HK40079937A

HK40079937A - Cd73 inhibitors

Info

Publication number: HK40079937A
Application number: HK62023067927.1A
Authority: HK
Inventors: 杜晓慧; 约翰·埃克斯特洛维奇; 瓦莱里娅·R·凡廷; 孙大庆; 叶秋萍; 贾瑞德·摩尔; 塔蒂亚娜·扎沃罗廷斯卡亚; 布莱恩·R·布朗克; 柳曜燮; 吴克佳; 朱柳生; 约翰尼·法姆; 川井弘之; 叶建宏
Original assignee: 欧瑞克制药公司
Priority date: 2019-10-30
Filing date: 2020-10-29
Publication date: 2023-04-28

Description

CD73 inhibitor

Cross-referencing

The present application claims the benefit of U.S. application serial No. 62/928,138 filed on 30/10/2019, U.S. application serial No. 62/987,806 filed on 3/10/2020, and U.S. application serial No. 63/088,646 filed on 7/10/2020, which are hereby incorporated by reference in their entireties.

Background

There is a need in the art for effective treatments of cancer, infections and neurodegenerative diseases.

Disclosure of Invention

Provided herein are compounds of formula (I) and/or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variations thereof, as well as pharmaceutical compositions comprising the compounds. The subject compounds and compositions are useful as CD73 inhibitors. In addition, the subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.

Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof:

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

each W is independently hydrogen, halogen, -CN, -OR ^b 、NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ A hydroxyalkyl group;

R ¹ and R ² Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^1a Substitution;

or R ¹ And R ² Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R ^1b Substituted heterocycloalkyl;

each R ^1a And R ^1b Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl);

R ³ is hydrogen, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl radical(heteroaryl) C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^3a Substitution;

each R ^3a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ⁴ and R ⁵ Independently hydrogen, halogen, -OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ⁶ is hydrogen, deuterium, halogen, -CN, -OR ¹³ 、-SR ¹³ 、-S(＝O)R ¹⁴ 、-NO ₂ 、-NR ¹⁵ R ¹⁶ 、-S(＝O) ₂ R ¹⁴ 、-NR ¹³ S(＝O) ₂ R ¹⁴ 、-S(＝O) ₂ NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁴ 、-OC(＝O)R ¹⁴ 、-C(＝O)OR ¹³ 、-OC(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、-OC(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)R ¹⁴ 、-NR ¹³ C(＝O)OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and pharmaceutically acceptable salts thereof,C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^6a Substitution;

each R ^6a Is oxo, halogen, -CN, -OR ¹³ 、-SR ¹³ 、-S(＝O)R ¹⁴ 、-NO ₂ 、-NR ¹⁵ R ¹⁶ 、-S(＝O) ₂ R ¹⁴ 、-NR ¹³ S(＝O) ₂ R ¹⁴ 、-S(＝O) ₂ NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁴ 、-OC(＝O)R ¹⁴ 、-C(＝O)OR ¹³ 、-OC(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、-OC(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)R ¹⁴ 、-NR ¹³ C(＝O)OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R ⁷ 、R ⁸ 、R ⁹ and R ¹⁰ Independently hydrogen, deuterium, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl;

x is-S-, -O-or-NR ^N -；

R ^N Is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl, cycloalkyl or heterocycloalkyl;

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R ^A Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

n is 0, 1,2,3 or 4;

each R ¹³ Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^13a Substitution;

each R ¹⁴ Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^14a Substitution;

each R ¹⁵ And R ¹⁶ Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^15a Substitution;

or R ¹⁵ And R ¹⁶ Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R ^15b Substituted heterocycloalkyl;

each R ^13a 、R ^14a 、R ^15a And R ^15b Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl);

R ²¹ and R ²² Independently of each other is hydrogen, C ₁ -C ₂₀ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl group,Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three R ^21a Substitution;

or R ²¹ And R ²² Together with the atoms to which they are attached form an optionally substituted one, two or three R ^21b Substituted heterocycloalkyl;

each R ^21a And R ^21b Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl);

each R ^a Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution;

each R ^b Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution; and is

Each R ^c And R ^d Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution;

or R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three oxo, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Hydroxyalkyl-substituted heterocycloalkyl;

with the proviso that said compound is not

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of inhibiting CD73 comprising contacting CD73 with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments of the method of treating cancer, the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, or lymphoma. In some embodiments of the methods of treating cancer, the cancer expresses CD 73. In some embodiments of the method of treating cancer, CD73 is up-regulated in the cancer to be treated. In some embodiments of the method of treating cancer, the method further comprises administering a second therapeutic agent. In some embodiments of the method of treating cancer, the second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

Also disclosed herein is a method of treating an infection in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of treating an infection in a subject, the method comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments of the method of treating an infection, the infection is a viral infection. In some embodiments of the method of treating an infection, the infection is a parasitic infection.

Also disclosed herein is a method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments of the method of treating a neurodegenerative disease, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia or autism.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose to which this specification pertains.

Detailed Description

CD73 is a Glycosylphosphatidylinositol (GPI) -anchored cell surface protein that catalyzes the hydrolysis of AMP to adenosine, and acts synergistically with CD39, which converts ATP to AMP. The resulting adenosine acts as a signaling molecule that activates the P1 receptor expressed on the cell surface in many different tissues. Four G-protein coupled P1 or adenosine receptors have been cloned and designated a1, A2A, A2B, and A3. Adenosine affects a wide range of physiological processes, including neural function, vascular perfusion, and immune response. In this case, this metabolite modulates CNS, cardiovascular and immune system functions, to name a few.

There is increasing evidence that the interaction between tumor cells and their microenvironment is essential for tumorigenesis. The purinergic signaling pathway in which CD73 plays a critical role has become an important player in cancer progression. In recent years, it has become clear that adenosine is one of the most important immunosuppressive regulatory molecules in the tumor microenvironment and contributes to immune escape and tumor progression.

CD73 is a key protein molecule in cancer development. CD73 has been found to be overexpressed in a number of cancer cell lines and tumor types, including, for example, breast cancer, colorectal cancer, ovarian cancer, gastric cancer, gallbladder cancer, and cancers associated with poor prognosis.

Expression of CD73 in tumors is regulated by a variety of mechanisms. In breast cancer, CD73 expression is negatively regulated by the Estrogen Receptor (ER). Thus, CD73 is highly expressed in ER negative breast cancer patients. Hypoxia inducible factor-1 alpha (HIF-1 alpha) has also been shown to regulate CD73 transcription. In addition, inflammatory factors such as IFN- γ affect CD73 levels. CD73 expression is also epigenetically regulated by CpG island methylation in cell lines and clinical tumor samples.

In addition to being a prognostic biomarker in cancer patients, overexpression of CD73 has also been found to be functionally linked to therapy resistance. Elevated levels of CD73 were initially associated with resistance to a variety of chemotherapeutic agents including vincristine (vincristine) and doxorubicin (doxorubicin).

CD73 has also been shown to be involved in immunotherapy resistance. This ectonucleotidase inhibits the activation, clonal expansion and homing of tumor-specific T cells, particularly T helper cells and cytotoxic T cells; impairing tumor cell killing by cytolytic effector T lymphocytes; the suppressive ability to drive Treg and Th17 cells by producing adenosine around the cells; enhancing the conversion of type 1 macrophages to tumor-promoting type 2 macrophages; and promoting the accumulation of MDSCs to participate in the process of tumor immune escape.

Small molecule inhibitors and monoclonal antibodies targeting CD73 have shown anti-tumor activity in a variety of immunocompetent mouse tumor models but not in immunodeficient mouse tumor models. Taken together, these studies indicate that the activity of anti-CD 73 therapy is dependent on its ability to elicit an immune response in vivo.

Antibodies that block PD-1, PD-L1 and CTLA-4 have shown impressive objective responses in cancer patients. Recent data demonstrated that anti-CD 73 mAb significantly enhanced the activity of both anti-CTLA-4 mAb and anti-PD-1 mAb in several mouse tumor models. In addition to checkpoint blockade, CD 73-mediated adenosine production may also contribute to resistance to additional immunotherapy modalities, including CAR-T cells and cancer vaccines.

Interference with CD73 activity represents a strategy to re-sensitize tumors to therapy. Based on the association between CD73 and therapy resistance, combining anti-CD 73 therapy with chemotherapy or immunotherapy is an effective method to enhance their activity in cancer patients with high CD73 levels. In some cases, CD73 expression serves as a biomarker to identify patients who may benefit from anti-CD 73 combination therapy.

In some cases, the CD39/CD73 pair (CD39/CD73 couple) shifts ATP-driven pro-inflammatory cellular activity toward an adenosine-mediated anti-inflammatory state. Numerous studies have shown that there is variation in the activity of the CD39/CD73 axis during infection induced by various microorganisms. Increased expression of CD73 has also been observed in the brain of mice infected with Toxoplasma gondii (Toxoplasma gondii), which promotes the parasite life cycle by producing adenosine. Thus, pharmacological blockade of CD73 is a promising therapeutic approach to the treatment of human toxoplasmosis.

Enhanced expression and activity of CD39 and CD73 has been observed in endothelial cells infected with Cytomegalovirus (CMV). The increased local adenosine production associated with the upregulation of extracellular nucleotidase creates an immunosuppressive and antithrombotic microenvironment that facilitates viral entry into target cells.

In some cases, inhibitors of CD73 are useful as antiviral agents by driving a decrease in adenosine production. Elevated expression/activity of CD39 and CD73 on lymphocytes of individuals infected with Human Immunodeficiency Virus (HIV) indicates that extracellular nucleotidase has a role in immune dysfunction associated with this disease. Indeed, an increased proportion of tregs expressing CD39 has been observed in a diverse cohort of HIV-infected patients and a positive association between CD39 expression on tregs and disease progression. HIV positive patients have also been shown to have a higher number of CD39+ tregs, and their teffs exhibit increased sensitivity to adenosine inhibition in vitro, which correlates with increased expression of immunosuppressive A2A receptors.

In the central nervous system, adenosine plays a key role in controlling numerous neurological functions. By activating the P1 receptor, adenosine is involved in a wide variety of physiological and pathological processes, such as the regulation of sleep, general arousal states and activity, local neuronal excitability, and the coupling of cerebral blood flow to energy requirements. In some instances, manipulation of adenosine production by CD73 inhibitors may be useful in the treatment of neurodegenerative diseases such as alzheimer's disease, parkinson's disease, and huntington's disease, as well as psychiatric disorders such as schizophrenia and autism.

Definition of

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. The term "about" when referring to a value or range of values means that the value or range of values referred to is an approximation within experimental variability (or within statistical experimental error), thus, in some cases, the value or range of values will vary between 1% and 15% of the stated value or range of values. The term "comprising" (and related terms such as "comprises" or "having") is not intended to exclude the case where "consists of or" consists essentially of the recited features in certain other embodiments described herein, e.g., any embodiment of a composition of matter, composition, method, or process, etc.

As used in the specification and the appended claims, the following terms have the meanings indicated below, unless specified to the contrary.

"alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monovalent group having one to about ten carbon atoms, or one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-pentyl, 2-pentyl, and, N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl etc. Whenever appearing herein, a range of values such as "C ₁ -C ₆ By alkyl is meant an alkyl group consisting of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms,5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C ₁ -C ₁₀ Alkyl radical, C ₁ -C ₉ Alkyl radical, C ₁ -C ₈ Alkyl radical, C ₁ -C ₇ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₅ Alkyl radical, C ₁ -C ₄ Alkyl radical, C ₁ -C ₃ Alkyl radical, C ₁ -C ₂ Alkyl or C ₁ An alkyl group. Unless specifically stated otherwise in the specification, alkyl is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, alkyl is optionally substituted with oxo, halo, -CN, -CF ₃ -OH or-OMe. In some embodiments, alkyl is optionally substituted with halo.

"alkenyl" refers to an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The groups may be in either the cis or trans conformation with respect to one or more double bonds and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH ═ CH) ₂ ) 1-propenyl (-CH) ₂ CH＝CH ₂ ) Isopropenyl [ -C (CH) ₃ )＝CH ₂ ]Butenyl, 1, 3-butadienyl and the like. Whenever appearing herein, a numerical range such as "C ₂ -C ₆ Alkenyl "means that an alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also encompasses occurrences of the term" alkenyl "where no numerical range is specified. In some embodiments, alkenyl is C ₂ -C ₁₀ Alkenyl radical, C ₂ -C ₉ Alkenyl radical, C ₂ -C ₈ Alkenyl radical, C ₂ -C ₇ Alkenyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₅ Alkenyl radical, C ₂ -C ₄ Alkenyl radical, C ₂ -C ₃ Alkenyl or C ₂ An alkenyl group. Unless specifically stated otherwise in the specification, alkenyl groups are optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, alkenyl is optionally substituted with oxo, halo, -CN, -CF ₃ -OH or-OMe. In some embodiments, the alkenyl is optionally substituted with halo.

"alkynyl" refers to an optionally substituted, straight chain or optionally substituted, branched chain hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C ₂ -C ₆ Alkynyl "means that alkynyl can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also encompasses occurrences of the term" alkynyl "where no numerical range is specified. In some embodiments, alkynyl is C ₂ -C ₁₀ Alkynyl, C ₂ -C ₉ Alkynyl, C ₂ -C ₈ Alkynyl, C ₂ -C ₇ Alkynyl, C ₂ -C ₆ Alkynyl, C ₂ -C ₅ Alkynyl, C ₂ -C ₄ Alkynyl, C ₂ -C ₃ Alkynyl or C ₂ Alkynyl. Unless specifically stated otherwise in the specification, alkynyl groups are optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halo, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, alkynyl is optionally substituted with oxo,Halogen, -CN, -CF ₃ -OH or-OMe. In some embodiments, alkynyl is optionally substituted with halo.

"alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless specifically stated otherwise in the specification, alkylene groups may be optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkylene is optionally substituted with oxo, halo, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, alkylene is optionally substituted with oxo, halo, -CN, -CF ₃ -OH or-OMe. In some embodiments, the alkylene is optionally substituted with halo.

"alkoxy" means a group of the formula-OR _a Group, wherein R _a Is an alkyl group as defined. Unless specifically stated otherwise in the specification, alkoxy groups may be optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkoxy is optionally substituted with oxo, halo, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, alkoxy is optionally substituted with oxo, halo, -CN, -CF ₃ -OH or-OMe. In some embodiments, alkoxy is optionally substituted with halo.

"aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused (aryl groups bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems. In some embodiments, aryl is 6 to 10 membered aryl. In some embodiments, aryl is 6 membered aryl. Aryl groups include, but are not limited to, those derived from anthracenylene, naphthylene, phenanthrenylene, anthracene, azulene, benzene, perylene,FluorantheneAryl groups of the hydrocarbon ring system of fluorene, as-indacene (indacene), s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidian, pyrene and triphenylene. In some embodiments, aryl is phenyl. Unless specifically stated otherwise in the specification, aryl groups may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ -OH or-OMe. In some embodiments, aryl is optionally substituted with halo.

"cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic, carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring system. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C) ₃ -C ₁₅ Cycloalkyl), three to ten carbon atoms (C) ₃ -C ₁₀ Cycloalkyl), three to eight carbon atoms (C) ₃ -C ₈ Cycloalkyl), three to six carbon atoms (C) ₃ -C ₆ Cycloalkyl), three to five carbon atoms (C) ₃ -C ₅ Cycloalkyl) or three to four carbon atoms (C) ₃ -C ₄ Cycloalkyl) groups. In some embodiments, cycloalkyl is 3 to 6 membered cycloalkyl. In some embodiments, cycloalkyl is 5 to 6 membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycle rings include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo [3.3.0]Octane, bicyclo [4.3.0]Nonanes, cis-decalin, trans-decalin, bicyclo [2.1.1]Hexane, bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonanes and bicyclo [3.3.2]Decane and 7, 7-dimethyl-bicyclo [2.2.1]A heptalkyl group. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctylAn alkenyl group. Unless specifically stated otherwise in the specification, cycloalkyl is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, cycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

"halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

"haloalkyl" means an alkyl group as defined above substituted with one or more halo groups as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl, and the like.

