2-aryl or heteroaryl-3-oxo-4-carbamido-6-cyclic-dihydropyrazine aryl hydrocarbon receptor modulators and their use in treating diseases and disorders

Abstract

Disclosed herein are compounds that can act as modulators of aryl hydrocarbon receptor (AHR).Further disclosed herein are methods for treating diseases and disorders, such as cancer and viral infections, using the compounds disclosed herein.

Description

[Technical field]

[0001] The present disclosure relates to compounds that are useful as aryl hydrocarbon receptor (AHR) activity modulators, pharmaceutical formulations thereof, and methods of using the compounds to treat diseases and disorders, such as cancer.

[0002] 2. Description of Related Art The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that regulates gene expression in various cells, such as epithelial cells and immune cells. Emerging evidence suggests that AHR plays a role in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Various tumor types and tumor cell lines show high AHR expression, suggesting that AHR is activated in tumors and promotes their growth. Immune evasion is recognized as a characteristic feature of cancer. A link between AHR and the immune system has been identified, and AHR has been suggested as an immunosuppressive effector on different types of immune cells. Certain cancers can escape immune recognition via the AHR signaling pathway. Overall, modulating AHR activity in cancer cells, immune cells, stromal cells, fibroblasts, and endothelial cells within tumors can slow down disease progression.

[0003] AHR is expressed at high levels and is chronically active in hematological tumors such as T-cell leukemia and lymphoma, as well as solid tumors such as glioblastoma, ovarian cancer, lung cancer, liver cancer, and head and neck cancer. It has been suggested that detection of AHR activity in the tumor microenvironment may serve as a powerful diagnostic indicator of tumor aggressiveness. Depending on the cancer type, two types of outcomes are related to AHR activity and prognosis. In hormone-dependent breast cancer, there is evidence that AHR activation is associated with attenuated aggressiveness and better prognosis. In contrast, higher AHR activity has been suggested to correlate with increased aggressiveness and poor prognosis in non-small cell lung cancer.

[0004] Recent reports have also demonstrated a role for the AHR as a modulator of the intrinsic, innate, and adaptive immune responses to viral infections. The role of AHR activation has been recognized to influence host resistance to infection with a variety of viruses, including influenza, coronaviruses (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), flaviviruses (such as Zika virus), retroviruses (such as HIV), and herpesviruses.

[0005] Thus, there is a need for novel compounds that modulate AHR activity to provide new and effective treatments for diseases and disorders such as cancer and viral infections. Summary of the Invention

[0006] One aspect of the disclosure is a compound having the structure of formula (I): [ka] In the formula, each R N are independently H or C 1-6 is alkyl, R 1 , H, C 1-6 Alkyl, C 1-6 Alkylene-NR N R N , C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-C(O)R 2 , C 1-6 Alkylene-NR N -C(O)-C 1-3 Alkyl, C 3-8 cycloalkyl, or 4-12 membered heterocyclyl, 1-3 ring atoms selected from O, N, and S, and the cycloalkyl or heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 Optionally substituted with alkyl and =O; R 2 OH, O.C. 1-6 Alkyl or NR N R N and Ar1 is C 6-10 aryl or 5-10 membered heteroaryl, 1-3 ring atoms selected from O, N, and S; Ar 1 is one or two R 3 and each R 3 Independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, Ar 2 is C 5-8 Cycloakly, C 5-8 Cycloalkenyl, C 6-10 aryl, or 5-12 membered heterocyclyl or heteroaryl, in which 1-3 ring atoms are selected from O, N, and S; Ar 2 1, 2, or 3 R 4 and each 4 are independently halo, OH, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR N R N ,CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, wherein 1-3 ring atoms are selected from O, N, and S, or phenyl, and the heterocyclyl, heteroaryl, or phenyl are selected from halo and C 1-6 substituted with 0, 1, or 2 substituents independently selected from alkyl, 1 Ar 2 (1) C 5-8 Cycloakly, C 5-8 Cycloalkenyl, C 10aryl, 4- to 12-membered heterocyclyl, or 5- or 7- to 12-membered heteroaryl; Ar 2 is one, two, or three R 4 or (2) phenyl or 6-membered heteroaryl, optionally substituted with Ar 2 CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 At least one R selected from cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and phenyl; 4 When replaced with C 2-6 hydroxyalkyl, and the phenyl, heterocyclyl, or heteroaryl may be halo and C 1-6 The present invention provides a compound, or a pharma- ceutically acceptable salt thereof, substituted with 0, 1, or 2 substituents independently selected from alkyl.

[0007] In some cases, each R N are independently H or methyl. 1 is H or C 1-6 In some cases, R 1 is methyl. In some cases, R 1 is C 1-6 Alkylene-NR N R N Or C 1-6 Alkylene-OC 1-6 In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 is C 1-6 Alkylene-C(O)R 2 or C 1-6 Alkylene-NR N -C(O)CH3. In some cases, R 2 is OH. In some cases, R 2 is NH2, NHCH3, or N(CH3)2. 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 is a heterocyclyl containing 4 to 12 total ring atoms, of which 1 to 3 ring atoms are selected from O, N, and S. Optionally, the heterocyclyl is unsubstituted. Optionally, the heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 Optionally, R is substituted with alkyl or ═O. 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 is C 2-6 Alkylene-C(O)-NR N R N In some cases, R 1 teeth, [ka] In some cases, R 1is C 2-6 Hydroxyalkyl, e.g. [ka] It is.

[0008] In some cases, Ar 1 is C 6-10 Aryl. In some cases, Ar 1 is phenyl. In some cases, Ar 1 is a 5-10 membered heteroaryl. 1 is unsubstituted. 1 teeth, [ka] In some cases, Ar 1 is one or two R 3 In some cases, R 3 is fluoro, chloro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. 1 teeth, [ka] In some cases, Ar 1 teeth, [ka] It is.

[0009] In some cases, Ar 2 is C 6-10 Aryl. In some cases, Ar 2 is phenyl. In some cases, Ar 2 is a 5-12 membered heteroaryl. 2 is C 5-8 Cycloalkyl, C 5-8 cycloalkenyl, or 5-12 membered heterocyclyl. 2is unsubstituted. 2 is one, two, or three R 4 In some cases, Ar 2 is one or two R 4 In some cases, at least one R 4 is halo. In some cases, at least one R 4 is chloro. In some cases, Ar 2 teeth, [ka] In some cases, at least one R 4 is fluoro, chloro, OH, CN, CH3, OCH3, CF3, OCF3, CHF2, CH2F, OCHF2, NH2, N(CH3)2, CONH2, COOH, SO2CH3, cyclopropyl, or morpholino. 4 CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, and phenyl, wherein phenyl, heterocyclyl, or heteroaryl is selected from halo and C 1-6 Optionally, Ar is substituted with 0, 1, or 2 substituents independently selected from alkyl. 2 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or triazolyl, and at least one R 4 is phenyl or halo-substituted phenyl.

[0010] In some cases, Ar 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] [ka] It is.

[0011] In another aspect, the disclosure provides a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0012] In a further aspect, the disclosure provides a pharmaceutical formulation comprising a compound or salt of the disclosure (e.g., a compound of Formula (I), a compound of Table 1, and salts thereof) and a pharma- ceutically acceptable excipient.

[0013] Yet another aspect of the present disclosure provides a method for modulating aryl hydrocarbon receptor (AHR) activity in a subject, comprising contacting the AHR with a compound or salt of the present disclosure (e.g., a compound of formula (I), a compound of Table 1, and salts thereof) or a pharmaceutical composition thereof, as disclosed herein.

[0014] Another aspect of the present disclosure provides a method for treating or preventing a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt of the present disclosure (e.g., a compound of Formula (I), a compound of Table 1, and salts thereof) disclosed herein, or a pharmaceutical composition thereof. In some cases, the disease or disorder is cancer, a viral infection, or pulmonary arterial hypertension (PAH). In some cases, the viral infection is a flavivirus infection or a coronavirus infection. In some cases, the viral infection is a flavivirus infection. In some cases, the flavivirus infection is a Zika virus infection. In some cases, the viral infection is a coronavirus infection. In some cases, the coronavirus infection is Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus Disease 2019 (COVID-19). In some cases, the coronavirus infection is Coronavirus Disease 2019 (COVID-19). In some cases, the disease or disorder is cancer. In some cases, the cancer is a liquid or solid tumor, a blood cancer, a lymphoma, a myeloma, a leukemia, a sarcoma, an eye cancer, a thyroid cancer, a parathyroid cancer, a neurological cancer, a skin cancer, a breast cancer, a uterine cancer, an endometrial cancer, a prostate cancer, a colorectal cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, a renal cancer, or a vascular cancer. In some cases, the method further comprises administering a therapeutic agent. In some cases, the therapeutic agent is an immune checkpoint inhibitor. In some cases, the immune checkpoint is PD1 or PDL1. In some cases, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarimab, durvalumab, avelumab, or a combination thereof.

[0015] Another aspect of the disclosure relates to the use of a compound or salt disclosed herein (e.g., compounds of formula (I), compounds of Table 1, and salts thereof), or a pharmaceutical composition disclosed herein, to modulate AHR activity in a subject. A further aspect of the disclosure relates to the use of a compound disclosed herein (e.g., compounds of formula (I), compounds of Table 1, and salts thereof), or a pharmaceutical composition disclosed herein, to treat or prevent a disease or disorder in a subject.

[0016] A compound of formula (A) or (B), [ka] In the formula, Ar 1 But, C 6-10 aryl or 5-10 membered heteroaryl, 1-3 ring atoms selected from O, N, and S; Ar 1 But 1 or 2 R 3 and each R 3 But independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 cycloalkyl, R 1 But, H, C 1-6 Alkyl, C 1-6 Alkylene-NR N R N , C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-C(O)R 2 , C 1-6 Alkylene-NR N -C(O)-C 1-3 Alkyl, C 3-8 cycloalkyl, or 4-12 membered heterocyclyl, in which 1-3 ring atoms are selected from O, N, and S, and the cycloalkyl or heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 Optionally substituted with alkyl and =O; R 2 But, OH, O.C. 1-6 Alkyl or NR N R NAnd each R N are independently H or C 1-6 alkyl, X is a leaving group, and R is H, C 1-6 Further provided are compounds in which X is chloro, fluoro, mesyl, tosyl, or triflyl.

