ', -NR ⁵ S (O) ₂ R ⁵ ', NR ⁵ S (O) R ⁵ , -C (O) R ⁵ and -C (O) OR ⁵ ;
each R ⁵ and R ⁵ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', -S (O) R ⁶ , S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) ₂ R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ or -C (O) OR ⁶ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen
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[3]
3/20 nio, -CN, -R ⁶ , -OR ⁶ , -SR ⁶ , -NO2, -NR ⁶ R ⁶ ', -S (O) 2R ⁶ , -S (O) 2NR ⁶ R ⁶ ', S (O) R ⁶ , -S (O) NR ⁶ R ⁶ , -NR ⁶ S (O) ₂ R ⁶ ', -NR ⁶ S (O) R ⁶ ', -C (O) R ⁶ and -C ( O) OR ⁶ ;
or two R ⁵ at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
or two R ⁵ 'at adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heteroaryl ring optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a cycloalkyl ring (Cs-Cs) optionally substituted with one or more R ⁶ ; or two R ⁵ 'at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
each R ⁶ and R ⁶ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), -alquinyl (C2-C6), -cycloalkyl (Cs-Cs), -cycloalkenyl (C4-Cs), heterocyclyl, aryl, heteroaryl, halogen, -CN, -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O) R ⁷ , S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) ₂ R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ or -C (O) OR ⁷ , where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen
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[4]
4/20 nio, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, -NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', S (O) R ⁷ , -S (O) NR ⁷ R ⁷ , -NR ⁷ S (O) ₂ R ⁷ ', -NR ⁷ S (O) R ⁷ ', -C (O) R ⁷ and -C ( O) OR ⁷ ;
each R ⁷ and R ⁷ 'is independently, at each occurrence, H, -alkyl (Ci-Ce), -alkenyl (C2-C6), - alkynyl (C2-C6), -cycloalkyl (C3Cs), -cycloalkenyl (C4 -Cs), heterocyclyl, aryl, heteroaryl, halogen, CN, -OH, -SH, -NO2, -NH ₂ , -S (O) ₂ H, -S (O) ₂ NH ₂ , -S (O) H , -S (O) NH ₂ , NHS (O) ₂ H, -NHS (O) H, -C (O) H, or -C (O) OH, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of oxo, halogen, -CN, -OH, -SH, -NO2, -NH ₂ , -S (O) ₂ H, -S ( O) ₂ NH ₂ , -S (O) H, -S (O) NH ₂ , -NHS (O) ₂ H, NHS (O) H, -C (O) H and -C (O) OH;
each R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ and R ¹¹ are independently, in each occurrence, -H, -alkyl (Ci-Ce), -alkenyl (C2-C6) , alkynyl (C2-C6), -cycloalkyl (Cs-Cs) or -cycloalkenyl (C4-Cs), where each alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo , halogen, -CN, -R ⁷ , -OR ⁷ , -SR ⁷ , -NO2, NR ⁷ R ⁷ ', -S (O) 2R ⁷ , -S (O) 2NR ⁷ R ⁷ ', -S (O ) R ⁷ , -S (O) NR ⁷ R ⁷ ', -NR ⁷ S (O) ₂ R ⁷ ', NR ⁷ S (O) R ⁷ , -C (O) R ⁷ and -C (O) OR ⁷ ;
and t is 0, 1,2 or 3.
2. Compound, according to claim 1, characterized by the fact of having Formula (la-1):

[5]
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[6]
Compound according to claim 2 or 3, characterized in that R ¹ is optionally substituted -alkyl (C 1 -C), optionally substituted aryl or optionally substituted heteroaryl.
[7]
Compound according to any one of claims 1 to 4, characterized in that R ¹ and R ³ , taken together with the atoms to which they are attached, combine to form a 5- to 6-membered heterocyclic ring optionally replaced.
[8]
A compound according to any one of claims 1 to 4, characterized by the fact that R ³ is optionally substituted hydrogen or -alkyl (Ci-Ce).