"heterocycloalkyl" refers to a stable 3 to 24 membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. Unless specifically stated otherwise in the specification, a heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. In some embodiments, the heterocycloalkyl group is a3 to 6 membered heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a 5 to 6 membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl [1,3]]Dithiacyclohexane, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, azobenzoxy, naphthoxy, and naphthoxy,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiahexonyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl has 2 to 10 carbons in the ring. It will be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms (including heteroatoms) comprising the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). Unless specifically stated otherwise in the specification, heterocycloalkyl is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halo.

"heteroalkyl" refers to an alkyl in which one or more of the backbone atoms of the alkyl is selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, heteroalkyl is C ₁ -C ₆ A heteroalkyl group, wherein the heteroalkyl group contains 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, or combinations thereof, wherein the heteroalkyl group is attached at a carbon atom of the heteroalkyl groupAttached to the rest of the molecule. Examples of such heteroalkyl radicals are, for example, -CH ₂ OCH ₃ 、-CH ₂ CH ₂ OCH ₃ or-CH (CH) ₃ )OCH ₃ . Unless specifically stated otherwise in the specification, heteroalkyl is optionally substituted, for example, with oxo, halo, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF ₃ -OH or-OMe. In some embodiments, the heteroalkyl is optionally substituted with halo.

"heteroaryl" refers to a 5 to 14 membered ring system group containing a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. Heteroaryl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. In some embodiments, the heteroaryl is a 5 to 10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b][1,4]Dioxepin, 1, 4-benzodioxan, benzonaphthofuryl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuryl, benzofuranonyl, benzothienyl (benzothienyl), benzotriazolyl, benzo [4,6 ] benzol]Imidazo [1,2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiaThienyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxetanyl, 1-oxyanionylpyridinyl, 1-oxyanionopyrimidinyl, 1-oxyanionylpyrazinyl, 1-oxyanionylpyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, oxazolyl, oxazolinyl, oxazolyl, pyrazinyl, oxazolyl, and the like, Triazolyl, tetrazolyl, triazinyl and thienyl (thiophenyl) (i.e., thienyl (thiophenyl)). Unless specifically stated otherwise in the specification, heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ 、-OH、-OMe、-NH ₂ or-NO ₂ And (4) substitution. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃ -OH or-OMe. In some embodiments, heteroaryl is optionally substituted with halo.

"hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more-OH groups, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, dihydroxymethyl, dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, and the like.

"oxo" refers to ═ O.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, optionallyThe optionally substituted group may be unsubstituted (e.g. -CH) ₂ CH ₃ ) Fully substituted (e.g., -CF) ₂ CF ₃ ) Are monosubstituted (e.g., -CH) ₂ CH ₂ F) Or substituted at a level between fully substituted and mono-substituted (e.g. -CH) ₂ CHF ₂ 、-CH ₂ CF ₃ 、-CF ₂ CH ₃ 、-CFHCHF ₂ Etc.). With respect to any group containing one or more substituents, those skilled in the art will appreciate that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or not feasible with respect to synthesis (e.g., substituted alkyl includes optionally substituted cycloalkyl, which in turn is defined as including optionally substituted alkyl, which may be endless). Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons.

The terms "inhibit," "block," "suppress," and grammatical variations thereof are used interchangeably herein and refer to any statistically significant reduction in biological activity, including complete blocking of activity. In some embodiments, "inhibit" refers to a decrease in biological activity of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%. Thus, when the term "inhibit" or "suppression" is applied to describe the effect on enzymatic activity of CD73, for example, the term means that the compounds disclosed herein are capable of statistically significantly reducing the 5 'nucleotidase activity of CD73 (catabolism occurs to hydrolyze adenosine monophosphate AMP to adenosine) relative to the CD73 mediated 5' nucleotidase activity in untreated (control) cells. In some cases, the cell expressing CD73 is a naturally occurring cell or cell line (e.g., a cancer cell), or is recombinantly produced by introducing a nucleic acid encoding CD73 into a host cell. In some aspects, the compounds disclosed herein statistically significantly reduce the 5' nucleotidase activity of soluble forms of CD73 in biological fluids. In one aspect, a compound disclosed herein inhibits CD 73-mediated 5' nucleotidase activity by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100%, as determined, for example, by the methods described in the examples and/or by methods known in the art.

As used herein, "treatment" or "alleviating" or "improving" are used interchangeably. These terms refer to methods for obtaining beneficial or desired results, including but not limited to therapeutic benefits and/or prophylactic benefits. By "therapeutic benefit" it is meant eradication or amelioration of the underlying disorder being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, even though the patient remains afflicted with the underlying disorder. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease, or a patient reporting one or more physiological symptoms of a disease, although a diagnosis of this disease has not yet been made.

Compound (I)

Described herein are compounds that are inhibitors of CD 73. These compounds and compositions comprising these compounds are useful for treating cancer, infections and neurodegenerative diseases.

In some embodiments, provided herein is a compound having the structure of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof:

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

R ³ is hydrogen, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^3a Substitution;

R ⁶ is hydrogen, deuterium, halogen, -CN, -OR ¹³ 、-SR ¹³ 、-S(＝O)R ¹⁴ 、-NO ₂ 、-NR ¹⁵ R ¹⁶ 、-S(＝O) ₂ R ¹⁴ 、-NR ¹³ S(＝O) ₂ R ¹⁴ 、-S(＝O) ₂ NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁴ 、-OC(＝O)R ¹⁴ 、-C(＝O)OR ¹³ 、-OC(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、-OC(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)R ¹⁴ 、-NR ¹³ C(＝O)OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^6a Substitution;

R ⁷ 、R ⁸ 、R ⁹ and R ¹⁰ Independently hydrogen, deuterium, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical、C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl;

x is-S-, -O-or-NR ^N -；

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

n is 0, 1,2,3 or 4;

each R ¹³ Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^13a Substitution;

each R ¹⁵ And R ¹⁶ Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^15a Substitution;

R ²¹ and R ²² Independently of each other is hydrogen, C ₁ -C ₂₀ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^21a Substitution;

each R ^a Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl group,Alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution;

or R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three oxo groups, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Hydroxyalkyl-substituted heterocycloalkyl;

with the proviso that said compound is not

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

R ⁷ 、R ⁸ 、R ⁹ and R ¹⁰ Independently hydrogen, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl;

x is-S-, -O-or-NR ^N -；

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R ^A Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ HydroxyalkanesBase, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

n is 0, 1,2,3 or 4;

R ²¹ and R ²² Independently of one another is hydrogen, C ₁ -C ₂₀ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^21a Substitution;

Each R ^c And R ^d Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, or a salt thereof,Aryl or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution;

with the proviso that said compound is not

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

R ¹ and R ² Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R ^1a Substitution;

R ³ is hydrogen, halogen, -CN, -OR ^b 、-SR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl))、C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^3a Substitution;

R ⁶ is hydrogen, deuterium, halogen, -CN, -OR ¹³ 、-SR ¹³ 、-S(＝O)R ¹⁴ 、-NO ₂ 、-NR ¹⁵ R ¹⁶ 、-S(＝O) ₂ R ¹⁴ 、-NR ¹³ S(＝O) ₂ R ¹⁴ 、-S(＝O) ₂ NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁴ 、-OC(＝O)R ¹⁴ 、-C(＝O)OR ¹³ 、-OC(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、-OC(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)NR ¹⁵ R ¹⁶ 、-NR ¹³ C(＝O)R ¹⁴ 、-NR ¹³ C(＝O)OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl groups, cycloalkyl groups, alkyl groups, cycloalkyl groups, and the like,Heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one, two, or three R ^6a Substitution;

x is-S-, -O-or-NR ^N -；

R ^N Is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ A hydroxyalkyl group,Cycloalkyl or heterocycloalkyl;

ring a is heterocycloalkyl or heteroaryl;

n is 0, 1,2,3 or 4;

R ²¹ and R ²² Independently of each other is hydrogen, C ₁ -C ₂₀ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl), C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each one ofIndependently optionally substituted with one, two or three R ^21a Substitution;

each R ^b Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution; and is provided with

Each R ^c And R ^d Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution;

or R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three oxo, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ Hydroxyalkyl-substituted heterocycloalkyl.

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

each W is independently hydrogenHalogen, -CN, -OR ^b 、NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or C ₁ -C ₆ A hydroxyalkyl group;

x is-S-, -O-or-NR ^N -；

ring a is heterocycloalkyl or heteroaryl;

n is 0, 1,2,3 or 4;

each R ^b Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution; and is

In some embodiments, a compound having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, has the structure of formula (Ia):

in some embodiments, the compound having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, has the structure of formula (Ib):

in some embodiments of compounds of formula (I), (Ia) or (Ib), Q ¹ Is N. In some embodiments of compounds of formula (I), (Ia) or (Ib), Q ¹ Is CW.

In some embodiments of compounds of formula (I), (Ia) or (Ib), Q ² Is N, and Q ³ Is CW. In some embodiments of the compounds of formula (I), (Ia) or (Ib), Q ² Is CW, and Q ³ Is N. In some embodiments of compounds of formula (I), (Ia) or (Ib), Q ² Is N, and Q ³ Is N.

In some embodiments of the compounds of formula (I), (Ia) or (Ib), each W is independently hydrogen, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds of formula (I), (Ia) or (Ib), each W is independently hydrogen, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia) or (Ib), each W is hydrogen.

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), X is-O-. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), X is-S-. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), X is-NR ^N -。

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ^N Is hydrogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^N Is hydrogen.

In some embodiments, a compound having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, has the structure of formula (Ic):

in some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two or three R ^3a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein each alkyl and alkynyl is independently optionally substituted with one, two or three R ^3a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl. Some of the compounds of formula (I), (Ia), (Ib) or (Ic)In embodiments, R ³ Is halogen or C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ A heteroalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is a halogen. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, -OR ^b 、C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein each alkyl and alkynyl is independently optionally substituted with one, two or three R ^3a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, -OR ^b 、C ₂ -C ₆ Alkynyl or C ₁ -C ₆ A hydroxyalkyl group; wherein each alkyl and alkynyl is independently optionally substituted with one, two or three R ^3a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen or C ₁ -C ₆ A hydroxyalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ³ Is halogen, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ A hydroxyalkyl group; wherein each alkyl and alkynyl is independently optionally substituted with one, two or three R ^3a And (4) substitution.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^3a Independently oxo, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently oxo, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A fluoroalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently of one another is halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently halogen, -OR ^b 、C ₁ -C ₆ Alkyl or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^3a Independently oxo, halogen OR-OR ^b 。

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is C ₁ -C ₆ Alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^1a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is C ₁ -C ₆ Alkyl, cycloalkyl, heterocycloalkyl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^1a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is cycloalkyl or C ₁ -C ₆ Alkyl (cycloalkyl); wherein each alkyl and cycloalkyl is independently optionally substituted with one, two or three R ^1a And (4) substitution. In the formula (I), (Ia),In some embodiments of the compounds of (Ib) or (Ic), R ¹ Is optionally substituted by one, two or three R ^1a A substituted cycloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl, heterocycloalkyl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^1a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is C ₁ -C ₆ Alkyl, cycloalkyl, C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (cycloalkyl); wherein each alkyl, cycloalkyl and aryl is independently optionally substituted with one, two or three R ^1a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is cycloalkyl or C ₁ -C ₆ Alkyl (cycloalkyl). In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ Is a cycloalkyl group.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1a Independently of one another oxo, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1a Independently oxo, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A fluoroalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1a Independently of one another is halogen or C ₁ -C ₆ An alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1a Independently oxo, halogen, -CN, -OR ^b 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ A fluoroalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1a Independently is halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ² Is hydrogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ² Is hydrogen.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ¹ And R ² Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R ^1b Substituted heterocycloalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1b Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1b Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1b Independently is oxoRadical, halogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Fluoroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^1b Independently oxo, halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A fluoroalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^1b Independently is halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁴ And R ⁵ Independently hydrogen, halogen, -OR ^b 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁴ And R ⁵ Independently hydrogen OR-OR ^b . In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ⁴ And R ⁵ is-OH.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ²¹ And R ²² Independently of each other is hydrogen, C ₁ -C ₂₀ Alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^21a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ²¹ And R ²² Independently of each other is hydrogen, C ₁ -C ₂₀ An alkyl or aryl group; wherein each alkyl and aryl is independently optionally substituted with one, two or three R ^21a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ²¹ And R ²² Independently hydrogen, optionally substituted by one, two or three R ^21a Substituted C ₁ -C ₂₀ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ²¹ And R ²² Is hydrogen.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^21a Independently oxo, halogen、-CN、-OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b Or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^21a Independently is-C (═ O) R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b or-OC (═ O) NR ^c R ^d . In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^21a Independently is-C (═ O) OR ^b OR-OC (═ O) OR ^b 。

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ²¹ And R ²² Together with the atoms to which they are attached form an optionally substituted one, two or three R ^21b Substituted heterocycloalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^21b Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^21b Independently halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^21b Independently of one another is halogen or C ₁ -C ₆ An alkyl group.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Independently hydrogen, deuterium, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Independently hydrogen, halogen or C ₁ -C ₆ An alkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁷ 、R ⁸ 、R ⁹ And R ¹⁰ Is hydrogen.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is 5 membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is tetrazolyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is aryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), ring a is cycloalkyl or heterocycloalkyl.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 0. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 1. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 2. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 3. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 4. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 0 or 1. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 0, 1, or 2. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), n is 1 or 2.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^A Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ HydroxyalkanesBase, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^A Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^A Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^A Independently of one another is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^A Independently a halogen.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is hydrogen, -C (═ O) R ¹⁴ 、-C(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl radicals or C ₁ -C ₆ Alkyl (heteroaryl); wherein said alkyl and heteroAryl is independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl radicals or C ₁ -C ₆ Alkyl (heteroaryl); wherein said alkyl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl radicals or C ₁ -C ₆ Alkyl (heteroaryl); wherein said alkyl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein said alkyl is independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is hydrogen, C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein said alkyl is independently optionally substituted with one, two or three R ^6a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ⁶ Is C ₁ -C ₆ A hydroxyalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^6a Is oxo, halogen, -CN, -OR ¹³ 、-NR ¹⁵ R ¹⁶ 、-C(＝O)R ¹⁴ 、-C(＝O)OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^6a Is oxo, halogen, -CN, -OR ¹³ 、-NR ¹⁵ R ¹⁶ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^6a Is halogen, -CN, -OR ¹³ 、-NR ¹⁵ R ¹⁶ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^6a Is halogen, -CN, -OR ¹³ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or cycloalkyl.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹³ Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Deuterated alkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two or three R ^13a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹³ Independently of each other is hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group; wherein each alkyl group is independently optionally substituted with one, two or three R ^13a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹³ Independently is hydrogen or C ₁ -C ₆ An alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹³ Independently is C ₁ -C ₆ An alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹³ Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, arylIndependently, the radicals and heteroaryl are optionally substituted by one, two or three R ^13a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹³ Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two or three R ^13a And (4) substitution.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^13a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^13a Independently halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^13a Independently of one another is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^13a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two OR three oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ And (3) halogenated alkyl substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^13a Independently is-OR ^b 、-C(＝O)OR ^b Cycloalkyl, aryl orA heteroaryl group; wherein each cycloalkyl, aryl and heteroaryl is independently optionally substituted by one, two OR three oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^13a Independently is-OR ^b 、-C(＝O)OR ^b Cycloalkyl, aryl or heteroaryl.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹⁴ Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two or three R ^14a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹⁴ Independently is C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group; wherein each alkyl group is independently optionally substituted with one, two or three R ^14a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹⁴ Independently is C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^14a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^14a Independently halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^14a Independently of one another is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹⁵ And R ¹⁶ Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one, two or three R ^15a And (4) substitution. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ¹⁵ And R ¹⁶ Independently of each other is hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group; wherein each alkyl group is independently optionally substituted with one, two or three R ^15a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹⁵ And R ¹⁶ Independently of one another is hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group; wherein each alkyl group is independently optionally substituted with one, two or three R ^15a And (4) substitution. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ¹⁵ And R ¹⁶ Independently is hydrogen or C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^15a Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^15a Independently halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^15a Independently of one another is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹⁵ And R ¹⁶ Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three R ^15b Substituted heterocycloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ¹⁵ And R ¹⁶ Together with the nitrogen atom to which they are attached form a heterocycloalkyl group.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^15b Independently oxo, halogen, -CN, -OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^15b Independently halogen, -CN, -OR ^b 、-NR ^c R ^d 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^15b Independently of one another is halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^a Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^a Independently is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^a Independently is C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^a Independently isC ₁ -C ₆ An alkyl group.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^b Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^b Independently of each other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or cycloalkyl. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^b Independently of one another is hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^b Independently is hydrogen or C ₁ -C ₆ An alkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), each R ^b Is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ib), or (Ic), each R ^b Independently is C ₁ -C ₆ An alkyl group.