[0017] A process for preparing a compound of formula (I) or a salt thereof, comprising reacting a compound of formula (B) disclosed herein with Ar 2 -boronic acid or Ar 2 -boronic ester to form a compound of formula (I). A method for preparing a compound or salt of formula (I) is also provided, comprising reacting a compound of formula (A) with Ar 2 -boronic acid or Ar 2 -boronic ester to form an intermediate, and then converting the -OR moiety of the intermediate to -N(R N )R 1 Further provided is a method comprising converting a -OR moiety of the ester intermediate to a -N(R -OH moiety) to form a compound of formula (I). In various cases, the catalyst comprises a palladium catalyst. Also provided is a method of preparing a compound of formula (I) or a salt comprising combining a compound of formula (B) with an amine nucleophile, optionally in the presence of a catalyst, to form an aromatic intermediate, and then reacting the aromatic intermediate with a reagent to form a compound of formula (I). A method of preparing a compound of formula (I) or a salt comprises (i) combining a compound of formula (A) with an amine nucleophile, optionally in the presence of a catalyst, to form an aromatic intermediate, (ii) reacting the aromatic intermediate with a reagent to form an ester intermediate, and (iii) converting the -OR moiety of the ester intermediate to a -N(R -OH moiety) to form a -N(R -OH moiety). N )R 1 and c) converting the moiety to form a compound of formula (I).

[0018] Further aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description taken in conjunction with the drawings. While the compounds and methods disclosed herein are susceptible to embodiment in various forms, the following description includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the invention to the specific embodiments described herein. [Brief description of the drawings]

[0019] [Figure 1] 1 shows tumor volume over time in mice bearing CT26 tumor cells administered (a) vehicle, (b) anti-PD1 antibody, (c) compound Example 184, or (d) a combination of compound Example 184 and anti-PD1 antibody. [Diagram 2] 1 shows survival of mice bearing CT26 tumor cells administered (a) vehicle, (b) anti-PD1 antibody, (c) compound Example 184, or (d) a combination of compound Example 184 and anti-PD1 antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] A compound of formula (I) [ka] In the formula, Ar 1 , Ar 2 , R 1 , and R N Provided herein are compounds that are as described herein and that can function as modulators of AHR activity. For example, the compounds can increase or decrease AHR activity.

[0021] The compounds disclosed herein are useful for targeting and selectively inhibiting AHR.It has been found that multiple tumor types have high levels of AHR signaling, as determined by AHR gene signatures.The high levels of AHR activation caused by the elevated levels of kynurenine and other ligands, as well as its role in driving immunosuppressive tumor microenvironment (TME), make AHR an attractive therapeutic target in multiple cancer types.

[0022] Many viral infections have also been found to involve AHR signaling. AHR is involved in regulating immune response, and AHR activation is associated with impaired adaptive immune response and poor health outcomes in various viral infections (e.g., influenza). Inhibition of AHR is also associated with reduced production of viral particles in vivo (e.g., dengue fever). AHR appears to play a role in controlling lipid biosynthesis, a hallmark of Hepatitis C (HCV) infection. The role of AHR in regulating host immune response to many viruses, such as the above examples, makes AHR regulation an attractive therapeutic target for viral infections.

[0023] AHR regulation is also involved in the treatment of pulmonary arterial hypertension (PAH).

[0024] Thus, in some cases, the present disclosure provides compounds useful for treating a disease or disorder in a subject, such as cancer, a viral infection, or PAH. Also provided are methods of treating a disease or disorder in a subject, such as cancer, a viral infection, or PAH, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, such as a compound of formula (I) or Table 1, or a pharma- ceutically acceptable salt thereof. Further provided are pharmaceutical compositions comprising a compound disclosed herein, such as a compound of formula (I) or Table 1, or a pharma- ceutically acceptable salt thereof, and methods of using such pharmaceutical compositions in methods of treating a disease or disorder, such as cancer, a viral infection, or PAH.

[0025] Compounds of the Disclosure In one aspect, a compound having the structure of formula (I): [ka] During the ceremony, Each R N are independently H or C 1-6 is alkyl, R 1 But, H, C 1-6 Alkyl, C 1-6 Alkylene-NR N R N , C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-C(O)R 2 , C 1-6 Alkylene-NR N -C(O)-C 1-3 Alkyl, C 3-8 cycloalkyl, or 4-12 membered heterocyclyl, 1-3 ring atoms selected from O, N, and S, and the cycloalkyl or heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 optionally substituted with alkyl, and =O; R 2 But, OH, O.C. 1-6 Alkyl or NR N R N and Ar 1 But, C 6-10 aryl or 5-10 membered heteroaryl, 1-3 ring atoms selected from O, N, and S; Ar 1 But 1 or 2 R 3 and optionally substituted with Each R 3 But independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 is cycloalkyl, Ar 2 But, C 5-8 Cycloakly, C 5-8 Cycloalkenyl, C6-10 aryl, or 5-12 membered heterocyclyl or heteroaryl, in which 1-3 ring atoms are selected from O, N, and S; Ar 2 But there are 1, 2, or 3 R 4 and optionally substituted with Each R 4 are independently halo, OH, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR N R N ,CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, wherein 1-3 ring atoms are selected from O, N, and S, or phenyl, and the heterocyclyl, heteroaryl, or phenyl is selected from halo and C 1-6 substituted with 0, 1, or 2 substituents independently selected from alkyl; Or Ar 2 However, (1)C 5-8 Cycloakly, C 5-8 Cycloalkenyl, C 10 aryl, 4- to 12-membered heterocyclyl, or 5- or 7- to 12-membered heteroaryl; Ar 2 But there are 1, 2, or 3 R 4 or (2) phenyl or 6-membered heteroaryl, and Ar 2 But CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 At least one R selected from cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and phenyl;4 When replaced by R 1 But, C 2-6 hydroxyalkyl, and the phenyl, heterocyclyl, or heteroaryl may be halo and C 1-6 Disclosed herein are compounds that are substituted with 0, 1, or 2 substituents independently selected from alkyl.

[0026] In some cases, R N is H. In some cases, R N is C 1-6 In some cases, R N is methyl.

[0027] In some cases, R 1 is H. In some cases, R 1 is C 1-6 In some cases, R 1 is methyl, ethyl, propyl, or isopropyl. 1 is methyl.

[0028] In some cases, R 1 is C 1-6 Alkylene-NR N R N Or C 1-6 Alkylene-OC 1-6 In some cases, R 1 is C 1-6 Alkylene-NR N R N In some cases, R 1 is C 2-3 Alkylene-NR N R N In some cases, R 1 is C2 alkylene-NR N R N In some cases, R 1 is C3 alkylene-NR N R N In some cases, each R N is independently H or CH.N is H. In some cases, each R N is CH3. In some cases, one R N is H and one R N is CH3. In some cases, R 1 teeth, [ka] In some cases, R 1 is C 1-6 Alkylene-OC 1-6 In some cases, R 1 is C 2-3 alkylene-O-C1 alkyl. In some cases, R 1 is C2 alkylene-O-C1 alkyl. 1 is C alkylene-O-C alkyl. 1 teeth, [ka] In some cases, R 1 teeth, [ka] It is.

[0029] In some cases, R 1 , H, C 1-6 Alkyl, C 1-6 Alkylene-NR N R N , C 1-6 Alkylene-OC 1-6 Alkyl, C 1-6 Alkylene-C(O)R 2 , C 1-6 Alkylene-NR N -C(O)-C 1-3 alkyl, or heterocyclyl containing 4 to 12 total ring atoms, 1 to 3 of which are selected from O, N, and S, and the heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6Optionally, R is substituted with alkyl, or ═O. 1 is C 1-6 Alkylene-C(O)R 2 Or C 1-6 Alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C 1-6 Alkylene-C(O)R 2 Or C 1-6 Alkylene-NR N -C(O)-CH3. In some cases, R 1 is C 2-3 Alkylene-C(O)R 2 Or C 2-3 Alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C 2-3 Alkylene-C(O)R 2 Or C 2-3 Alkylene-NR N -C(O)-CH3. In some cases, R 1 is C 1-6 Alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C 2-3 Alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C2 alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C3 alkylene-NR N -C(O)-C 1-3 In some cases, R 1 is C 1-6 Alkylene-NR N -C(O)-CH3. In some cases, R 1 is C 2-3 Alkylene-NR N -C(O)-CH3. In some cases, R 1is C2 alkylene-NR N -C(O)-CH3. In some cases, R 1 is C3 alkylene-NR N -C(O)-CH3. In some cases, R 1 is C 1-6 Alkylene-C(O)R 2 In some cases, R 1 is C 1-3 Alkylene-C(O)R 2 In some cases, R 1 is C1 alkylene -C(O)R 2 In some cases, R 1 is C2 alkylene -C(O)R 2 In some cases, R 1 is C3 alkylene -C(O)R 2 In some cases, R 2 is OH. In some cases, R 2 is O.C. 1-6 In some cases, R 2 is O-CH3. In some cases, R N is H. In some cases, R N is CH3. In some cases, R 2 is NR N R N In some cases, R 2 is NH2. In some cases, R 2 is NHCH3. In some cases, R 2 is N(CH3)2. In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] It is.

[0030] In some cases, in some cases, R 1 1 or 2 C 1-6Alkyl, C(O)-C 1-6 C optionally substituted with alkyl or ═O 3-8 Optionally, R 1 is unsubstituted C 3-8 Optionally, R 1 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 C substituted with alkyl or =O 3-8 Optionally, R 1 is C substituted with 1 or 2 =O 3-8 Optionally, R 1 is C substituted with one =O. 3-8 Optionally, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] It is.