[9]
Compound according to any one of the claims
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6/20 tions 1 to 4, characterized by the fact that R ² and R ² 'are each independently hydrogen or -alkyl (Ci-Ce) optionally substituted.
[10]
Compound according to any one of claims 1 to 4, characterized in that R ⁴ is optionally substituted aryl or optionally substituted heteroaryl.
[11]
Compound according to any one of claims 1 to 4, characterized in that each R ⁵ is independently -H or -alkyl (Ci-Ce) optionally substituted, or two R ⁵ in adjacent atoms. atoms to which they are attached form an optionally substituted heterocycloalkyl ring.
[12]
A compound according to any one of claims 1 to 4, characterized in that each R ⁶ is independently -alkyl (Ci-Ce).
[13]
13. A compound according to any one of claims 1 to 4, characterized by the fact that:
Y, if present, is a link;
R ¹ is selected from the group consisting of hydrogen, optionally substituted (C1 -C) alkyl, optionally substituted aryl and optionally substituted heteroaryl;
R ¹ ', if present, is selected from the group consisting of hydrogen and optionally substituted -alkyl (Ci-Ce);
or R ¹ and R ¹ ', taken together with the atoms to which they are attached, combine to form an optionally substituted -cycloalkyl (C3-C4);
R ² and R ² 'are each independently hydrogen or methyl;
R ³ is hydrogen or methyl;
or R ¹ and R ³ , taken together with the atoms to which they are attached, combine to form a heterocyclic ring of
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5 to 6 members optionally replaced;
R ⁴ is aryl optionally substituted with 6 to 10 members or heteroaryl optionally substituted with 6 to 10 members, with aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of -R ⁵ and OR ⁵ ;
each R ⁵ is independently -H or -alkyl (Ci-Ce) optionally substituted;
or two R ⁵ at adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
each R ⁶ is independently -alkyl (Ci-Ce); and each R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ and R ¹¹ , if present, is hydrogen.
[14]
14. Compound according to claim 13, characterized by the fact that:
Y, if present, is a link;
R ¹ is selected from the group consisting of hydrogen, methyl optionally substituted with -OR ⁵ , ethyl, optionally substituted 6-membered aryl and optionally substituted 5-6 membered heteroaryl;
R ¹ ', if present, is selected from the group consisting of hydrogen and methyl;
or R ¹ and R ¹ ', taken together with the atoms to which they are attached, combine to form an optionally substituted cyclopropyl;
R ² and R ² 'are each independently hydrogen or methyl;
R ³ is hydrogen or methyl;
or R ¹ and R ³ , taken together with the atoms to which
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R ⁴ is aryl optionally substituted with 6 to 10 members or heteroaryl optionally substituted with 6 to 10 members, with aryl or heteroaryl being optionally substituted with one or more substituents selected from the group consisting of -R ⁵ and OR ⁵ ;
each R ⁵ is independently -H or -alkyl (Ci-Ce) optionally substituted;
or two R ⁵ at adjacent atoms, together with the atoms to which they are attached, form a heterocycloalkyl ring optionally substituted with one or more R ⁶ ;
each of R ⁶ is independently -alkyl (Ci-Ce); and each of R ⁸ , R ⁸ ', R ⁹ , R ⁹ , R ¹⁰ , R ¹⁰ , R ¹¹ and R ¹¹ , if present, is hydrogen.