In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each independently is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each independently of the other is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or cycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each independently is hydrogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each independently of the other is hydrogen or C ₁ -C ₆ An alkyl group. In thatIn some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each is hydrogen. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Each independently is C ₁ -C ₆ An alkyl group.

In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three halogen, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl-substituted heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three halogen or C ₁ -C ₆ Alkyl substituted pyrrolidines. In some embodiments of the compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three halogen or C ₁ -C ₆ An alkyl substituted piperidine. In some embodiments of compounds of formula (I), (Ia), (Ib) or (Ic), R ^c And R ^d Together with the nitrogen atom to which they are attached form an optionally substituted one, two or three halogen or C ₁ -C ₆ An alkyl substituted piperazine.

In some embodiments, the compound is not

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one of skill in the art to provide stable moieties and compounds.

In some embodiments is a compound having a structure selected from table 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

TABLE 1

Other forms of the compounds disclosed herein

Isomers/stereoisomers

In some embodiments, the compounds described herein exist in geometric isomeric forms. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (E) and cis (Z) isomers, and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration unless specifically defined otherwise. Unless specifically defined otherwise, the compounds described herein include all diastereomeric, enantiomeric and epimeric forms and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by: reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. Dissociable complexes are preferred in some embodiments. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated by exploiting these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered along with a resolving agent.

Labelled compounds

In some embodiments, the compounds described herein are present in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into a compound disclosed herein, or a solvate or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as respectively ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ^l5 N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and ³⁶ and (4) Cl. Compounds described herein, and metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof, that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds, e.g. radioactive isotopes such as ³ H and ¹⁴ those into which C is incorporated mayFor use in drug and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation) ³ H) And carbon-14 (i.e. ¹⁴ C) Isotopes are particularly preferred for their ease of preparation and detectability. In addition, with heavy isotopes such as deuterium (i.e. with deuterium) ² H) Substitution may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those salts prepared by the reaction of a compound described herein with a mineral acid, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumerate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate, hydroxybenezoate, dihydroxybenzoate, and the like, Gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, Tosylate, undecanoate, and xylenesulfonate.

In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic or organic acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, acetic acid, succinic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, and mixtures thereof, Lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

In some embodiments, those compounds described herein that contain a free acid group are combined with a suitable base of a pharmaceutically acceptable metal cation, such as hydroxide, carbonate, bicarbonate, sulfate; with ammonia; or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium and aluminum salts and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ⁺ (C _1-4 Alkyl radical) ₄ And the like.

Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It will be appreciated that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil soluble or dispersible products are obtained by such quaternization.

Solvates thereof

In some embodiments, the compounds described herein are present in the form of solvates. The invention provides methods of treating diseases by administering such solvates. The invention also provides methods of treating diseases by administering such solvates in the form of a pharmaceutical composition.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared by recrystallization from aqueous/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

In some cases, the compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the structural formulae described herein. Tautomers are compounds that can interconvert by migration of a hydrogen atom with the conversion of a single bond and an adjacent double bond. In a bonding arrangement where tautomerism is likely to occur, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors including temperature, solvent and pH.

Preparation of the Compounds

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "commercially available Chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemical Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemserevice Inc. (West Chemicals, PA), CreScent Chemical Co., Hauppauge, NY), Eastorganic Chemical, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co., Pittsburgh, Pidions, Fisonson, Chemical, cantilever Co., Inc., mineral Co., Inc, mineral Co., Inc., Chemical, mineral Co., Inc, mineral Co., Inc., mineral Co., R, mineral Co., Inc., mineral Co., N, mineral Co., Inc., mineral Co., N, mineral Co., Inc., mineral Co., Inc., mineral Co., Inc., mineral Co., Inc., mineral Co., U, mineral Co., U.S, mineral Co., U, mineral Co., Inc., mineral Co., mineral Co., mineral Co., mineral Co., mineral Co., mineral Co., mineral Co., mineral, germany), Spectrum Quality Product, Inc (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc (Rockville, MD), and Wako Chemicals USA, Inc.

Suitable reference books and monographs detailing the synthesis of reactants useful in the preparation of the compounds described herein, or providing citations to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, inc., New York; sandler et al, "Organic Functional groups preparation," 2 nd edition, Academic Press, New York, 1983; h.o. house, "Modern Synthetic Reactions", 2 nd edition, w.a. benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2 nd edition, John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4 th edition, Wiley-Interscience, New York, 1992. Additional suitable reference books and monographs detailing the Synthesis of reactants useful in the preparation of the compounds described herein, or providing citations to articles describing the preparation, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: conjugates, Methods, Starting Materials", second revised edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2 nd edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure", 4 th edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (eds) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry", 7 th edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2 nd edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in Vol.55; and "Chemistry of Functional Groups" John Wiley & Sons, volume 73.

Specific and similar reactants are optionally determined by known Chemical indexes established by the Chemical abstracts service of the American Chemical Society, which are available in most public and university libraries, and available through online databases (for more details, the American Chemical Society, Washington, d.c.) may be contacted in the colombian district, Washington). Known but not commercially available chemicals in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (such as those listed above) provide custom synthesis services. One reference to the preparation and selection of Pharmaceutical Salts of the compounds described herein is p.h. stahl and c.g. wermuth "handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

In some embodiments, the compounds described herein are prepared as outlined in schemes 1 and 2.

Scheme 1

Scheme 2

Pharmaceutical composition

In certain embodiments, the compounds disclosed herein are administered in pure chemical form. In some embodiments, The compounds disclosed herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected based on The chosen route of administration and standard pharmaceutical Practice, such as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st edition Mack pub. co., Easton, PA (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, and one or more pharmaceutically acceptable carriers. One or more carriers (or one or more excipients) are acceptable or suitable if they are compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

In certain embodiments, a compound disclosed herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts produced, for example, in one or more steps of a synthetic method.

The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. In general, the appropriate dosage and treatment regimen provides one or more compositions in an amount sufficient to provide a therapeutic and/or prophylactic benefit (e.g., an improvement in clinical outcome, such as more frequent complete or partial remission, or longer disease-free and/or overall survival, or reduction in severity of symptoms). The optimal dose is typically determined using experimental models and/or clinical trials. The optimal dose depends on the patient's body mass, weight or blood volume.

Oral dosages typically range from about 1.0mg to about 1000mg, one to four or more times per day.

Method of treatment

The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, are useful as inhibitors of CD73 and, therefore, are useful in the treatment of diseases or conditions in which CD73 activity is believed to play a role. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is an infection. In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the disease or disorder is a psychiatric disorder.

Disclosed herein are methods of treating a subject having a disorder mediated by CD73, comprising the step of administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

Cancer(s)

CD73 has been found to be overexpressed in a number of cancer cell lines and tumor types, including breast, colorectal, ovarian, gastric, and gallbladder cancers, and is associated with poor prognosis. There is increasing evidence that CD73 is a key protein molecule in cancer development.

Higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, resistance to chemotherapy, and metastasis, and with shorter patient survival in the case of cancer. In some embodiments, the compounds disclosed herein are useful for reducing tumor neovascularization, invasiveness, resistance to chemotherapy, and metastasis, as well as prolonging patient survival in cancer patients. In some embodiments, the CD73 inhibitors disclosed herein are used to control tumor neovascularization, progression, resistance to chemotherapy, and metastasis.

One embodiment provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

In some embodiments, the cancer is a chemoresistant cancer, a radiation resistant cancer, an anti-hormone therapy resistant cancer, or a refractory cancer. In some embodiments, the cancer is a recurrent cancer, a persistent cancer, or a recurrent cancer. Another embodiment provided herein describes a method of reducing the incidence of cancer recurrence. In some embodiments, provided herein is a method for treating a therapy-resistant cancer. In some embodiments, the cancer is a metastatic cancer.

In certain embodiments, cancers that may be treated with the methods provided herein include, but are not limited to, (1) leukemias, including, but not limited to, acute leukemias, acute lymphocytic leukemias, acute myelogenous leukemias such as myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, and myelodysplastic syndrome or symptoms thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia, or pancytopenia), Refractory Anemia (RA), RA (rars) with annular sideroblasts, RA (RAEB) with excess blasts, RAEB-T in transition, pre-leukemic, and chronic myelomonocytic leukemia (CMML); (2) chronic leukemias, including but not limited to chronic myelogenous (myelogenous) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including but not limited to Hodgkin's disease and non-Hodgkin's disease; (5) multiple myeloma, including but not limited to smoldering multiple myeloma, non-secretory myeloma, sclerosteous myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) waldenstrom's macroglobulinemia; (7) monoclonal gammaglobulin disease of unknown significance; (8) benign monoclonal gamma globulinosis; (9) heavy chain disease; (10) bone and connective tissue sarcomas including, but not limited to, skeletal sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angiosarcoma), fibrosarcoma, Kaposi's sarcoma (Kaposi's sarcoma), leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, schwannoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including but not limited to glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, non-glioma, acoustic neuroma, craniopharyngeal tumor, medulloblastoma, meningioma, pinealocytoma, pinealoblastoma, and primary brain lymphoma; (12) breast cancer, including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancer, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer including but not limited to pheochromocytoma and adrenocortical carcinoma; (14) thyroid cancer including, but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancers including but not limited to insulinomas, gastrinomas, glucagonoma, vipoma, somatostatin-secreting tumors, and carcinoid or islet cell tumors; (16) pituitary cancers including, but not limited to, Cushing's disease, prolactin-secreting tumors, acromegaly, and diabetes insipidus; (17) eye cancers including, but not limited to, ocular melanomas such as iris melanoma, choroidal melanoma, and ciliary melanoma, and retinoblastoma; (18) vaginal cancers including but not limited to squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancers including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and paget's disease; (20) cervical cancer including but not limited to squamous cell carcinoma and adenocarcinoma; (21) uterine cancers including but not limited to endometrial cancer and uterine sarcoma; (22) ovarian cancers including, but not limited to, ovarian epithelial cancers, borderline tumors, germ cell tumors, and stromal tumors; (23) esophageal cancer including, but not limited to, squamous carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) gastric cancer, including but not limited to adenocarcinoma, mycosis (polypoid), ulceration, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including but not limited to hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including but not limited to adenocarcinoma; (29) cholangiocarcinoma, including but not limited to papillary, nodular, and diffuse; (30) lung cancer including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; (31) testicular cancer including, but not limited to, germ cell tumor, seminoma, anaplastic, classical (classical), seminoma, non-seminoma, embryonal carcinoma, teratoma, and choriocarcinoma (yolk sac tumor); (32) prostate cancer including but not limited to adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penile cancer; (34) oral cancers, including but not limited to squamous cell carcinoma; (35) basal carcinoma; (36) salivary gland cancers including but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; (37) pharyngeal cancer, including but not limited to squamous cell carcinoma and verrucous carcinoma; (38) skin cancers including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial diffuse melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentigo melanoma; (39) renal cancers, including but not limited to renal cell carcinoma, adenocarcinoma, suprarenal adenoid tumor, fibrosarcoma, and transitional cell carcinoma (renal pelvis and/or ureter); (40) wilms' tumor (Wilms); (41) bladder cancer including, but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma; (42) reproductive cancers such as cervical, uterine, ovarian, or testicular cancer; (43) esophageal cancer; (44) laryngeal cancer; (45) head and neck cancer (including oral, nasal, throat, laryngeal, sinus, or salivary gland cancer); and other cancers including, but not limited to, myxosarcoma, osteogenic sarcoma, endothelial sarcoma, lymphatic endothelial sarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see Fishman et al, 1985, Medicine, 2 nd edition, J.B.Lippincott Co., Philadelphia and Murphy et al, 1997, information deficiencies: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S. A., Inc., United States of America).

In certain embodiments, the cancer treatable by the methods provided herein is a hematological malignancy. In certain embodiments, the hematologic malignancy is a T cell malignancy. In certain embodiments, the T cell malignancy comprises non-specific peripheral T cell lymphoma (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T cell lymphoma, adult T cell leukemia/lymphoma (ATLL), blastic NK cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic gamma-delta T cell lymphoma, lymphoblastic lymphoma, nasal NK/T cell lymphoma, or treatment-related T cell lymphoma.

In certain embodiments, the hematologic malignancy is a B cell malignancy. In certain embodiments, the B cell malignancy comprises Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma (AML), primary myelogenous leukemia (CML), Acute Monocytic Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Leukemia (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, Burkitt's lymphoma, high grade B-cell lymphoma, primary mediastink lymphoma (PMBL), primary PMBL, primary myelocytic lymphoma (lmmunocytic, and myelocytic lymphoma (lmb-cell lymphoma, Precursor B lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma or lymphoblastoid granulomatosis. In certain embodiments, the B cell malignancy is Diffuse Large B Cell Lymphoma (DLBCL). In certain embodiments, DLBCL is activated B cell DLBCL (ABC-DLBCL), germinal center B cell-like DLBCL (GBC-DLBCL), double hit DLBCL (DH-DLBCL), or triple hit DLBCL (TH-DLBCL).

In certain embodiments, the cancer that can be treated with the methods provided herein is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, or prostate cancer.

In certain embodiments, the cancers that can be treated with the methods provided herein express CD 73. In certain embodiments, the cancer that can be treated with the methods provided herein overexpresses CD 73. In certain embodiments, CD73 is up-regulated in cancers that can be treated with the methods provided herein.

Infection with viral infection

Many studies have shown that there is variation in the activity of the CD39/CD73 axis during infection induced by a variety of microorganisms. One embodiment provides a method of treating an infection in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

In some embodiments, the infection is a viral infection, a bacterial infection, or a parasitic infection.