[0031] In some cases, R 1 is a heterocyclyl containing 4 to 12 total ring atoms, 1 to 3 of which are selected from O, N, and S, and the heterocyclyl is selected from 1 or 2 C 1-6 Alkyl, C(O)-C 1-6 Optionally, R is substituted with alkyl, or ═O. 1 is a heterocyclyl containing 4 to 7 complete ring atoms. 1 is a heterocyclyl containing 4 complete ring atoms. 1 is a heterocyclyl containing 5 complete ring atoms. 1 is a heterocyclyl containing 6 complete ring atoms. 1is a heterocyclyl containing 7 total ring atoms. In some cases, the heterocyclyl is selected from the group consisting of oxetanyl, azetidinyl, diazepanyl (such as 1,4-diazepanyl), azepanyl, piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl), pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl), piperazinyl, pyrazolidinyl, imidazolidinyl, triazepanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazepanyl, thiazepanyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (such as 3-morpholino or 4-morpholino), thiomorpholino (such as 2 ... -thiomorpholino, 3-thiomorpholino, or 4-thiomorpholino), pyrrolidin-2-one, tetrahydropiperazinyl (such as 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, or 3-tetrahydropiperazinyl), pyrazolinyl (such as 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, or 5-pyrazolinyl), thiazolidinyl (such as 2-thiazolidinyl, 3-thiazolidinyl, or 4-thiazolidinyl), imidazolidinyl (such as 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, or 5-imidazolidinyl), or 1,3-dihydro-imidazol-2 only. In some cases, the heterocyclyl is oxetanyl, azetidinyl, diazepanyl (such as 1,4-diazepanyl), azepanyl, piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl), or pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl). In some cases, the heterocyclyl is oxetanyl, azetidinyl, diazepanyl, or azepanyl. In some cases, the heterocyclyl is diazepanyl or azepanyl. In some cases, the heterocyclyl is 1,4-diazepanyl or azepanyl. In some cases, the heterocyclyl is 1,4-diazepanyl. In some cases, the heterocyclyl is azepanyl. In some cases, R 1 is unsubstituted heterocyclyl. 1 1 or 2 C1-6 Alkyl, C(O)-C 1-6 alkyl, or heterocyclyl substituted with ═O. 1 is one C 1-6 Alkyl, C(O)-C 1-6 alkyl, or heterocyclyl substituted with ═O. 1 is two C's 1-6 Alkyl, C(O)-C 1-6 alkyl, or heterocyclyl substituted with ═O. 1 is C 1-6 Heterocyclyl substituted with alkyl. 1 is C(O)-C 1-6 Heterocyclyl substituted with alkyl. 1 is heterocyclyl substituted with ═O. 1 is a lactam. In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 is H, methyl, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 is C 2-6 Alkylene-C(O)-NR N R N In some cases, R 1 teeth, [ka] In some cases, R 1 is C 2-6 Optionally, R 1 teeth, [ka] It is.

[0032] In some cases, Ar 1 is C 6-10aryl or 5-10 membered heteroaryl, 1-3 ring atoms selected from O, N, and S; Ar 1 is one or two R 3 Optionally, Ar 1 is C6 aryl or 5-6 membered heteroaryl, Ar 2 is one or two R 3 Optionally, Ar 1 is C 6-10 Aryl. In some cases, Ar 1 is phenyl or naphthyl. 1 is phenyl. In some cases, Ar 1 is a 5-10 membered heteroaryl. 1 is a 5-6 membered heteroaryl. 1 is a 5-membered heteroaryl. 1 is a 6-membered heteroaryl. 1 is pyrazolyl, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, or thiadiazolyl; 3 Optionally, Ar 1 is pyrazolyl, and one or two R 3 Optionally, Ar 1 is unsubstituted. 1 is one or two R 3 In some cases, Ar 1 is one R 3 In some cases, Ar 1 is two R 3 In some cases, at least one R 3 is a halo. In some cases, each R 3is halo. In some cases, at least one R 3 is C 1-6 In some cases, each R 3 is C 1-6 In some cases, each R 3 is independently fluoro or methyl. 3 is fluoro. 3 is methyl. In some cases, R 3 is fluoro, chloro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. 1 teeth, [ka] In some cases, Ar 1 teeth, [ka] In some cases, Ar 1 teeth, [ka] In some cases, Ar 1 teeth, [ka] In some cases, Ar 1 teeth, [ka] It is.

[0033] In some cases, Ar 2 is C 6-10 aryl or 5-12 membered heteroaryl, 1-3 ring atoms selected from O, N, and S; Ar 2 is one, two, or three R 4 Optionally, Ar 2is C6 aryl or 5-6 membered heteroaryl, Ar 2 is one or two R 4 Optionally, Ar 2 is C 6-10 Aryl. In some cases, Ar 2 is phenyl or naphthyl. 2 is phenyl. In some cases, Ar 2 is a 5- to 12-membered heterocyclyl having one, two, or three R 4 Optionally, Ar 2 is a 5-12 membered heteroaryl. 2 is a 5-6 membered heteroaryl. 2 is a 5-membered heteroaryl. 2 is a 6-membered heteroaryl. 2 is piperindinyl, piperazinyl, pyrazolyl, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, or thiadiazolyl; 4 In some cases, Ar 2 is pyrazolyl and 0, 1 or 2 R 4 In some cases, Ar 2 is unsubstituted. 2 is one, two, or three R 4 (For example, one or two R 4 ) are substituted. In some cases, Ar 2 is one R 4 In some cases, Ar 2 is two R 4 In some cases, at least one R 4 is halo. In some cases, at least one R 4is OH. Optionally, at least one R 4 is CN. In some cases, at least one R 4 is C 1-6 Optionally, at least one R 4 is methyl, ethyl, propyl, or isopropyl. 4 is methyl. Optionally, at least one R 4 is C 1-6 haloalkyl. Optionally, at least one R 4 is CF3 or CHF2, or CH2F. Optionally, at least one R 4 is C 1-6 Optionally, at least one R 4 is C 1-6 Optionally, at least one R 4 is OCH3. In some cases, at least one R 4 is C 1-6 haloalkoxy. Optionally, at least one R 4 is OCF3 or OCHF2. Optionally, at least one R 4 is NR N R N In some cases, at least one R 4 is NH2, NHCH3, or N(CH3)2. Optionally, at least one R 4 is NH2 or N(CH3)2. Optionally, at least one R 4 CONR N R N In some cases, at least one R 4 is CON(CH3)2, CONHCH3, or CONH2. 4 is N(CH3)2, NHCH3, or CONH2. 4 is COOH. In some cases, at least one R 4 is the COO-C1-6 Optionally, at least one R 4 is C(O)-C 1-6 Optionally, at least one R 4 is COCH3. In some cases, at least one R 4 is SO2-C 1-6 Optionally, at least one R 4 is SO2CH3. In some cases, at least one R 4 is C 3-8 cycloalkyl. Optionally, at least one R 4 includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4 Optionally, at least one R 4 is 4-12 membered heterocyclyl. 4 In some cases, at least one R 4 is fluoro, chloro, OH, CN, CH3, OCH3, CF3, OCF3, CHF2, CH2F, OCHF2, NH2, N(CH3)2, CONH2, COOH, SO2CH3, cyclopropyl, or morpholino. 4 is fluoro or chloro. 4 is fluoro. Optionally, at least one R 4 is chloro. In some cases, each R 4 is a halo. In some cases, each R 4 is independently Cl or F. 4 is OH. In some cases, each R 4 is CN. In some cases, each R 4 is C 1-6 haloalkyl. In some cases, each R 4 is C 1-6 Optionally, each R 4 is C 1-6Optionally, each R 4 is C 1-6 haloalkoxy. In some cases, each R 4 is NR N R N In some cases, each R 4 CONR N R N In some cases, each R 4 is COOH. In some cases, each R 4 is the COO-C 1-6 In some cases, each R 4 is C(O)-C 1-6 In some cases, each R 4 is SO2-C 1-6 In some cases, each R 4 is C 3-8 Optionally, each R 4 is 4-12 membered heterocyclyl. 4 CONR N R N , COOH, COO-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C 3-8 cycloalkyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl, and phenyl, wherein phenyl, heterocyclyl, or heteroaryl is selected from halo and C 1-6 Optionally, Ar is substituted with 0, 1, or 2 substituents independently selected from alkyl. 2 is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or triazolyl, and at least one R 4 is phenyl or halo-substituted phenyl.

[0034] Ar 2 But there are 1, 2, or 3 R 4 If replaced by R 4 may be present at any position on the ring. 2 is one or two R at any position on the ring.4 Optionally, Ar 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] and R 4 is fluoro, chloro, OH, CN, CH3, CH2CH3, CH(CH3)2, C(CH3)3, OCH3, CF3, OCF3, CHF2, CH2F, OCHF2, NH2, N(CH3)2, CONH2, COOH, SO2CH3, cyclopropyl, or morpholino. 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] And each R 4 are independently fluoro, chloro, OH, CN, CH3, CH2CH3, CH(CH3)2, C(CH3)3, OCH3, CF3, OCF3, CHF2, CH2F, OCHF2, NH2, N(CH3)2, CONH2, COOH, SO2CH3, cyclopropyl, or morpholino. 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] In some cases, Ar 2 teeth, [ka] In some cases, Ar2 teeth, [ka] In some cases, Ar 2 teeth, [ka] [ka] [ka] It is.

[0035] Contemplated compounds of formula (I) include, but are not limited to, those listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0036] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the disclosure unless only one of the isomers is specifically indicated. Thus, single stereochemical isomers of the compounds of the invention, as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures, are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomer" refers to a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein may exist as single stereoisomers or as mixtures of stereoisomers. The stereochemistry of the compounds depicted herein indicates relative, not absolute, stereochemistry, unless otherwise discussed. As used herein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least 50% or more of the depicted stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the depicted stereoisomer, diastereomer, or enantiomer.

[0037] The compound of formula (I) is sp 3The carbon atom can have any stereochemical configuration. In some cases, the compounds of the present disclosure are optically pure. As used herein, "optically pure" refers to the presence of only one enantiomer of a compound when multiple stereochemical configurations can exist. In various cases, the chiral moiety present in the compounds of the present disclosure is derived from either natural or unnatural amino acids or monosaccharides.

[0038] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0039] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the structure of the present invention, except for the replacement of carbon with C-enriched carbon, are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, may also be therapeutically useful. Thus, further disclosed herein are deuterated compounds or salts of formula (I), in which one or more isotopes of hydrogen are replaced with deuterium.

