Inhibitors of cGAS activity as therapeutic agents

Abstract

The present disclosure relates to compounds, pharmaceutical compositions containing them, and methods of using those compounds and compositions for treating or preventing inappropriate activation of a type I interferon (IFN) response in a subject in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 148,201, filed February 11, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure relates to compounds, pharmaceutical compositions containing them, and methods of using the compounds and compositions to treat or prevent inappropriate activation of a type I interferon (IFN) response in a subject in need thereof. [Background technology]

[0003] Lupus is the second most prevalent autoimmune disease, affecting at least 300,000 people in the United States and millions of people worldwide, causing severe pain and suffering that is exacerbated by exposure to sunlight, inability to work, and early death for millions of people worldwide, and there is no cure.Most investigational lupus drugs target the downstream effects of type I IFN.These include IFNα or IFNAR1 blocking mAbs that block IFNAR1 signaling, and JAK inhibitors that target cell types activated by type I IFN, such as B cells and T cells.

[0004] Cyclic GMP-AMP synthase (cGAS) (UniProtKB-Q8N884) is a recently discovered enzyme that functions as a DNA sensor to trigger immune responses to pathogens via activation of the stimulator of interferon genes (STING) receptor. Shortly after its discovery in 2013, aberrant activation of cGAS by self-DNA was shown to underlie debilitating and sometimes fatal autoimmune diseases such as systemic lupus erythematosus (SLE), scleroderma, and Aicardi-Goutiéres syndrome (AGS). Knockout studies in animal models have shown that inhibiting cGAS is a promising approach for therapeutic intervention. Furthermore, recent studies have shown that the cGAS-STING pathway plays a key role in the innate immune response to tumors, and stimulation of the pathway is a promising strategy being clinically tested for cancer immunotherapy. However, there are no reports of molecules being tested in animal models for lupus or any other autoimmune disease, except for compounds related to the antimalarial hydroxychloroquine, which inhibit cGAS by binding to DNA.

[0005] There are no drugs specifically approved for AGS or any other monogenic type I interferonopathies. Current treatment options are limited to intravenous or oral immunosuppressants and intravenous immunoglobulin during the acute phase, often with only partial control of inflammation. Similarly, SLE is treated with over-the-counter anti-inflammatory drugs, corticosteroids, and immunosuppressants such as cyclophosphamide and methotrexate, which are associated with severe side effects, including cancer. The only targeted therapy approved for SLE is BENLYSTA (belimumab), a monoclonal antibody (mAb) against B-cell activating factor (BAFF). BENLYSTA reduces the risk of severe inflammation and allows for low-dose immunosuppression in most patients, but is not curative.

[0006] Thus, there remains a need for compounds that can effectively inhibit cGAS activity and treat diseases resulting from the aberrant activation of cGAS. Summary of the Invention

[0007] It is against the above background that the present invention offers certain advantages over the prior art.

[0008] Although the invention disclosed herein is not limited to a particular benefit or functionality (e.g., novel inhibitors of cGAS activity, etc.), the invention encompasses compounds of formula (I) [ka] or a pharma- ceutically acceptable salt, N-oxide, and / or solvate or hydrate thereof, wherein: m is an integer of 1, 2, or 3; n is an integer of 0, 1, 2, 3, or 4; Ring A represents a 4- to 8-membered heterocyclyl ring; each R1 is independently selected from halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, and C1-C6 haloalkoxy; R2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R3 is -CO2R5, -COR5, -C(O)NR5R6, -CONH-OH, -S(O) 0-2 -R5, -SO2OR5, or -SO2NR5R6, R4 is -C(O)NR6R7, -CO2R7, -SO2OR7, or -SO2NR6R7; During the ceremony, R5 is hydrogen or C1-C6 alkyl; R6 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is selected from the group consisting of aryl(C0-C4 alkyl) optionally substituted with one or more R9, heteroaryl(C0-C4 alkyl) optionally substituted with one or more R9, heterocyclyl(C0-C4 alkyl) optionally substituted with one or more R8, and cycloalkyl(C0-C4 alkyl) optionally substituted with one or more R8; each R8 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -N3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(O)R6, -C(O)OR6, and -C(O)NR5R6, or two R8 together form an oxo; Each R9 is independently selected from halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -N3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, optionally one or more R 10 Aryl (C0-C1 alkyl) optionally substituted with one or more R 10 Heteroaryl(C0-C1 alkyl) optionally substituted with one or more R 10 heterocyclyl(C-C alkyl) substituted with, and optionally one or more R 10 cycloalkyl(C0-C1 alkyl) substituted with Each R 10 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -N3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, and -methyl-OH, or a pharma- ceutically acceptable salt, N-oxide, and / or solvate or hydrate thereof.

[0009] In certain embodiments, the compound of formula (I) is (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(pyridin-4-ylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-pyrazol-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d ]pyrimidin-4-yl)-4-(2-oxo-2-(pyridin-2-ylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(cyclopentyl-amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, or (2S,4R)1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(phenylamino)ethyl)pyrrolidine-2-carboxylic acid.

[0010] Another aspect of the disclosure provides pharmaceutical compositions comprising one or more of the compounds of the disclosure (e.g., compounds as described above with respect to Formula (I)) and a suitable carrier, solvent, adjuvant, or diluent.

[0011] The present disclosure also provides a method for treating or preventing inappropriate activation of a type I interferon (IFN) response in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds of formula (I), as discussed above.

[0012] In embodiments of the methods disclosed herein, the inappropriate activation of a type I IFN response comprises an autoimmune disorder (e.g., Aicardi-Goutieres syndrome (AGS), retinal vasculopathy with cerebral leukodystrophy (RVCL), lupus erythematosus (SLE), scleroderma, or Sjogren's syndrome (SS)). Other aspects of the present disclosure will be apparent to those of skill in the art in light of the disclosure herein.

[0013] Another aspect of the present disclosure provides a method of treating an autoimmune disorder, comprising administering to a subject in need of such treatment an effective amount of one or more compounds of the present disclosure (e.g., a compound as described above with respect to Formula (I)) or a pharmaceutical composition of the present disclosure.

[0014] In certain embodiments of this aspect, the autoimmune disorder is AGS, RVCL, SLE, scleroderma, SS, age-related macular degeneration (AMD), pancreatitis, ischemia (e.g., ischemic injury), inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), or Parkinson's disease.

[0015] These and other features and advantages of the present invention will be more fully understood from the following detailed description taken in conjunction with the appended claims, which are noted to be defined by the enumeration herein, and not by the specific discussion of the features and advantages described herein.

[0016] The accompanying drawings are included to provide a further understanding of the disclosed methods and compositions, and are incorporated in and constitute a part of this specification. These drawings illustrate one or more embodiment(s) of the disclosure and, together with the description, serve to explain the principles and operation of the disclosure. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 is a schematic showing that activation of cGAS by cytoplasmic DNA initiates activation of the innate immune response via induction of type I interferon (IFN-1). [Diagram 2] 1 is a bar graph showing the effect of compounds 4 and 5 at 20 μM on IFNβ mRNA levels in human THP-1 dual cells normalized to β-actin. BX is the BTK1 inhibitor BX-795 (N-[3-[[5-iodo-4-[[3-[(2-thienylcarbonyl)amino]propyl]amino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide) at 1 μM. [Diagram 3]1 shows dose-dependent stabilization of cGAS by compound 5 in cells as measured using a cellular thermal shift assay (CETSA). Panel A is an image of a Western blot and Panel B is a bar graph of the stabilization scale. Heat treatment was performed at 51.5° C. [Figure 4-1] FIG. 1 shows plasma (a) concentration-time profiles of compound 5 (BBL-100455) over time in C57BL / 6 mice (n=3) following intravenous (IV) and oral (PO) dosing. [Figure 4-2] FIG. 1 shows plasma log(b) concentration-time profiles of compound 5 (BBL-100455) over time for C57BL / 6 mice (n=3) following intravenous (IV) and oral (PO) dosing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to particular embodiments, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, unless specifically defined herein.

[0019] In view of the present disclosure, the methods and compositions described herein can be configured by those skilled in the art to meet the desired needs. In general, the disclosed materials and methods provide improvements in the treatment of diseases or disorders associated with abnormal activation of cGAS. Specifically, the inventors have found that the compounds of the present disclosure can inhibit cGAS activity and thus treat or prevent inappropriate activation of type I IFN response. The compounds of the present disclosure are generally defined in terms of formula (I) and in terms of the various subgenera defined below.

[0020] Thus, one aspect of the disclosure provides a compound of formula (I) as described above. [ka]

[0021] In certain embodiments, the compound of formula (I) is (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(pyridin-4-ylamino)ethyl)-pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-pyrazol-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl) -4-(2-oxo-2-(pyridin-2-ylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(cyclopentylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, or (2S,4R)-1-(2-methylbenzofuro)-[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(phenylamino)-ethyl)pyrrolidine-2-carboxylic acid.

[0022] One embodiment of the disclosure provides a compound of formula (I) as described herein, wherein n is 0, 1, 2, or 3. In certain embodiments, the compound of formula (I) is one in which n is 0, 1, or 2. In certain embodiments, the compound of formula (I) is one in which n is 0 or 1. In certain embodiments of the compound of formula (I) as described herein, n is 2, 3, or 4, and each R1 is the same. In certain embodiments of the compound of formula (I) as described herein, n is 2, 3, or 4, and each R1 is different. One embodiment of the disclosure provides a compound of formula (I) as described herein, wherein n is 0.

[0023] One embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R1 is halogen, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, C1-C4 alkoxy, or C1-C4 haloalkoxy. In certain embodiments, each R1 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, and C1-C6 alkoxy. In certain embodiments of the compound of formula (I), each R1 is independently selected from C1-C3 alkyl, -OH, and C1-C3 alkoxy.

[0024] Another embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R2 is hydrogen or C1-C6 alkyl. In certain embodiments, R2 is hydrogen or C1-C4 alkyl. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is C1-C4 alkyl, such as methyl.

[0025] In certain embodiments of the compounds of Formula (I) described herein, n is 0 and R2 is hydrogen.

[0026] In certain embodiments of the compounds of Formula (I) as described, n is 0 and R2 is methyl.

[0027] One embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein Ring A is a 5- or 6-membered heterocycloalkyl. In certain embodiments, Ring A is pyrrolidinyl, azetidinyl, or piperidinyl.

[0028] In certain embodiments of the compounds of formula (I) described herein, n is 0, R2 is hydrogen, and Ring A is pyrrolidinyl, azetidinyl, or piperidinyl. In certain embodiments of the compounds of formula (I) described herein, n is 0, R2 is C1-C4 alkyl, such as methyl, and Ring A is pyrrolidinyl, azetidinyl, or piperidinyl.

[0029] In certain embodiments of the compounds of formula (I) described herein, ring A is pyrrolidinyl. For example, in certain embodiments, ring A has the structure: [ka] In certain other embodiments, ring A is of the structure: [ka] In certain other embodiments, ring A is the S-enantiomer of the structure [ka] It is the 2S,4R-enantiomer of

[0030] Another embodiment of the disclosure provides a compound of formula (I) as described herein, wherein m is 1, 2, or 3. In certain embodiments, m is 1 or 2. In certain embodiments, m is 1.

[0031] In certain embodiments, the compound of formula (I) has the structure: [ka] and m is 1 or 2 (eg, m is 1).

[0032] In certain embodiments, the compound of formula (I) has the structure: [ka] and m is 1 or 2 (for example, m is 1).

[0033] One embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R3 is -CO2R5, -COR5, -C(O)NR5R6, -CONH-OH, -SO2R5, -SO2OR5, or -SON2NR5R6. In certain embodiments, R3 is -CO2R5, -COR5, -SO2R5, -SO2OR5, or -SON2NR5R6. In certain embodiments, R3 is -CO2R5, -SO2R5, -SO2OR5, or -SON2NR5R6. In certain other embodiments, R3 is -CO2R5, -COR5, -C(O)NR5R6, or -CONH-OH. In certain other embodiments, R3 is -CO2R5, -C(O)NR5R6, or -CONH-OH. In certain other embodiments, R3 is -CO2R5 or -C(O)NR5R6. In certain other embodiments, R3 is -CO2R5. In some embodiments, each R5 is independently hydrogen or methyl, and each R6 is independently hydrogen or methyl. In certain embodiments of the compounds of formula (I) described herein, R3 is -CO2H.

[0034] In certain embodiments of the compounds of Formula (I) described herein, each R5 is independently hydrogen or methyl, and each R6 is independently hydrogen or methyl.

[0035] In exemplary embodiments, R3 is -C(O)H, -C(O)CH3, -C(O)C2H6, -C(O)OCH3, -C(O)OC2H6, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -C(O)NCH3CH3, -S(O)CH3, -S(O)C2H6, -S(O)2CH3, -S(O)2C2H6, -S(O)OH, -S(O)2OH, -S(O)2OCH3, or -S(O)2OC2H6. In certain embodiments, compounds of formula (I) described herein are those in which R3 is -C(O)OCH3, -C(O)OC2H6, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -C(O)NCH3CH3, -S(O)CH3, or -S(O)C2H6. In certain embodiments, compounds of formula (I) described herein are those in which R3 is -C(O)OH.

[0036] Another embodiment of the present disclosure provides a compound of formula (I) described herein, wherein R4 is selected from -C(O)NR6R7, -CO2R7, and -SO2NR6R7. For example, in certain embodiments, R4 is -C(O)NR6R7 or -SO2NR6R7. In certain embodiments, R4 is -C(O)NR6R7. In the compounds of formula (I) described herein, R6 is hydrogen or C1-C4 alkyl. For example, R6 is hydrogen. In another example, R6 is methyl.

[0037] In certain embodiments of compounds of Formula (I), ring A has the structure: [ka] and R4 is -C(O)NR6R7. For example, the compounds of formula (I) described herein are of the formula: [ka] where R2 is hydrogen or C1-C4 alkyl, such as methyl.

[0038] In one embodiment of the compound of formula (I) described herein, R6 is hydrogen or C1-C4 alkyl. In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is methyl.