Parasitic infection

In some embodiments, the infection is a parasitic infection. In some embodiments, the parasitic infection is caused by infection of the subject with a protozoan organism. In some embodiments, the protozoan organism is selected from the group consisting of Acanthamoeba (Acanthamoeba), Babesia (Babesia), echinococcus (Balantidium), Cryptosporidium (Cryptosporidium), dicamba (dientemoeba), Eimeria (Eimeria), enta (Entamoeba), Giardia (Giardia), Isospora (Isospora), Leishmania (Leishmania), Naegleria (Naegleria), Neospora (Neospora), Plasmodium (Plasmodium), sarcocysticeris (sarcocystictis), Theileria (Theileria), Toxoplasma (Toxoplasma), Trichomonas (trichomas), Trypanosoma (Trypanosoma) or any combination thereof. In some embodiments, the parasitic infection is caused by infection with Toxoplasma gondii (Toxoplasma gondii/t. In some embodiments, the parasitic infection is toxoplasmosis. In some embodiments, the toxoplasmosis is acute toxoplasmosis, latent toxoplasmosis, or cutaneous toxoplasmosis.

Acute toxoplasmosis: in healthy adults, acute toxoplasmosis is often asymptomatic. However, symptoms can manifest, and are often flu-like: swollen lymph nodes, headache, fever, fatigue or muscle pain lasting for one month or more. A person with a fully functioning immune system will rarely develop severe symptoms after infection. Persons with weakened immune systems may experience headaches, confusion, poor coordination, seizures, lung problems that may resemble tuberculosis or yersinia jerviceni (a common opportunistic infection occurring in persons with AIDS), or blurred vision due to severe inflammation of the retina (toxoplasmosis oculi). Young children and immunocompromised people, such as those with HIV/AIDS, those that are taking certain types of chemotherapy, or those that have recently received organ transplants, can develop severe toxoplasmosis. In some cases, toxoplasmosis causes damage to the brain (encephalitis) or eye (necrotic retinochoroiditis). Infants infected by placental transfer can live with any of these problems, or with nasal malformations, although these complications are rare in newborns. Toxoplasma trophozoites, which cause acute toxoplasmosis, are called tachyzoites and are commonly found in body fluids.

Latent toxoplasmosis: due to its asymptomatic nature, the host easily becomes infected with toxoplasma gondii and, unknowingly, becomes infected with toxoplasmosis. Although mild flu-like symptoms occasionally appear during the first few weeks after exposure, Toxoplasma gondii infection does not produce readily observable symptoms in healthy adults. In most immunocompetent people, the infection enters a latent period during which only bradyzoites (tissue cysts) are present; these tissue cysts, and thus lesions, can occur in the retina, the alveolar lining of the lung (where acute infections can mimic yersinia pneumocystis infections), the heart, skeletal muscles, and the Central Nervous System (CNS), including the brain. After Toxoplasma gondii infection, cysts form in the CNS (brain tissue) and persist throughout the life of the host. Most infants infected while in the uterus are asymptomatic at birth, but may develop symptoms later in life.

Toxoplasmosis of the skin: in some embodiments, skin lesions occur in acquired forms of the disease, including, but not limited to, rosettes and polymorphous erythematoid rashes, prurigo-like nodules, urticaria and maculopapular lesions. Neonates may have punctate macula or ecchymosis. The diagnosis of cutaneous toxoplasmosis is based on the finding of the tachyzoite form of toxoplasma gondii in the epidermis.

Viral infection

In some embodiments, the infection is a viral infection. In certain embodiments, viral infections that can be treated with the methods provided herein include, but are not limited to, fowl pox, influenza (influenza), herpes, human immunodeficiency virus (HIV/AIDS), Human Papilloma Virus (HPV), infectious mononucleosis, mumps, measles, rubella, herpes zoster, viral gastroenteritis (stomach cold), viral hepatitis, viral meningitis, and viral pneumonia.

Neurodegenerative diseases

In the central nervous system, adenosine plays a key role in controlling numerous neurological functions. By activating the P1 receptor, adenosine is involved in a wide variety of physiological and pathological processes, such as the regulation of sleep, general arousal states and activity, local neuronal excitability, and the coupling of cerebral blood flow to energy requirements. In some embodiments, manipulation of adenosine production by CD73 inhibitors has therapeutic potential in neurodegenerative diseases. One embodiment provides a method of treating a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof. In certain embodiments, neurodegenerative diseases that can be treated with the methods provided herein include, but are not limited to, alzheimer's disease, parkinson's disease, and huntington's disease. One embodiment provides a method of treating a psychiatric disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof. In some embodiments, the psychiatric disorder is schizophrenia or autism.

Combination therapy

In certain instances, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is administered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a treatment regimen) that also has therapeutic benefit.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is co-administered with a second therapeutic agent, wherein the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing greater overall benefit as compared to the administration of either therapeutic agent alone.

In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is only additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

In certain embodiments, when a compound disclosed herein is administered in combination with a second therapeutic agent, different therapeutically effective doses of the compound disclosed herein will be used to formulate a pharmaceutical composition, and/or in a treatment regimen. The therapeutically effective dose of the drug and other agents for use in the combination treatment regimen is optionally determined by means similar to those set forth above for the active agents themselves. Furthermore, the prophylactic/therapeutic methods described herein encompass the use of metronomic dosing, i.e., providing lower doses more frequently to minimize toxic side effects. In some embodiments, the combination treatment regimen encompasses the following treatment regimens: wherein administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is initiated before, during, or after treatment with a second agent described herein, and continues until any time during or after termination of treatment with the second agent. It also includes the following treatments: wherein a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof and a second agent for use in a combination are administered simultaneously during a treatment period, or at different times and/or at decreasing or increasing intervals. Combination therapy also includes periodic treatments that start and stop at various times to assist in clinical management of patients.

It will be appreciated that the dosage regimen for treating, preventing or ameliorating the condition or conditions sought to be alleviated will be modified depending upon a variety of factors, such as the disease, disorder or condition suffered by the subject, the age, weight, sex, diet and medical condition of the subject. Thus, in some instances, the dosage regimen actually employed can vary, and in some embodiments, departs from the dosage regimen set forth herein.

For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug employed, the particular drug employed, the disease or condition being treated, and the like. In additional embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, then, for example only, multiple therapeutic agents are provided in a single combination or in multiple forms (e.g., in a single pill form or in two separate pills).

The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof, and the combination therapies are administered before, during, or after the onset of the disease or condition, and the timing of administration of the composition containing the compound can vary. Thus, in one embodiment, the compounds described herein are used as prophylactic agents and are continuously administered to a subject having a propensity to develop a condition or disease to prevent the disease or condition from occurring. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In particular embodiments, the compounds described herein are administered once practicable after the onset of a disease or disorder is detected or suspected, and for a period of time necessary to treat the disease. In some embodiments, the length of time required for treatment may vary, and the length of treatment is adjusted to suit the particular needs of each subject. For example, in particular embodiments, a compound or formulation containing the compound described herein is administered for at least 2 weeks, about 1 month to about 5 years.

In certain embodiments, the second therapeutic agent is an adjuvant. In certain embodiments, the second therapeutic agent is an anti-cancer agent. In certain embodiments, the second therapeutic agent is an antiemetic agent. In certain embodiments, the second therapeutic agent is an anti-infective agent. In certain embodiments, the second therapeutic agent is an antiviral agent. In certain embodiments, the second therapeutic agent is an antibacterial agent.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is administered in combination with an anti-cancer agent.

In some embodiments, the anti-cancer agent is a hormone-block therapy. Hormone blockade therapy involves the use of agents that block estrogen production or block estrogen receptors. In some embodiments, the hormone blockade therapy comprises the use of estrogen receptor modulators and/or aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g., tamoxifen (tamoxifen), toremifene (toremifene), droloxifene (droloxifene), 3-hydroxytamoxifene, idoxifene (idoxifene), TAT-59 (phosphorylated derivative of 4-hydroxytamoxifene), and GW5638 (carboxylic acid derivative of tamoxifen)); non-steroidal estrogen receptor modulators (e.g., raloxifene (raloxifene), LY353381(SERM3), and LY 357489); steroid estrogen receptor modulators (e.g., ICI-182,780). Aromatase inhibitors include both steroidal aromatase inhibitors and non-steroidal aromatase inhibitors. Steroid aromatase inhibitors include, but are not limited to, exemestane (exemestane). Non-steroidal aromatase inhibitors include, but are not limited to, anastrozole (anastrozole) and letrozole (letrozole).

In certain embodiments, the compounds disclosed herein are used in combination with one or more passive immunotherapies, including but not limited to naked and conjugated monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab (rituximab), an antibody directed against the CD20 antigen; trastuzumab (trastuzumab), an antibody directed against the HER2 protein; alemtuzumab (alemtuzumab), an antibody directed against the CD52 antigen; cetuximab (cetuximab), an antibody directed against the EGFR protein; and bevacizumab (bevacizumab), an anti-angiogenic inhibitor of VEGF protein.

Examples of conjugated monoclonal antibodies include, but are not limited to, the radiolabeled antibody ibritumomab tiuxetan; radiolabeled antibody tositumomab (tositumomab); and an immunotoxin ozomicin gemtuzumab (gemtuzumab ozogamicin) containing calicheamicin (calicheamicin); BL22, an anti-CD 22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint (registered trademark) and ProstaScint (registered trademark); weibutituximab vedotin (brentuximab vedotin); and ado-enrituzumab (ado-trastuzumab emtansine).

Other examples of therapeutic antibodies that can be used include, but are not limited to, abciximab (abciximab), an antibody directed against the glycoprotein IIb/IIIa receptor on platelets; daclizumab (daclizumab), an immunosuppressive humanized anti-CD 25 monoclonal antibody; edrecolomab (edrecolomab), a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN (registered trademark), a humanized anti-aV.beta.3 integrin antibody; campath 1H/LDP-03, a humanized anti-CD 52 IgG1 antibody; smart M195, a humanized anti-CD 33 IgG antibody; epratuzumab (epratuzumab), a humanized anti-CD 22 IgG antibody; lymphosocan; vislizumab (visilizumab); CM3, a humanized anti-ICAM 3 antibody; IDEC-114, a primatized anti-CD 80 antibody; IDEC-131, a humanized anti-CD 40L antibody; IDEC-151, a primatized anti-CD 4 antibody; IDEC-152, a primatized anti-CD 23 antibody; SMART anti-CD 3, a humanized anti-CD 3 IgG; 5G1.1, a humanized anti-complement factor 5(C5) antibody; D2E7, a humanized anti-TNF- α antibody; CDP870, a humanized anti-TNF- α Fab fragment; IDEC-151, a primatized anti-CD 4IgG 1 antibody; MDX-CD4, a human anti-CD 4IgG antibody; CD 20-streptavidin (+ biotin-yttrium 90); CDP571, a humanized anti-TNF- α IgG4 antibody; LDP-02, a humanized anti- α 4 β 7 antibody; ortho clone OKT4A, a humanized anti-CD 4IgG antibody; ANTOVA (registered trademark), a humanized anti-CD 40L IgG antibody; ANTEGREN (registered trademark), a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-. beta.2 antibody.