[0040] The compounds of the present disclosure are defined herein by their chemical structure and / or chemical name. If a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0041] As used herein, "alkyl" refers to straight-chain and branched saturated hydrocarbon groups containing 1 to 30 carbon atoms, e.g., 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). nThe term means that the alkyl group has "n" carbon atoms. For example, C3 alkyl refers to an alkyl group having 3 carbon atoms. C1-6 alkyl refers to an alkyl group having any number of carbon atoms (i.e., 1-6 carbon atoms) including all ranges, as well as all subgroups (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, 5-6, 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and t-butyl (1,1-dimethylethyl). Unless otherwise indicated, the alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0042] As used herein, "alkylene" refers to a divalent saturated aliphatic radical. n The term alkylene means that the group has "n" carbon atoms. For example, C 1-6 Alkylene refers to alkylene groups having any number of carbon atoms, including all of the subgroups as described above for "alkyl" groups.

[0043] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be further substituted or unsubstituted, and in some cases, for example, C 1-6 haloalkyl, such as haloalkyl having 1 to 6 carbon atoms.

[0044] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced by a hydroxyl group (OH). Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like. Hydroxyalkyl can be further substituted or unsubstituted, and in some cases includes, for example, C 1-6 It relates to hydroxyalkyl having 1 to 6 carbon atoms, such as hydroxyalkyl.

[0045] As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms). n The term means that the cycloalkyl group has "n" carbon atoms. For example, C5 cycloalkyl refers to a cycloalkyl group having 5 carbon atoms in the ring. C3-C8 cycloalkyl refers to a cycloalkyl group having any number of carbon atoms (e.g., 3-8 carbon atoms) including the full range, as well as all subgroups (e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 4-8, 5-6, 5-7, 5-8, 6-7, 6-8, 7-8, 3, 4, 5, 6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group, heterocycloalkyl group, aryl group, and / or heteroaryl group. When a cycloalkyl group is fused to another cycloalkyl group, unless otherwise specified, each of the cycloalkyl groups can contain from 3 to 8 carbon atoms. Unless otherwise indicated, the cycloalkyl groups can be unsubstituted or substituted.

[0046] The term "heterocyclyl," as used herein, refers to a non-aromatic monocyclic, fused, spiro, or bridged ring system, which may be saturated or may contain one or more units of unsaturation, having 4 to 12 total ring atoms, in which 1 to 3 (e.g., 1 to 3, or 1, 2, or 3) ring atoms are heteroatoms selected from N, S, and O. When the heterocyclyl is spiro, the group can include, for example, a 4-membered ring and a spiro 5-membered ring, a 4-membered ring and a spiro 6-membered ring, a 4-membered ring and a spiro 7-membered ring, a 5-membered ring and a spiro 6-membered ring, a 5-membered ring and a spiro 7-membered ring, a 6-membered ring and a spiro 6-membered ring, a 6-membered ring and a spiro 7-membered ring, or a 7-membered ring and a spiro 7-membered ring, in which each ring of the spiro system can include at least one ring heteroatom, or only one ring can include at least one ring heteroatom, and the other ring can be carbocyclic. In some cases, the heterocyclyl contains 5 to 6 ring members. In some cases, the heterocyclyl contains 5 ring members. In some cases, the heterocyclyl contains 6 ring members. Examples of heterocyclyl groups include oxetanyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazepanyl, thiazepanyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (including, for example, 3-morpholino, 4-morpholino), 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidin-2-yl ... Examples of imidazolidinyl include, but are not limited to, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, and 1,3-dihydro-imidazol-2-onyl.In some cases, the heterocyclyl is oxetanyl, azetidinyl, diazepanyl (such as 1,4-diazepanyl), azepanyl, piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl), or pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl). In some cases, the heterocyclyl is oxetanyl, azetidinyl, diazepanyl, or azepanyl. In some cases, the heterocyclyl is diazepanyl or azepanyl. In some cases, the heterocyclyl is 1,4-diazepanyl or azepanyl. In some cases, the heterocyclyl is 1,4-diazepanyl. In some cases, the heterocyclyl is azepanyl. The heterocyclyl ring is unsubstituted or substituted as described herein.

[0047] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 10 ring atoms. Unless otherwise indicated, an aryl group can be unsubstituted or substituted. An aryl group can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, or anthracenyl) or to a cyclic group (e.g., indene, dihydroindene).

[0048] As used herein, the term "heteroaryl" refers to a heteroaryl group that is aromatic and has 5 to 12 total ring atoms (e.g., a monocyclic aromatic ring having 5 to 6 total ring atoms) and contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted. A heteroaryl group can be isolated (e.g., pyridyl) or fused to another heteroaryl group (e.g., purinyl), a cycloalkyl group (e.g., tetrahydroquinolinyl), a non-aromatic heterocyclyl group (e.g., dihydronaphthyridinyl), and / or an aryl group (e.g., benzothiazolyl and quinolyl). Examples of heteroaryl groups include, but are not limited to, pyrazolyl, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl group is fused to another heteroaryl group, each ring can contain 5 or 6 total ring atoms and 1 to 3 heteroatoms in the aromatic ring.

[0049] As used herein, the term "alkoxy" refers to an "-O-alkyl" group. An alkoxy group can be unsubstituted or substituted.

[0050] As used herein, the term "haloalkoxy" refers to an "-O-haloalkyl" group. A haloalkoxy group can be unsubstituted or substituted.

[0051] As used herein, the term "halo" refers to a fluoro (F), chloro (Cl), bromo (Br), or iodo (I) group.

[0052] A "substituted" functional group (e.g., substituted heterocyclyl, aryl, or heteroaryl refers to alkyl, heterocyclyl, aryl, or heteroaryl) is a functional group having at least one hydrogen radical replaced with a non-hydrogen radical (i.e., a substituent). Examples of non-hydrogen radicals (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, heteroaryl, heterocycloalkyl, hydroxyl, oxy (or oxo), alkoxyl, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl, and halo. When a substituted alkyl group contains more than one non-hydrogen radical, the substituents can be attached to the same carbon or to two or more different carbon atoms. Other substitutions are discussed herein with respect to the specific functional group or moiety.

[0053] Pharmaceutically acceptable salts The compounds described herein can be in free form or, where appropriate, as salts.Pharmaceutically acceptable salts are particularly interesting because they are useful for administering the compounds described herein for medical purposes.Pharmaceutically unacceptable salts are useful in the manufacturing process, for the purpose of isolation and purification, and in some cases, for use in the separation of stereoisomeric forms of the compounds of the present disclosure or their intermediates.

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue adverse effects, such as toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio.

[0055] Pharmaceutically acceptable salts are well known in the art.For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66,1-19, which is incorporated herein by reference.The pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.These salts can be prepared in situ during the final isolation and purification of the compound.

[0056] When the compounds described herein contain a basic group, or a sufficiently basic bioisostere, an acid addition salt can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, the acid addition salt may be a more convenient form for use, and use of the salt amounts to use of the free base form.

[0057] Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethoxybenzoate ... Examples of salts that can be used include benzenesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0058] When the compounds described herein contain a carboxyl group or a sufficiently acidic bioisostere, a base addition salt can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base, and 2) isolating the salt thus formed. In practice, the use of a base addition salt may be a more convenient form, and the use of the salt form is essentially equivalent to the use of the free acid form. Salts derived from appropriate bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, and N +(C1-4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0059] Basic addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include amine cations formed with non-toxic ammonium, quaternary ammonium, and counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates, where appropriate. Suitable inorganic basic addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine basic addition salts are prepared from amines that are frequently used in medicinal chemistry due to their low toxicity and acceptability for medical applications. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

[0060] Other acids and bases may be used in the preparation of salts which, while not themselves pharma- ceutically acceptable, are useful as intermediates to obtain the compounds described herein and their pharma- ceutically acceptable acid or base addition salts.

[0061] It is understood that the compounds disclosed herein can exist as mixtures / combinations of different pharma-ceutically acceptable salts. Also contemplated are mixtures / combinations of the free form of the compounds and pharma-ceutically acceptable salts.

[0062] Pharmaceutical preparations Also provided herein is a pharmaceutical formulation comprising an effective amount of a compound of the present disclosure and one or more pharma- ceutically acceptable excipients. As used herein, the term "formulation" is used interchangeably with "composition."

[0063] An "effective amount" includes a "therapeutically effective amount" and a "prophylactically effective amount." The term "therapeutically effective amount" refers to an amount effective to treat and / or ameliorate a disease or condition in a subject. The term "prophylactically effective amount" refers to an amount effective to prevent and / or substantially reduce the likelihood of a disease or condition in a subject. As used herein, the terms "patient" and "subject" may be used interchangeably and refer to animals such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) as well as humans. A particular patient or subject is a mammal (e.g., a human). The terms "patient" and "subject" include both genders.

[0064] As used herein, the term "excipient" means any pharma- ceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API), suitably selected with regard to the intended form of administration and consistent with conventional pharmaceutical practice.

[0065] The compound of the present disclosure can be administered alone or as part of a pharma-ceutically acceptable composition or formulation.In addition, the compound can be administered once, for example, by bolus injection, or can be administered multiple times, for example, by a series of tablets, or can be delivered substantially uniformly over a period of time, for example, by using transdermal delivery.It should also be noted that the dose of the compound can vary over time.

[0066] The compounds disclosed herein and other pharmaceutically active compounds can be administered to a subject or patient by any suitable route, for example, orally, topically, rectally, parenterally (e.g., subcutaneous injection, intravenous, intramuscular, intrasternal, and intrathecal injection or infusion techniques), or as a buccal, inhalation, or nasal spray, as desired. Administration can be to produce a systemic effect (e.g., enterally or parenterally). All methods that can be used by those skilled in the art to administer pharmaceutically active agents are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0067] Suitable oral compositions or formulations according to the present disclosure include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions or formulations suitable for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0068] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0069] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium laurate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0070] Solid compositions of a similar type may also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient only, or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polethylene glycols, and the like.

[0071] The active compound may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may also be of a composition that releases the active ingredient only, or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0072] The pharmaceutical compositions and formulations described herein can be administered topically or transdermally, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.Suitable topical formulations are easily prepared for each of these areas or organs.Topical application for the lower intestinal tract can be carried out, for example, in a rectal suppository formulation or in a suitable enema formulation.The dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0073] For topical application, pharmaceutical compositions can be formulated into suitable ointments, creams, lotions, or gels, containing the active ingredient suspended or dissolved in one or more carriers, and any necessary preservatives or buffers as may be required.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, pharmaceutical compositions can be formulated into suitable lotions or creams, containing the active ingredient suspended or dissolved in one or more pharma- ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyl dodecanol, benzyl alcohol, and water.