[0039] Another embodiment of the present disclosure provides a compound of formula (I) as described herein, wherein R7 is selected from the group consisting of aryl (C0-C1 alkyl) optionally substituted with one or more R9, heteroaryl (C0-C1 alkyl) optionally substituted with one or more R9, heterocyclyl (C0-C1 alkyl) optionally substituted with one or more R8, and cycloalkyl (C0-C1 alkyl) optionally substituted with one or more R8. In certain embodiments, R7 is selected from the group consisting of aryl optionally substituted with one or more R9, heteroaryl optionally substituted with one or more R9, heterocyclyl optionally substituted with one or more R8, and cycloalkyl optionally substituted with one or more R8. In certain embodiments, R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, 5-12 membered heteroaryl optionally substituted with one or more R9, 5-12 membered heterocyclyl optionally substituted with one or more R8, and C3-C8 cycloalkyl optionally substituted with one or more R8. In certain other embodiments, R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, 5-12 membered heteroaryl optionally substituted with one or more R9, and C3-C8 cycloalkyl optionally substituted with one or more R8. In certain other embodiments, R7 is C3-C8 cycloalkyl optionally substituted with one or more R8 (e.g., optionally substituted cyclopentane). In certain other embodiments, R7 is phenyl optionally substituted with one or more R9, or 5-12 membered heteroaryl optionally substituted with one or more R9. In certain other embodiments, R7 is phenyl optionally substituted with one or more R9. In certain other embodiments, R7 is phenyl substituted with one or more R9. In certain other embodiments, R7 is 5-12 membered heteroaryl (e.g., pyridinyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl) optionally substituted with one or more R9.In certain embodiments, R7 is a bicyclic heteroaryl (eg, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl) optionally substituted with one or more R9.

[0040] In one embodiment of the compound of formula (I) described herein, R7 is phenyl, pyridinyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl, each optionally substituted with one or more R9, or cyclopentanyl, optionally substituted with one or more R8.

[0041] In one embodiment of the compound of formula (I) described herein, R7 is phenyl substituted with one or more R9, pyridinyl substituted with one or more R9, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl, each optionally substituted with one or more R9, or cyclopentanyl substituted with one or more R8.

[0042] In one embodiment of the compounds of formula (I) described herein, each R is independently selected from the group consisting of halogen, -NO, -CN, C-C alkyl, C-C haloalkyl, -NH, -NH(C-C alkyl), -N(C-C alkyl), -OH, C-C alkoxy, C-C haloalkoxy, -C(O)R, -C(O)OR, and -C(O)NR, or two R form oxo. In certain embodiments, each R is independently selected from the group consisting of halogen, -NO, -CN, C-C alkyl, C-C haloalkyl, -NH, -NH(C-C alkyl), -N(C-C alkyl), -OH, C-C alkoxy, and C-C haloalkoxy, or two R form oxo. In certain embodiments, each R is independently halogen, C 1-In certain other embodiments, each R is independently selected from the group consisting of C4 alkyl, C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -OH, C1-C4 alkoxy, and C1-C4 haloalkoxy. 10 In certain other embodiments, each R is independently selected from the group consisting of halogen, -NO, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl-methyl-, heteroaryl, heteroaryl-methyl-, and heterocyclyl, each optionally substituted with one or more R 10 substituted with, C1-C4 alkyl, C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

[0043] In certain embodiments, the compounds of formula (I) described herein are of the formula: m is an integer equal to 1; n is an integer of 0 or 1, Ring A represents a pyrrolidinyl, azetidinyl, or piperidinyl ring; each R1 is independently selected from C1-C3 alkyl, -OH, and C1-C3 alkoxy; R2 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R3 is -CO2R5 or -C(O)NR5R6; R4 is -C(O)NR6R7 or -SO2NR6R7; During the ceremony, R5 is hydrogen or C1-C4 alkyl; R6 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, 5-12 membered heteroaryl optionally substituted with one or more R9, 5-12 membered heterocyclyl optionally substituted with one or more R8, and C3-C8 cycloalkyl optionally substituted with one or more R8; each R8 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, and C1-C6 haloalkoxy, or two R8 together form an oxo; Each R9 is independently selected from one or more of R 10 substituted with, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NH, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

[0044] In certain embodiments, the compounds described herein have the formula [ka] wherein: R2 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R4 is -C(O)NR6R7 or -SO2NR6R7; During the ceremony, R6 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, 5-12 membered heteroaryl optionally substituted with one or more R9, 5-12 membered heterocyclyl optionally substituted with one or more R8, and C3-C8 cycloalkyl optionally substituted with one or more R8; each R8 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, and C1-C6 haloalkoxy, or two R8 together form an oxo; Each R9 is independently selected from one or more of R 10 substituted with, C1-C4 alkyl, C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

[0045] In certain embodiments, the compounds of formula (I) described herein are m is an integer equal to 1; n is an integer of 0 or 1; Ring A represents a pyrrolidinyl, azetidinyl, or piperidinyl ring; each R1 is independently selected from C1-C3 alkyl, -OH, and C1-C3 alkoxy; R2 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R3 is -CO2R5 or -C(O)NR5R6; R4 is -C(O)NR6R7 or -SO2NR6R7; During the ceremony, R5 is hydrogen or C1-C4 alkyl; R6 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, pyridinyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl, each optionally substituted with one or more R9, and cyclopentyl optionally substituted with one or more R8; each R8 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, and C1-C6 haloalkoxy, or two R8 form an oxo; Each R9 is independently selected from one or more of R 10 substituted with, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NH, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

[0046] In certain embodiments, the compounds described herein have the formula [ka] wherein: m is an integer equal to 1; n is an integer of 0 or 1; Ring A represents a pyrrolidinyl, azetidinyl, or piperidinyl ring; each R1 is independently selected from C1-C3 alkyl, -OH, and C1-C3 alkoxy; R2 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R3 is -CO2R5 or -C(O)NR5R6; R4 is -C(O)NR6R7 or -SO2NR6R7; During the ceremony, R5 is hydrogen or C1-C4 alkyl; R6 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; R7 is selected from the group consisting of phenyl optionally substituted with one or more R9, pyridinyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl, each optionally substituted with one or more R9, and cyclopentyl optionally substituted with one or more R8; each R8 is independently selected from the group consisting of halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, and C1-C6 haloalkoxy, or two R8 form an oxo; Each R9 is independently selected from one or more of R 10 substituted with, C1-C4 alkyl, C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, C1-C4 alkoxy, C1-C4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

[0047] In certain embodiments, a compound of formula (I) as otherwise described herein is one of the compounds listed in Example 2.

[0048] In certain embodiments, the present disclosure also provides Mn 2+ IC of the above compounds under otherwise identical conditions 50 At least 5 times more than Mn 2+ IC in the presence of 50The present invention provides a cGAS inhibitor compound (e.g., a compound of formula (I) discussed above) having the following structure:

[0049] In one embodiment of the disclosure, a compound disclosed elsewhere herein (eg, a compound of formula (I), or a compound listed in Example 2) is in the form of an N-oxide.

[0050] In one embodiment of the present disclosure, the compounds disclosed elsewhere herein (e.g., compounds of formula (I) or listed in Example 2) are in the form of pharmaceutically acceptable salts. Those skilled in the art will appreciate that various pharmaceutically acceptable salts can be provided, as further detailed below. Those skilled in the art will appreciate that the phrase "optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate" includes compounds in the form of a pharmaceutically acceptable salt of N-oxide. However, in the above specific embodiment, the compounds are not in the form of a pharmaceutically acceptable salt. Thus, in one embodiment, the compounds disclosed elsewhere herein are in the form of a base compound.

[0051] In one embodiment of the present disclosure, the compounds disclosed elsewhere herein (e.g., compounds of formula (I) or compounds listed in Example 2) are in the form of a solvate or hydrate. Those skilled in the art will appreciate that various solvates and / or hydrates may be formed. Those skilled in the art will appreciate that the phrase "optionally in the form of a pharma-ceutically acceptable salt or N-oxide, or a solvate or hydrate" includes the compounds in the form of base compounds, pharma-ceutically acceptable salts, and N-oxide solvates and hydrates as described above. However, in certain embodiments above, the compounds are not in the form of a solvate or hydrate.

[0052] In one embodiment of the present disclosure, a compound disclosed elsewhere herein (e.g., a compound of formula (I) or a compound listed in Example 2) is in the form of an N-oxide. However, in certain embodiments above, the compound is not in the form of an N-oxide.

[0053] therapeutic use The inventors have determined that in certain embodiments, the compounds described herein can inhibit cGAS. Accordingly, one aspect of the present disclosure provides a method for treating or preventing inappropriate activation of type I interferon (IFN) response in a subject in need thereof, the method comprising administering to the subject an effective amount of one or more compounds of the present disclosure described herein (e.g., a compound of formula (I) or a compound provided in Example 3) or a pharmaceutical composition of the present disclosure described herein. In certain embodiments of the methods described elsewhere herein, the inappropriate activation of type I IFN comprises an autoimmune disorder. In certain such embodiments, the autoimmune disorder is Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, lupus erythematosus, scleroderma, or Sjogren's syndrome.

[0054] The present disclosure also provides a method for treating an autoimmune disorder.Such a method comprises administering to a subject in need of such treatment an effective amount of one or more compounds of the present disclosure as described herein or a pharmaceutical composition of the present disclosure as described herein.

[0055] Many different autoimmune disorders can be treated using the compounds and compositions of the present disclosure. Particularly suitable autoimmune disorders to be treated by the methods of the present disclosure include, but are not limited to, Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, lupus erythematosus, scleroderma, or Sjogren's syndrome.

[0056] The compounds and compositions of the present disclosure as described herein may also be administered in combination with one or more second therapeutic agents.Thus, in certain embodiments, the method also includes administering to a subject in need of such treatment an effective amount of one or more compounds of the present disclosure described herein (e.g., compounds of formula (I) or those provided in Example 3) or pharmaceutical compositions of the present disclosure described herein and one or more second therapeutic agents.

[0057] "Combination therapy," in defining the use of a compound of the present disclosure and another therapeutic agent, is intended to encompass administration of each agent in a sequential manner in a regimen that provides a beneficial effect of the drug combination (e.g., the compounds and compositions of the present disclosure described herein, and the second therapeutic agent, can be formulated as separate compositions administered sequentially), as well as co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple or separate capsules for each agent. The present disclosure is not limited to the order of administration, and the compounds and compositions of the present disclosure can be administered either before or after (i.e., sequentially), or at the same time (i.e., simultaneously) as the administration of the second therapeutic agent.

[0058] In certain embodiments, the second therapeutic agent is administered at a concentration lower than its established 50% inhibitory concentration (IC 50 For example, the second therapeutic agent may be administered in an amount less than the inhibitory concentration (IC 50 ), for example, less than 1%, for example, less than 10%, or less than 25%, or less than 50%, or less than 75%, or less than 90%.

[0059] Pharmaceutical Compositions In another aspect, the present disclosure provides a composition comprising one or more of the compounds as described above with respect to formula (I) and a suitable carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent depends on the desired use of the composition and may range from suitable or acceptable for veterinary use to suitable or acceptable for human use. The composition may optionally include one or more additional compounds. In certain embodiments, the composition may include one or more antibiotic compounds.

[0060] When used to treat or prevent such diseases, the compounds described herein may be administered alone as a mixture of one or more compounds, or in mixtures or combinations with other drugs useful for treating such diseases and / or symptoms associated with such diseases. The compounds may also be administered in mixtures or combinations with drugs useful for treating other disorders or diseases, such as steroids, membrane stabilizers, 5LO inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, inhibitors of IgG isotype switching or IgG synthesis, beta agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines. The compounds may be administered in the form of the compounds themselves or as pharmaceutical compositions containing the compounds.

[0061] Pharmaceutical compositions containing the compound(s) can be manufactured by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that facilitate processing of the compounds into preparations that can be used medicaments.

[0062] The compound may be formulated as a pharmaceutical composition itself, or in the form of a hydrate, solvate, N-oxide or pharma-ceutically acceptable salt, as described above.Typically, such salts are more soluble in aqueous solution than the corresponding free acid and base, but salts that have lower solubility than the corresponding free acid and base may also be formed.

[0063] The pharmaceutical compositions can be in a form suitable for virtually any mode of administration, including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0064] For local administration, the compound(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0065] Useful injectable preparations include sterile suspensions, solutions or emulsions of active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. The injectable preparations may be presented in unit dosage form, for example, in ampoules or multi-dose containers, and may contain added preservatives. Alternatively, the injectable preparations may be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, and the like, before use. For this purpose, the active compound(s) may be dried by any technique known to those skilled in the art, such as lyophilization, and reconstituted before use.

[0066] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation, and such penetrants are known in the art.

[0067] For oral administration, the pharmaceutical compositions may take the form of lozenges, tablets or capsules prepared by conventional means with pharma- ceutically acceptable excipients, such as, for example, binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated, for example, with sugar, film or enteric coatings, by methods well known in the art.

[0068] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as dry products for constitution with water or other suitable vehicles before use.Such liquid preparations may be prepared by conventional means using pharma- ceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™ or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweeteners, as necessary.

[0069] Preparations for oral administration may be appropriately formulated to give controlled release of compound, as is well known.For oral administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.For rectal and vaginal administration, compound(s) may be formulated as a solution (for retention enemas) suppository or ointment containing a conventional suppository base such as cocoa butter or other glycerides.

[0070] For nasal administration or administration by inhalation or insufflation, the compound(s) can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges (for example, capsules and cartridges made of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0071] For ocular administration, the compound(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.

[0072] For long-term delivery, the compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection.The compound(s) can be formulated as suitable polymeric or hydrophobic materials (e.g., as an emulsion in acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., sparingly soluble salts.Alternatively, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases the compound(s) for percutaneous absorption.To this end, permeation enhancers can be used to facilitate the percutaneous penetration of the compound(s).

[0073] Alternatively, other pharmaceutical delivery systems can be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compound(s). Certain organic solvents such as dimethylsulfoxide (DMSO) can also be used, usually at the expense of greater toxicity.

[0074] The pharmaceutical composition may be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the compound(s), if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0075] The compound(s) or compositions described herein are generally used in an amount effective to achieve the intended result, for example, an amount effective to treat or prevent the particular disease being treated.Therapeutic benefit refers to eradication or improvement of the underlying disease being treated, and / or eradication or improvement of one or more of the symptoms associated with the underlying disease, such that the patient reports an improvement in mood or condition, even though the patient may still suffer from the underlying disease.Therapeutic benefit also generally includes stopping or slowing the progression of the disease, regardless of whether improvement is realized.

[0076] The amount of compound(s) administered will depend on a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated, and the age and weight of the patient, the bioavailability of the particular compound(s), the rate and efficiency of interaction with the active drug compound under the selected route of administration, etc.

[0077] Determining the effective dose of a compound(s) for a particular use and mode of administration is well within the capabilities of one of ordinary skill in the art. Effective doses can be estimated initially from in vitro activity and metabolism assays. For example, the initial dose of a compound for use in animals may be determined based on the IC 50 The active compound may be formulated to achieve a circulating blood or serum concentration of the metabolite active compound that is equal to or greater than 100 mg / kg. It is well within the ability of a person skilled in the art to calculate the dosage to achieve such a circulating blood or serum concentration, taking into account the bioavailability of a particular compound via a desired route of administration. The initial dose of the compound may also be estimated from in vivo data, such as animal models. Animal models useful for testing the effectiveness of active metabolites for treating or preventing various diseases described above are well known in the art. Animal models suitable for testing the bioavailability and / or metabolism of a compound to active metabolites are also well known. A person skilled in the art can routinely adapt such information to determine the dosage of a particular compound suitable for human administration.