In some embodiments, the second therapeutic agent for use in combination with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, comprises one or more of: abiraterone (abiraterone); abarelix (abarelix); doxorubicin (adriamycin); actinomycin (actinomycin); acivicin (acivicin); aclarubicin; aridazole hydrochloride (acodazole hydrochloride); crohn (acronine); adozelesin (adozelesin); aldesleukin (aldesleukin); alemtuzumab (alemtuzumab); allopurinol (allopurinol); alitretinoin (alitretinin); altretamine (altretamine); ambomycin (ambomacin); amenthraquinone acetate (ametantrol acetate); aminoglutethimide (aminoglutethimide); aminolevulinic acid (aminolevulinic acid); amifostine (amifostine); amsacrine (amsacrine); anastrozole (anastrozole); antrocin (antrramycin); aprepitant (aprepitant); arsenic trioxide (arsenical trioxide); asparaginase (asparaginase); triptyline (asperlin); azacitidine (azacitidine); atenpi (azetepa); azomycin (azotomycin); batimastat (batimastat); bendamustine hydrochloride (bendamustine hydrochloride); benzotepa (benzodepa); bevacizumab (bevacizumab); bexarotene (bexarotee); bicalutamide (bicalutamide); bisantrene hydrochloride (bisantrene hydrochloride); bisnefade dimesylate (bisnafide dimesylate); bizelesin (bizelesin); bleomycin (bleomycin); bleomycin sulfate (bleomycin sulfate); bortezomib (bortezomib); brequinar sodium (brequinar sodium); briprimine (bropirimine); busulfan; actinomycin c (cactinomycin); carposterone (calusterone); carthamine (caracemide); carbathim (carbbeimer); carboplatin (carboplatin); carmustine (carmustine); casubicin hydrochloride (carobic hydrochloride); kazelesin (carzelesin); capecitabine (capecitabine); cedefingol (cedefingol); cetuximab (cetuximab); chlorambucil (chlorambucil); siromycin (cirolemycin); cisplatin (cissplatin); cladribine (cladribine); clofarabine (clofarabine); cllinalto mesylate (crisnatol mesylate); cyclophosphamide (cyclophosphamide); cytarabine (cytarabine); dacarbazine (dacarbazine); dasatinib (dasatinib); daunorubicin hydrochloride (daunorubicin hydrochloride); dactinomycin (dactinomycin); alfa bepotin (darbepoetin alfa); decitabine (decitabine); degarelix (degarelix); diney interleukin-2 (denileukin difttox); dexomaplatin (dexrmaplatin); dexrazoxane hydrochloride (dexrazoxane hydrochloride); dizaguanine (dezaguanine); dizyguanine mesylate (dezaguanine mesylate); diazaquinone (diazizquone); docetaxel (docetaxel); doxorubicin (doxorubicin); doxorubicin hydrochloride (doxorubicin hydrochloride); droloxifene (droloxifene); droloxifene citrate (droloxifene citrate); dromostanolone propionate; daptomycin (duazomycin); edatrexate (edatrexate); eflornithine hydrochloride (eflornithine hydrochloride); elsamitrucin (elsamitrustin); eltrombopag ethanolamine (eltrombopag olamine); enloplatin (enloplatin); enpromethane (enpromate); epipipridine (epidopidine); epirubicin hydrochloride (epirubicin hydrochloride); alfa-eptine (epoetin alfa); erbulozole (erbulozole); erlotinib hydrochloride (erlotinib hydrochloride); esorubicin hydrochloride (esorubicin hydrochloride); estramustine (estramustine); estramustine phosphate sodium (estramustine phosphate sodium); etanidazole (etanidazole); etoposide (etoposide); etoposide phosphate (etoposide phosphate); chloroacetyl pyrimethanil (etoprine); everolimus (everolimus); exemestane (exemestane); fadrozole (fadrozole hydrochloride); fazarabine (fazarabine); fenretinide (fenretinide); filgrastim (filgrastim); floxuridine (floxuridine); fludarabine phosphate (fludarabine phosphate); fluorouracil (fluorouracil); flucitabine (fluoroocitabine); praziquantel (fosquidone); fostricin sodium (fosstricin sodium); fulvestrant (fulvestrant); gefitinib (gefitinib); gemcitabine (gemcitabine); gemcitabine hydrochloride (gemcitabine hydrochloride); gemcitabine cisplatin (gemcitabine cissplatin); ozomicin gemtuzumab (gemtuzumab ozogamicin); goserelin acetate (goserelin acetate); histaminic acetate relin (histrelin acetate); hydroxyurea (hydroxyurea); idarubicin hydrochloride (idarubicin hydrochloride); ifosfamide (ifosfamide); rimofoxin (limofosine); ibritumomab tiuxetan (ibritumomab tiuxetan); idarubicin (idarubicin); ifosfamide (ifosfamide); imatinib mesylate (imatinib mesylate); imiquimod (imiquimod); interleukin I1(interleukin I1) (including recombinant interleukin II or rll2), interferon alpha-2 a (interferon alfa-2 a); interferon alpha-2 b (interferon alfa-2 b); interferon alpha-n 1(interferon alfa-n 1); interferon alpha-n 3(interferon alfa-n 3); interferon beta-1a (interferon beta-1 a); interferon gamma-1b (interferon gamma-1 b); iproplatin (iproplatin); irinotecan hydrochloride (irinotecan hydrochloride); ixabepilone (ixabepilone); lanreotide acetate (lanreotide acetate); lapatinib (lapatinib); lenalidomide (lenalidomide); letrozole (letrozole); leuprolide acetate (leuprolide acetate); calcium leucovorin (leucovorin calcium); leuprolide acetate (leuprolide acetate); levamisole (levamisole); liposomal cytarabine (liposomal cytarabine); liarozole (liarozole hydrochloride); lometrexol sodium (lomerexol sodium); lomustine (lomustine); losoxantrone hydrochloride (losoxantrone hydrochloride); maoprocol (masoprocol); maytansine (maytansine); dichloromethyldiethanamine hydrochloride (mechloroethylamine hydrochloride); megestrol acetate (megestrol acetate); melengestrol acetate (melengestrol acetate); melphalan (melphalan); melanoril (menogaril); mercaptopurine (mercaptoprine); methotrexate (methotrexate); methotrexate sodium (methotrexate sodium); methoxsalen (methoxsalen); chlorpheniramine (metoprine); meurtetipa (meturedepa); mitodomide (mitindoside); mitocrocin (mitocarcin); mitorubin (mitocromin); mitogin (mitogillin); mitomalamycin (mitomalacin); mitomycin c (mitomycin c); mitosper (mitosper); mitotane (mitotane); mitoxantrone hydrochloride (mitoxantrone hydrochloride); mycophenolic acid (mycophenolic acid); nandrolone propionate (nandrolone phenanprionate); nelarabine (nelarabine); nilotinib (nilotinib); nocodazole (nocodazole); norfitumomab (nofetumomab); nogalamycin (nogalamycin); ofatumumab (ofatumumab); omprey interleukin (oprelkin); ormaplatin; oxaliplatin (oxaliplatin); oxicam (osisuran); paclitaxel (paclitaxel); palifermin (palifermin); palonosetron hydrochloride (palonosetron hydrochloride); pamidronate (pamidronate); pegfilgrastim (pegfilgrastim); pemetrexed disodium (pemetrexed disodium); pentastatin (pentostatin); panitumumab (panitumumab); pazopanib hydrochloride (pazopanib hydrochloride); pemetrexed disodium (pemetrexed disodium); plerixafor; pralatrexate (pralatrexate); pegapase (pegaspargase); pelycomycin (pelycomycin); pentazocine (pentamustine); pelomomycin sulfate (polypromycin sulfate); phosphoramide (perfosfamide); pipobromane (pipobroman); piposulfan; piroxantrone hydrochloride (piroxanthone hydrochloride); plicamycin (plicamycin); pramipexole (plomestane); porfimer sodium (porfimer sodium); porfimycin (porfiromycin); prednimustine (prednimustine); procarbazine hydrochloride (procarbazine hydrochloride); puromycin (puromycin); puromycin hydrochloride (puromycin hydrochloride); pyrazolofuroxin (pyrazofurin); quinacrine (quinacrine); raloxifene hydrochloride (raloxifene hydrochloride); labyrinase (rasburicase); a recombinant HPV bivalent vaccine; a recombinant HPV tetravalent vaccine; lyboadenosine (ribopine); roglutamide (rogletimide); rituximab (rituximab); romidepsin (romidepsin); romidepsin (romiplostim); saffingol (safingol); saffinge hydrochloride (safingol hydrochloride); sargramostim (sargramostim); semustine (semustine); octrazine (simtrazene); sipuleucel-T; sorafenib (sorafenib); sodium phosphonoaspartate (sparfosate sodium); sparsomycin (sparnomycin); helical germanium hydrochloride (spirogyranium hydrochloride); spiromustine (spiromustine); spiroplatin (spirosplatin); streptonigrin (streptonigrin); streptozotocin (streptozocin); sulfochlorpheniramine (sulofenur); sunitinib malate (sunitinib mallate); talithromycin (talisomycin); tamoxifen citrate (tamoxifen citrate); sodium tegaserod (tecogalan sodium); tegafur (tegafur); tiaxantrone hydrochloride (teloxantrone hydrochloride); temozolomide (temozolomide); temoporfin (temoporfin); temsirolimus (temsirolimus); teniposide (teniposide); tiroxirone (teroxirone); testolactone (testolactone); thalidomide (thalidomide); thiamiprine (thiamiprine); thioguanine (thioguanine); thiotepa (thiotepa); thiazolfurin (tiazofurin); tirapazamine (tirapazamine); topotecan hydrochloride (topotecan hydrochloride); toremifene (toremifene); tositumomab (tositumomab) and I131 iodotositumomab (I131 Iodine tositumomab); trastuzumab (trastuzumab); tritolone acetate; tretinoin (tretinoin); triciribine phosphate (triciribine phosphate); trimetrexate (trimetrexate); tritetraxate glucuronate (trimetrexate glucuronate); triptorelin (triptorelin); tobramzole hydrochloride (tubulozole hydrochloride); uracil mustard (uracil mustard); uretepa (uredepa); valrubicin (valrubicin); vapreotide (vapreotide); verteporfin (verteporfin); vinblastine (vinblastine); vinblastine sulfate (vinblastine sulfate); vincristine sulfate (vincristine sulfate); vindesine (vindesine); vindesine sulfate (vindesine sulfate); vinepidine sulfate (vinapidine sulfate); vinglycinate sulfate (vinglycinate sulfate); vinblastine sulfate (vinleucine sulfate); vinorelbine tartrate (vinorelbine tartrate); vinblastine sulfate (vinrosidine sulfate); vinzolidine sulfate (vinzolidine sulfate); vorinostat (vorinostat); vorozole (vorozole); zeniplatin (zeniplatin); abstatin (zinostatin); zoledronic acid (zoledronic acid); and zorubicin hydrochloride (zorubicin hydrochloride).

In some embodiments, the second therapeutic agent is an alkylating agent. Examples of alkylating agents for use in combination with the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variations thereof, include, but are not limited to, nitrogen mustards (e.g., dichloromethyl diethylamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methyl melamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.), or triazenes (dacarbazine, etc.).

Other agents optionally used in the methods and compositions described herein to treat or prevent cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

In some embodiments, the second therapeutic agent is an immunotherapeutic agent. Examples of immunotherapeutic agents for use in combination with the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof, include, but are not limited to, checkpoint inhibitors (e.g., anti-PD 1 and anti-PD-L1 inhibitors), cancer vaccines (e.g., sipuleucel-T), oncolytic viruses (e.g., latanogene laherparpvec), cytokines (e.g., IL-2 and INF- α), CAR-T cells.

In some embodiments, the second therapeutic agent is an immune checkpoint inhibitor.

In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, an OX40 agonist, and a 4-1BB agonist.

In some embodiments, the checkpoint inhibitor is a programmed cell death protein 1(PD-1) inhibitor or a programmed cell death ligand 1(PD-L1) inhibitor. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is an antibody or antigen-binding fragment directed against PD-1 or PD-L1.

In some embodiments, the PD-1 inhibitor is selected from the group consisting of Pabolizumab (pembrolizumab), Nabrieuzumab (nivolumab), cimeprinizumab (cemipimab), Lamborlizumab (lambrolizumab), AMP-224, Centilizumab (sintilimab), Tereprinimab (toriplalimab), Carrilizumab (camrelizumab), Terralizumab (tirelizumab), Dutalizumab (Dostalumab), Dutalimab (DOSTARLImab) (GSK), PDR001(Novartis), MGA012 (Macrogenics/Inc), GLS-010(Arcus/Wuxi), AGEN2024(Agenus), Cetrolizumab (cetrilimansen) (Janssen), ABBV-181(Abbvie), AMG-404 (Amgenebi-754091 (Bohringinger), Apogeluciger (JT), Apogelie-9 (Jomlocu), and Pfilizumab (Jomlocu) 40138 (Biomycin/06801591), and Pfimllizumab (Jamercurizumab/Biomycin). In some embodiments, the PD-1 inhibitor is pabulizumab. In some embodiments, the PD-1 inhibitor is nivolumetrizumab. In some embodiments, the PD-1 inhibitor is cimetiprizumab. In some embodiments, the PD-1 inhibitor is lanblelizumab. In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-1 inhibitor is sildenumab. In some embodiments, the PD-1 inhibitor is terieprinimab. In some embodiments, the PD-1 inhibitor is carpriclizumab. In some embodiments, the PD-1 inhibitor is tirizumab.

In some embodiments, the PD-L1 inhibitor is selected from the group consisting of amitrazumab (atezolizumab), avilimumab (avelumab) and covalenuzumab (durvalumab), ASC22 (Alphamab/ascitis), CX-072(Cytomx), CS1001(Cstone), cosibelimumab (cosibelimab) (Checkpoint Therapeutics), inccb 86550(Incyte), and TG-1501(TG Therapeutics). In some embodiments, the PD-L1 inhibitor is amituzumab. In some embodiments, the PD-L1 inhibitor is avilimumab. In some embodiments, the PD-L1 inhibitor is bevacizumab.

In some embodiments, the immune checkpoint inhibitor is a cytotoxic T-lymphocyte protein 4(CTLA4) inhibitor. In some embodiments, the CTLA4 inhibitor is an antibody or antigen-binding fragment directed against CTLA 4. In some embodiments, the CTLA4 inhibitor is ipilimumab (ipilimumab) or tremelimumab (tremelimumab).

In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is selected from tremelimumab, ipilimumab, and age-1884 (Agenus). In some embodiments, the CTLA-4 inhibitor is tremelimumab. In some embodiments, the CTLA-4 inhibitor is ipilimumab.

In some embodiments, the checkpoint inhibitor is a programmed cell death ligand 2(PD-L2) inhibitor.

In some embodiments, the immune checkpoint inhibitor is an OX40 agonist.

In some embodiments, the immune checkpoint inhibitor is a 4-1BB agonist.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is used in combination with an antiemetic agent to treat nausea or vomiting resulting from the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, one or more anti-cancer agents, and/or radiotherapy. Antiemetics include, but are not limited to: neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABAB receptor agonists (such as baclofen), corticosteroids (such as dexamethasone, prednisone, prednisolone or other corticosteroids), dopamine (dopamine) antagonists (such as but not limited to domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, trimethoprim, promethazine, prochlorperazine, oxyproline, oxyphenhydramine (such as oxyphenhydrazine), oxyphenhydrazine (such as oxyphenryptazine), oxyphenhydramine (such as but not limited to oxyphenhydrazine), oxyphenhydramine (such as oxyphenhydramine), oxyphenhydramine (such as oxyphenhydrazine), oxyphenhydramine (1), oxyphenhydramine (such as oxyphenhydramine), oxyphenhydramine (hydrazine), oxyphenhydramine (hydramine), hydramine (such as hydrazine), hydramine (hydramine), hydramine (hydramine), hydramine (such as hydramine), hydramine (such as hydramine (hydramine), hydramine (such as hydramine), hydramine (hydramine), hydramine (such as hydramine (such as, hydramine), hydramine (hydramine), hydramine (hydramine), hydramine (hydramine), hydramine (1), hydramine (hydramine), hydramine (1), hydramine (1), hydramine (hydramine)), hydramine (, Cannabinoids (such as, but not limited to, cannabis (cannabis), marinol, dronabinol) and other anti-emetic agents (such as, but not limited to, trimethobenzamide (trimethobenzamide); ginger, emetrol (emetrol), propofol (propofol)).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is used in combination with an agent useful for treating anemia. Such anemia therapeutics are, for example, continuous erythropoiesis receptor activators such as epoetin-alpha (epoetin-alpha).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is used in combination with an agent useful for treating neutropenia. Examples of agents useful for treating neutropenia include, but are not limited to, hematopoietic growth factors that modulate neutrophil production and function, such as human granulocyte colony-stimulating factor (G-CSF). Examples of G-CSF include filgrastim.

In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is administered to a mammal in combination with a non-steroidal anti-inflammatory drug (NSAID). NSAIDs include, but are not limited to: aspirin (aspirin), salicylic acid (salicylic acid), gentisic acid (gentisic acid), choline magnesium salicylate (choline magnesium salicylate), choline salicylate (choline salicylate), magnesium salicylate (magnesium salicylate), sodium salicylate (sodium salicylate), diflunisal (diflunisal), carprofen (carprofen), fenoprofen (fenoprofen), fenoprofen calcium (fenoprofen calcium), flurbiprofen (fluoroobrofen), ibuprofen (ibuprofen), ketoprofen (ketoprofen), ketorolac (ketorolac), tromethamine (ketorolac), naphthoquinone (naphthoquinone), naphthoquinone (ketoprofen) (oxaprofen), ketoprofen (ketoprofen), oxaprofen (oxaprofen), ketoprofen (oxaprofen), etofenac (oxaprofen), ketoprofen (sodium chloride (oxaprofen), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin), ketoprofen (neomycin, Piroxicam (piroxicam), meloxicam (meloxicam), COX-2 specific inhibitors (such as but not limited to celecoxib (celecoxib), rofecoxib (rofecoxib), valdecoxib (valdecoxib), parecoxib (parecoxib), etoricoxib (etoricoxib), lumiracoxib (lumiracoxib), CS-502, JTE-522, L-745337, and NS 398).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, is used in combination with radiation therapy (or radiotherapy). Radiotherapy is the treatment of cancer and other diseases with ionizing radiation. Radiotherapy is optionally used to treat local solid tumors, such as skin cancer, tongue cancer, laryngeal cancer, brain cancer, breast cancer, prostate cancer, colon cancer, uterine cancer and/or cervical cancer. It is also optionally used for the treatment of leukemia and lymphoma (cancers of the hematopoietic and lymphatic systems, respectively).

Examples

I. Chemical synthesis

Unless otherwise indicated, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture and/or oxygen sensitive synthetic transformations. The yield was not optimized. The reaction times were approximate and not optimized. Unless otherwise indicated, column chromatography and Thin Layer Chromatography (TLC) were performed on silica gel.

EXAMPLE 1 ((R) -1- ((1H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3- (2-methoxyethoxy) propan-2-yl) phosphonic acid

Step A. (2R,3R,4R,5R) -diacetic acid 2- (acetoxymethyl) -5- (4, 6-dichloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydrofuran-3, 4-diyl ester (1a)

1,2,3, 5-Tetraacetic acid beta-D-ribofuranose (5.73g, 17.99mmol) was heated at 90 ℃ for 10min, and 4, 6-dichloro-1H-pyrazolo [3,4-D ] was added successively]Pyrimidine (1.5g, 17.99mmol) and SnCl ₄ (60 mg). After the mixture was heated at 130 ℃ under reduced pressure for 15min, it was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic phases were washed with water, brine, dried and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate, from 10:1 to 5:1) to give the title compound (1a) (2.4g, 68%) as a yellow solid.