[0074] Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0075] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or di-glycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0076] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0077] In order to prolong the effect of the compounds described herein, it is often desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material that is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0078] Compositions for rectal or vaginal administration are specifically suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0079] Sterile injectable forms of the compositions disclosed herein may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharma- ceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailable solvents, commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0080] Pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0081] The compounds for use in the methods of the present disclosure can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for the subject undergoing treatment, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, optionally with a suitable pharmaceutical carrier. The unit dosage form can be one daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

[0082] The compounds of the present disclosure can be administered to a subject or patient at dosage levels ranging from about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage ranging from about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range used can potentially depend on a number of factors, including the requirements of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determination of dosage ranges and optimal dosages for a particular subject or patient is within the skill of the art.

[0083] Treatment methods The compounds disclosed herein (e.g., compounds of formula (I), compounds of Table 1, and salts thereof) can modulate the aryl hydrocarbon receptor (AHR) pathway, for example, by modulating AHR in cells. AHR is a ligand-activated transcription factor that is involved in a variety of conditions, including regulating the immune system during steady state and during infection and inflammation. The AHR pathway is recognized for its role in the pathogenesis of diseases and disorders, including cancer and viral infections.

[0084] Thus, the present disclosure provides a method of modulating aryl hydrocarbon receptor (AHR) in a cell, comprising contacting the cell with a therapeutically effective amount of a compound or salt disclosed herein (such as the compound of formula (I), the compounds of Table 1, and salts thereof), or a formulation thereof, in an amount effective to modulate AHR. In some cases, the contacting occurs in vitro. In some cases, the contacting occurs in vivo. In some cases, the contacting includes administering to a subject in need thereof. As used herein, the terms "patient" and "subject" may be used interchangeably and refer to animals such as dogs, cats, cows, horses, and sheep (i.e., non-human animals), as well as humans. Particular patients are mammals (e.g., humans). In some cases, the subject is suffering from a disease or disorder, such as cancer or a viral infection.

[0085] Another aspect of the disclosure provides a method of treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound or salt disclosed herein (such as a compound of Formula (I), a compound of Table 1, and salts thereof), or a composition thereof. In some cases, the terms "treating," "treat," or "treatment," and the like, can include preventative (e.g., prophylactic) and palliative treatment. In some cases, the disease or disorder is cancer or a viral infection.

[0086] In some cases, the disease or disorder is cancer. In some cases, the cancers treated using the compounds and methods described herein include, but are not limited to, blood cancer, lymphoma, myeloma, leukemia, neurological cancer, skin cancer, breast cancer, prostate cancer, respiratory cancer, reproductive cancer, gastrointestinal cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary cancer, bone cancer, kidney cancer, and vascular cancer. In some cases, the cancer is liquid or solid tumor, blood cancer, lymphoma, myeloma, leukemia, sarcoma, eye cancer, thyroid cancer, parathyroid cancer, neurological cancer, skin cancer, breast cancer, endocrine cancer, uterine cancer, endometrial cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary cancer, bone cancer, kidney cancer, or vascular cancer. In some cases, the cancer is bone cancer. Contemplated bone cancers include, but are not limited to, histiocytoma of bone. In some cases, the cancer is an endocrine cancer. Contemplated endocrine cancers include, but are not limited to, multiple endocrine neoplasia syndrome, adrenal cancer (such as, but not limited to, adrenocortical carcinoma, adrenal cortical carcinoma, or adrenal cortical adenoma), thyroid cancer (such as, but not limited to, anaplastic thyroid cancer), and parathyroid cancer. In some cases, the cancer is breast cancer. Contemplated breast cancers include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. In some cases, the cancer is a respiratory cancer. Contemplated respiratory cancers include, but are not limited to, bronchial carcinoma, lung cancer (such as, but not limited to, small cell and non-small cell lung cancer), as well as bronchial adenoma and pleuropulmonary blastoma. In some cases, the cancer is a central nervous system cancer. Contemplated central nervous system cancers include, but are not limited to, spinal axis tumors, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNSTs), and brain cancer. In some cases, the cancer is brain cancer.Brain cancers contemplated include glioma, low grade glioma, astrocytoma (e.g., grade I-pilocytic astrocytoma, grade II-low grade astrocytoma, grade III-anaplastic astrocytoma, or grade IV-glioblastoma (GBM)), glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal parenchymal tumor of intermediate differentiation, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, nasal neuroblastoma, or retinoblastoma, medulloblastoma, brain stem, and hypophthalmic glioma. glioma), cerebellar and cerebral astrocytoma, as well as neuroectodermal and pineal tumors, chordoma, mixed glioma, optic nerve glioma, subependymoma, metastatic brain tumor, pituitary tumor, pituitary adenoma, primitive neuroectodermal (PNET) tumor, or schwannoma. In some cases, the cancer is of a type that is more commonly found in children than adults, such as brain stem glioma, juvenile pilocytic astrocytoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some cases, the patient is an adult human. In some cases, the patient is a child or pediatric patient. In some cases, the cancer is a cancer of the male reproductive system. Contemplated cancers of the male reproductive system include, but are not limited to, embryonal carcinoma, seminoma, penile cancer, prostate cancer, and testicular cancer. In some cases, the cancer is a cancer of the female reproductive system. Contemplated female reproductive cancers include, but are not limited to, epithelial ovarian cancer, fallopian tube cancer, uterine papillary serous carcinoma (UPSC), choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and vulvar cancer, as well as uterine sarcoma. In some cases, the cancer is ovarian cancer. Contemplated ovarian cancers include, but are not limited to, serous tumors, papillary serous cystadenocarcinoma, endometrioid tumors, mucinous cystadenocarcinoma, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenic tumors. In some cases, the cancer is cervical cancer. Contemplated cervical cancers include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, neuroendocrine tumors, vitreous cell carcinoma, and villous tubular adenocarcinoma. In some cases, the cancer is gastrointestinal cancer.Contemplated gastrointestinal cancers include, but are not limited to, anal cancer, colon cancer, colon carcinoma, colorectal cancer, esophageal cancer, stomach cancer, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), duodenal cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer. In some cases, the cancer is esophageal cancer. Contemplated esophageal cancers include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma. In some cases, the cancer is gastric cancer. Contemplated gastric cancers include, but are not limited to, intestinal type and diffuse gastric adenocarcinoma. In some cases, the cancer is pancreatic cancer. Contemplated pancreatic cancers include, but are not limited to, pancreatic adenocarcinoma, pancreatic adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors. In some cases, the cancer is a urinary tract cancer. Contemplated urinary tract cancers include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary carcinoma. In some cases, the cancer is a kidney cancer. Contemplated kidney cancers include, but are not limited to, renal cell carcinoma, renal pelvis carcinoma, urothelial cell carcinoma, juxtaglomerular cell carcinoma (reninoma), angiomyolipoma, renal cell tumor, Bellini duct carcinoma, renal clear cell sarcoma, mesodermal nephroma, and Wilms tumor. In some cases, the cancer is a bladder cancer. Contemplated bladder cancers include, but are not limited to, bladder cancer, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. In some cases, the cancer is an eye cancer. Contemplated eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. In some cases, the cancer is liver cancer. Contemplated liver cancers include, but are not limited to, cystadenoma, hepatoma, cholangiocarcinoma, extrahepatic cholangiocarcinoma, hepatobiliary carcinoma (hepatic duct and bile duct) carcinoma, hepatoblastoma, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), hepatic cholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma. In some cases, the cancer is skin cancer.Contemplated skin cancers include, but are not limited to, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. In some cases, the cancer is head and neck cancer. Contemplated head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma. In some cases, the cancer is lymphoma. Contemplated lymphomas include, but are not limited to, lymphocytic lymphoma, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. In some cases, the cancer is a sarcoma. Sarcomas contemplated include, but are not limited to, soft tissue sarcoma, fibrosarcoma, neurofibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In some cases, the cancer is leukemia. Leukemias contemplated include, but are not limited to, acute leukemias (such as acute myeloid leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, and acute erythroleukemia), chronic leukemias (such as, but not limited to, chronic myelogenous leukemia and chronic myelogenous leukemia), and hairy cell leukemia.

[0087] Other cancers contemplated for treatment by the compounds of the present disclosure (such as compounds of formula (I), compounds of Table 1, and salts thereof) and the methods described herein can be selected from, for example, urothelial cancer (including, but not limited to, bladder cancer and all transitional cell carcinomas), head and neck squamous cell carcinoma, melanoma (including, but not limited to, uveal melanoma), ovarian cancer (including, but not limited to, serous subtypes of ovarian cancer), renal cell carcinoma (including, but not limited to, clear cell renal cell carcinoma subtypes), cervical cancer, gastrointestinal / gastric (GIST) cancer (including, but not limited to, gastric cancer), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and esophageal cancer. In some cases, the cancer is urothelial cancer. In some cases, the cancer is bladder cancer. In some cases, the cancer is transitional cell carcinoma. In some cases, the cancer is head and neck squamous cell carcinoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma. In some cases, the cancer is ovarian cancer. In some cases, the cancer is a serous subtype of ovarian cancer. In some cases, the cancer is renal cell carcinoma. In some cases, the cancer is a clear cell renal cell carcinoma subtype. In some cases, the cancer is cervical cancer. In some cases, the cancer is gastrointestinal / gastric (GIST) cancer. In some cases, the cancer is gastric cancer. In some cases, the cancer is non-small cell lung cancer (NSCLC). In some cases, the cancer is advanced and / or metastatic NSCLC. In some cases, the cancer is esophageal cancer.