[0078] Dosages typically range from about 0.0001 mg / kg / day, 0.001 mg / kg / day, or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower depending, among other things, on the activity of the active compound, the bioavailability of the compound, its metabolic kinetics and other pharmacokinetic properties, the mode of administration, and various other factors discussed above. Dosage amounts and intervals may be individually adjusted to provide plasma levels of the compound(s) and / or active metabolite compound(s) that are sufficient to maintain therapeutic or prophylactic effects. For example, the compound may be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, depending, among other things, on the mode of administration, the particular indication being treated, and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of the compound(s) and / or active metabolite compound(s) may not be related to the plasma concentration. One of ordinary skill in the art can optimize the effective dosage without undue experimentation.

[0079] definition As used herein, the following terms and expressions have the meanings indicated.

[0080] Throughout this specification, unless the context requires otherwise, the terms "comprise" and "include", as well as variations (e.g., "comprises", "comprising", "includes", "including") are understood to imply the inclusion of a referenced component, feature, element, or step, or group of components, features, elements, or steps, but not the exclusion of any other integer or step, or group of integers or steps.

[0081] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0082] Terms used herein may be preceded or followed by a single dash "-" or a double dash "=" to indicate the bond order between the named substituent and its parent moiety, with a single dash indicating a single bond and a double dash indicating a double bond. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety, and further, the substituents are intended to be read "left to right" (i.e., the bond is through the last part of the name) unless the dash indicates otherwise. For example, C1-C6 alkoxycarbonyloxy and -OC(O)C1-C6 alkyl indicate the same functionality, and similarly, arylalkyl and -alkylaryl indicate the same functionality.

[0083] The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0084] The term "alkyl" as used herein, unless otherwise specified, means a straight or branched chain hydrocarbon containing 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl" group is a linking group between two other moieties, it may also be straight or branched, examples include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, and -CH2CH(CH2CH3)CH2-.

[0085] The term "aryl" as used herein refers to at least one phenyl ring or phenyl containing aromatic bicyclic rings containing only carbon atoms in the aromatic bicyclic ring system (i.e., monocyclic aryl), or bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, monocyclic cycloalkenyl, or monocyclic heterocyclyl. The bicyclic aryl is bonded to the parent molecular moiety through any carbon atom contained in the phenyl portion of the bicyclic system or any carbon atom associated with the naphthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portion of the bicyclic aryl is optionally substituted with one or two oxo and / or thia groups. Representative examples of bicyclic aryls include azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, and 2,3-dihydrobenzofuran-4-yl. , 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-one-5-yl, 2H-chromen-2-one-6-yl, 2H-chromen-2-one-7-yl, 2H-chromen-2-one-8-yl, isoindoline-1,3-dione-4-yl, isoindoline-1,3-dione-5-yl, inden-1-one-4-yl, inden-1-one-5-yl, inden-1-one-6-yl, inden-1-one-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-5-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-7-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-8-yl, benzo[d]oxazin-2(3H)-one-5-yl, benzo[d]oxazin-2(3H)-one-6-yl, benzo[d]oxazin-2(3H)-one-7-yl, benzo[d]oxazin-2(3H)-one-8-yl, quinazolin-4(3H)-one-5-yl, These include, but are not limited to, quinazolin-4(3H)-one-6-yl, quinazolin-4(3H)-one-7-yl, quinazolin-4(3H)-one-8-yl, quinoxalin-2(1H)-one-5-yl, quinoxalin-2(1H)-one-6-yl, quinoxalin-2(1H)-one-7-yl, quinoxalin-2(1H)-one-8-yl, benzo[d]thiazol-2(3H)-one-4-yl, benzo[d]thiazol-2(3H)-one-5-yl, benzo[d]thiazol-2(3H)-one-6-yl, and benzo[d]thiazol-2(3H))-one-7-yl. In certain embodiments, the bicyclic aryl is (i) a naphthyl, or (ii) a phenyl ring fused to either a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, or a 5- or 6-membered monocyclic heterocyclyl, where the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups that are independently oxo or thia.

[0086] The term "cycloalkyl" as used herein refers to a monocyclic or bicyclic cycloalkyl ring system. A monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, and such groups may be saturated or unsaturated, but are not aromatic. In certain embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. A bridged monocyclic ring includes a monocyclic cycloalkyl ring, in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge (i.e., -(CH2)) between 1 to 3 additional carbon atoms. w -, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group is optionally substituted with one or two groups that are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, where the fused bicyclic cycloalkyl is optionally substituted by one or two groups that are independently oxo or thia.

[0087] The term "halo" or "halogen" as used herein means -Cl, -Br, -I, or -F.

[0088] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, as the case may be, substituted with one or more halogen atoms.

[0089] The term "heteroaryl" as used herein refers to a monocyclic heteroaryl or bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5- or 6-membered ring. The 5-membered ring consists of two double bonds and one, two, three, or four nitrogen atoms, and optionally one oxygen or sulfur atom. The 6-membered ring consists of three double bonds and one, two, three, or four nitrogen atoms. The 5- or 6-membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. Bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups, which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained in the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring, the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom in the bicyclic ring system.Representative examples of bicyclic heteroaryls include benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-1- ... -tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, 2,3-dihydrothieno[3,4-b][1,4]dioxan-5-yl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, where the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups that are independently oxo or thia.

[0090] The terms "heterocyclyl" and "heterocycloalkyl" as used herein refer to a monocyclic or bicyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, and oxazolinyl. Bicyclic heterocycles include, but are not limited to, sazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholinsulfone), thiopyranyl and trithianyl. Bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. The heterocyclyl group is optionally substituted with one or two groups that are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl fused to a phenyl ring, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups that are independently oxo or thia.

[0091] The term "oxo" as used herein, means a =O group.

[0092] The term "saturated" as used herein means that the chemical structure being referred to does not contain any multiple carbon-carbon bonds. For example, saturated cycloalkyl groups as defined herein include cyclohexyl, cyclopropyl, and the like.

[0093] The term "substituted," as used herein, means that a hydrogen group of the specified moiety can be replaced with a specified substituent group, provided that such replacement results in a stable or chemically viable compound. The term "substitutable," when used in reference to a specified atom, means that bonded to the atom is a hydrogen group, which can be replaced with a suitable substituent group.

[0094] The phrase "one or more" substituents, as used herein, refers to a number of substituents equal to one to the maximum number of possible substituents based on the number of available binding sites, provided that the above stability and chemical feasibility conditions are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be the same or different. As used herein, the term "independently selected" means that the same or different values ​​may be selected for multiple instances of a given variable in a single compound.

[0095] The term "thia" as used herein means a ═S group.

[0096] The term "unsaturated" as used herein means that the chemical structure referred to contains at least one carbon-carbon bond, but is not aromatic. For example, unsaturated cycloalkyl groups as defined herein include cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

[0097] It is clear to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.Unless otherwise specified, the structures shown herein are also meant to include all stereochemical forms of the structures, i.e., the R and S configurations of each asymmetric center.Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomeric and diastereomeric mixtures, are within the scope of the present disclosure.Both R and S stereochemical isomers, and all mixtures thereof, are included within the scope of the present disclosure.

[0098] "Pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, or otherwise approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0099] "Pharmaceutically acceptable salts" refers to both acid and base addition salts.

[0100] "Therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to result in treatment of a disease or disorder as described herein. The amount of a compound that constitutes a "therapeutically effective amount" varies depending on the compound, the disorder and its severity, and the age of the subject being treated, but can be routinely determined by one of ordinary skill in the art.

[0101] "Subject" refers to a warm-blooded animal, such as a mammal, preferably a human, or human child, that is afflicted with or capable of being afflicted with one or more of the diseases and disorders described herein.

[0102] Preparation method Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0103] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as HPLC, preparative thin-layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most typically, the disclosed compounds are purified via silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. LRSnyder and JJKirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed E.Stahl, Springer-Verlag, New York, 1969.

[0104] During any of the processes for the preparation of the compounds of interest, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules concerned. This is described in standard works such as J.F.W.MacOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973, in T.W.Greene and P.G.M.Weuts, “Protective Groups in Organic Synthesis,” Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organischen Chemie,” Houben-Weyl, 4th edition, Vol.15 / l, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H.Jescheit, “Aminosauren, Peptide, Protein,” Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or in Jochen This can be achieved by conventional protecting groups as described in Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient later stage using methods known from the art.

[0105] The compounds disclosed herein can be made using procedures well known to those skilled in the art. For example, the compounds of structural formula (I) can be prepared according to the general procedures of the examples and / or similar synthetic procedures. Those skilled in the art can adapt the reaction sequence of these examples and general procedures to the desired target molecule. Of course, in certain situations, those skilled in the art will use different reagents to affect one or more of the individual steps or use specific protected versions of the substituents. Furthermore, those skilled in the art will recognize that the compounds disclosed herein can be fully synthesized using different routes. EXAMPLES

[0106] The compounds and methods of the present disclosure are further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures and compounds described therein.

[0107] Example 1. General Method for the Synthesis of Compounds of the Present Disclosure All solvents were purchased from commercial suppliers and used without further purification. 1 H and 13 C NMR spectra were recorded on a Varian Mercury 300 MHz or Bruker BioSpin spectrometer at 400 / 500 MHz. Mass spectra were measured using liquid chromatography mass spectrometry (LC / MS) in electrospray ionization (ESI) mode at an ionization potential of 70 eV. The purity of all final compounds (>95%) was determined by analytical high performance liquid chromatography (HPLC).

[0108] Benzofuro[3,2-d]pyrimidine precursors such as 4-chloro-2-methylbenzofuro[3,2-d]pyrimidine, 6, were prepared essentially according to the following procedure. [ka]

[0109] The benzofuro[3,2-d]pyrimidine precursors can be functionalized to arrive at compounds of formula (I) essentially according to the following procedure. [ka]

[0110] To a suspension of tert-butyl 2-(diethoxyphosphoryl)acetate (1) (34.2 g / 31.9 mL, 136 mmol) in anhydrous THF (100 mL) under nitrogen and vigorous stirring, LHMDS (45 mL of 1 M / THF) was added dropwise at 0° C. After stirring for 30 min at 0° C., 1-(tert-butyl) 2-methyl(S)-4-oxopyrrolidine-1,2-dicarboxylate (2) (30.0 g, 123 mmol) in THF (100 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organics were washed successively with water, brine and dried (Na2SO4). Filtration and concentration in vacuo gave the crude product, which was purified by Yamazen silica gel flash chromatography using 0-20% EtOAc in hexanes to give 1-(tert-butyl) 2-methyl(S,E)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylate (3) (40 g, 95%) as an oil. LCMS [M+H] + C 17 H 27 NO6342.37.

[0111] A suspension of 1-(tert-butyl) 2-methyl (S)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylate (3) (40 g, 120 mmol), Pd / C (20%, 50% wet) (19 g, 18 mmol) and EtOAc (300 mL) was stirred under H2 atmosphere overnight. The reaction mixture was filtered, washed with EtOAc and concentrated to give compound 4 in quantitative yield as a colorless oil, which was used in the next step without further purification. LC-MS 344.26 (ES+); 1H NMR (400 MHz, CDCl3) δ 4.29 and 4.28 (two, ratio=1.2:1, 1H), 3.82 (m, 1H), 3.71 and 3.72 (two, ratio=2:1, 3H), 3.09 (m, 1H), 2.51 and 2.39 (two m, 2H + 1H), 2.45 (m 1H), 1.66 (m, 1H), 1.55 and 1.44 (four s, 9H + 9H): rotamer ratio = ca. 1.5:1.

[0112] To a solution of 1-(tert-butyl) 2-methyl(2S,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (4) (40 g, 116 mmol) in DCM (300 mL) was added TFA (13.28 g, 116 mmol) dropwise. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo to give compound 5 (approximately 30 g, 90% yield) as an oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.46 (two d, 1H), 3.75 (s, 3H), 3.40 (dd, 1H), 2.92 (dd, 1H), 2.45-2.6 (m set, solvent overlap, 4H), 1.68 (two t, J = 8Hz, 1H); ratio = 93:7.

[0113] To a solution of methyl (2S,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylate (5) (TFA salt, 21.7 g, 72.2 mmol) in NMP (125 mL) was added 4-chloro-2-methylbenzofuro[3,2-d]pyrimidine (11.3 g, 56 mmol) and K2CO3 (25 g, 180 mmol). The reaction mixture was stirred at 80 °C overnight, after which water and EtOAc were added and the layers were separated. The organics were washed successively with water, brine and dried (Na2SO4). Filtration and concentration in vacuo gave the crude product which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound 7 (9.5 g, 51% yield). 1HNMR (400MHz, DMSO) δ 8.05 (d, J = 8Hz, 1H), 7.77 (br, 0.5H), 7.67(t, 1.5H), 7.46 (two d, J = 4, 8Hz, 1H), 5.17 (br, 0.5H), 4.48 and 4.62 (two br, 1H), 4.26 (br, 0.5H), 3.68 (s, 3H), 3.57 (br, 1H), 2.68 (m, 1H), 2.48 (m, overlap with DMSO, 3H + 3H), 1.66 and 1.81 (two br, 1H); oscillating temperature (60 °C) δ 8.05 (d, J = 8Hz, 1H), 7.67 (dd and dt, 2H), 7.47 (two d, J = 4, 8Hz, 1H), 4.82 (br, 1H), 4.43 (br, 1H), 3.68 (s, 3H), 3.57 (br, 1H), 2.65 (m,1H + 1H), 2.48 (m, overlap with DMSO, 3H + 2H ), 1.75 (m, 1H);LC-MS 369.8 (ES+) 368.2 (ES-). [ka]

[0114] Synthesis of 10-1 or 10-2: To a stirred solution of carboxylic acid 7 (11 mmol, 1 equiv.) in DMF (40 mL), DIEA (3 equiv.) was added followed by HATU (1.1 equiv.) in an ice-water bath and stirred at room temperature for 10 min. The corresponding aniline 8 or 9 (1.1 equiv.) was added to this solution and stirred at room temperature for 6 h. After workup, the crude was purified by flash chromatography (MeOH:DCM=0:100 to 5:95) to give the ester 10-1 or 10-2 in good yield.

[0115] Synthesis of target via route A: To a suspension of 10-1 (133.4 mg, 248.1 μmol) in THF (3 mL) and water (1 mL), LiOH (25 eq) was added and stirred at room temperature for 4 h and warmed to 37° C. for an additional 4 h. After cooling to room temperature, the solution was acidified with 6 N HCl (pH ∼5) and purified by preparative HPLC to give 11.