Step B. (2R,3R,4R,5R) -diacetic acid 2- (acetoxymethyl) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydrofuran-3, 4-diyl ester (1B)

To the oven dried flask was added 1a (5.2g, 11.63mmol) followed by ethanol (53.24 mL). To this solution was added triethylamine (2.43mL, 17.44mmol) followed by cyclopentylamine (1.38mL, 13.95 mmol). After stirring and heating the mixture at 50 ℃ for 15min, it was cooled to room temperature, concentrated, and purified by column chromatography (20 to 45% ethyl acetate/hexane, gradient elution) to provide the title compound (1b) as a white solid (5.02g, 87%). M/z (ESI, positive ion) ═ 496.1[ M + H] ⁺ 。

Step C. (2R,3R,4R,5R) -diacetic acid 2- (acetoxymethyl) -5- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) tetrahydrofuran-3, 4-diyl ester (1C)

To a solution of 1b (12.6g, 25.4mmol) in MeCN (120mL) was added triethylamine (5.14g, 50.9mmol), followed by di-tert-butyl dicarbonate (44.35g, 203.6mmol) and 4-dimethylaminopyridine (0.31g, 2.54 mmol). After the mixture was stirred overnight, it was concentrated and partitioned between EtOAc (50mL) and saturated NaHCO ₃ In the meantime. The organic layer was washed with brine and Na ₂ SO ₄ Dried, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 8:1) to give the title compound (1c) as a yellow solid (10.56g, 70% yield). M/z (ESI, positive ion) ═ 596.72[ M + H] ⁺ 。

Step D tert-butyl (6-chloro-1- ((2R,3R,4S,5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-yl) (cyclopentyl) carbamate (1D)

To the dried flask was added 1c (10.56g, 17.78mmol) followed by a solution of ammonia in methanol (5.0M, 140 mL). The mixture was stirred overnight, then concentrated. The crude oil was purified by column chromatography to afford the title compound (1d) as a yellow solid (7.39g, 89% yield). M/z (ESI, positive ion) ═ 470.3[ M + H ]] ⁺ 。

Step E tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (1E)

To a solution of 1d (7.39g, 15.75mmol) and 2, 2-dimethoxypropane (4.92g, 47.27mmol) in DMF (75mL) was added TsOH. H ₂ O (0.6g, 3.15 mmol). After stirring the mixture at 70 ℃ for 1h, it was cooled and washed with saturated NaHCO ₃ (100mL) quench. The mixture was extracted with EtOAc (50mL) and the combined organic layers were washed with brine, Na ₂ SO ₄ Dried, filtered, and concentrated. The crude oil was purified by column chromatography (petroleum ether/ethyl acetate: 8:1) to provide the title compound (1e) (5.5g, 68% yield) as a yellow solid. M/z (ESI, positive ion) ═ 510.4[ M + H] ⁺ 。

Step F.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) acetic acid ethyl ester (1f)

In N ₂ Next, Rh was added to a solution of ethyl 2-diazo-2- (diethoxyphosphoryl) acetate (13.5g, 54.13mmol) and 1e (5.5g, 10.83mmol) in toluene (80mL) ₂ (OAc) ₄ (0.96g, 2.17 mmol). After the mixture was stirred at 95 ℃ overnight, it was concentrated and purified by column chromatography (petroleum ether/ethyl acetate: 5:1) to give the title compound (1f) as a yellow oil (6g, 76% yield). M/z (ESI, positive ion) ═ 732.2[ M + H] ⁺ 。

Step G.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) -3- (2-methoxyethoxy) propionic acid ethyl ester (1g)

To a solution of 1f (750mg, 1.02mmol) in THF (20mL) at-15 deg.C was added dropwise bis (trimethylsilyl) amide (1.0M in THF, 1.33mL,1.33 mmol). After stirring at-15 ℃ for 25min, tetra-n-butylammonium iodide (189.19mg, 0.5122mmol) was added, immediately followed by the dropwise addition of 1- (chloromethoxy) -2-methoxyethane (0.41mL, 3.59 mmol). After stirring the reaction at-15 ℃ for 65min, it was washed with saturated NH ₄ Aqueous Cl solution was quenched. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-20% acetone/hexane, gradient elution) to give the title compound (1g) (525.3mg, 63% yield) as a colorless oil. M/z (ESI, positive ion) ═ 820.3[ M + H] ⁺ 。

Step H tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1-hydroxy-3- (2-methoxyethoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (1H)

To a solution of 1g (513mg, 0.625mmol) in ethanol (13mL) at 0 deg.C was added calcium dichloride (143mg, 1.25mmol), immediately followed by the addition of sodium borohydride (94.6mg, 2.5 mmol). The mixture was then removed from the ice bath and stirred at room temperature for 3 h. The reaction was cooled back to 0 ℃ and then saturated NH was used ₄ Aqueous Cl solution was quenched. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-50% acetone/hexane, gradient elution) to provide the title compound (1h) (322mg, 66% yield) as a colorless syrup. M/z (ESI, positive ion) ═ 778.3[ M + H] ⁺ 。

Step I.2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole-5-carboxylic acid ethyl ester (1i-1) and 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazole-5-carboxylic acid ethyl ester (1i-2)

To a stirred solution of tetrazole-5-carboxylic acid ethyl ester (70g, 493mmol) in THF (850mL) at 0 deg.C was added sodium hydride (60% in mineral oil, 22.7g, 566mmol) in three portions. The mixture was allowed to warm to room temperature and stirred for 15 min. The mixture was cooled back to 0 ℃ and 2- (trimethylsilyl) ethoxymethyl chloride (99.4mL, 566mmol) was added dropwise over a period of 10 min. After allowing the mixture to warm to room temperature and stir for 2.5h, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed (brine) and dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (0% to 50% ethyl acetate/hexanes, gradient elution) provided a mixture of 1i-1 and 1i-2 as a colorless oil (114.8g, 85%, according to ¹ H NMR was 70: 30).

Note that: the regioisomer ratio of 1i-1 to 1i-2 can vary from 55:45 to 70:30, and the ratio depends on the scale of the reaction and the temperature (it is likely that higher reaction temperatures will provide more 1 i-1).

Step J. (2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methanol (1J-1) and (1- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methanol (1J-2)

To a stirred solution of 1i-1 and 1i-2(1i-1:1i-2 ═ 70:30, 57.4g, 211mmol) in MeOH (450mL) at 0 ℃ NaBH was added in three portions ₄ (15.9g, 421 mmol). After stirring at 0 ℃ for 10min, the reaction mixture was allowed to warm to room temperature and vigorous gas evolution was observed (exothermic reaction). The mixture was immediately placed back in the ice bath. After the evolution of gas had almost ceased, the reaction mixture was again allowed to warm to room temperature and stirred at room temperature for a further 10 min. The mixture was cooled to 0 ℃ and then quenched with water. The solution was extracted with EtOAc and the combined organic layers were washed (salt)Water), drying (Na) ₂ SO ₄ ) And concentrated under reduced pressure to give a mixture of 1j-1 and 1j-2 as a colorless oil (48g, 99%, 1j-1:1j-2 ═ 70: 30).

Step K.5- (bromomethyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole (1k-1) and 5- (bromomethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole (1k-2)

N-bromosuccinimide (50.7g, 284mmol) was added in three portions to a stirred solution of 1j-1 and 1j-2(1j-1:1j-2 ═ 68:32, 32.8g, 142mmol) and triphenylphosphine (74.7g, 285mmol) in DCM (1L) at-40 ℃. After the mixture was stirred at the same temperature for 1.5h, it was passed through saturated NaHCO ₃ Aqueous solution to quench. The solution was extracted (3 × DCM) and the combined organic layers were washed (brine), dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure to give an off-white solid. The residue was suspended in hexane (about 500mL) and the suspension was stirred vigorously at room temperature for 1 h. The mixture was filtered and washed with hexane. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0% to 40% ethyl acetate/hexanes, gradient elution) to provide the title compound (1k-1) (faster eluting isomer, 25.3g, 61%) and 1k-2 (slower eluting isomer, 11.1g, 27%). 1k-1 of ¹ H NMR(400MHz,CDCl ₃ ) Delta ppm5.88(s,2H),4.66(s,2H),3.58-3.80(m,2H),0.81-1.05(m,2H),0.01(s, 9H). 1k-2 of ¹ H NMR(400MHz,CDCl ₃ )δppm 5.83(s,2H),4.72(s,2H),3.56-3.65(m,2H),0.87-0.99(m,2H),0.01(s,9H)。

Step L tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1- (2-methoxyethoxy) -3- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (1L)

To a solution of 1h (320mg, 0.411mmol) and 1k-2(0.36g, 1.23mmol) in DMF (2mL) at 0 deg.C was added sodium hydride (60% dispersion in mineral oil, 32.9mg, 0.822 mmol). After stirring the mixture at 0 ℃ for 1h, it was washed with saturated NH ₄ Aqueous Cl solution was quenched. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-50% acetone/hexane, gradient elution) to provide the title compound (1l) as a pale yellow syrup (338mg, 83% yield). M/z (ESI, positive ion) 990.4[ M + H [ ]] ⁺ 。

Step M tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1- (2-methoxyethoxy) -3- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (1M-1) and (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((((S) -2- (diethoxyphosphoryl) -1- (2-methoxyethoxy) -3- ((1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamic acid tert-butyl ester (1m-2)

The mixture of diastereomers was separated by chiral chromatography (CHIRALPAK AD-H, 21X 250mm, 5 μm, 5% IPA/hexane, isocratic elution, flow rate of 20 mL/min). The isomer eluting first from the column is arbitrarily designated 1m-1 and the other isomer eluting second is arbitrarily designated 1 m-2.

Step N. ((R) -1- ((1H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3- (2-methoxyethoxy) propan-2-yl) phosphonic acid (1)

To a solution of 1m-1(117mg, 0.118mmol) in MeCN (6mL) was added triethylamine (0.33mL, 2.36mmol) at room temperature, followed by dropwise addition of bromo (trimethyl) silane (0.24mL, 1.77 mmol). After the mixture was stirred at room temperature for 21H, it was concentrated under reduced pressure, and the resulting residue was dissolved in H ₂ 1:1 mixture of O and TFA (6 mL). The mixture was stirred at room temperature for 16 h. After concentration under reduced pressure, the resulting residue was purified by reverse phase HPLC (25-45% ACN H) ₂ O, 0.1% TFA, gradient elution) to provide the title compound (1) as a TFA salt (41.5mg, 45% yield). M/z (ESI, positive ion) ═ 664.2[ M + H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δppm 8.07(s,1H),6.24-6.15(m,1H),4.94(s,2H),4.76-4.71(m,1H),4.59-4.44(m,2H),4.20-4.11(m,1H),4.07-3.90(m,4H),3.85(d,2H,J＝8.8Hz),3.62-3.55(m,2H),3.51-3.43(m,2H),3.32(s,3H),2.18-2.01(m,2H),1.88-1.74(m,2H),1.74-1.54(m,4H)。

EXAMPLE 2 ((S) -1- ((1H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3- (2-methoxyethoxy) propan-2-yl) phosphonic acid

The title compound was prepared from 1m-2 by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) ═ 664.2[ M + H] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δppm 8.09(s,1H),6.26-6.11(m,1H),4.93(s,2H),4.77-4.69(m,1H),4.58-4.45(m,2H),4.19-4.11(m,1H),4.10-4.02(m,1H),4.02-3.80(m,5H),3.65-3.54(m,2H),3.52-3.45(m,2H),3.33(s,3H),2.17-2.02(m,2H),1.87-1.74(m,2H),1.74-1.54(m,4H)。

EXAMPLE 3 ((R) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- ((2-chlorophenylmethyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-hydroxy-3- (2H-tetrazol-5-yl) propan-2-yl) phosphonic acid

Step A.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (2-chlorophenylmethyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) acetic acid ethyl ester (3a)

The title compound was prepared by a procedure similar to that described in example 1, steps a-F.

Step B.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (2-chlorophenylmethyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) -3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) propionic acid ethyl ester (3b)

To a solution of 3a (5g, 6.35mmol) in toluene (80mL) was added TBAI (1.17g, 3.17mmol) at 0 deg.C, followed by slow addition of a solution of 1k-2(3.52g, 12.1mmol) in toluene (15mL) and 50% aqueous KOH (14.2g, 127 mmol). After stirring the reaction mixture at 0 ℃ for 3h, it was washed with saturated NH ₄ Aqueous Cl solution was quenched. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The crude product is processedThe oil was purified by silica gel column chromatography (hexanes/ethyl acetate 5:1 to 3:1, gradient elution) to provide the title compound (3b) (5.2g, 82% yield). M/z (ESI, positive ion) 1000.4[ M + H [ ]] ⁺ 。

Step C tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1-hydroxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (2-chlorophenylmethyl) carbamate (3C)

CaCl was added to a solution of 3b (3.5g, 3.5mmol) in ethanol (70mL) at 0 deg.C ₂ (1.36g, 12.25mmol) and NaBH ₄ (463mg, 12.25 mmol). The reaction mixture was stirred at room temperature for 4h, followed by saturated NH ₄ Aqueous Cl solution was quenched. The resulting solution was extracted with EtOAc. The organic layer was washed with brine, over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 2:1 to 1:1, gradient elution) to provide the title compound (3c) (2.35g, 70% yield). M/z (ESI, positive ion) 958.3[ M + H [ ]] ⁺ 。

Step D tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-hydroxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-D ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-yl) (2-chlorophenylmethyl) carbamate (3D-1) and (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((((S) -2- (diethoxyphosphoryl) -1-hydroxy-3- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (2-chlorophenylmethyl) carbamic acid tert-butyl ester (3d-2)

The mixture of diastereomers was separated by chiral chromatography (CHIRALPAK AD-H, 50X 500mm, 20 μm, 5% IPA/hexane with 0.1% DEA, gradient elution, flow rate of 70 mL/min). The isomer eluting first from the column is arbitrarily designated 3d-1 and the other isomer eluting second is arbitrarily designated 3 d-2.