[0088] Other cancers contemplated include polycythemia vera, Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, epithelial cancer, appendix cancer, atypical teratoid / rhabdoid tumors, central nervous system atypical teratoid / rhabdoid tumors, central nervous system embryonal tumors, bronchial tumors, carcinoid tumors, cancer of unknown primary, central nervous system cancer, childhood cancer, spinal cord tumors, chronic myeloproliferative disorders, ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, epithelial blastoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibroblastic germ cell tumors, gastric trophoblastic tumors, cardiac cancer, histiocytosis, Langerhans cell carcinoma, hypopharyngeal cancer, islet cell tumors, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity Cavity cancer, Lobular carcinoma in situ (LCIS), Macroglobulinemia, Medulloepithelioma, Merkel cell carcinoma, Midline duct carcinoma with NUT gene, Mouth cancer, Lip cancer, Multiple endocrine neoplasia syndrome, Plasmacytoma, Mycosis fungoides, Myelodysplastic syndrome, Myelodysplastic / myeloproliferative tumor, Myeloma, Chronic myeloproliferative disease, Nasal cavity cancer, Paranasal sinus cancer, Nasopharyngeal cancer, Oral cancer, Oral cavity cancer, Oropharyngeal cancer, Papillomatosis, Paraganglioma, Paranasal sinus cancer, Nasal cavity cancer, Pheochromocytoma, Pineoblastoma, Plasmacytoma, Pleuropulmonary blastoma, Transitional cell carcinoma, Sézary syndrome, Supratentorial primitive neuroectodermal tumor, Supratentorial primary neuroectodermal tumor, Thymoma, Thymic carcinoma, Transitional cell gestational trophoblastic tumor, Unknown primary, Unknown unusual cancer of childhood Examples of cancer include, but are not limited to, primary, unusual cancer of childhood, or diffuse large B-cell lymphoma (DLBCL).

[0089] Also provided are methods and compositions for the diagnosis, prognosis, and treatment of virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and CD4+ T-cell leukemia caused by human T-cell leukemia type I (HTLV-I) and characterized by clonal integration of HTLV-I in leukemic cells, as well as virus-associated tumors in gastric, nasopharyngeal, cervical, vaginal, vulvar, head and neck squamous cell carcinoma, and Merkel cell carcinoma.

[0090] In some cases, the compounds of the present disclosure (such as compounds of formula (I), compounds of Table 1, and salts thereof), or compositions thereof, are useful for treating viral infections. In some cases, viral infections treated using the compounds and methods described herein include, but are not limited to, coronavirus infections and flavivirus infections. In some cases, the viral infection is a coronavirus infection. As used herein, "coronavirus infection" refers to a disease caused by infection with a coronavirus. Coronaviruses are a family of viruses that cause disease in mammals and birds. Coronaviruses are in the Orthocoronavirinae subfamily of the Coronaviridae family, order Nidovirales. There are four major genera of coronaviruses, known as alpha, beta, gamma, and delta. Coronaviruses that affect humans include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome-related coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63, New Haven coronavirus), human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus (MERS-CoV, formerly known as novel coronavirus 2012 and HCoV-EMC), and SARS-CoV-2 (also known as 2019-nCoV).

[0091] In humans, coronaviruses generally cause respiratory infections, including a mild cold, although rare forms such as SARS, MERS, and SARS-CoV-2 (responsible for the 2019-20 COVID-19 outbreak) can be fatal. Symptoms vary in other species: in chickens, coronaviruses cause upper respiratory tract disease, while in cattle and pigs, coronaviruses cause diarrhea. There are no vaccines or antiviral drugs to prevent or treat human coronavirus infections. Coronaviruses HCoV-229E, -NL63, -OC43, and -HKU1 circulate continuously in the human population and cause respiratory infections in adults and children worldwide. Non-limiting examples of coronaviruses include severe acute respiratory syndrome-related coronavirus (SARS), Middle East respiratory syndrome-related coronavirus (MERS), and SARS-CoV-2 virus (also known as 2019-nCoV). Thus, in some cases, compounds of the present disclosure (e.g., compounds of Formula (I), compounds of Table 1, and salts thereof), or pharma- ceutically acceptable salts thereof, may be used to treat SARS, MERS, and COVID-19 (i.e., SARS-CoV infection, MERS-CoV infection, and SARS-CoV-2 infection, respectively).

[0092] In some cases, the viral infection is a flavivirus infection. As used herein, the term "flavivirus infection" refers to a disease caused by infection with a flavivirus.

[0093] Flaviviruses are a family of viruses that cause disease in mammals and insects. Flaviviruses are in the order Amarillovirales, family Flaviviridae. Flaviviruses have a net single-stranded RNA genome that is nonsegmented and is approximately 10-11 kbp in length. In humans, flaviviruses cause hemorrhagic fever, encephalitis, and congenital microcephaly. Flavivirus infections range from asymptomatic to causing death. There are vaccines or antiviral drugs to prevent or treat some, but not all, human flavivirus infections. Non-limiting examples of flaviviruses include West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus, and several other viruses that can cause encephalitis. Thus, in some cases, the compounds of the present disclosure (such as compounds of Formula (I), compounds of Table 1, and salts thereof), or pharma- ceutically acceptable salts thereof, may be used to treat flavivirus infections, such as West Nile fever, dengue fever, tick-borne encephalitis, yellow fever, and Zika fever (i.e., West Nile virus infection, dengue virus infection, tick-borne encephalitis virus infection, yellow fever virus infection, and Zika virus infection, respectively).

[0094] Another aspect of the disclosure provides the use of a compound or salt disclosed herein (such as a compound of formula (I), a compound of Table 1, and salts thereof), or a composition comprising a compound or salt disclosed herein (such as a compound of formula (I), a compound of Table 1, and salts thereof), in the treatment of a disease or disorder (e.g., cancer or a viral infection).

[0095] Also contemplated is the use of a compound or salt disclosed herein (such as a compound of Formula (I), a compound of Table 1, and salts thereof), or a composition comprising a compound or salt disclosed herein (such as a compound of Formula (I), a compound of Table 1, and salts thereof), in the manufacture of a medicament in the treatment of a disease or disorder (e.g., cancer or a viral infection).

[0096] The use of the compounds disclosed herein (such as the compounds of formula (I), the compounds of Table 1, and salts thereof), or pharma- ceutically acceptable salts thereof, to treat a disease or disorder in a subject (e.g., cancer or a viral infection) is also contemplated. Additionally, the use of the compounds disclosed herein (such as the compounds of formula (I), the compounds of Table 1, and salts thereof), or pharma- ceutically acceptable salts thereof, is also contemplated. Additionally, the use of the compounds disclosed herein (such as the compounds of formula (I), the compounds of Table 1, and salts thereof), or pharma- ceutically acceptable salts thereof, in the preparation of a medicament for use in the treatment of the aforementioned conditions is also contemplated.

[0097] In some cases, the compounds disclosed herein (such as compounds of formula (I), compounds of Table 1, and salts thereof), or pharmaceutically acceptable salts thereof, may be administered in combination with another therapeutic agent to treat a disease or disorder (e.g., cancer or viral infection). Thus, in any of the methods disclosed herein, treating a disease or disorder (e.g., cancer or viral infection) includes co-administering a compound of formula (I), Table 1, or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent. In some cases, the therapeutic agent is an immune checkpoint inhibitor. Non-limiting examples of immune checkpoint inhibitors include PD1 or PDL1 antibodies, such as pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarimab, durvalumab, or avelumab.

[0098] In jurisdictions that prohibit the patenting of processes performed on the human body, the meaning of "administering" a composition to a human subject or patient should be limited to prescribing a controlled substance to be self-administered by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation governing patentable subject matter is intended. In jurisdictions that do not prohibit the patenting of processes performed on the human body, "administering" a composition includes both the process performed on the human body and the aforementioned acts.

[0099] Synthesis of Compounds of the Disclosure The compounds of the present disclosure can be synthesized by any method known in the art. For example, the compounds of formula (I) or the compounds of Table 1, and salts thereof, can be synthesized according to Scheme 1 or Scheme 2.

[0100] [ka] In some cases, compounds of formula (I) having structure c can be synthesized using the procedures shown in Scheme 1. Coupling of a substituted 3-oxo-2,3-dihydropyridazine-4-carboxylic acid a with an amine compound b produces a substituted 3-oxo-2,3-dihydropyridazine-4-amide compound having structure c.

[0101] Alternatively, compound c can also be prepared via a cross-coupling reaction, such as Suzuki coupling, to afford Ar as the final step, as shown in Scheme 2. 2 It can also be made by attaching groups to the backbone.

[0102] [ka] An optional further derivatization step produces compounds as described herein, i.e., compounds of formula I having structure c or modified structure c.

[0103] The coupling of compounds a and b and a' and b' can be catalyzed or promoted by suitable reagents selected based on the exact nature of compounds a and b and a' and b'. For example, carbodiimide chemistry can be used to effect the coupling of carbodiimide compound a and amine compound b, for example, by using CDI or DIEA / HATU in a suitable solvent, for example, DMF.

[0104] Compounds a and b, as well as a' and b', can be purchased commercially or prepared by a variety of methods from commercially available starting materials. The optional derivatization reaction to convert a compound having structure c to a compound having modified structure c can be carried out by derivatizing the substituent R 1 and the functionality desired in the modified structure c. For example, when compound c is 1 In the case of having a primary amine group thereon, the terminal amine functionality can be further derivatized by methods known in the art to form various functional groups, for example, the amine moiety can be acylated with, for example, an acid chloride or other suitable reagent.

[0105] Also disclosed herein are compounds useful as synthetic intermediates in the synthesis of the AHR modulators disclosed herein, for example, compounds of formula (A) or (B): [ka] In the formula, Ar 1 , R 3 , R 1 , and R N is as defined above, X is a leaving group, R is H, C 1-6 Provided herein are compounds in which X is alkyl, alkyl, or phenyl. As used herein, a leaving group is a functional group compatible with aryl coupling, for example Suzuki coupling, such as halo (e.g., chloro), alkylsulfonyloxy, or arylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, tosyloxy, triflyl). In some cases, X is chloro, fluoro, mesyl, tosyl, or triflyl. Compounds of formula A or B can be converted to Ar under suitable coupling conditions (e.g., in the presence of a coupling catalyst). 2 React with the precursor to Ar 2can be coupled to a compound of formula A or B at the "X" position, thereby forming a compound of formula I. The coupling catalyst can be, for example, a palladium catalyst (e.g., chloro(crotyl)(tri-tert-butylphosphine)palladium(II), or Pd(dppf)Cl2). Ar 2 The precursor is Ar 2 It may be a boronic acid or a boronic ester.