[0116] Synthesis of target via route B: A suspension of 10-2 (1 equiv), boronic acid (1.5 equiv), potassium carbonate (2 equiv), and tetrakis(triphenylphosphine)palladium(0) (0.1 equiv) in dioxane (2 mL) and water (1 mL) was degassed and recharged with Ar five times. The resulting reaction mixture was heated to 90 °C for 2 h to give a dark solution. Activated charcoal was added to the solution, stirred for 15 min, and filtered. The filtrate was concentrated and purified by flash chromatography (MeOH:DCM = 0:100 to 10:90) to give the ester.

[0117] The ester was hydrolyzed by the same method as in Route A. The synthesis of compounds 47, 48, 51, 59, and 60 (notes below) was carried out as Route B.

[0118] Example 2. Compounds of the present disclosure The following compounds were prepared substantially according to the procedures described above and procedures well known to those skilled in the art: Compound A is a comparative compound. Compound A: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(pyridin-4-ylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL0100352) [ka] Compound 1: (2S,4R)-4-(2-((1H-indol-5-yl)amino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100462) [ka] Compound 2: (2S,4R)-4-(2-(cyclopentyl(methyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100461) [ka] Compound 3: (2S,4R)-4-(2-((1H-indazol-5-yl)amino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100459) [ka] Compound 4: (2S,4R)-4-(2-(benzo[d]thiazol-6-ylamino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100458) [ka] Compound 5: (2S,4R)-4-(2-([1,1'-biphenyl]-4-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100455) [ka]

[0119] 1 HNMR (500MHz, DMSO-d6) δ 12.4-13.2 (br, 1H).10.10 (s, 1H), 8.05 (br d, J = 8 Hz, 1H), 7.76 (ABqB, J = 8 Hz, 2H), 7.71 (d and t, J = 8 Hz, 6H), 7.43 (t, J = 8 Hz, 3H), 7.31 (t both, J = 8 Hz, 1H), 5.13 (br, 1H), 4.59 - 4.29 (m, 1H), 3.73 (br, 1H), 3.01 - 2.92 (m, 7H), 1.90 - 1.74 (m, 1H), (ESI) m / z C 30 H 26 Calculated for N4O4: 506.20. Found: 507.06 (M+H) + . Compound 6: (2S,4R)-4-(2-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL0100460) [ka] Compound 7: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(piperidin-1-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100711) [ka]

[0120] 1 HNMR (400MHz, DMSO-d6) δ 12.83 (br, 1H), 10.16 (br, 1H), 8.14 (d, J = 8Hz, 1H), 7.88 (br, 1H), 7.75 (m, 4H), 7.55 (m, 1H), 7.40 (br, 1H), 5.24 (br, 1H), 4.68 (br m, 1H), 4.35 - 3.80 (br, 1H), 3.39 (br, 4H), 2.9 - 2.4 (m, overlapped with DMSO, 7H ), 1.95 (br, overlap, 1H), 1.80 (br, 4H), 1.60 (br, 2H);(ESI) m / z C 29 H 31 Calculated for N5O4: 513.24. Found: 514.25 (M+H) + . Compound 8: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(piperazin-1-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100716) [ka]

[0121] 1 HNMR (400MHz, DMSO-d6) δ 10.84 (s, 1H), 8.66 (br, 1H), 8.08 (d, J = 10Hz, 1H), 7.79 (br, 1H), 7.68 (m, 1H), 7.49 (t, J = 10Hz, 3H), 6.96 (d. 1H);(ESI) m / z C 28 H 30 Calculated for N6O4: 514.23. Found: 515.32 (M+H) + . Compound 9: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxoethyl)pyrrolidine-2-carboxylic acid (BBL-0100717) [ka]

[0122] 1 HNMR (500MHz, DMSO-d6) δ 12.73 (br, 1H), 9.86 (s, 1H), 9.72 (br, 1H), 8.12 (d, J = 10Hz, 1H), 7.83 (br, 1H), 7.70 (m, 1H), 7.50 (t and B of ABq, J = 10Hz, 3H), 6.95 (A of ABq, J = 10Hz, 2H), 5.25 (br, 1H), 4.66 - 4.42 (br s, 1H), 3.75 (br, overlap, 4H), 3.13 - 2.90 (m, 4H), 2.85 (s, 3H), 2.9 - 2.4 (m, overlap with DMSO, 8H), 1.80 (br d, 1H).(ESI) m / z C 29 H 32Calculated for N6O4: 528.25. Found: 529.37 (M+H) + . Compound 10: (2S,4R)-4-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100718) [ka]

[0123] 1 HNMR (500MHz, DMSO-d6) δ 12.79 (br, 1H), 9.98 (s, 1H), 8.07 (d, J = 5Hz, 1H), 7.98 (s, 2H), 7.76 (br, 1H), 7.66 (m, 1H), 7.60 (d, J = 10Hz, 2H), 7.53 (d, J = 10Hz, 2H), 7.45 (t, 1H), 5.13 (br, 1H), 4.60 - 4.26 (br s, 1H), 3.71 (br, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H ), 1.80 (br d, 1H);(ESI) m / z C 27 H 24 Calculated for N6O4: 496.19. Found: 497.36 (M+H) + . Compound 11: (2S,4R)-4-(2-((3-(1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100730) [ka]

[0124] 1HNMR (500MHz, DMSO-d6) δ 12.80 (br, 1H), 10.00 (s, 1H), 8.05 (d, J = 5Hz, 1H), 7.95 (s, 2H), 7.79 (br, 2H), 7.66 (m, 1H), 7.45 (t, 2H), (ESI) m / z C 27 H 24 Calculated for N6O4: 496.19. Found: 497.17 (M+H) + . Compound 12: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(trifluoromethoxy)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100724) [ka]

[0125] 1 HNMR (500MHz, DMSO-d6) δ 12.67 (br, 1H), 10.10 (s, 1H), 8.06 (d, J = 8Hz, 1H), 7.77 (br, 1H), 7.72 (d, J = 10Hz, 2H), 7.65 (m, 1H), 7.45 (t, 1H), 7.31 (d, J = 10Hz, 2H), 5.12 (br, 1H), 4.60 - 4.25 (m, 1H), 3.72 (br, 1H), 2.4~2.9 (m, overlap with DMSO, 7H ), 1.80 (br d, 1H);(ESI) m / z C 25 H 21 Calculated for F3N4O5: 514.15. Found: 514.94 (M+H) + . Compound 13: (2S,4R)-4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100701) [ka]

[0126] 1 HNMR (400MHz, DMSO-d6) δ 12.40 (br, 1H), 9.99 (s, 1H), 8.06 (d, J = 8Hz, 1H), 7.80 (br, 1H), 7.67 (d, J = 8Hz, 1H), 7.45 (t, 1H), 7.32 (s, 1H), 7.18 (m, 1H), 7.13 (d, 1H), 6.63 (dt, 1H), 5.10 (br, 1H), 4.56 - 4.26 (br s, 1H), 3.72 (s, overlap, 4H), 2.9 - 2.4 (m, overlap with DMSO, 7H), 1.80 (br d, 1H);(ESI) m / z C 25 H 24 Calculated for N4O5: 460.17. Found: 461.9 (M+H) + . Compound 14: (2S,4R)-4-(2-((2-methoxyphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100726) [ka]

[0127] 1HNMR (400MHz, DMSO-d6) δ 9.19 (br, 1H), 8.05 (d, J = 8Hz, 1H), 7.77 (br, 1H), 7.65 (m, 1H), 7.45 (t, 1H), 7.1 - 7.0 (m, 2H), 6.92 (dt, J = (ESI) m / z C 25 H 24 Calculated for N4O5: 460.17. Found: 461.01 (M+1) + . Compound 15: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(p-tolylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100702) [ka]

[0128] 1 HNMR (400MHz, DMSO-d6) δ 13.10 (br, 1H), 9.92(s, 1H), 8.14 (d, 1H), 7.78 (br, 1H), 7.76 (m, 1H), 7.56 (t, 1H), 7.49 (B of ABq, J = 8Hz, 2H), 7.10 (A of ABq, J = 8Hz, 2H), 5.13 (br, overlap with H2O, 1H), 4.68 (br d, 1H), 4.38 (br s, 0.5H), 3.79 (br, 0.5H), 3.42 (m, 0.5H), 2.4~2.9 (m, overlap with DMSO, 3H + 3H + 1.5H ), 2.24 (s, 3H), 1.76 and 2.00 (two br, 1H); (ESI) m / z C 25 H 24 Calculated for N4O4: 444.18. Found: 444.94 (M+1) + . Compound 16: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(m-tolylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100703) [ka]

[0129] 1 HNMR (400MHz, DMSO-d6) δ 13.05 (br, 1H), 9.94 (s, 1H), 8.15 (d, 1H), 7.89 (br, 1H), 7.76 (m, 1H), 7.56 (t, 1H), 7.46 (s, 1H), 7.38 (br d, 1H), 7.19 (t, 1H), 6.86 (d, 1H), 5.27 (br, 1H), 4.70 - 4.39 (br s, 1H), 3.79 - 3.42 (m, 1H), 2.9 - 2.4 (m, overlaps with DMSO, 7H ), 2.27 (s, 3H), 2.00 - 1.76 (m, 1H);(ESI) m / z C 25 H 24 Calculated for N4O4: 444.18. Found: 444.94 (M+1) + . Compound 17: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(o-tolylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100725) [ka]

[0130] 1HNMR (400MHz, DMSO-d6) δ 12.69 (br, 1H), 9.39 (br, 1H), 8.05 (d, J = 8Hz, 1H), 7.75 (br, 1H), 7.66 (m, 1H), 7.46 (t, 1H), 7.40 (d, 1H), 7.20 (m, 2H), 7.09 (m, 1H), 5.13 (br, 1H), 4.62 -4.28 (m, 1H), 3.74 (br, 1H), 2.9 - 2.4 (m, overlaps with DMSO, 7H ), 2.24 (s, 3H), 1.80 (br d, 1H);(ESI) m / z C 25 H 24 Calculated for N4O4: 444.18. Found: 445.01 (M+1) + . Compound 18: (2S,4R)-4-(2-((4-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100704) [ka]

[0131] 1 HNMR (400MHz, DMSO-d6) δ 12.72 (br, 1H), 10.06 (s, 1H), 8.12 (d, J = 8Hz, 1H), 7.80 (br, 1H), 7.7 - 7.5 (m, 3H), 7.48 (t, 1H), 7.14 (d and t, 2H), 5.15 (br, 1H), 4.56 - 4.28 (m, 1H), 3.72 (br, duplicated, 1H), 2.9 - 2.4 (m, duplicated with DMSO, 7H ), 1.85 (m, 1H); (ESI) m / z C 24 H 21 Calculated for FN4O4: 448.50. Found: 449.91 (M+1) + . Compound 19: (2S,4R)-4-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100719) [ka]

[0132] 1 HNMR (500MHz, DMSO-d6) δ 13.08 (br, 1H), 10.23 (s, 1H), 8.12 (d, J = 10Hz, 1H), 7.85 (br, 0.5H), 7.74 (m, 1.5H), 7.63 (d, J = 10Hz, 1H), 7.54 (t, 1H), 7.31 (m, 2H), 6.86 (m 1H), 5.28 (br, 1H), 4.67 - 4.34 (m, 1H), 3.71 (br, overlap, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H ), 1.80 (br d, 1H);(ESI) m / z C 24 H 21 Calculated for FN4O4: 448.50. Found: 449.91 (M+1) + . Compound 20: (2S,4R)-4-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100720) [ka]

[0133] 1HNMR (500MHz, DMSO-d6) δ 12.70 (br, 1H), 9.80 (s, 1H), 8.06 (d, J = 8Hz, 1H), 7.87 (m, 1H), 7.78 (br, 1H), 7.66 (m, 1H), 7.46 (t, 1H), (ESI) m / z C 24 H 21 Calculated for FN4O4: 448.50. Found: 449.91 (M+1) + . Compound 21: (2S,4R)-4-(2-((4-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100713) [ka]

[0134] 1 HNMR (500MHz, DMSO-d6) δ 12.66 (br, 1H), 10.14(s, 1H), 8.06 (d, J = 8Hz, 1H), 7.77 (br, 1H), 7.67 (d, J = 8Hz, 3H), 7.45 (t, J = 4Hz, 1H), (ESI) m / z C 24 H 21 Calculated for ClN4O4: 464.13. Found: 465.04 (M+1) + . Compound 22: (2S,4R)-4-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100705) [ka]

[0135] 1 HNMR (400MHz, DMSO-d6) δ 12.69 (br, 1H), 10.21 (s, 1H), 8.09 (d, J = 8Hz, 1H), 7.84 (m, 2H), 7.79 (dd, 1H), 7.52 (t, 1H), 7.46 (d, 1H), 7.35 (t, 1H), 7.11(d, 1H), 5.19 (br, 1H), 4.64 - 4.32 (m, 1H), 3.74 (br, duplicated, 1H), 2.9 - 2.4 (m, duplicated with DMSO, 7H ), 1.85 (br d, 1H); m / z C 24 H 21 Calculated for ClN4O4: 464.13. Found: 465.24 (M+1) + . Compound 23: (2S,4R)-4-(2-((2-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100706) [ka]

[0136] 1HNMR (400MHz, CD3OD) δ 8.13 (d, J = 8Hz, 1H), 7.73 (m, 3H), 7.40~7.60 (m, 2H), 7.34 (t, 1H), 7.22 (t, 1H), 5.20 (br, 1H), 4.9 - 4.51 (m, 1H), 3.94 (m, 1H), 3.0 - 2.5 (m, 7H), 2.00 (br d, 1H);(ESI) m / z C 24 H 21 Calculated for ClN4O4: 464.13. Found: 465.19 (M+1) + . Compound 24: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100721) [ka]

[0137] 1 HNMR (500MHz, CD3OD) δ 12.59 (br, 1H), 8.13 (d, J = 10Hz, 1H), 7.85 - 7.65 (m, 4H), 7.60 - 7.50(m, 3H), 5.55 - 5.25 (br, 1H), 4.52 - 4.06 (m, 1H)), 3.90 - 3.61 (m, 1H), 2.91 - 2.50 (m, 7H ), 2.42 -1 1.95 (m, 1H):(ESI) m / z C 25 H 21 Calculated for F3N4O4: 498.46. Found: 500.02 (M+1) + . Compound 25: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100712) [ka]