[15]
15. Compound, according to claim 1, characterized by the fact that it is selected from the group consisting of:
Example Structure Name 1 0 (S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 2 0 (R) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one
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Example Structure Name 3 0ΗΟ ^ '^ ’Χ ^ Ν ^ νN | Ί ' Znx' U / γγW (R) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy -2-(pi ridi n-2-i l) propan-1-one 4 0 Ηθ ' ^χ ^ γ ^χ Ν ^ _χ NA // ° U / γγ W (S) -1- (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy -2-(pi ridi n-2-i l) propan-1-one 5^l ~ C ¹ N p (R) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydro -2Hpiran-3-yl) methanone 6 city., _the 'XO (S) - (5 - ((2,3-dihydro-[1,4] dioxy at [2,3-b] pyridi n7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydro -2Hpiran-3-yl) methanone 7_F q ° Of ^N 00 <F 1 OH 1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy-2,2dimethylpropan- 1-one 8 O . vCQT rO '° Ho ^ xX ^ N ^ y ^0 1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one
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Example Structure Name 9 Μ Φ °0 1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 10 HO. / N%l rv HO ^ yNVO 1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2-(hydroxymethyl) -2methylpropan-1-one 11 % JCOHO,x / rvHO ΎγΝχ /0 1- (5- (benzofuran-5ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -2,2bis (hydroxymethyl) butan-1one 12 ο. Γ0 '°0 (R) - (5- (benzofuran-5ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydrofuran3-yl) methanone 13 grandfather)0 (S) - (5- (benzofuran-5ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydrofuran3-yl) methanone 14 o O / ° A- / § ' ^N CX / ^N ^ F— ' - 'OO F (R) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) (tetrahydrofuran-3-yl) methanone
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11/20
Example Structure Name 15 0° Ύ T /> (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydro-2H-piran-3-yl) methanone 16 the C F— 'o 0F (S) - (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) (tetrahydrofuran-3-yl) methanone 17 > 0 '·O (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1H) -yl) (1 (methoxymethyl) cyclopropyl) methanone 18 O 0X0 T rO ^ho Ov ^N 0 0 1- (5 - ((2,3-di-hydrobenzo [b] [1,4] dioxin-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 19 0° Ύ T /> 1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2,2-dimethylpropan-1-one 20 00 ^! 0 O (R) - (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydrofuran3-yl) methanone
Petition 870180159548, of 12/06/2018, p. 54/201
12/20
Example Structure Name 21 0° TfN 3-hydroxy-2,2-di methyl-1 - (5-((2-methylbenzo [d] oxazole-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1H) -yl) propan-1-one 22 rO '°0 1- (5- (benzofuran-5ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxypropan1-one 23 ROÕH 0 (R) -1 - (5- (benzofuran-5ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) -3-hydroxybutan1-one 24 ROOH O (S) -1 - (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxybutan-1-one 25 rO '°HOT V 1- (5- (benzofuran-5-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-3methylbutan-1-one 26 / - ⁰ r - ^ - ) - o — y— SN II N— / OH F— (o O ^F (♦ / -) (2S, 3Re2R, 3S) -1- (5 ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyric [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy-2-phenylbutan-1 one
Petition 870180159548, of 12/06/2018, p. 55/201
13/20
Example Structure Name 27 F- <# ASN ^ C / ^N ^ OFI οχ / 6 ^H (+/-) (2R, 3R and 2S, 3S) -1- (5 ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) - il) -3hydroxy-2-phenylbutan-1 one 28 0 — S-dP N— / F- ( = / ο XoH F / ⁼ 'w (S) -1 - (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy- 3-methyl-2-phenylbutan-1-one 29 0 A w ⁰ ϊ X 'Χ'Λ (S) -1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 30 0O ' (R) -1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 31 . . o ___o O— / Vs-n / PN— ^F d / = / (3 ~ y ' d ^OH(S) -1 - (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy- 2-phenylpropan-1 one
Petition 870180159548, of 12/06/2018, p. 56/201
14/20