Step E. ((R) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- ((2-chlorophenylmethyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-hydroxy-3- (2H-tetrazol-5-yl) propan-2-yl) phosphonic acid (3)

The title compound was prepared from 3d-1 by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) ═ 632.2[ M + H] ⁺ 。 ¹ H NMR(400MHz,D ₂ O)δ7.99(s,1H),7.28-7.32(m,2H),7.15-7.17(m,2H),5.93-5.94(d,J＝5.2Hz,1H),4.6-4.8(m,3H),3.92-4.04(m,2H),3.78-3.85(m,2H),3.47-3.66(m,3H),2.99-3.03(d,J＝15.2Hz,1H)。

EXAMPLE 4 ((S) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- ((2-chlorophenylmethyl) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-hydroxy-3- (2H-tetrazol-5-yl) propan-2-yl) phosphonic acid

The title compound was prepared from 3d-2 by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) ═ 632.1[ M + H] ⁺ 。 ¹ H NMR(400MHz,D ₂ O)δ7.95(s,1H),7.26-7.29(m,2H),7.14-7.15(m,2H),5.92-5.93(d,J＝5.6Hz,1H),4.54-4.57(m,1H),4.6-4.7(s,2H),3.99-4.09(m,2H),3.73-3.78(m,2H),3.46-3.68(m,3H),3.02-3.06(d,J＝16.4Hz,1H)。

EXAMPLE 5 (2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-hydroxy-5- (2H-tetrazol-5-yl) pentan-2-yl) phosphonic acid

Step A.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -5-cyano-2- (diethoxyphosphoryl) pentanoic acid ethyl ester (5a)

To a solution of compound 1f (4.5g, 6.2mmol) in THF (60mL) at-15 deg.C was added NaHMDS (2M in THF, 4mL, 8.1 mmol). The mixture was stirred at-15 ℃ for 0.5h and TBAI (1.13g, 3.1mmol) and 4-iodobutyronitrile (3.67g, 18.6mmol) were added. After the reaction mixture was stirred at room temperature for 2h, it was washed with saturated NH ₄ Aqueous Cl solution was quenched. The solution was extracted with EtOAc, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (5a) as a yellow oil (1.08g, 22% yield). M/z (ESI, positive ion) ═ 799.3[ M + H] ⁺ 。

Step B.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) -5- (2H-tetrazol-5-yl) pentanoic acid ethyl ester (5b)

At room temperature, in N ₂ Next, 5a (850mg, 1.06mmol) in toluene (20mL) was addedTMSN ₃ (734mg, 6.38mmol) and dibutyltin oxide (263mg, 1.06 mmol). After the reaction mixture was stirred at 98 ℃ for 20h, it was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (5b) (130mg, 14.5% yield) as a yellow oil. M/z (ESI, positive ion) ═ 842.2[ M + H] ⁺ 。

Step C. (2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-hydroxy-5- (2H-tetrazol-5-yl) pentan-2-yl) phosphonic acid (5)

The title compound was prepared from 5b by a procedure similar to that described in example 3, steps C and E. M/z (ESI, positive ion) ═ 604.3[ M + H] ⁺ 。 ¹ H NMR(400MHz,D ₂ O)δ7.8-8.0(m,1H),6.04(dd,J＝10.4,3.6Hz,1H),4.81-4.9(m,1H),4.40-4.60(m,1H),4.05-4.3(m,2H),3.84-3.64(m,4H),2.42-2.75(m,2H),1.85-2.07(m,2H),1.4-1.84(m,10H)。

Example 6.4- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -5-methoxy-4-phosphonopentanoic acid

Step A.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) glutaric acid 5- (tert-butyl) ester 1-ethyl ester (6a)

To a solution of 1f (620mg, 0.847mmol) in THF (18mL) at 0 deg.C was added bisSodium (trimethylsilyl) amide (1.0M in THF, 3.39mL, 3.39 mmol). After stirring for 25min, tetra-n-butylammonium iodide (0.16g, 0.423mmol) was added, immediately followed by dropwise addition of tert-butyl 3-bromopropionate (0.42mL, 2.54 mmol). After stirring at 0 ℃ for 75min, the reaction was quenched by addition of saturated NH ₄ Aqueous Cl solution. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-30% acetone/hexane, gradient elution) to give the title compound (6a) as a colorless oil (345mg, 47% yield). M/z (ESI, positive ion) ═ 860.3[ M + H] ⁺ 。

Step B.4- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -4- (diethoxyphosphoryl) -5-hydroxypentanoic acid tert-butyl ester (6b)

The title compound was prepared from 6a by a procedure similar to that described in example 3, step C. M/z (ESI, positive ion) ═ 818.3[ M + H ] +.

Step C.4- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -4- (diethoxyphosphoryl) -5-methoxypentanoic acid tert-butyl ester (6c)

To a solution of 6b (252mg, 0.308mmol) in DMF (2mL) at 0 deg.C was added iodomethane (0.29mL, 4.62mmol) dropwise. After stirring at this temperature for 5min, sodium hydride (60% dispersion in mineral oil, 37mg, 0.924mmol) was added. After stirring at 0 ℃ for 45min, the reaction was saturated with NH ₄ Cl waterThe solution was quenched. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-30% acetone/hexane, gradient elution) to provide the title compound (6c) as a colorless syrup (150mg, 58% yield). M/z (ESI, positive ion) ═ 832.3[ M + H] ⁺ 。

Step D.4- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -5-methoxy-4-phosphonovaleric acid (6)

The title compound was prepared from 6c by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) ═ 580.2[ M + H] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δppm 8.21-8.09(m,1H),6.29-6.16(m,1H),4.81-4.72(m,1H),4.60-4.46(m,2H),4.22-4.11(m,1H),4.00-3.76(m,2H),3.76-3.57(m,2H),3.33(s,3H),2.61-2.40(m,2H),2.30-2.03(m,4H),1.89-1.74(m,2H),1.74-1.52(m,4H)。

EXAMPLE 7 ((S) - (2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -4- (hydroxyamino) -1-methoxy-4-oxobutan-2-yl) phosphonic acid

Step A.2- (((3aR,4R,6R,6aR) -6- (4- ((tert-butoxycarbonyl) (cyclopentyl) amino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -2- (diethoxyphosphoryl) pent-4-enoic acid ethyl ester (7a)

To a stirred solution of 1f (4.5g, 6.15mmol) in THF (100mL) was added dropwise sodium bis (trimethylsilyl) amide (1.0M in THF, 8.0mL, 8.0mmol) at-15 ℃ (ice/salt bath). After stirring at the same temperature for 25min, allyl iodide (1.68mL, 18.4mmol) was added at-15 ℃. After stirring at the same temperature for 1h, the reaction was quenched by addition of saturated NH ₄ Aqueous Cl solution. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (5% to 40% acetone/hexane, gradient elution) afforded the title compound (7a) (4.2g, 88%) as a yellow gum. M/z (ESI, positive ion) ═ 772.3[ M + H [ ]] ⁺ 。

Step B tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1-hydroxypent-4-en-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (7B)

To a stirred solution of 7a (4.2g, 5.44mmol) in EtOH (82mL) at 0 deg.C was added calcium dichloride (2.72g, 24.5mmol) followed by a one-shot addition of NaBH ₄ (926mg, 24.5 mmol). The mixture was allowed to warm to room temperature and was then stirred at room temperature for 2.5 h. The mixture was cooled to 0 ℃ and quenched by addition of 1H aqueous HCl. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (1% to 5% MeOH in DCM, gradient elution) afforded the title compound (7b) (2.97g, 75%) as a white foamy solid. M/z (ESI, positive ion) ═ 730.3[ M + H]+。

Step C tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1-methoxypent-4-en-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (7C)

To a stirred solution of (7b) (3.1g, 4.25mmol) and iodomethane (2.9mL, 46.7mmol) in DMF (20mL) at 0 deg.C was added sodium hydride (60% in mineral oil, 509mg, 12.7mmol) in one portion. After the resulting mixture was stirred at the same temperature for 10min, it was passed through saturated NH ₄ Aqueous Cl solution. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (1% to 5% MeOH in DCM, gradient elution) afforded the title compound (7c) (1.81g, 57%) as a yellow gum. M/z (ESI, positive ion) ═ 744.3[ M + H] ⁺ 。

Step D tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1-methoxy-4-oxobutan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-D ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-yl) (cyclopentyl) carbamate (7D)

To a solution of 7c (1.71g, 2.30mmol) and 2, 6-lutidine (0.53mL, 4.60mmol) in THF (74mL) and water (37mL) was added sodium periodate (2.95g, 13.8mmol) followed by potassium osmate (VI) dihydrate (42.3mg, 0.115 mmol). The mixture was stirred at room temperature overnight, then diluted with water and extracted with EtOAc (× 3). The combined organic layers were washed with 10% Na ₂ S ₂ O ₃ Washed with aqueous solution, brine and dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (5% to 40% acetone/hexane, gradient elution) provided the title compound (7d) (1.55g, 90%) as a colorless gum. M/z (ESI, positive ion) ═ 746.3[ M + H] ⁺ 。

Step E tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -4- (hydroxyamino) -1-methoxy-4-oxobutan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (7E)

To a mixture of N-hydroxysuccinimide (359mg, 3.11mmol) and iodobenzene diacetate (1.0g, 3.11mmol) was added MeCN (6.5mL) at room temperature. The resulting dark green suspension was cooled to 0 ℃ and a solution of 7d (1.55g, 2.08mmol) in MeCN (6.5mL) was added. The mixture was stirred at the same temperature for a further 1 h. To this colorless cloudy solution was added hydroxylamine solution (50 wt% in water, 274mg, 4.15mmol) at 0 ℃. After allowing the reaction to warm to room temperature and stir for 1h, it was diluted with DCM. The solution was extracted with EtOAc and the combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (1% to 5% MeOH in DCM, gradient elution) afforded the title compound (7e) (1.26g, 78%) as a white foamy solid. M/z (ESI, positive ion) 777.2[ M + H [ ]] ⁺ 。

Step F. (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -4- (hydroxyamino) -1-methoxy-4-oxobutan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamic acid tert-butyl ester (7F-1) and (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -4- (hydroxyamino) -1-methoxy-4-oxol Butan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamic acid tert-butyl ester (7f-2)

The diastereomers were separated by means of a chiral column (CHIRALPAK AD-H, 21X 250mm, 5 μm, 10% IPA/hexane, isocratic elution, flow rate of 20 mL/min). The isomer eluting first from the column is arbitrarily designated 7f-1, and the other isomer eluting second is arbitrarily designated 7 f-2.

Step G. (2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -4- (hydroxyamino) -1-methoxy-4-oxobutan-2-yl) phosphonic acid (7)

The title compound was prepared from 7f-1 by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) ═ 581.2[ M + H] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ8.18-8.14(1H,m),6.24-6.20(1H,m),4.73(1H,t,J＝4.0Hz),4.58-4.46(2H,m),4.18-4.14(1H,m),4.08-4.04(1H,m),3.87-3.79(2H,m),3.71-3.66(1H,m),3.30(3H,s),2.82-2.66(2H,m),2.14-2.06(2H,m),1.83-1.57(6H,m)。

EXAMPLE 8 ((R) - (2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -4- (hydroxyamino) -1-methoxy-4-oxobutan-2-yl) phosphonic acid

The title compound was prepared from 7f-2 by a procedure similar to that described in example 1, step N. M/z (ESI, positive ion) 581.2[ M + H [ ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ8.18-8.13(1H,m),6.24-6.19(1H,m),4.74(1H,t,J＝4.0Hz),4.58-4.47(2H,m),4.17-4.14(1H,m),4.03-4.00(1H,m),3.95-3.92(1H,m),3.87-3.82(1H,m),3.71-3.66(1H,m),3.55(3H,s),2.77-2.73(2H,m),2.13-2.08(2H,m),1.83-1.59(6H,m)。

EXAMPLE 9 ((R) -2- (((2R,3S,4R,5R) -5- (4- (cyclobutylamino) -6- (hydroxymethyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-methoxy-3- (2H-tetrazol-5-yl) propan-2-yl) phosphonic acid

Step A. (tert-butyl 6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-hydroxy-3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclobutyl) carbamate (9a)

The title compound was prepared by a procedure similar to that described in example 3, steps a-D.

Step B. tert-butyl cyclobutyl (1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-hydroxy-3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -6- ((E) -styryl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) carbamate (9b)

To a flask containing 9a (220mg, 0.25mmol) was added THF (5.3mL) and water (1.77 mL). To this mixture was added styrylboronic acid (56.7mg, 0.37mmol) and sodium carbonate (70.9mg, 0.67 mmol). After the reaction mixture was purged with argon, tetrakis (triphenylphosphine) palladium (0) (28.6mg, 0.02mmol) was added, and the mixture was again purged with argon. The reaction was heated at 85 ℃ for 17 h. After cooling the reaction to room temperature, it was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue is treatedPurification by silica gel chromatography (10% to 25% acetone/hexanes) afforded the title compound (9b) (210mg, 89%) as a pale yellow foam. M/z (ESI, positive ion) 956.4[ M + H [ ]] ⁺ 。

Step C. cyclobutyl (1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-methoxy-3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -6- ((E) -styryl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) carbamic acid tert-butyl ester (9c)

The title compound was prepared from 9b by a procedure similar to that described in example 7, step C. M/z (ESI, positive ion) ═ 970.5[ M + H] ⁺

Step D tert-butyl cyclobutyl (1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-methoxy-3- (2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -6-formyl-1H-pyrazolo [3,4-d ] pyrimidin-4-yl) carbamate (9d)

To a flask containing 9c (173mg, 0.18mmol) was added THF (5.94mL) and water (2.97 mL). To this solution was added 2, 6-lutidine (0.04mL, 0.36mmol) and sodium periodate (229mg, 1.07mmol), followed by potassium osmate (3.3mg, 0.01 mmol). After the reaction mixture was stirred at room temperature for 6.5h, it was quenched with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude product (9d) (159mg) as a colorless oil, which was used directly in the next step without further purification. M/z (ESI, positive ion) ═ 896.4[ M + H] ⁺

Step E. ((R) -2- (((2R,3S,4R,5R) -5- (4- (cyclobutylamino) -6- (hydroxymethyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -1-methoxy-3- (2H-tetrazol-5-yl) propan-2-yl) phosphonic acid (9)

The title compound was prepared from 9d by a procedure similar to that described in example 3, steps C and E. M/z (ESI, positive ion) 572.2[ M + H [ ]] ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δppm 8.41-8.27(m,1H),6.38(m,1H),4.56-4.80(m,5H),4.25(q,J＝4.73Hz,1H),4.09-4.18(m,1H),3.93(br dd,J＝9.65,4.38Hz,1H),3.72-3.83(m,1H),3.52-3.67(m,2H),3.37-3.49(m,1H),3.20-3.21(m,3H),2.43-2.68(m,2H),2.11-2.30(m,2H),1.83-2.06(m,2H)。

Example 10.2- ((S) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-methoxy-2-phosphonopropoxy) acetic acid

M/z (ESI, positive ion) ═ 596.2[ M + H] ⁺ . Method for producing TFA salts ¹ H NMR(400MHz,CD ₃ OD)δppm 1.54-1.76(m,4H),1.76-1.88(m,2H),2.04-2.18(m,2H),3.32(s,3H),3.75(d,J＝9.35Hz,2H),3.86-3.96(m,3H),4.03(dd,J＝10.01,4.46Hz,1H),4.12(s,2H),4.17(q,J＝4.58Hz,1H),4.49(t,J＝4.82Hz,1H),4.54(t,J＝6.87Hz,1H),4.78(t,J＝4.82Hz,1H),6.20(d,J＝4.39Hz,1H),8.14(s,1H)。

Examples 11 to 24: examples 11-24 were synthesized as described in examples 1-10 and 25.