[0138] 1 HNMR (400MHz, DMSO-d6) δ 12.89 - 12.59 (br, 1H), 10.32(s, 1H), 8.12 (s, 1H), 8.06 (d, J = 8Hz, 1H), 7.79 (m, 1H), 7.67 (d, J = 8Hz, 2H), 7.57 (t, J = 8Hz, 1H), 7.45 (t, J = 4Hz, 1H), 7.40 (d, J = 8Hz, 1H), 5.13 (br, 1H), 4.61 - 4.27 (m, 1H), 3.73 (br, 1H), 2.9 - 2.4 (m, Overlapping with DMSO, 7H), 1.80 (br d, 1H);(ESI) m / z C 25 H 21 Calculated for F3N4O4: 498.46. Found: 500.12 (M+1) + . Compound 26: (2S,4R)-4-(2-((3,4-dichlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100710) [ka]

[0139] 1 HNMR (400MHz, DMSO-d6) δ 12.62 (br, 1H), 10.31(s, 1H), 8.06 (d, J = 8Hz, 1H), 8.02 (d, J = 4Hz, 1H), 7.78 - 7.60 (br, 2H), 7.55 (d, J = 12Hz, 1H), 7.50 - 7.40 (m, 1H + 1H), 5.10 (br, 1H), 4.56 - 4.24 (m, 1H), 3.71 (br, 1H), 2.65 (overlapping, 1H), 2.48 (m, overlapping with DMSO, 6H ), 1.75 (br d, 1H);(ESI) m / z C24 H 20 Calculated for Cl2N4O4: 498.09. Found: 498.91 (M+1) + . Compound 27: (2S,4R)-4-(2-((4-ethynylphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100709) [ka]

[0140] 1 HNMR (400MHz, DMSO-d6) δ 12.77 (br, 1H), 10.20 (s, 1H), 8.12 (d, J = 8Hz, 1H), 7.87 (br, 1H), 7.75 (m, 1), 7.63 (B, J of ABq = 8Hz, 2H), 7.55 (t, J = 8Hz, 1H), 7.42 (ABq A, J = 8Hz, 2H), 5.21 (br, 1H), 4.66 - 4.36 (m, 1H), 4.07 (s, 1H), 3.78 - 3.43 (m, 1H), 2.9 - 2.4 (br m, 7H), 1.76 and 1.93 (m, 1H); (ESI) m / z C 26 H 22 Calculated for N4O4: 454.16. Found: 455.12 (M+1) + . Compound 28: (2S,4R)-4-(2-((1H-indazol-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100707) [ka]

[0141] 1HNMR (500MHz, DMSO-d6) δ 13.05 (br, 1H), 10.06 (s, 1H), 8.29 (s, 1H), 8.09 (d, J = 8Hz, 1H), 7.81 (br, 1H), 7.69 (m, 2H), 7.50 (t, 1H), (ESI) m / z C 25 H 22 Calculated for N6O4: 470.17. Found: 471.20 (M+1) + . Compound 29: (2S,4R)-4-(2-((1H-benzo[d]imidazol-6-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100714) [ka]

[0142] 1 HNMR (400MHz, DMSO-d6) δ 12.72 (br, 1H), 10.14 (s, 1H), 8.17 (s, 1H), 8.07 (d, J = 8Hz, 1H), 7.96 (s, 1H), 7.77 (br, 1H), 7.66 (m, 2H), (ESI) m / z C 25 H 22 Calculated for N6O4: 470.17. Found: 471.10 (M+1) + . Compound 30: (2S,4R)-4-(2-((1H-indazol-6-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100715) [ka]

[0143] 1 HNMR (400MHz, DMSO-d6) δ 12.50 (br, 1H), 10.00 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8Hz, 2H), 7.78 (br, 1H), 7.66 (m, 1H), 7.50 (t and m, (ESI) m / z C 25 H 22 Calculated for N6O4: 470.17. Found: 471.10 (M+1) + . Compound 31: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-(naphthalen-2-ylamino)-2-oxoethyl)pyrrolidine-2-carboxylic acid (BBL-0100728) [ka]

[0144] 1HNMR (400MHz, DMSO-d6) δ 10.22 (s, 1H), 8.34 (s, 1H), 8.04 (br, 1H), 7.90 - 7.70 (m, 3.5H), 7.70 - 7.50 (m, 2.5H), 7.50 - -7.30 (m, (ESI) m / z C 28 H 24 Calculated for N4O4: 480.18. Found: 481.01 (M+1) + . Compound 32: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(quinolin-6-ylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100729) [ka]

[0145] 1 HNMR (400MHz, DMSO-d6) δ 12.80 (br, 1H), 10.35 (s, 1H), 8.78 (m, J = 5Hz,1H), 8.43 (d, J = approx. 2Hz, 1H), 8.29 (d, J = 10Hz, 1H), 8.07 (d, J = 10Hz, 1H), 7.95 (d, J = 10Hz, 1H), 7.80 (m, 2H), 7.66 (m, 1.5H), 7.47 (t, J = 10Hz, 2H), 5.13 (br, 1H), 4.60 - 4.30 (m, 1H), 3.75 (br, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H), 1.80 (m, 1H):(ESI) m / z C 27 H 23 Calculated for N5O4: 481.18. Found: 482.01 (M+1) + . Compound 33: (2S,4R)-4-(2-(isoquinolin-6-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100708) [ka]

[0146] 1 HNMR (400MHz, CD3OD) δ 9.54 (s, 1H), 8.82 (br s, 1H), 8.45 (m, 2H), 8.30 (d, 1H), 8.15 (d, J = 8Hz, 1H), 8.04 (m, 1H), 7.75 - 7.75 (m, 3H), 7.62 (m, 1H), 5.50 (br, 1H), 4.97 - 4.67 (m, 1H), 4.05 - 3,66 (m, 1H), 3.1 - 2.7 (m, 4H), 2.75 (s, 3H), 2.1 - 1.9 (m, 1H);(ESI) m / z C 27 H 23 Calculated for N5O4: 481.18. Found: 482.31 (M+1) + . Compound 34: (2S,4R)-4-(2-(isoquinolin-7-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100722) [ka]

[0147] 1HNMR (500MHz, CD3OD) δ 9.14 (br, 1H), 8.58 (br, 1H), 8.34 (br, 1H), 8.09 (br, 1H), 7.82 (m, 2H), 7.88 (m, 1H), 7.66 (m, 2H), 7.46 (m, (ESI) m / z C 27 H 23 Calculated for N5O4: 481.18. Found: 482.21 (M+1) + . Compound 35: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(quinolin-7-ylamino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100723) [ka]

[0148] 1 HNMR (500MHz, CD3OD) δ 9.14 (br, 1H), 8.48 (br, 1H), 8.31 (br, 1H), 8.12 (br, 1H), 7.88 (m, 1H), 7.77 (m, 1H), 7.66 (m, 2H), 7.46 (m, (ESI) m / z C 27 H 23 Calculated for N5O4: 481.18. Found: 482.22 (M+1) + . Compound 36: (2S,4R)-4-(2-([1,1'-biphenyl]-3-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100727) [ka]

[0149] 1 HNMR (400MHz, DMSO-d6) δ 12.63 (br, 1H), 10.11 (s, 1H), 8.06 (d, J = 4Hz, 1H), 7.95 (m, 1H), 7.76 (br, 1H), 7.70 - 7.55 (m, 4H), 7.50 - 7.42 (m, 3H), 7.40 - 7.30 (m, 3H), 5.3 (br, 1H), 4.60 - 4.28 (m, 1H), 3.73 (br, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H ), 1.80 (br d, 1H); (ESI) m / z C 30 H 26 Calculated for N4O4: 506.20. Found: 507.01 (M+1) + . Compound 37: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100735) [ka]

[0150] 1HNMR (500MHz, DMSO-d6) δ 12.85(br, 1H), 10.16 (s, 1H), 8.87 (d, J = 1Hz, 1H), 8.53 (d, J = 5, 1Hz, 1H), 8.06 (m, 2H), 7.79 (br 1H), 7.68 (A and B of ABq, J = 10Hz, 2H + 2H), 7.65 (m, 1H), 7.46 (m, 2H), 5.11 (br, 1H), 4.60 - 4.26 (m, 1H), 3.73 (br s, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H) ), 1.90 - 1.74 (m, 1H);(ESI) m / z C 29 H 25 Calculated for N5O4: 507.19. Found: 508.51 (M+1) + . Compound 38: (2S,4R)-4-(2-((4-(1H-indazol-5-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100743) [ka]

[0151] 1 HNMR (500MHz, DMSO-d6) δ 8.12 (d, 1H, NH), 8.08 (d, 1H), 7.97 (s, 1H), 7.62~7.75 (m, 6H), 7.60 (m, 2H), 7.46 (m, 2H), 5.23 (m, 1H), (ESI) m / z C 31 H 26 Calculated for N6O4: 546.20. Found: 547.51 (M+1) + . Compound 39: (2S,4R)-4-(2-((4-(1H-indazol-6-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100741) [ka]

[0152] 1 HNMR (500MHz, DMSO-d6) δ 13.08 (m, 1H), 10.28 (s, 1H), 8.07 (m, 2H), 7.80 (d, J = 5Hz, 2H), 7.73 (m, 1H), 7.69 (m, 3H), 7.62 (br, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 5.19 (br s, 1H), 4.63 - 4.26 (m, 1H), 3.87 - 3.74 (m, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H), 1.91 - 1.75(m, 1H) ;(ESI) m / z C 31 H 26 Calculated for N6O4: 546.20. Found: 547.52 (M+1) + . Compound 40: (2S,4R)-4-(2-((4-(6-aminopyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150979) [ka]

[0153] 1HNMR (500MHz, CD3OD) δ 8.24 (s, 1H), 8.11 (br, 2H), 7.90 (d, 1H), 7.68 (B, J of ABq = 8Hz, 2H), 7.62 (m, 2H), 7.51 (A, J of ABq = 8Hz, 2H), 7.44 (m, 1H), 6.80 (br d, J = 10Hz, 1H), 5.18 (br s, 1H), 4.76 - 4.36 (m, 1H), 3.95 - 3.60 (m, 1H), 3.0 - 2.5 (m, 7H), 2.07 - 1.89 (m, 1H) ;(ESI) m / z C 29 H 26 Calculated for N6O4: 522.20. Found: 523.52 (M+1) + . Compound 41: (2S,4R)-4-(2-((4-(2-aminopyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150980) [ka]

[0154] 1 HNMR (500MHz, CD3OD) δ 8.27 (s, 1H), 8.12 (br, 1H), 7.86 (d, 1H), 7.77 (B of ABq, 2H), 7.71 (A of ABq, 2H), 7.64 (m, 2H), 7.43 (m, 1H), 7.07 (br d, J = 10Hz, 1H), 7.02 (s, 1H), 5.16 (br s, 1H), 4.76 - 4.35 (m, 1H), 3.94 - 3.60 (m, 1H), 3.0 - 2.5 (m, 7H ), 2.16 - 1.89 (m, 1H);(ESI) m / z C 29 H 26 Calculated for N6O4: 522.20. Found: 523.42 (M+1) + . Compound 42: (2S,4R)-4-(2-((4-(6-aminopyridin-2-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150981) [ka]

[0155] 1 HNMR (500MHz, DMSO-d6) δ 10.10 (s, 1H), 8.14 (s, 1H), 8.06 (d, 1H), 7.93 (d, J = 10Hz, 2H), 7.77 (br, 1H), 7.68 (d, J = 10Hz, 2H), 7.65 (br t, 1H), 7.43 (m, 2H), 7.01 (d, J = 10Hz, 1H), 6.38 (d, J = 10Hz, 1H), 5.91 (s, 2H), 5.11 (br s, 1H), 4.61 - 4.27 (m,1H), 3.72 (m, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H), 1.90 - 1.73 (m, 1H) ;(ESI) m / z C 29 H 26 Calculated for N6O4: 522.20. Found: 523.42 (M+1) + . Compound 43: (2S,4R)-4-(2-((4-(2-aminopyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150982) [ka]

[0156] 1HNMR (500MHz, CD3OD) δ 8.12 (br, 1H), 7.89 (m, 1H), 7.74 (d, 2H), 7.64 (m, 2H), 7.56 (d, 1H), 7.46 (m, 3H), 6.82 (dd, J = 10Hz, 1H), 5.19 (br s, 1H), 4.76 - 4.36 (m, 1H), 3.92 - 3.58 (m, 1H), 3.0 - 2.5 (m, 7H), 1.99 - 1.89 (m, 1H);(ESI) m / z C 29 H 26 Calculated for N6O4: 522.20. Found: 523.52 (M+1) + . Compound 44: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridazin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150972) [ka]

[0157] 1 HNMR (500MHz, DMSO-d6) δ 12.63 (br, 1H), 10.25 (s, 1H), 9.16 (dd, 1H), 8.18 (dd, J = 10Hz, 1H), 8.13 (ABqB, 2H), 8.05 (d, 1H), 7.80 (ABqA, J = 10Hz, 2H), 7.74 (m, 1H), 7.65 (t, 1 H), 7.46 (t, 1H), 5.15 (br s, 1H), 4.62 - 4.42 (m, 1H), 3.7 (br, 1H), 2.9 - 2.4 (m, overlap with DMSO, 7H), 1.90 - 1.75 (m, 1H);(ESI) m / z C 28 H 24 Calculated for N6O4: 508.20. Found: 509.42 (M+1) + . Compound 45: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridazin-4-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150991) [ka]

[0158] 1 HNMR (400MHz, CD3OD) δ 9.44 (m, J = <1Hz, 1H), 9.06 (d, J = 4Hz, 1H), 8.02 (m, 1H), 7.89 (m, 1H), 7.72 (m, 4H), 7.55 (m, 2H), 7.36 (m, (ESI) m / z C 28 H 24 Calculated for N6O4: 508.20. Found: 509.32 (M+1) + . Compound 46: (2S,4R)-4-(2-((4-(1H-indazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100742) [ka]

[0159] 1HNMR (500MHz, DMSO-d6) δ 8.17 (d, 1H), 8.13 (d, 1H), 7.77 (d, 1H), 7.69 (m, 2H), 7.65 (m, 2H), 7.51 (d, J = 10Hz, 1H), 7.46 (m, 2H), 7.24 (d, J = 10Hz, 1H), 5.22 (m, 1H), 4.63 - 4.43 (m, 1H), 3.91 - 3.58 (m, 1H), 2.91 - 2.52 (m, overlap with DMSO, 7H), 2.06 - 2.90 (m, 1H);(ESI) m / z C 31 H 26 Calculated for N6O4: 546.20. Found: 547.52 (M+1) + . Compound 47: (2S,4R)-4-(2-((4-(6-hydroxypyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150984) [ka]

[0160] 1 HNMR (500MHz, CD3OD) δ 8.11 (br d, 1H), 7.94 (dd, J = 5, 10Hz, 1H), 7.66 (m, 5H), 7.45~7.55(m, 3H), 6,64 (d, J = 5Hz, 1H), 5.23 (br s, (ESI) m / z C 29 H 25 Calculated for N5O5: 523.19. Found: 524.37 (M+1) + . Compound 48: (2S,4R)-4-(2-((4-(2-hydroxypyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150985) [ka]