Example Structure Name 32 o .aXC ^ T rO ^{H HO} o ' ^, _n x ^N ' A O (S) -1- (5 - ((2,2-dimethyl-3,4dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3 , 4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 33 RCP ^S O (S) - (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydro-2Hpyran-3-yl) methanone 34 A rCP ^S Α · _υ ν ^ 0 (R) - (5 - ((3,4-dihydro-2H-benzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydro-2Hyran-3-yl ) methanone 35 ^ xx) A ho ho. AvJ ^{0 H} JL _z ⁿ -a ^ U 0 (S) -1- (5 - ((3,4-dihydro2H-benzo [b] [1,4] oxazin6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 36 ΑΛ} i ^z ríj ^ °> 4 ° ^ 0 (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1H) - il) (1 (methoxymethyl) cyclopropyl) methanone
Petition 870180159548, of 12/06/2018, p. 57/201
15/20
Example Structure Name 37 x0 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2,2dimethylpropan-1-one 38_Η ° γ j 1 - (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-3-methylbutan-1-one 39 9'XX}0 (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydrofuran3-yl) methanone 40 o ^H ° ' ^xx ^ N ^x y ^ _o ° XX 1 3-hydroxy-1- (5 - ((4methoxyphenyl) sulfonyl) 3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1H) -yl) propan-1-one 41⁰ / u ^_N JL ^N F- ( = / o / FN = OH O (S) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy-2- (pyridin-2yl) propan-1-one
Petition 870180159548, of 12/06/2018, p. 58/201
[16]
16/20
Example Structure Name 42 o— ( ^z y — sn | n — χ F- (^ = ⁷ 0 FN = <OH w (R) -1- (5 - ((4-(difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyl [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy-2- (pyridin-2yl) propan-1-one 43 ° ^J ° TT /> (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (2,3-dihydrobenzofuran-3yl) methanone 44 O zN 0 <___ _t - / <CjH ^_n 0C ⁿ X '-' 0 0 (R) - (5- (pyridin-2ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydro-2Hyran-3-yl) methanone 45 ⁰ z — N o -----) - ⁷ X V- s- ⁿ XX ⁿ - ^ = ⁷ Ó 0 (S) - (5- (pyridin-2-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydro-2Hpyran-3-yl) methanone 46 0 Ho ' ^x ^ y ^k N'X_ ó 3-hydroxy-1 - (5 - ((4-methyl3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4 -c] pyrrole2 (1 H) -yl) -2-phenylpropan-1 one 47 'Ό0 (5 - ((4-methyl-3,4-dihydro-2H-benzo [b] [1,4] oxazin-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) (tetrahydrofuran-3-yl) methanone
Petition 870180159548, of 12/06/2018, p. 59/201
[17]
17/20
Example Structure Name 48 0 Λ w ⁰ ΪΧ 1 - (5- (benzo [d] thiazole-6-ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one 49 O 9 o— ( ^z y — sn | n— ^F_ (~ o JXa W 1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3hydroxy-2-phenylpropan- 1 ounce 50 N = / ° 4 7-SN II Η / ^0H(2S) -3-hydroxy-2-phenyl I-1 -[5- (pyridine-3-sulfonyl) -1H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrole-2yl] propan-1-one 51 Z ^ N 9 / -, - X zP z * ^- h ^_n jl = / £ / ^0H(2S) -3-hydroxy-2-phenyl I-1 -[5- (pyridine-2-sulfonyl) -1H, 2H, 3H, 4H, 5H, 6Hpyrrolo [3,4-c] pyrrole-2yl] propan-1-one 52 / ^N = 9 r-rf-x / 9 ^F : KJu ^N UVZ / ⁼ ° ^H(2S) -3-hydroxy-2-phenyl I-1 -(5 - {[6- (trifluormethyl) pyridin3-yl] sulfonyl} -1H, 2H, 3H, 4H, 5H, 6H-pyrrole [3,4-c] pyrrole-2-il) propan-1-one 53 0^ ~ v-Nx 9 1xo 3-methoxy-1 - (5 - ((4-methyl3,4-dihydro-2Hbenzo [b] [1,4] oxazin-6yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4 -c] pyrrole2 (1H) -yl) propan-1-one; and
Petition 870180159548, of 12/06/2018, p. 60/201
[18]
18/20
Example Structure Name 54 , 0 — YY — S-N ^ T ^ N— / F— (OF OH 1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) -yl) -3hydroxypropan-1-one. 55 ° C / ^N ^ ^N. , P ^^ 0 (5- (benzofuran-5ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrol2 (1 H) -yl) (tetrahydrofuran3-yl) methanone 56^{0 0} I JL /> (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl) (morpholin-3yl) methanone 57 OO 1- (5 - ((2,3-dihydrobenzo [b] [1,4] dioxin6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl ) -3-methoxypropan-one; and 58 O - <'N. 'z° χχγ 1- (5- (benzofuran-5ylsulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-methoxypropan1-one,
or a pharmaceutically acceptable salt thereof.