[0106] In some cases, compound (A) or (B) is reacted with an amine nucleophile (Ar 2 moiety) and optionally further modified (e.g., to form -NR N R 1 moieties) to form a compound of formula (I). EXAMPLES

[0107] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0108] Example 1: Preparation of Analogs Scheme A [ka] A solution of 3,6-dichloropyridazine-4-carboxylic acid (15.0 g, 0.078 mol) in AcOH (150 ml) was heated to 120° C. and stirred for 4 h. After cooling, the reaction mixture was poured into water (300 ml) to precipitate a solid, which was filtered, washed with water and dried to give compound A. C5H3ClN2O3[M+H] + LCMS (ESI) calculated for ms / z = 175.1, found 175.1.

[0109] To a solution of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (174 mg, 1.0 mmol) in DMF (1.0 ml) was added DIEA (387 mg, 3.0 mmol) and HATU (760 g, 2.0 mmol). After 10 min, the corresponding amine (1.2 mmol) was added. The reaction mixture was stirred at 25° C. for 2 h. LCMS showed that the desired MS was detected. The solvent was removed under vacuum and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product, which was purified by flash chromatography to give the corresponding amide.

[0110] A solution of the resulting amide compound (1.0 mmol), 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (266.0 mg, 1.2 mmol), DIEA (154.8 mg, 1.2 mmol), pyridine (2.0 mmol), and Cu(OAc)2 (218 mg, 1.3 mmol) in ACN (2.0 ml) was stirred at 25° C. for 16 h. The solvent was removed under vacuum, and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the desired product, which was then purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give intermediate B.

[0111] To a solution of intermediate B (0.2 mmol) in 1,4-dioxane / HO (2 mL / 0.2 mL) was added 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.24 mmol), Pd(dppf)Cl2 (0.02 mmol), and K2CO3 (0.4 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 16 h. LCMS showed the desired MS was detected. The solvent was removed under vacuum. The residue was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give the desired product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 50–95, 6.5 min) to give the final analogue.

[0112] Example 2. Preparation of Analogs Scheme B [ka] A solution of the corresponding amide (1.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.2 mmol), DIEA (154.8 mg, 1.2 mmol), pyridine (2.0 mmol), and Cu(OAc)2 (218 mg, 1.3 mmol) in ACN (2.0 ml) was stirred at 25° C. for 16 h. The solvent was removed in vacuo and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the desired product, which was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give intermediate C.

[0113] To a solution of intermediate C (0.2 mmol) in 1,4-dioxane / HO (2 mL / 0.2 mL) was added 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.24 mmol), Pd(dppf)Cl2 (0.02 mmol) and K2CO3 (0.4 mmol). The reaction mixture was stirred under nitrogen at 100° C. for 16 h. LCMS showed the desired MS was detected. The solvent was removed under vacuum. The residue was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give the desired product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 50–95, 6.5 min) to give the final analogue.

[0114] Example 3. Preparation of Analogs Scheme C [ka] To a solution of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (3.0 g, 0.017 mol) in DMF (20 ml) was added DIEA (6.66 g, 0.052 mol) and HATU (13.1 g, 0.034 mol). After 10 min, (2S)-1-methoxypropan-2-amine (1.84 g, 0.021 mol) was added. The reaction mixture was stirred at 25° C. for 2 h. The solvent was removed under vacuum and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product, which was purified by flash chromatography (eluted with PE / EtOAc 100:0 to 50:50 in 30 min) to give compound B. C9H 12 ClN3O3[M+H] + LCMS (ESI) calculated for ms / z = 246.2, found 246.2.

[0115] A solution of compound B (300.0 mg, 1.22 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.47 mmol), DIEA (189.4 mg, 1.47 mmol), pyridine (193.2 mg, 2.44 mmol), and Cu(OAc)2 (277.3 g, 1.53 mmol) in ACN (10 ml) was stirred at 25° C. for 16 h. LCMS showed the desired MS was detected. The solvent was removed under vacuum and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the desired product, which was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give intermediate D. 13 H 16 ClNO3[M+H] + LCMS (ESI) calculated for ms / z = 326.2, found 326.2.

[0116] To a solution of intermediate D (0.2 mmol) in 1,4-dioxane / HO (2 mL / 0.2 mL) was added the corresponding borate (0.24 mmol), Pd(dppf)Cl2 (0.02 mmol), and K2CO3 (0.4 mmol). The reaction mixture was stirred under nitrogen at 100 °C for 16 h. LCMS showed the desired MS was detected. The solvent was removed under vacuum. The residue was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give the desired product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150 × 21.2 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 50 to 95, 6.5 min) to give the analogs.

[0117] Example 4. Preparation of Compound 57 [ka] A solution of compound B (300.0 mg, 1.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-([2-(trimethylsilyl)ethoxy]methyl)-1H-pyrazole (476.7 mg, 1.47 mmol), DIEA (189.4 mg, 1.47 mmol), pyridine (193.2 mg, 2.44 mmol), and Cu(OAc)2 (277.3 g, 1.53 mmol) in ACN (10 ml) was stirred for 16 h at 25° C. The solvent was removed in vacuo and the residue was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product, which was then purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give compound C.

[0118] To a solution of compound C (53.0 mg, 0.2 mmol) in 1,4-dioxane / HO (2 mL / 0.2 mL) was added 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.2 mg, 0.24 mmol), Pd(dppf)Cl (0.02 mmol), and KCO (0.4 mmol). The reaction mixture was stirred at 100° C. under nitrogen for 16 h. The solvent was removed under vacuum. The residue was purified by flash chromatography (eluted with DCM / MeOH 100:0 to 90:10 in 30 min) to give the desired product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150×21.2 mm, mobile phase: MeCN-HO (0.1% FA), gradient: 50-95, 6.5 min) to give compound D. 24 H 32 ClNO4Si[M+H] + LCMS (ESI) calculated for ms / z = 518.2, found 518.2.

[0119] A solution of compound D (40.0 mg, 0.093 mmol) in HCl-dioxane was stirred at 25° C. for 120 h. The solvent was removed under vacuum to give the desired product, which was purified by preparative HPLC (column: Gemini 5 μm C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% NH3.H2O), gradient: 50-95, 11.25 min) to give compound 101. 18 H 18 ClNO3[M+H] + LCMS (ESI) calculated for ms / z = 388.0, found 388.0.

[0120] Example 5 - Additional synthetic routes Method 1 - Compounds 134, 135, 136, 137, 138, 142, 143, 151, 158, 159, 160, 161, 162, 188, 189, and 190 To a solution of 6-chloro-3-oxopyridazine-4-carboxamide derivative (0.092 mmol), the corresponding diazole or triazole or indole derivative (0.111 mmol), cesium carbonate (60.0 mg, 0.1842 mmol), and catalytic agent [copper(I) iodide (17.5 mg, 0.092 mmol) or Pd-PEPPSI-IPentCl2-MePy (3.7 mg, 0.0046 mmol)] in dry DMF (3 ml). The reaction mixture was stirred at 100 °C for 1-16 h. LCMS showed that the desired MS was detected. The reaction mixture was concentrated. The crude product was purified by preparative TLC (PE / EtOAc=1 / 1) to give the crude product, which was purified by preparative HPLC (column: Gemini 5um C18 150×21.2mm, mobile phase: ACN-HO (0.1% FA), gradient: 30-95, 11.25 min) to give the desired product.

[0121] Method 2 - Compounds 110, 114, 116, 117, 125, 127, 145 A solution of 6-chloro-N-[(2S)-1-methoxypropan-2-yl]-2-(1-methylpyrazol-4-yl)-3-oxopyridazine-4-carboxamide (30.0 mg, 0.0880 mmol) in MeCN (3 mL) was stirred with the corresponding secondary amine (0.176 mmol) and potassium carbonate (24.3 mg, 0.176 mmol) at 100 °C for 12 h. LCMS showed that the desired MS was detected. The reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Gemini 5um C18 150 x 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 30-95, 10.25 min) to give the desired product.

[0122] Method 3 - Compounds 115, 119, 149, 152 To a solution of 6-chloro-N-[(2S)-1-methoxypropan-2-yl]-2-(1-methylpyrazol-4-yl)-3-oxopyridazine-4-carboxamide (50.0 mg, 0.1535 mmol) in 1,4-dioxane / H2O=5:1 (3 mL), the borate derivative (0.1842 mmol), Pd(dppf)Cl2 (11.2 mg, 0.01535 mmol), and K2CO3 (42.4 mg, 0.307 mmol) were added and stirred at 100° C. for 12 hours. LCMS showed that the desired MS was detected. The reaction mixture was concentrated. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-95, 11.00 min) to give the desired product.

[0123] Mass spectrometry data for the compounds synthesized herein are shown below in Table 2. Table 3 shows the NMR and mass spectrometry data for the compounds synthesized via the above methods. [Table 2-1] [Table 2-2] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12]

[0124] Example 5 - AHR antagonist reporter assay in human cell lines AhR reporter assays were performed according to the protocol for the Human Aryl Hydrocarbon Receptor (AhR) Reporter Assay System (INDIGO Bioscience, #IB06001-32). AhR reporter cells were thawed and pre-incubated in cell recovery medium (CRM) for 6 hours. The medium was then removed and cells were incubated for 24 hours with compound screening medium (CSM) supplemented with 200 μM kynurenic acid in the absence (negative control) or presence of increasing concentrations of test compounds (typical dilutions: 128 pM, 640 pM, 3.2 nM, 16 nM, 80 nM, 400 nM, 2 μM, 10 μM in duplicate). For positive inhibition controls, cells activated with 200 μM kynurenic acid were incubated in the presence of literature AHR antagonists. Alternatively, non-activated cells were used as a positive inhibition control. After 24 hours of incubation, the medium was removed and luciferase detection reagent (LDR) was added. Firefly luciferase activity was quantified using a plate reader and results were normalized by positive and negative controls.

[0125] Example 6 - AHR-regulated CYP1A1 expression in human cell lines To evaluate the AHR inhibitory activity of test compounds, quantitative PCR analysis was used to determine the expression levels of the AHR-regulated gene CYP1A1 in the human monocytic U937 cell line upon stimulation with 200 μM kynurenic acid (KA) in the absence or presence of AHR inhibitors. U937 cells were cultured at 5 × 10 in 200 μL of growth medium in a 96-well cell culture microplate. 5Cells were seeded at a concentration of 10 ... Taqman probes for human CYP1A1 (Hs01054797_g1) and human GAPDH (Hs02786624_g1) were used to analyze fold expression of CYP1A1 over GAPDH.