[0161] 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (br, 1H), 10.22 (s, 1H), 8.04 (s, 1H), 7.77 (m, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.68 - 7.56 (m, 4H), 7.50 - 7.36 (m, 2H), 6.55 (s, 1H), 6.52 - 6.44 (m, 1H), 5.20 - 4.58 (m, 1H), 4.57 - 4.16 (m, 1H), 3.79 - 3.65 (m, 1H), 2.88 - 2.51 (m, 7H), 1.98 - 1.66 (m, 1H);(ESI) m / z C 29 H 25 Calculated for N5O5: 523.19. Found: 524.37 (M+1) + . Compound 49: (2S,4R)-4-(2-((3-(1H-imidazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100747) [ka]

[0162] 1HNMR (500MHz, DMSO-d6) δ 12.16 (br, 1H), 10.02 (s, 1H), 8.02 (br, 2H), 7.75 (m, 1H), 7.68 (s, 1H), 7.58 (br, 2H), 7.3~7.5 (m, 3H), 7.25 (br, 1H), 4.98 (br s, 1H), 4.60 - 4.15 (m 1H), 3.76 (m, 1H), 3.01 - 2.53 (m, overlap with DMSO, 7H), 1.92 - 1.79 (m, 1H) :(ESI) m / z C 27 H 24 Calculated for N6O4: 496.19. Found: 497.4 (M+H) + . Compound 50: (2S,4R)-4-(2-((3'-methoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150971) [ka]

[0163] 1 HNMR (500MHz, DMSO-d6) δ 10.11 (d, 1H), 8.10 (br, 1H), 7.78 (br, 1H), 7.68 (m, 1H), 7.62 (m, 3H), 7.44 (br, 1H), 7.20 (d, J = 5Hz, 1H), 7.15 (s, 1H), 6.88 (m, 1H), 5.16 (br s, 1H), 4.74 - 4.22 (m, 1H), 3.91 (s, 3H), 3.73 (br s, 1H), 2.91 - 2.50 (m, overlaps with DMSO, 7H), 1.90 - 1.75 (m, 1H);(ESI) m / z C 31 H 28 Calculated for N4O5: 536.21. Found: 537.4 (M+H) + . Compound 51: (2S,4R)-4-(2-((3'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150983) [ka]

[0164] 1 HNMR (500MHz, CD3OD) δ 8.13 (d, 1H), 7.65 (m, 4H), 7.56 (d, J = 10Hz, 2H), 7.46 (m, 1H), 7.23 (m, 1H), 7.07 (d, J = 10Hz, 1H), 7.02 (m, (ESI) m / z C 30 H 26 Calculated for N4O5: 522.19. Found: 523.38 (M+H) + Compound 52: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150986) [ka]

[0165] 1HNMR (500MHz, DMSO-d6) δ 10.00 (br, 1H), 8.06 (d, 1H), 7.79 (br, 1H), 7.6~7.7 (m, 3H), 7.4~7.5 (m, 3H), 5.15 (br s, 1H), 4.61 - 4.27 (m, 1H), 4.42 (dd, 2H), 4.03 (dd, 2H), 3.72 (m, 1H), 2.90 - 2.51 (m, overlap with DMSO, 7H ), 1.90 - 1.75 (m, 1H);(ESI) m / z C 27 H 25 Calculated for N5O6: 515.18. Found: 516.32 (M+H) + Compound 53: (2S,4R)-4-(2-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100748) [ka]

[0166] 1 HNMR (500MHz, DMSO-d6) δ 8.13 (d, 1H), 7.86 (br, 1H), 7.75 (br, 1H), 7.5~7.65 (m, 2H), 6.98, 7.08, 7.18 (m, 3H), 5.23 (br s, 1H), 4.68 - 4.35 (m, 1H), 3.53 (m, 10H), 3.01 - 2.52 (m, overlap with DMSO, 7H), 1.92 - 1.61 (m, 1H);(ESI) m / z C 29 H 31 Calculated for N5O5: 529.23. Found: 530.50 (M+H) + Compound 54: (2S,4R)-4-(2-((4-benzylphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0100745) [ka]

[0167] 1 HNMR (500MHz, DMSO-d6) δ 9.94 (s, 1H), 8.03 (br, 1H), 7.77 (br, 1H), 7.59 (br, 1H), 7.51 (d, 1H), 7.42 (br, 1H), 7.27 (m, 2H), 7.1~7.21 (m,5H), 5.01 (br s, 1H), 4.59 - 4.16 (m, 1H), 3.87 (s, 2H), 3.69 (br s, 1H), 3.01 - 2.52 (m, overlap with DMSO, 7H), 1.89 - 1.70 (m, 1H) ;(ESI) m / z C 31 H 28 Calculated for N4O4: 520.21. Found: 521.55 (M+H) + Compound 55: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-3-ylmethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150992) [ka]

[0168] 1HNMR (500MHz, CD3OD) δ 8.43 (br s, 1H), 8.37 (br, 1H), 8.12 (d, 1H), 7.69 (m, 1H), 7.66 (d, 2H), 7.53 (d, J = 10Hz, 2H), 7.46 (m, 1H), 7.37 (m, 1H), 7.19 (d, J = 10Hz, 2H), 5.21(br s, 1H), 4.74 - 4.41 (m, 1H), 4.00 (s, 2H), 3.86 - 3.52 (m, 1H), 3.01 - 2.52 (m, Overlapping with DMSO, 7H), 2.05 - 1.86 (m, 1H);(ESI) m / z C 30 H 27 Calculated for N5O4: 521.21. Found: 522.37 (M+H) + . Compound 56: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-2-ylmethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150975) [ka]

[0169] 1 HNMR (500MHz, DMSO-d6) δ 9.94 (s, 1H), 8.47 (d, J =5Hz, 1H), 8.06 (br, 1H), 7.77 (br, 1H), 7.70 (td, 1H), 7.62 (br, 1H), 7.51 (B, J = ABq 10Hz, 2H), 7.45 (br, 1H), 7.24 (d, J = 10Hz, 2H), 7.19 (A of ABq, J = 10Hz, 2H), 5.10 (br s, 1H), 4.60 - 4.24 (m, 1H), 4.01 (s, 2H), 3.69 (m, 1H), 3.01 - 2.52 (m, overlap with DMSO, 7H), 1.90 - 1.70 (m, 1H);(ESI) m / z C 30 H 27Calculated for N5O4: 521.21. Found: 522.50 (M+H) + Compound 57: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-((3-morpholinophenyl)amino)-2-oxoethyl)pyrrolidine-2-carboxylic acid (BBL-0150974) [ka]

[0170] 1 HNMR (500MHz, DMSO-d6) δ 8.05 (br, 1H), 9.87 (s, 1H), 7.80 (br, 1H), 7.65 (br, 1H), 7.45 (br, 1H), 7.29 (s, 1H), 7.13 (t, 1H), 7.02 (d, 1H), 6.61 (d, 1H), 5.10 (br s, 1H), 4.60 - 4.24 (m, 1H), 3.70 (m, 1H), 3.74 (t, 4H), 3.06 (t, 4H), 2.81 - 2.42 (m, overlap with DMSO, 7H), 1.87 - 1.71 (m, 1H) ;(ESI) m / z C 28 H 29 Calculated for N5O5: 515.22. Found: 516.51 (M+H) + Compound 58: (2S,4R)-4-(2-((3-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150973) [ka]

[0171] 1HNMR (500MHz, DMSO-d6) δ 9.87 (s, 1H), 8.06 (br, 1H), 7.78 (br, 1H), 7.63 (br, 1H), 7.45 (br, 1H), 7.26 (s, 1H), 7.10 (t, 1H), 6.97 (m, 1H), 6.61 (d, 1H), 5.10 (br s, 1H), 4.60 - 4.23 (m, 1H), 3.91 - 3.31 (m, 4H), 2.82 (d of t, 1H), 2.81 - 2.42 (m, overlap with DMSO, 8H), 1.90 - 1.60 (m, 4H), 1.45 (m, 1H) ;(ESI) m / z C 29 H 31 Calculated for N5O5: 529.23. Found: 530.50 (M+H) + Compound 59: (2S,4R)-4-(2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150987) [ka]

[0172] 1 HNMR (400MHz, DMSO-d6) δ 12.80 (br, 1H), 10.21 (s, 1H), 8.06 (m, 1H), 7.79 (br, 1H), 7.55~7.75 (m, 6H), 7.49 (m, 1H), 7.45 (br s, 1H), 7.38 (m, 1H), 7.26 (d, J = 8Hz, 1H), 5.23 (m, 1H), 5.12 - 4.62 (m, 1H), 4.55 (s, 2H), 4.26 - 3.72 (m, 1H), 2.70 - 2.21 (m, Overlapping with DMSO, 7H), 1.89 - 1.73 (m, 1H) ;(ESI) m / z C 31 H 28Calculated for N4O5: 536.21. Found: 537.36 (M+H) + . Compound 60: (2S,4R)-4-(2-((4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150988) [ka]

[0173] 1 HNMR (400MHz, DMSO-d6) δ 12.68 (br, 1H), 10.11 (s, 1H), 8.06 (br, 1H), 7.79 (br, 1H), 7.71 (d, J = 8Hz, 2H), 7.55~7.65 (m, 5H), 7.46 (m, 1H), 7.38 (d, J = 8Hz, 2H), 5.15 (m, 1H), 4.61 - 4.56 (m, 1H), 4.51 (d, 2H), 4.27 - 3.72 (m, 1H), 2.71 - 2.35 (m, overlap with DMSO, 7H), 1.89 - 1.73 (m, 1H);(ESI) m / z C 31 H 28 Calculated for N4O5: 536.21. Found: 537.37 (M+H) + . Compound 61: (2S,4R)-4-(2-((2-methoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150993) [ka]

[0174] 1HNMR (400MHz, CD3OD) δ 8.11 (br d, 1H), 7.66 (br d, 2H), 7.42 ~7.55 (m, 4H), 7.35 (m, 2H), 7.25 (m, 2H), 7.18 (dd, J = 8Hz, 1H), 5.24 (m, (ESI) m / z C 31 H 28 Calculated for N4O5: 536.21. Found: 537.30 (M+H) + . Compound 62: (2S,4R)-4-(2-((2-amino-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150994) [ka]

[0175] 1 HNMR (400MHz, CD3OD) δ 8.12 (br d, 1H), 7.65 (br d, 2H), 7.37 ~7.50 (m, 5H), 7.30~7.35 (m, 1H), 7.20 (d, J = <1Hz, 1H), 7.01 (d, J = 8Hz, (ESI) m / z C 30 H 27 Calculated for N5O4: 521.21. Found: 522.31 (M+H) + . Compound 63: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0100746) [ka]

[0176] 1 HNMR (500MHz, DMSO-d6) δ 8.18 (d, J = 1Hz, 1H), 8.07 (d, 1H), 7.88 (d, 1H), 7.79 (br, 1H), 7.66 (br, 1H), 7.51 (d, 1H), 7.37~7.50 (m, 3H), 7.35 (d, 1H), 7.30 (d, 2H), 5.14 (br s, 1H), 4.64 - 4.29 (m, 1H), 3.88 (m, 1H), 3.01 - 2.51 (m, overlap with DMSO, 7H), 1.90 - 1.75 (m, 1H);(ESI) m / z C 31 H 25 Calculated for F3N4O4: 574.18. Found: 575.61 (M+H) + . Compound 64: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((6-phenylpyridazin-3-yl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150989) [ka]

[0177] 1HNMR (500MHz, CD3OD) δ 8.53 (d, 1H), 8.18 (s, 1H), 8.11 (m, 2H), 8.02 (d, 2H), 7.63 (m, 2H), 7.45~7.55 (m, 3H), 7.41 (m, 1H), 5.25 (br s, 1H), 3.81 - 3.57 (m, 1H), 2.93 - 2.83 (m, 5H), 2.56 (s, 3H), 2.00 (m, 1H);(ESI) m / z C 28 H 24 Calculated for N6O4: 508.19. Found: 509.33 (M+H) + . Compound 65: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((2-phenylpyrimidin-5-yl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150990) [ka]

[0178] 1 HNMR (500MHz, CD3OD) δ 9.10 (s, 2H), 8.34 (m, 2H), 8.11 (d, 1H), 7.6 ~7.75 (m, 2H), 7.46 (m, 4H), 5.25 (br s, 1H), 4.74 - 4.35 (m, (ESI) m / z C 28 H 24 Calculated for N6O4: 508.19. Found: 509.33 (M+H) + . Compound 66: (2S,4R)-4-(2-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (BBL-0150995) [ka]

[0179] 1 HNMR (500MHz, CD3OD) δ 8.11 (d, J = 10Hz, 1H), 7.66 (m, 3H), 7.53 (d, J = 10Hz, 2H), 7.4~7.5 (m, 4H), 7.35 (m, 2H), 5.24 (m, 1H), 4.75 - 4.44 (m, 1H), 3.88 - 3.57 (m, 1H), 3.01 - 2.52 (m, 7H), 2.15 - 1.88 (m, 1H);(ESI) m / z C 30 H 25 Calculated for FN4O4: 524.19 Found: 525.27 (M+H) + . Compound 67: (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((5-phenylpyridin-2-yl)amino)ethyl)pyrrolidine-2-carboxylic acid (BBL-0150969) [ka]

[0180] Example 3. Development of cGAS inhibitors Detection of foreign nucleic acids is a critical first line of defense in the immune response against microbial pathogens. However, aberrant induction of type I interferon (IFN) by self-nucleic acids leads to devastating autoimmune diseases such as AGS, SLE and Sjögren's syndrome (Figure 1). Type I IFN (IFN-I) is strongly involved in the pathogenesis of SLE, and approximately two-thirds of SLE patients have a blood interferon (IFN) signature. Plasmacytoid dendritic cells (pDCs) are the most prolific producers of type I IFN, and their continuous stimulation is the main driving force in the progression of SLE.

[0181] The key molecular trigger for nucleic acid-driven type I IFN induction is the production of a unique cyclic dinucleotide, cGAMP, by the cytoplasmic DNA sensor, cGAS. The cGAS apoenzyme is enzymatically inactive, and binding of nonspecific dsDNA induces its transition to an active conformation that catalyzes the formation of cGAMP from ATP and GTP. cGAMP binds to the STING (stimulator of interferon genes) receptor to initiate signaling for the induction of type I IFN. Knockout studies in animal models have clearly demonstrated that inhibiting cGAS is a promising approach for therapeutic intervention in monogenic type I interferonopathies such as AGS, and thus in complex diseases such as SLE.