EXAMPLE 25((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid

Step A.2- [ [ (3aR,4R,6R,6aR) -4- [4- [ tert-butoxycarbonyl (cyclopentyl) amino ] -6-chloro-pyrazolo [3,4-d ] pyrimidin-1-yl ] -2, 2-dimethyl-3 a,4,6,6 a-tetrahydrofuro [3,4-d ] [1,3] dioxol-6-yl ] methoxy ] -2-diethoxyphosphoryl-3- (2-trimethylsilylethoxy) propionic acid ethyl ester (25a)

To a solution of compound (1F) (1.2g, 1.64mmol) from step F of example 1 in THF (33mL) was added dropwise sodium bis (trimethylsilyl) amide (1.0M in THF, 2.13mL, 2.13mmol) at-15 ℃. After stirring at-15 ℃ for 25min, tetra-n-butylammonium iodide (303mg, 0.820mmol) was added, immediately followed by the addition of 2- (chloromethoxy) ethyl](trimethyl) silane (0.863mL, 4.92mmol) was added dropwise to the solution. The mixture was stirred at the same temperature for 1h, followed by saturated NH ₄ Aqueous Cl solution was quenched. The solution was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed (brine) and dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (5-30% acetone/hexanes gradient elution) provided the title compound (25a) (1.03g, 73%) as a pale yellow oil. M/z (ESI, positive ion) 862.3[ M + H [ ]] ⁺ 。

Step B.N- [1- [ (3aR,4R,6R,6aR) -6- [ [ 1-diethoxyphosphoryl-1- (hydroxymethyl) -2- (2-trimethylsilylethoxy) ethoxy ] methyl ] -2, 2-dimethyl-3 a,4,6,6 a-tetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl ] -6-chloro-pyrazolo [3,4-d ] pyrimidin-4-yl ] -N-cyclopentyl-carbamic acid tert-butyl ester (25b)

To 2- [ [ (3aR,4R,6R,6aR) -4- [4- [ tert-butoxycarbonyl (cyclopentyl) amino group at 0 deg.C]-6-chloro-pyrazolo [3,4-d]Pyrimidin-1-yl]-2, 2-dimethyl-3 a,4,6,6 a-tetrahydrofuro [3,4-d ] d][1,3]Dioxol-6-yl]Methoxy radical]To a stirred solution of ethyl (25a) (1.03g, 1.19mmol) 2-diethoxyphosphoryl-3- (2-trimethylsilylethoxy) propionate in EtOH (18mL) was added calcium dichloride (596g, 5.37mmol) followed by sodium borohydride (203mg, 5.37mmol) in one portion. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was then cooled back to 0 ℃ and the mixture was quenched with 1N aqueous HCl, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (1-5% MeOH/DCM, gradient elution) afforded the title compound (25b) (755mg, 77%) as a white foamy solid. M/z (ESI, positive ion) ═ 820.3[ M + H] ⁺ 。

Step C tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- (((2- (diethoxyphosphoryl) -1- (2- (trimethylsilyl) ethoxy) -3- ((2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (25C)

To N- [1- [ (3aR,4R,6R,6aR) -6- [ [ 1-diethoxyphosphoryl-1- (hydroxymethyl) -2- (2-trimethylsilylethoxy) ethoxy at 0 deg.C]Methyl radical]-2, 2-dimethyl-3 a,4,6,6 a-tetrahydrofuro [3,4-d ] d][1,3]Dioxol-4-yl]-6-chloro-pyrazolo [3,4-d]Pyrimidin-4-yl]-N-cyclopentyl-carbamic acid tert-butyl ester (25b) (632mg, 0.770mmol) and a solution of 5- (bromomethyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole (1k-1) (1.13g, 3.85mmol) in DMF (5.0mL) are given in one portionNaH (60% mineral oil, 77.0mg, 1.93mmol) was added. After stirring the mixture at 0 ℃ for 30min, the mixture was passed through saturated NH ₄ Aqueous Cl, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone/hexanes, gradient elution) to provide the title compound (25c) as a pale yellow gum (697mg, 88%).

Step D tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1- (2- (trimethylsilyl) ethoxy) -3- ((2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-D ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-D ] pyrimidin-4-yl) (cyclopentyl) carbamate (25D)

The diastereomer from step C (25C) was separated by chiral chromatography (CHIRALPAK, AD-H, 21 x 250mm, 5 μm, 5% IPA/hexanes, isocratic elution, flow rate of 20 mL/min) and the second eluting isomer was identified as the title compound (25d) and collected.

Step E. ((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((3aR,4R,6R,6aR) -6- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid diethyl ester (25E)

To (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1- (2- (trimethylsilyl) ethoxy) -3- ((2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofurano [3, 4-d) at 0 deg.C][1,3]Dioxolen-4-yl) -1H-pyrazolo [3,4-d]To a solution of t-butyl pyrimidin-4-yl) (cyclopentyl) carbamate (25d) (325mg, 0.315mmol) in DCM (16mL) was added boron trifluoride etherate (0.233mL, 1.89mmol) dropwise. The reaction was allowed to warm to room temperature. After stirring at room temperature for 3.5h, the reaction was quenched with triethylamine (3.6mL) and the resulting mixture was stirred at room temperature for 10 min. Saturated NaHCO ₃ Aqueous solution (7.2mL) was added to the mixture and the solution was diluted with DCM and water. The solution was extracted (DCM) and the combined organic layers were washed (brine), dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0-20% MeOH in DCM, gradient elution) to provide the title compound (25e) as an off-white foamy solid (189mg, 86%). M/z (ESI, positive ion) ═ 702.3[ M + H]+。

Step F. ((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid (25)

To ((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((3aR,4R,6R,6aR) -6- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3, 4-d) was added at room temperature under an argon atmosphere]Pyrimidin-1-yl) -2, 2-dimethyltetrahydrofuro [3,4-d][1,3]Dioxolen-4-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid diethyl ester (25e) (189mg, 0.269mmol) to a solution in MeCN (13.5mL) was added triethylamine (0.751mL, 5.38mmol) followed by bromotrimethylsilane (0.528mL, 4.04 mmol). After the solution was stirred at room temperature for 4h, it was concentrated under reduced pressure. The residue was dissolved in TFA/water (1/3, 10mL) and it was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (15-40% ACN/H) ₂ O, 0.1% TFA, gradient elution) to afford the title compound (25) (TFA salt, 107mg, 55%) as an off-white solid. ¹ H NMR (400MHz, methanol-d) ₄ )δ8.08(d,J＝0.8Hz,1H) 6.25-6.20(m,1H),4.96(s,2H),4.72-4.69(m,1H),4.57-4.47(m,2H),4.19-4.16(m,1H),4.08(dd, J ═ 10.4,4.0Hz,1H),4.01-3.92(m,4H),3.84(dd, J ═ 12.4,7.6Hz,1H),2.13-2.06(m,2H),1.84-1.57(m, 6H); m/z (ESI, positive ion) ═ 606.1[ M + H] ⁺ 。

Alternatively, example 25((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid was prepared by the following steps G to I.

Step G tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-hydroxy-3- (2- (trimethylsilyl) ethoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (25G)

The diastereomer from example 25, step B (25B) was isolated by chiral chromatography (CHIRALPAK, AD-H, 21 x 250mm, 5 μm, 5% IPA/hexanes isocratic elution, flow rate of 20 mL/min) and the second eluting isomer was identified as the title compound (25g) and collected.

Step H tert-butyl (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1- (2- (trimethylsilyl) ethoxy) -3- ((2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) (cyclopentyl) carbamate (25H)

To (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1-hydroxy-3- (2- (trimethylsilyl) ethoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyll-kyl at 0 deg.CTetrahydrofuro [3,4-d][1,3]Dioxolen-4-yl) -1H-pyrazolo [3,4-d]Pyrimidin-4-yl) (cyclopentyl) carbamic acid tert-butyl ester (25g) (2.07g, 2.52mmol) and 5- (bromomethyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazole (1k-1) (2.96g, 10.1mmol) in DMF (12.5mL) were added NaH (60% mineral oil, 252mg, 6.31mmol) in one portion. After stirring the mixture at 0 ℃ for 30min, the mixture was passed through saturated NH ₄ Aqueous Cl, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone/hexanes, gradient elution) to provide the title compound (25h) (2.2g, 84%) as a pale yellow gum.

Step I((S) -1- ((2H-tetrazol-5-yl) methoxy) -2- (((2R,3S,4R,5R) -5- (6-chloro-4- (cyclopentylamino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) -3-hydroxypropan-2-yl) phosphonic acid (25)

To (6-chloro-1- ((3aR,4R,6R,6aR) -6- ((((R) -2- (diethoxyphosphoryl) -1- (2- (trimethylsilyl) ethoxy) -3- ((2- ((2- (trimethylsilyl) ethoxy) methyl) -2H-tetrazol-5-yl) methoxy) propan-2-yl) oxy) methyl) -2, 2-dimethyltetrahydrofuro [3, 4-d) was added under an argon atmosphere at room temperature][1,3]Dioxolen-4-yl) -1H-pyrazolo [3,4-d]To a solution of pyrimidin-4-yl) (cyclopentyl) carbamic acid tert-butyl ester (25h) (8.00g, 7.75mmol) in MeCN (300mL) was added triethylamine (16.2mL, 116mmol) followed by bromotrimethylsilane (10.1mL, 77.5 mmol). After the solution was stirred for 15h, it was concentrated under reduced pressure and azeotropically distilled with toluene (2 times). The residue was partitioned between EtOAc and water. The organic layer was collected and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed again with water and concentrated under reduced pressure. The crude solid was dissolved in TFA/water (1/1, 280mL) and it was stirred at room temperature for 24 h. Concentrating the mixture under reduced pressureCondensed and the residue was purified by reverse phase HPLC (15-35% ACN/H) ₂ O, 0.1% TFA, gradient elution) to afford the title compound (25) (TFA salt, 3.1g, 56%) as a white solid. ¹ H NMR (400MHz, methanol-d) ₄ ) δ 8.08(d, J ═ 0.8Hz,1H),6.25-6.20(m,1H),4.96(s,2H),4.72-4.69(m,1H),4.57-4.47(m,2H),4.19-4.16(m,1H),4.08(dd, J ═ 10.4,4.0Hz,1H),4.01-3.92(m,4H),3.84(dd, J ═ 12.4,7.6Hz,1H),2.13-2.06(m,2H),1.84-1.57(m, 6H); m/z (ESI, positive ion) 606.1[ M + H [ ]] ⁺ 。

Examples 26 to 60: examples 26-60 were synthesized as described in examples 1-10 and 25.

Biological evaluation

Example a 1: biochemical assay

Determination of reaction conditions

● measurement volume: 70 μ l

● reaction volume: 50 μ l

●CD73：0.3208nM

●AMP：15μM

● assay buffer: 25mM Tris-HCl, pH 7.4, 0.01% Brij-35,

0.01％BSA，5mM MgCl ₂

the measurement procedure was as follows:

a 384 transparent plate is used.

Dose titrations of test compounds were performed in assay buffer, starting at 100 μ M, in duplicate with a 10 point 1/2log titration.

25 μ l of CD73 was added to each well to obtain a final concentration of 320 pM.

Incubate at room temperature for 15 min.

Add 25. mu.l AMP to each well to obtain a final concentration of 15. mu.M.

Incubate at room temperature for 10 min.

Add 10. mu.l of Malachite Green (Malachite Green) reagent A and incubate at room temperature for 10 min.

Add 10. mu.l of Malachite Green reagent B and incubate at room temperature for 45 min.

Using an excitation filter: cy 5620 nM, absorbance read on Envision plate reader.

The ability of the compounds disclosed herein to inhibit CD73 activity was quantified, and the corresponding IC was determined ₅₀ The value is obtained. Table 2 provides the biochemical IC of the compounds disclosed herein ₅₀ The value is obtained.

TABLE 2

A：IC ₅₀ ≤10nM；

B：10nM<IC ₅₀ ≤100nM

C：100nM<IC ₅₀ ≤1μM

NT: not tested

The examples and embodiments described herein are for illustrative purposes only and, in some embodiments, various modifications or changes will be included within the purview of the disclosure and scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof:

wherein:

Q ¹ is N or CW;

Q ² and Q ³ Independently N or CW;

x is-S-, -O-or-NR ^N -；

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

n is 0, 1,2,3 or 4;

each R ^13a 、R ^14a 、R ^15a And R ^15b Independently oxo, halogen, -CN, -OR ^b 、-SR ^b 、-S(＝O)R ^a 、-NO ₂ 、-NR ^c R ^d 、-S(＝O) ₂ R ^a 、-NR ^b S(＝O) ₂ R ^a 、-S(＝O) ₂ NR ^c R ^d 、-C(＝O)R ^a 、-OC(＝O)R ^a 、-C(＝O)OR ^b 、-OC(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OC(＝O)NR ^c R ^d 、-NR ^b C(＝O)NR ^c R ^d 、-NR ^b C(＝O)R ^a 、-NR ^b C(＝O)OR ^b 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl radical(cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl);

each R ^b Independently of one another is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three oxo, halo, -OH, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl substitution; and is

with the proviso that said compound is not

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

Q ¹ is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

Q ¹ is CW.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

Q ² is N, and Q ³ Is CW.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

Q ² is CW, and Q ³ Is N.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

Q ² is N, and Q ³ Is N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

each W is independently hydrogen, halogen or C ₁ -C ₆ An alkyl group.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

each W is hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ³ is halogen, C ₂ -C ₆ Alkynyl or C ₁ -C ₆ A hydroxyalkyl group; wherein each alkyl and alkynyl is independently optionally substituted with one, two or three R ^3a And (4) substitution.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ³ is a halogen.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ¹ is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, cycloalkyl, heterocycloalkyl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one, two or three R ^1a And (4) substitution.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ¹ is C ₁ -C ₆ Alkyl, cycloalkyl, C ₁ -C ₆ Alkyl (aryl) or C ₁ -C ₆ Alkyl (cycloalkyl); wherein each alkyl, cycloalkyl and aryl is independently optionally substituted with one, two or three R ^1a And (4) substitution.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ¹ is optionally substituted by one, two or three R ^1a A substituted cycloalkyl group.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ¹ is a cycloalkyl group.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

each R ^1a Independently oxo, halogen, -CN, -OR ^b 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ A fluoroalkyl group.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

each R ^1a Independently is halogen or C ₁ -C ₆ An alkyl group.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ² is hydrogen or C ₁ -C ₆ An alkyl group.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ² is hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁴ and R ⁵ Independently hydrogen, halogen, -OR ^b 、C ₁ -C ₆ Alkyl or C ₁ -C ₆ A haloalkyl group.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁴ and R ⁵ Independently hydrogen OR-OR ^b 。

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁴ and R ⁵ is-OH.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

x is-O-.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁷ 、R ⁸ 、R ⁹ and R ¹⁰ Independently hydrogen, halogen or C ₁ -C ₆ An alkyl group.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁷ 、R ⁸ 、R ⁹ and R ¹⁰ Is hydrogen.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

ring a is heteroaryl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

n is 0.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is hydrogen, -C (═ O) R ¹⁴ 、-C(＝O)OR ¹³ 、-C(＝O)NR ¹⁵ R ¹⁶ 、C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C ₁ -C ₆ Alkyl (aryl), C ₁ -C ₆ Alkyl (heteroaryl), C ₁ -C ₆ Alkyl (cycloalkyl) or C ₁ -C ₆ Alkyl (heterocycloalkyl); wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is hydrogen, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl radicals or C ₁ -C ₆ Alkyl (heteroaryl); wherein said alkyl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Heteroalkyl radicals or C ₁ -C ₆ Alkyl (heteroaryl); wherein said alkyl and heteroaryl are independently optionally substituted with one, two or three R ^6a And (4) substitution.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein said alkyl is independently optionally substituted with one, two or three R ^6a And (4) substitution.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is hydrogen, C ₁ -C ₆ Hydroxyalkyl or C ₁ -C ₆ A heteroalkyl group; wherein said alkyl is independently optionally substituted with one, two or three R ^6a And (4) substitution.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ⁶ is C ₁ -C ₆ A hydroxyalkyl group.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein:

R ²¹ and R ²² Is hydrogen.

34. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein the compound is:

35. a compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, which compound is:

36. a pharmaceutical composition comprising a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

37. A method of inhibiting CD73, the method comprising contacting CD73 with the compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

38. A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

39. A method of treating cancer in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 36.

40. The method of any one of claims 38 or 39, wherein the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, or lymphoma.

41. The method of any one of claims 38-40, wherein the cancer expresses CD 73.

42. The method of any one of claims 38-40, wherein CD73 is up-regulated in the cancer to be treated.

43. The method of any one of claims 38-42, further comprising administering a second therapeutic agent.

44. The method of claim 43, wherein the second therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

45. A method of treating an infection in a subject, the method comprising administering to the subject a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

46. A method of treating an infection in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 36.

47. The method of any one of claims 45 or 46, wherein the infection is a viral infection.

48. The method of any one of claims 45 or 46, wherein the infection is a parasitic infection.

49. A method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

50. A method of treating a neurodegenerative disease in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 36.

51. The method of any one of claims 49 or 50, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, or autism.