[0126] The results are shown in Table 4 below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0127] Example 7 - Evaluation of antitumor activity Female BALB / C mice were inoculated with CT26 tumor cells (3 × 10 5) was subcutaneously inoculated into the right flank. Mice were randomized into four groups according to their body weight on the fourth day after inoculation. Tumor-bearing mice were treated with vehicle, anti-PD-1 antibody (RMP1-14, BioXCell Catalog No. BP0146), AHR antagonist compound disclosed herein, and combination therapy of AHR antagonist compound disclosed herein and anti-PD-1 (or established treatment). AHR antagonist compound was administered orally for 16 days, for example at 10 mg / kg alone or in combination with established treatment. When established treatment was PD-1 antibody, the antibody was administered via intraperitoneal injection at 10 mg / kg twice a week. The results of tumor growth inhibition using Example 184 as the AHR antagonist compound are shown in Figure 1. All treatment groups showed a significant reduction in tumor volume compared to the vehicle group, with p values ​​of <0.0001, 0.0083, and <0.0001 for the anti-PD-1 antibody group, Example 184 group, and combination group, respectively. Compared to the anti-PD-1 antibody group and Example 184 group, the combination group showed a significant reduction in tumor volume, with p values ​​of 0.0235 and <0.0001, respectively.

[0128] The synergistic tumor growth inhibition of Example 184 and the anti-PD-1 antibody also translated into a significant survival benefit, as shown in the survival curves in Figure 2, with a p-value vs. vehicle of 0.0049 and a p-value vs. the standalone group of Example 184 of 0.0011.

[0129] It should be understood that all combinations of the above concepts and implementations, as well as additional concepts and implementations discussed in more detail below, are contemplated as being part of the inventive subject matter disclosed herein and may be used in any suitable combination to achieve the benefits described herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are contemplated as being part of the inventive subject matter disclosed herein. The foregoing description is given solely for clarity of understanding, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the present disclosure may be apparent to those skilled in the art.

[0130] As used throughout this specification, the terms "substantially" and "about" are used to describe and account for small variations, for example, they can refer to ±5% or less, such as ±2% or less, such as ±1% or less, such as ±0.5% or less, such as ±0.2% or less, such as ±0.1% or less, such as ±0.05% or less.

[0131] Throughout this specification and the claims that follow, unless the context clearly indicates otherwise, the term "comprise" and variations such as "comprises" and "comprising" are understood to imply the inclusion of a stated integer or step, or group of integers or steps, but not the exclusion of any other integer or step, or group of integers or steps.

[0132] Throughout this specification, when a composition is described as comprising components or materials, it is contemplated that the composition can also consist essentially of or consist of any combination of the recited components or materials, unless otherwise stated. Similarly, when a method is described as comprising particular steps, it is contemplated that the method can also consist essentially of or consist of any combination of the recited steps, unless otherwise stated. The present disclosure illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0133] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with the aid of electronic devices, or using automation provided by electronic devices. Although the processes have been described with reference to specific implementations, those skilled in the art will readily appreciate that other ways of performing the operations associated with the methods may be used. For example, the order of various steps may be changed without departing from the scope or spirit of the methods, unless otherwise noted. In addition, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0134] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemical 1】 During the ceremony, Each R Ｎ are independently H or C １－６ is alkyl, R １ But H, C １－６ Alkyl, C １－６ Alkylene -NR Ｎ R Ｎ , C １－６ Alkylene -O-C １－６ Alkyl, C １－６ Alkylene -C(O)R ２ , C １－６ Alkylene -NR Ｎ -C(O)-C １－３ Alkyl, C ３－８ cycloalkyl, or 4- to 12-membered heterocyclyl, wherein 1 to 3 ring atoms are selected from O, N, and S, and said cycloalkyl or heterocyclyl is selected from 1 or 2 C １－６ Alkyl, C(O)-C １－６ optionally substituted with alkyl, and =0; R ２ But, OH, O-C １－６ Alkyl, or NR Ｎ R Ｎ and Ar １ But C ６－１０ aryl or 5-10 membered heteroaryl, wherein 1-3 ring atoms are selected from O, N, and S; Ar １ is one or two R ３ optionally substituted with Each R ３ But independently, Halo, C １－６ Alkyl, C １－６ haloalkyl, or C ３－６ is cycloalkyl, Ar ２ But C ５－８ Cycloakly, C ５－８ Cycloalkenyl, C ６－１０ aryl, or 5-12 membered heterocyclyl or heteroaryl, wherein 1-3 ring atoms are selected from O, N, and S; Ar ２ is one, two, or three R ４ optionally substituted with Each R ４ are independently halo, OH, ═O, CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, NR Ｎ R Ｎ , C.O.R. Ｎ R Ｎ , COOH, COO-C １－６ Alkyl, C(O)-C １－６ Alkyl, SO ２ -C １－６ Alkyl, C ３－８ cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, wherein 1 to 3 ring atoms are selected from O, N, and S, or phenyl, and said heterocyclyl, heteroaryl, or phenyl is selected from halo and C １－６ substituted with 0, 1, or 2 substituents independently selected from alkyl; or Ar ２ However, (1) C ５－８ Cycloakly, C ５－８ Cycloalkenyl, C １０ aryl, 4- to 12-membered heterocyclyl, or 5- or 7- to 12-membered heteroaryl; Ar ２ is one, two, or three R ４ or (2) phenyl or 6-membered heteroaryl, and Ar ２ However, CONR Ｎ R Ｎ , COOH, COO-C １－６ Alkyl, C(O)-C １－６ Alkyl, SO ２ -C １－６ Alkyl, C ３－８ at least one R selected from cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and phenyl; ４ When substituted with １ But C ２－６ hydroxyalkyl, and the phenyl, heterocyclyl, or heteroaryl may be halo and C １－６ A compound, or a pharmaceutically acceptable salt thereof, substituted with 0, 1, or 2 substituents independently selected from alkyl.

2. R １ But H, C １－６ The compound or salt according to claim 1, which is alkyl, C 1-6 alkylene-NR N R N or C 1-6 alkylene-O-C 1-6 alkyl, C 1-6 alkylene-C(O)R 2 or C 1-6 alkylene-NR N -C(O)CH 3 .

3. R ２ 2. The compound or salt of claim 1, wherein is OH, NH2, NHCH3, or N(CH3)2.

4. R １ 2. The compound or salt of claim 1, wherein is heterocyclyl containing from 4 to 12 total ring atoms, and 1 to 3 of said ring atoms are selected from O, N, and S.

5. R １ but, 【Chemistry 2】 5. The compound or salt of claim 4, wherein:

6. R １ But C ２－６ Alkylene-C(O)-NR Ｎ R Ｎ or C 2-6 hydroxyalkyl.

7. Ar １ But C ６－１０ The compound or salt of claim 1, which is aryl or 5- to 10-membered heteroaryl.

8. Ar ２ But C ６－１０ The compound or salt according to any one of claims 1 to 7, which is aryl or 5- to 12-membered heteroaryl.

9. At least one R ４ Fluoro, chloro, OH, CN, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , OCH ３ , C.F. ３ , OCF ３ , CHF ２ , C.H. ２ F, OCHF ２ , N.H. ２ , N(CH ３ ) ２ , C.O.N.H. ２ , COOH, SO ２ CH ３ 9. The compound or salt of claim 8, wherein the aryl group is cyclopropyl, cyclopropyl, or morpholino.

10. At least one R ４ However, CONR Ｎ R Ｎ , COOH, COO-C １－６ Alkyl, C(O)-C １－６ Alkyl, SO ２ -C １－６ Alkyl, C ３－８ cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and phenyl, wherein said phenyl, heterocyclyl, or heteroaryl is selected from halo and C １－６ 9. The compound or salt of claim 8, substituted with 0, 1, or 2 substituents independently selected from alkyl.

11. Ar ２ but, 【Chemistry 3】 The compound or salt according to any one of claims 1 to 7,

12. Ar ２ but, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 The compound or salt according to any one of claims 1 to 7,

13. A compound listed in Table 1, or a pharmaceutically acceptable salt thereof.

14. 10. A pharmaceutical formulation comprising the compound or salt of claim 1 and a pharmaceutically acceptable excipient.

15. 15. A compound or salt of claim 1, or a pharmaceutical composition of claim 14, in the preparation of a medicament for treating or preventing a disease or disorder in a subject.

16. 16. The use according to claim 15, wherein the disease or disorder is cancer, a viral infection, or pulmonary arterial hypertension (PAH).

17. 16. The use of claim 15, wherein the medicament further comprises an immune checkpoint inhibitor.

18. A compound having the structure of formula (A) or (B): 【Chemistry 5】 During the ceremony, Ar １ But C ６－１０ aryl or 5-10 membered heteroaryl, wherein 1-3 ring atoms are selected from O, N, and S; Ar １ is one or two R ３ optionally substituted with Each R ３ But independently, Halo, C １－６ Alkyl, C １－６ haloalkyl, or C ３－６ is cycloalkyl, R １ But H, C １－６ Alkyl, C １－６ Alkylene -NR Ｎ R Ｎ , C １－６ Alkylene -O-C １－６ Alkyl, C １－６ Alkylene -C(O)R ２ , C １－６ Alkylene -NR Ｎ -C(O)-C １－３ Alkyl, C ３－８ cycloalkyl, or 4- to 12-membered heterocyclyl, wherein 1 to 3 ring atoms are selected from O, N, and S, and said cycloalkyl or heterocyclyl is selected from 1 or 2 C １－６ Alkyl, C(O)-C １－６ optionally substituted with alkyl, and =0; R ２ But, OH, O-C １－６ Alkyl, or NR Ｎ R Ｎ and Each R Ｎ are independently H or C １－６ is alkyl, X is a leaving group; R is H, C １－６ Alkyl, C １－６ A compound that is alkylenephenyl, aryl, or heteroaryl, where the alkyl, aryl, or heteroaryl can be optionally substituted.

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