[0182] For example, studies in mice have established compelling support for targeting cGAS to block type I IFN production in SLE and AGS, both diseases characterized by high levels of circulating type I IFN and autoantibodies against nucleic acids and other nuclear antigens. 90% of AGS patients have mutations in one of five different DNA-modifying enzymes that lead to the accumulation of cytoplasmic DNA, most notably the dsDNA exonuclease Trex1 (23%) or RNaseH2 (53%), which remove RNA from DNA:RNA hybrids. Knocking out these nucleases causes lethal autoimmune disease in mice. Genetic ablation of cGAS or STING in nuclease-deficient mice protects against lethality and eliminates the autoimmune phenotype, including interferon-stimulated gene (ISG) induction, autoantibody production, and T cell activation.

[0183] Mutations that impair the function of RNAse H2, Trex1, and other nucleic acid modifying enzymes also occur at low frequency in SLE, including the TREX1 D18N mutation that causes familial lupus pernio. Although less lethal than knocking out TREX1, TREX1 D18N mice have a lupus-like inflammatory disease, with nearly half dying within a few months, knocking out a single cGAS allele dramatically improves symptoms and survival, and the disease is cured in cGAS double knockout mice, including the restoration of normal ISG expression and the elimination of anti-DNA and anti-nuclear antibodies. However, TREX1 D18N mice do not have skin symptoms.

[0184] Blocking cGAS is likely to affect immune responses to some viral and bacterial infections, however, evidence suggests that an appropriate balance between immunosuppression and efficacy is possible. First, knocking out a single copy of cGAS in mouse models of AGS and lupus results in dramatic improvements in autoimmune symptoms and survival. Second, there is considerable redundancy in the innate immune response to dsDNA from microbial pathogens, with at least three additional pattern recognition receptors, IFI16, AIM2, TLR9, responding to dsDNA. In addition, the immune system responds to multiple pathogen-associated molecular patterns from a single pathogen, e.g., LPS, peptidoglycan, and DNA from gram-negative bacteria, as well as RNA and DNA from retroviruses. Third, the Mn sensitivity of cGAS inhibitors may be exploited to provide higher efficacy in the autoimmune context compared to the antibacterial context.

[0185] Using cGAS HTS (i.e., high-throughput screening) assays, we have discovered several novel cGAS inhibitors with favorable structural, physicochemical, and ADME / PK properties that function via distinct mechanisms. We also identified physiological cGAS effector molecules (Mn 2+)determined to profoundly affect the efficacy of the disclosed compounds, which may facilitate the development of cGAS drugs with more specific effects on autoimmune pathogenesis and less impact on antimicrobial immunity.

[0186] Structure-driven ligand optimization was used to advance the disclosed compounds by testing efficacy using SAR and structural models. Structure-driven ligand optimization and MOA analysis were performed on the disclosed compounds using human and mouse cGAS, and IC 50 IC ≤ 100 nM and ≤ 500 nM with mouse cGAS, as well as off-targets (e.g., kinases, GTPases, PDEs, OAS) 50 Compounds having a concentration of > 10 μM were provided.

[0187] In summary, we have made co-crystals of human cGAS lacking the unstructured N-terminal domain with compounds A, 5, and BBL0100243 ((2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-L-proline) (data not shown). The tricyclic core of these compounds binds at the active site where the adenosine of ATP binds, and surprisingly, they induce the formation of a substantial pocket adjacent to the active site. Analysis of the structure of compound A found that there is substantial room to build in the ligand-induced pocket, and that there is an opportunity at the back of the pocket to hydrogen bond with one or more amino acid side chains or backbone amides. Structural data from the co-crystal of compound 5 confirms this strategy and, in addition, shows that there is further flexibility in the induced pocket. These results suggest that the compounds may have allosteric binding properties over at least short distances and stabilize the inactive cGAS conformation, a property essential for developing highly selective drugs with long residence times. Furthermore, structural information from co-crystals allows us to design analogs with non-polar interactions in the ligand-induced pocket and physicochemical properties favorable for membrane permeability.

[0188] Using SAR-driven pharmaceutical chemistry, the compounds of the present disclosure were designed to increase potency to the nanomolar range.Specifically, the compounds were designed to increase non-polar and hydrogen-bonding interactions, especially in the ligand-induced pocket, to maintain predominantly lipophilicity, and to minimize polar surface area and conformational flexibility, imparting physicochemical properties known to increase cell permeability and oral bioavailability.Compound design efforts have been biased toward allosteric inhibitors, since allosteric drugs often have longer residence times and higher selectivity compared to purely competitive drugs.

[0189] The following criteria were developed to evaluate the compounds of the present disclosure. 1. Biochemical potency and selectivity: IC in cGAS enzyme assay 50 ≦100nM and IC 50 ≥ 50 μM off-target. 2. Cellular activity: IC of 1 μM for inhibition of type I IFN expression in monocytes and primary human cells 50 , as well as evidence of target binding in cells by cellular thermal shift assay (CETSA). 3. ADME properties: Mouse and human microsomal stability 1 / 2 >60 min, dynamic water solubility >100 μg / mL, Caco-2 and MDCK-MDR1 permeability A→B >1×10 -6 , outflow ratio <2.5.

[0190] Through this structure-driven approach, we have produced a range of analogs with significantly improved biochemical (~100 nM) and cellular (<1 μM) potency, as well as promising ADME properties (Table 1). We have found that the combined structural and biochemical results suggest that the disclosed compounds have a similar mechanism of action as type II or DGF-out kinase inhibitors, such as imatinib mesylate (GLEEVEC®, Novartis Pharmaceuticals, Basel, Switzerland), which binds to the ATP site, extends into an induced hydrophobic pocket, and stabilizes the inactive conformation.

[0191] Example 4. Adsorption, distribution, metabolism, and excretion profiles ADME Studies: Compound A and compounds of the present disclosure were tested for water solubility (KSOL), metabolic stability (human and mouse liver microsomes) and permeability (Caco-2 and / or MDR1-MDCK cells) to provide initial indications of oral bioavailability.

[0192] The compounds of the present disclosure generally have physicochemical properties predictive of good oral bioavailability (Table 1). None of the analogs shown in Table 1 have Lipinski violations, except for a few compounds that are slightly over 500 Da in MW. However, many recently approved drugs exceed the 500 Da Lipinski rule. In addition to Lipinski parameters, numerous studies on the properties of approved drugs and failed new chemical entities have shown that the number of rotatable bonds (RB), total polar surface area (TPSA) and lipophilicity (logD) are key determinants of oral bioavailability. For example, 81% of drugs with oral bioavailability >20% in humans have TPSA<140 Å2 and RB<10. All of the compounds in Table 1 also meet these criteria.

[0193] The favorable physicochemical properties are reflected in encouraging results in in vitro ADME studies. The kinetic solubility (K SOL ) was measured for several compounds of the present disclosure and found to be greater than 100 μM for most compounds. Metabolic stability, routinely measured in mouse and human hepatocytes, was excellent, with t 1 / 2 Cell permeability was measured using MDCK cells expressing human MDR1 (P-glycoprotein) to assess passive permeability as well as active transport out of the cells. Passive membrane permeability (PAPP) was 1×10 -6A permeability index of >1.001 cm / sec and a low efflux ratio (PAPP(BA) / PAPP(AB)) of <2.5 are generally considered to indicate good intestinal absorption. Many compounds in Table 1 meet these permeability criteria, as do compounds with a TPSA <140 Å. 2 and consistent with their design for increased lipophilicity.

[0194] Nearly half of the compounds have less than 10-fold lower potency in the cellular assay than in the cGAS enzyme assay under physiological conditions (1 mM ATP / GTP) (i.e., cellular IC 50 is a biochemical IC 50 (less than 10-fold greater than for 63). This is a smaller difference than for many kinase inhibitors. However, the biochemical / cellular potencies were essentially identical for compounds 5 and 63, likely due to their higher lipophilicity and cell permeability (see logD and MDCK data in Table 1), which is very promising from an overall ligand design perspective. The increased affinity of compounds 4 and 5 incorporating a hydrophobic bicyclic moiety linked to pyrrolidine further validates the structure-driven approach.

[0195] MDCK-MDR1 permeability A→B is shown in Table 2 below, where A is 5-10 cm / s×10 -6 and B is 1~5cm / s×10 -6 and C is <1cm / s×10 -6 The metabolic stability half-times in both mouse and human hepatocytes are also shown in Table 2 below, where A' represents 100-200 min, B' represents 200-300 min, and C' represents >300 min. [Table 1-1] [Table 1-2] [Table 1-3]

[0196] Example 5. cGAS inhibitor enzyme assay Structural, biochemical and biophysical analysis and selectivity profiling: Mn 2+ Potency and MOA testing, including sensitivity, was performed using the Transcreener cGAS enzyme assay manufactured by BellBrook Labs (Fitchburg, Wisconsin, USA). This homogeneous cGAS enzyme assay was developed with fluorescence polarization (FP) and time-resolved Forster resonance energy transfer (TR-FRET) readout as described in International Patent Publication No. WO2020 / 142729, which is incorporated herein by reference in its entirety. Plates are read on a PHERAstar FSX multimode reader (BMG). Compounds of the present disclosure were tested for inhibition of cGAS (30 nm) using this cGAS enzyme assay under standard conditions (100 μM ATP and GTP, 62.5 nM bpISD, 60 min reaction), under high ATP and GTP (1 mM) to mimic physiological conditions, in the presence of 200 μM MnCl2, and with mouse cGAS under standard conditions.

[0197] Release of MnCl2 from organelles into the cytoplasm can play an important role in initiating cGAS-dependent antiviral immune responses in both cells and mice, and the release of MnCl2 from cGAS may play a key role in initiating cGAS-dependent antiviral immune responses in both cells and mice. 2+ Binding stimulates cGAMP production in the presence of very low concentrations of dsDNA that are otherwise non-stimulatory. 2+ We confirmed that Mn increased the sensitivity of cGAS to DNA and found that this effect was inversely correlated with DNA length, ranging from 5-fold for 40-mers to 40-fold for 15-mers (data not shown), indicating that human cGAS, like mouse cGAS, can be activated by shorter DNA fragments than previously thought. Thus, the effect of Mn on the pharmacological modulation of cGAS is unclear. 2+ The effects of known human cGAS inhibitors (antimalarial quinacrine and PF06928215) on Mn 2+ is significantly less effective when present at physiological concentrations (200 μM), with an IC 50The compounds disclosed also showed a 10-fold increase in Mn 2+ negative sensitivity to IC 50 The shifts ranged from 4-fold to 10-fold for the different analogs (data not shown). Without wishing to be bound by theory, it is hypothesized that the inverse Mn-dependence of cGAS antagonists can be exploited to provide an enhanced therapeutic window by more effectively blocking cGAS under pathogenic conditions while having less impact on the response to microbial pathogens.

[0198] IC of FP under standard and physiological conditions 50 Values ​​were determined for several exemplary compounds of the invention. FP Standard IC 50の The relative activities are shown in Table 2 below, where A stands for <50 nM, B stands for 50-100 nM, C stands for 100-200 nM, D stands for 200 nM-1 μM, and E stands for 1-10 μM. FP physiological IC 50 Regarding the relative activity, A' represents <200 nM, B' represents 200 to 500 nM, C' represents 500 nM to 1 μM, D' represents 1 to 5 μM, and E' represents >5 μM. [Table 2-1] [Table 2-2]

[0199] More than one-third of the compounds had IC values ​​below 100 nM as measured by the cGAS FP assay under standard conditions. 50 The potencies of the cGAS active site inhibitors were 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 μM, 0.9 μM, 0.9 μM, 0.9 μM, 0.1 μM, 0.2 μM, 0.3 μM, 0.4 μM, 0.5 μM, 0.5 μM, 0.6 μM, 0.7 μM, 0.8 μM, 0.9 ...

[0200] Longer residence times, i.e., slower dissociation, can also result in improved cellular activity, due to slower equilibration with competing molecules in the cytoplasm. A cGAS enzyme assay using jump dilution techniques was used to measure the residence time (1 / k) of inhibitors. オフ ) were measured. For early compounds, dissociation half-times of less than 10 min were observed, whereas some more recent compounds have longer half-times, up to 2 h (Figure 2). These results are encouraging as a 2-3 h residence time may have a significant positive impact on pharmacokinetics and pharmacodynamics.

[0201] Potency of mcGAS is important for in vivo efficacy studies and represents a challenge for lead development because mcGAS shares only 57% amino acid identity with the human enzyme and has significant functional differences. Exemplary compounds initially had undetectable inhibition of mcGAS but showed low IC 50 Values ​​below 10 μM were observed for some compounds such as 1-5, e.g., 8.3 and 4.23 μM for compounds 4 and 5, respectively (data not shown).

[0202] The selectivity of the compounds was tested using a panel of nucleotides that utilize enzymes functionally related to cGAS and / or in the cGAS / STING pathway: TBK1, IKKβ, OAS1, ENPP1, and PDE4. No inhibition of any off-target enzymes was observed in dose-response experiments up to a concentration of 50 μM, using enzyme assays based on homogeneous immunodetection of AMP or ADP, alone or in combination with coupling enzymes (data not shown).

[0203] Example 6. Cellular studies to demonstrate target engagement, blockade of the CGAS-STING pathway, and therapeutic efficacy Cellular assays: The human monocytic cell line THP-1 and human primary PBMCs were used to evaluate the cellular activity of compounds with good biochemical potency. These cells generated a robust cGAS / STING-dependent type I IFN response when stimulated with dsDNA and other pathogen-associated molecular patterns, which was detected using a standard ELISA for IFNβ (R&D Systems). The TBK1 inhibitor BX-795, which acts downstream of cGAS / STING, was used as a probe.

[0204] CETSA was used to confirm that the compounds bound to cGAS in cells, and THP-1 cells were used for this analysis. Compounds were tested in a dose-response mode by incubating with cells at 37°C for 1.5 hours, followed by pelleting and resuspension in PBS, heating at 51.5°C for 3 minutes, and cooling to room temperature. Cells were then lysed, debris containing denatured cGAS was pelleted, and the supernatant was analyzed for soluble cGAS by Western blot using an anti-cGAS primary Ab (Cell Signaling). Band intensity was analyzed using Image J software. Stimulation with cGAMP directly activated STING and bypassed cGAS. This was used to determine whether compounds affected downstream components of cGAS / STING signaling. IFN-β ELISA was used as the primary measure of cellular potency and selectivity (Table 3), and reporter gene assays were used to assess off-target activity with other pattern recognition receptors.