16. Compound according to claim 15, characterized in that the compound is (S) -1- (5 - ((2,3-dihydro- [1,4] dioxin [2,3-b ] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-
c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenyl propan-1-one.
17. Compound according to claim 15, characterized by the fact that the compound is (R) -1- (5 - ((2,3-dihydro-
Petition 870180159548, of 12/06/2018, p. 61/201
[19]
19/20 [1,4] dioxin [2,3-b] pyridin-7-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4c] pyrrole-2 (1 H) - il) -3-hydroxy-2- (pyridin-2-yl) propan-1-one.
18. Compound according to claim 15, characterized by the fact that the compound is (2S, 3R and 2R, 3S) -1- (5 - ((4 (difluormethoxy) phenyl) sulfonyl) -3,4,5 , 6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenylbutan-1-one.
19. Compound according to claim 15, characterized by the fact that the compound is (2S, 3R and 2R, 3S) -1- (5 - ((4 (difluormethoxy) phenyl) sulfonyl) -3,4,5 , 6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenylbutan-1-one.
[20]
20. Compound according to claim 15, characterized in that the compound is (S) -1- (5- (benzo [d] thiazol-6ilsulfonyl) -3,4,5,6-tetrahydropyrrolo [ 3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1-one.
[21]
21. Compound according to claim 15, characterized in that the compound is (S) -1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrole [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenylpropan-1-one.
[22]
22. Compound according to claim 15, characterized in that the compound is 1- (5 - ((3,4-dihydro-2Hbenzo [b] [1,4] oxazi n-6-yl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole2 (1 H) -yl) -3-hydroxy-2,2-di methyl propan-1-one.
[23]
23. Compound according to claim 15, characterized in that the compound is (S) -1- (5 - ((4 (difluoromethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrole [3,4-c] pyrrole-2 (1 H) yl) -3-hydroxy-2- (pyridin-2-yl) propan-1-one.
[24]
24. Compound according to claim 15, characterized in that the compound is 1- (5- (benzo [d] thiazol-6-ylsulfonyl) -
3,4,5,6-tetrahydropyrrolo [3,4-c] pyrrole-2 (1 H) -yl) -3-hydroxy-2-phenylpropan-1 one.
Petition 870180159548, of 12/06/2018, p. 62/201
20/20
[25]
25. Compound according to claim 15, characterized in that the compound is 1- (5 - ((4 (difluormethoxy) phenyl) sulfonyl) -3,4,5,6-tetrahydropyrrolo [3,4 -c] pyrrole-2 (1 H) yl) -3-hydroxy-2-phenylpropan-1-one.
[26]
26. Compound according to claim 15, characterized in that the compound is (2S) -3-hydroxy-2-phenyl-1- [5- (pyridine2-sulfoni I) - 1 H, 2H, 3H, 4H, 5H, 6H-pyrrolo [3,4-c] pyrrol-2-yl] propan-1-one.
[27]
27. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 26, and a pharmaceutically acceptable carrier.

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法律状态:
2021-05-11| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-06-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-10-05| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762473751P| true| 2017-03-20|2017-03-20|

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PCT/US2018/023405|WO2018175474A1|2017-03-20|2018-03-20|Pyrrolopyrrole compositions as pyruvate kinaseactivators|

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