[0205] IC of THP-1, PBMC, DNA, and cGAMP stimulated IFNβ ELISA 50 Values ​​were determined for several exemplary compounds of the invention and are provided in Table 3, where A represents <1 μM, B represents 1-2.5 μM, C represents 2.5-10 μM, D represents 10-20 μM, and E represents >20 μM. [Table 3-1] [Table 3-2]

[0206] Dose-response experiments in THP-1 cells using the IFNβ ELISA showed IC <10 μM for approximately one-third of the compounds. 50 values, and IC<1 μM for some compounds 50 Values ​​were observed. Importantly, the inhibition of IFNβ expression observed in DNA-stimulated cells was 3-10-fold more potent than in cGAMP-stimulated cells. These results clearly demonstrate selective inhibition of cGAS-driven IFN-β expression. RT-PCR was used to confirm that representative compounds inhibited expression of IFN-β mRNA (Figure 2). Reporter gene assays were used to evaluate off-target activity with IRF30Luc (RIG-1) or NFκB (TLR4). CellTiter Glo (ATP levels) and Presto Blue (reducing equivalents) were used to evaluate cytotoxicity. All assays were performed in dose-response mode. Compound 5 showed some off-target activity with the TLR4 pathway and cytotoxicity at concentrations above 25 μM, whereas compound 4 showed no detectable inhibition of RIG-1 or TLR4 signaling and no cytotoxicity at concentrations up to 100 μM (data not shown). Compound 4 also appreciably inhibited isolated Luc or SEAP reporter enzymes, inhibiting Luc by 50% at 80 μM (data not shown). We have recently begun to assess cellular potency in a more physiologically relevant context using human PBMCs. Many compounds have IC values ​​below 10 μM. 50 The results showed a dose-dependent inhibition of IFN-β production in PBMCs with β-blockers values. Finally, we were able to demonstrate intracellular target engagement of compound 5 in THP-1 cells using a cellular thermal shift assay (CETSA) (Figure 3). Compound 4 also stabilized cGAS in CETSA, although the concentration dependency was less clear.

[0207] Example 7. Mouse model of cGAS-driven type I IFN induction In lupus and related autoimmune diseases, cGAS is activated by DNA released from dying cells, and the resulting type I IFN production drives inflammation and tissue damage. Studies have shown that oxidized DNA (oxDNA) containing 8-hydroxyguanosine (8-OHG), present in microparticles formed by dying cells in the serum of lupus patients, is a more potent stimulator of cGAS-driven IFN induction in mice than unmodified DNA, as measured by type I IFN levels in plasma and expression of interferon-sensitive gene (ISG) mRNA. Thus, testing cGAS antagonists for their ability to block type I IFN induction in oxDNA-stimulated mice is a simple model to assess their in vivo efficacy as lupus therapeutics. Because our cGAS antagonists have high potency against human cGAS and more than 10-fold lower activity against mouse cGAS, we use humanized mice to test their efficacy in vivo; for example, we use irradiated NSG-SGM3 mice engrafted with human hematopoietic stem cells (CD34+) to reconstitute the human immune system.

[0208] Study design. The study includes one test compound, vehicle control (DMSO), and untreated (no stimulation with oxDNA) mice as positive control, seven female 12-31 week old HuCD34-NCG+ mice for each group, totaling 21 mice. Note that female mice are used because a much more pronounced ISG upregulation is observed in the UVB model compared to males, and the prevalence of lupus is much higher in females compared to males. oxDNA is generated by irradiation with UVC light as previously described. Test compounds are administered orally at a dose of 30-60 mg / kg, 2 hours prior to injection of oxDNA. Additional doses may be administered immediately after stimulation with oxDNA if necessary to achieve sufficient serum levels of test compound. Mice are injected intravenously at time=0 with 20 μg oxDNA combined with 100 μg DOTAP. At study 3 hours, blood is collected via the submandibular vein among all groups, plasma is prepared and stored at -80°C for INFβ multiplex analysis. At study 6 hours, animals are culled, blood is collected by cardiac puncture, and spleens are harvested for ISG mRNA expression analysis.

[0209] Endpoints included ISG mRNA expression in the spleen and IFN-β in plasma. ISG mRNA Expression and IFN-β Levels. mRNA was extracted from the spleen, cDNA was synthesized, and ISG transcripts, selected based on previous studies of IFN responses to UV, were quantified by real-time quantitative PCR (qPCR) and normalized to Gapdh transcript levels. Fold induction in ISG expression relative to baseline was calculated using the standard formula 2. (-ΔΔCt) i.e., without oxDNA stimulation. Plasma IFNβ and other inflammatory cytokine levels are measured using the Legendplex Mouse Inflammation Panel and quantified by FACS analysis. The greater than 30% reduction in plasma IFNβ and ISG mRNA expression levels in oxDNA-stimulated mice with orally administered cGAS antagonist is a strong indicator that may have therapeutic value for the treatment of lupus and related autoimmune diseases.

[0210] Example 8. Pharmacokinetic evaluation of compound 5 (BBL0100455) The pharmacokinetic properties of compound 5 (BBL-100455) were estimated in C57BL / 6 female mice following intravenous (IV) bolus and oral (PO) administration.

[0211] Briefly, compounds of the present disclosure were administered by IV injection (3mg / kg) at 0.6mg / mL in PBS containing 5% DMSO and 25% PEG-400. Compounds of the present disclosure were administered orally at 3mg / mL in PBS containing 10% DMSO and 50% PEG-400 for PO (30mg / kg). At given time points (0.083 hours, 0.167 hours, 0.25 hours, 0.50 hours, 1 hour, 2 hours, 4 hours, 7 hours, 16 hours and 24 hours), blood samples were taken using a heparin-calibrated pipette. Samples were centrifuged at 15000rpm for 10 minutes. Plasma was then collected from the top layer. Plasma was frozen at -80°C for later analysis. At 2 hours, 7 hours and 24 hours, brain samples were collected and immediately stored at 80°C for later analysis.

[0212] Analytical curves were constructed using 10 non-zero standards with compound 5 (BBL-100455) concentrations ranging from 1 to 2500 ng / mL in blank plasma and brain tissue. Blank samples (matrix samples processed without internal standard) were used to exclude contamination. Linear regression analysis of BBL-100455 was performed by plotting peak area ratio (y) against the concentration in ng / mL of BBL-100455 (x). The linearity of the relationship between peak area ratio and concentration was demonstrated by the correlation coefficient (R) obtained for the linear regression of (r =>0.990 in all samples).

[0213] Individual and mean Compound 5 concentration-time data for IV and PO dose groups are presented for plasma concentrations in Figure 4. Pharmacokinetic parameters are listed in Table 4. All PK parameters were estimated using non-compartmental analysis with Phoenix / WINONLIN. [Table 4-1] [Table 4-2]

[0214] Several embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Naturally, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will employ such variations as necessary, and the inventors intend the invention to be practiced other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

[0215] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in view thereof will be suggested to those skilled in the art, which should be incorporated within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference for all purposes.

Claims

1. Compounds according to formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, N-oxide, and / or solvate or hydrate thereof, wherein: m is an integer of 1, 2, or 3; n is an integer of 0, 1, 2, 3, or 4; Ring A represents a 4- to 8-membered heterocyclyl ring; Each R １ are independently halogen, -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, C １ -C ６ Alkoxy, and C １ -C ６ haloalkoxy; R ２ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ３ But -CO ２ R ５ , -COR ５ , -C(O)NR ５ R ６ , -CONH-OH, -S(O) ０－２ -R ５ , -SO ２ OR ５ , or -SO ２ N.R. ５ R ６ and R ４ is -C(O)NR ６ R ７ , -CO ２ R ７ , -SO ２ OR ７ , or -SO ２ N.R. ６ R ７ and During the ceremony, R ５ is hydrogen or C １ -C ６ is alkyl, R ６ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, R ７ optionally one or more R ９ Aryl substituted with (C ０ -C ４ alkyl), optionally one or more R ９ Heteroaryl substituted with (C ０ -C ４ alkyl), optionally one or more R ８ Heterocyclyl substituted with (C ０ -C ４ alkyl), and optionally one or more R ８ Cycloalkyl (C ０ -C ４ alkyl), Each R ８ are independently halogen, -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -N ３ , -NH ２ , -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, —C(O)R ６ , -C(O)OR ６ and -C(O)NR ５ R ６ or two R ８ forms an oxo, Each R ９ are independently halogen, -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -N ３ , -NH ２ , -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ haloalkoxy, optionally one or more R １０ Aryl substituted with (C ０ -C １ alkyl), optionally one or more R １０ Heteroaryl substituted with (C ０ -C １ alkyl), optionally one or more R １０ Heterocyclyl substituted with (C ０ -C １ alkyl), and optionally one or more R １０ Cycloalkyl (C ０ -C １ alkyl), Each R １０ are independently halogen, -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -N ３ , -NH ２ , -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ -haloalkoxy, -methyl-OH, However, the compound is not particularly limited, and the compound is not particularly limited. However, the compound is not particularly limited, and the compound is not particularly limited. 4-(2-(phenylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(cyclopentylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, or (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(phenylamino)ethyl)pyrrolidine-2-carboxylic acid, or a pharma- ceutically acceptable salt, N-oxide, and / or solvate or hydrate thereof.

2. The compound of claim 1, wherein (a) n is 0, 1, or 2, or (b) n is 0.

3. R １ are independently halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, and C １ -C ６ 3. The compound according to claim 1 or 2, wherein R 2 is selected from alkoxy or R 2 is methyl.

4. Ring A is pyrrolidinyl, azetidinyl, or piperidinyl, or Ring A has the structure: 【Chemistry 2】 4. The compound according to claim 1, which is the 2S,4R-enantiomer of

5. R ３ But -CO ２ R ５ , -C(O)NR ５ R ６ or -CONH-OH; optionally R 3 is -CO 2 R 5 or -C(O)NR 5 R 6 ; R 3 is -CO 2 R 5 ; or R 3 is -CO 2 H.

6. R ４ is -C(O)NR ６ R ７ 6. The compound of claim 1, wherein: optionally R 6 is hydrogen or C 1 -C 4 alkyl, or R 6 is hydrogen.

7. R ７ optionally one or more R ９ or R ７ However, one or more R ９ The compound according to any one of claims 1 to 6, which is phenyl substituted with

8. Each R ９ independently, each optionally containing one or more R １０ Halogen substituted with -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -NH ２ , -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , -OH, C １ -C ６ Alkoxy, C １ -C ６ 8. The compound of any one of claims 1 to 7, wherein R 9 is selected from the group consisting of haloalkoxy, aryl, aryl-methyl-, heteroaryl, heteroaryl-methyl-, and heterocyclyl, and optionally each R 9 is independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , -OH, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl, each optionally substituted with one or more R 10 .

9. m is an integer equal to 1; n is an integer of 0 or 1; Ring A represents a pyrrolidinyl, azetidinyl, or piperidinyl ring; Each R １ But independently, C １ -C ３ Alkyl, —OH, and C １ -C ３ alkoxy; R ２ is hydrogen, C １ -C ４ Alkyl, or C １ -C ４ is haloalkyl, R ３ But -CO ２ R ５ or -C(O)NR ５ R ６ and R ４ is -C(O)NR ６ R ７ or -SO ２ N.R. ６ R ７ and During the ceremony, R ５ is hydrogen or C １ -C ４ is alkyl, R ６ is hydrogen, C １ -C ４ Alkyl, or C １ -C ４ is haloalkyl, R ７ optionally one or more R ９ phenyl substituted with ９ pyridinyl, indolyl, indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl substituted with, and optionally one or more R ８ cyclopentyl substituted with Each R ８ are independently halogen, -NO ２ , -C.N., C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -NH ２ , -NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , -OH, C １ -C ６ Alkoxy, and C １ -C ６ haloalkoxy, or two R ８ forms an oxo, Each R ９ independently, each optionally containing one or more R １０ halogen substituted with C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -NH ２ , -NH(C １ -C ４ Alkyl), -N(C １ -C ４ Alkyl) ２ , -OH, C １ -C ４ Alkoxy, C １ -C ４ The compound of any one of claims 1 to 8, which is selected from the group consisting of haloalkoxy, phenyl, pyridinyl, phenylmethyl, pyridinylmethyl, piperidinyl, morpholinyl, piperazinyl, pyrazolyl, pyrimidinyl, indazolyl, pyridazinyl, imidazolyl, and 2-oxooxazolidinyl.

10. (2S,4R)-4-(2-((1H-indol-5-yl)amino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(cyclopentyl(methyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-indazol-5-yl)amino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(benzo[d]thiazol-6-ylamino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-([1,1′-biphenyl]-4-ylamino)-2-oxyethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-methoxypyridin-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(piperidin-1-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(piperazin-1-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-2-oxoethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-(1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(trifluoromethoxy)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-methoxyphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-methoxyphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(p-tolylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(m-tolylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(o-tolylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-fluorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-chlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(trifluoromethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3,4-dichlorophenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-ethynylphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-indazol-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-benzo[d]imidazol-6-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((1H-indazol-6-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-(naphthalen-2-ylamino)-2-oxoethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(quinolin-6-ylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(isoquinolin-6-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-(isoquinolin-7-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-(quinolin-7-ylamino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-([1,1′-biphenyl]-3-ylamino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(1H-indazol-5-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(1H-indazol-6-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(6-aminopyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(2-aminopyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(6-aminopyridin-2-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(2-aminopyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridazin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridazin-4-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(1H-indazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(6-hydroxypyridin-3-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(2-hydroxypyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-(1H-imidazol-4-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3'-methoxy-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4-benzylphenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-3-ylmethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((4-(pyridin-2-ylmethyl)phenyl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-((3-morpholinophenyl)amino)-2-oxoethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-methoxy-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-amino-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((6-phenylpyridazin-3-yl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((2-phenylpyrimidin-5-yl)amino)ethyl)pyrrolidine-2-carboxylic acid, (2S,4R)-4-(2-((2-fluoro-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid, (2S,4R)-1-(2-methylbenzofuro[3,2-d]pyrimidin-4-yl)-4-(2-oxo-2-((5-phenylpyridin-2-yl)amino)ethyl)pyrrolidine-2-carboxylic acid 2. The compound of claim 1, wherein:

11. The compound according to any one of claims 1 to 10, wherein the compound is in the form of a pharma- ceutically acceptable salt.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharma- ceutically acceptable carrier, solvent, adjuvant, or diluent.

13. 13. The pharmaceutical composition of claim 12 for treating or preventing inappropriate activation of a type I interferon (IFN) response in a subject in need thereof.

14. The pharmaceutical composition of claim 12 for treating an autoimmune disorder.

15. 15. The pharmaceutical composition of claim 14, wherein the autoimmune disorder is Acardi-Goutieres syndrome, retinal vascular disease with cerebral leukodystrophy, lupus erythematosus, scleroderma, Sjogren's syndrome, age-related macular degeneration, pancreatitis, ischemia, inflammatory bowel disease, nonalcoholic steatohepatitis, or Parkinson's disease.

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