WO2021206955A1

WO2021206955A1 - Macrocyclic compounds as kinases inhibitors and uses thereof

Info

Publication number: WO2021206955A1
Application number: PCT/US2021/024849
Authority: WO
Inventors: Wen-Lian Wu; Zhiqiang Yang; Francis Lee; John Qiang TAN
Original assignee: Angex Pharmaceutical, Inc.
Priority date: 2020-04-06
Filing date: 2021-03-30
Publication date: 2021-10-14

Abstract

The present disclosure describes kinases (ALK, ROS1, and TRK) inhibitors and their uses. The pharmaceutical compositions comprising such kinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders are also described.

Description

MACROCYCLIC COMPOUNDS AS KINASES INHIBITORS AND USES THEREOF

Inventors: Wen-Lian Wu, Zhiqiang Yang, Francis Lee, and John Qiang Tan

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application number 63/005,970, filed April 6, 2020; which is incorporated by reference herein in its entirety.

FIELD

The present disclosure relates to macrocyclic compounds, such as (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(3,2)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (A-1) analogs as kinase inhibitors, and pharmaceutical compositions containing such compounds. The present disclosure also relates to the use of the compounds and compositions to treat cancer, chronic pain, infectious diseases, neurodegenerative diseases, and certain infectious disorders.

BACKGROUND

Many cancer cells become excessively depend on a particular “driver” alteration for their survival, a phenomenon referred to as “oncogene addiction”. Cancers with these dependencies exhibit exquisite vulnerability to drugs that inhibit the drivers, are now commonly called “targeted therapies.” The past decade has witnessed numerous successes in targeting specific molecular subsets of cancer across a spectrum of different human malignancies, including notably lung adenocarcinoma (LADC). LADC is the most common type of lung cancer, which is the leading cause of cancer-related death worldwide. A large proportion of LADCs are attributed to chronic tobacco smoking. By generating genome-wide base substitutions that often target cancer-related genes (e.g., KRAS and TP53) and inducing global epigenetic modifications in the airway epithelial cells, tobacco smoking directly causes LADCs. In contrast, about 25% lung cancers develop in individuals who have not been smoking, and most of them are LADCs. LADCs of non-smokers have been associated with female sex and Asian ethnicity. Although certain studies have postulated various environmental factors — including secondhand smoke, radon, air pollution, household coal use, and occupational carcinogens — the etiology and oncogenesis of LADCs in non-smokers are still enigmatic. LADCs of non-smokers present frequent genetic alterations activating several oncogenes, e.g., EGFR, BRAF, MET, HER2 mutations and gene fusions involving ALK (anaplastic lymphoma kinase), ROS1 (ROS1 proto-oncogene receptor tyrosine kinase), TRK and RET. Previous studies confirmed transforming and tumorigenic activities of these oncogene alterations in experimental models, and the tumors were dependent on downstream signaling of these oncogenes for their growth and survival. Pharmacologic inhibition of corresponding kinases, notably with agents commonly called tyrosine kinase inhibitors (TKI), in patients with LADCs harboring these oncogene alterations has revolutionized treatment in advanced stages. All these findings point to the central role of these oncogene alterations in LADCs of non-smokers.

However, the inevitable barrier that limits the effectiveness of TKI therapy and tempers enthusiasm is the issue of resistance — today’s pervasive challenge for long-term disease control. Cancer is at its core a microcosm of evolution. Its survival is driven by genetic diversity and longitudinal accumulation of mutations, influenced by the selective pressures of TKI therapy. These rudimentary yet intricate principles underlie the refractory nature of TKI resistance, which is traditionally categorized as primary (intrinsic) or secondary (acquired). In primary resistance, patients lack any treatment response to targeted therapy. In secondary resistance, patients initially achieve some clinical benefit, followed by disease progression. With the discovery of each oncogenic driver and targeted inhibitor, a growing number and diversity of resistance mechanisms are being defined.

Secondary somatic mutations within the target kinase enable its persistent activation despite the presence of the inhibitor. In general, these alterations hinder the kinase’s ability to bind the drug or alter the kinase’s conformation when non-contact residues are involved. The classic example is the kinase domain mutations in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). These mutations were first described in CML patients treated with the TKI imatinib and affect the ability of imatinib to access the hydrophobic binding pocket, resulting in steric interference with the binding of imatinib to the kinase domain of ABL, but preserved kinase activity. Almost all of the resistance attributed to these mutations can be overcome by treatment with a second generation TKI, dasatinib, which was designed to have a different binding mode from imatinib.

For ALK, numerous kinase domain mutations have been reported in patients with acquired TKI resistance. The ALK-L1196M gatekeeper mutation confers resistance through steric interference. G1269A is the second most common ALK resistance mutation that causes resistance by interfering with TKI binding. Mutations 11151Tins, L1152R, and C1156Y are located near the aC-helix outside the drug-binding region and may cause TKI resistance by increasing catalytic activity. Solvent front mutations G1202R and S1206Y alter residues in the solvent-exposed region of ALK. These mutations lower the drug binding affinity. The G1202R mutation in particular is refractory to most ALK-TKIs including crizotinib, ceritinib, alectinib, and brigatinib. Secondary mutations in the target have also been reported in ROS1 driven LADCs. Solvent front mutations in ROS1 , G2032R (analogous to ALK G1202R) and D2033N cause crizotinib resistance in ROS1 -rearranged NSCLC. The ROS1 gatekeeper mutation L2026M confers resistance to crizotinib but has not yet been observed clinically.

For NTRK1 (also known as TRKA), secondary resistance mutations against entrectinib were recently described in colorectal cancer, including the G595R solvent front mutation (analogous to ALK G1202R), and the G667C mutation (analogous to ALK G1269A and EGFR T854A).

Activated Cdc42-associated kinase 1 (ACK1 also known as TNK2), a non-receptor tyrosine kinase (NRTK), represents a paradigm of tyrosine kinase signaling that appears to be addictive in cancer cells. The overexpression of Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase, is associated with increased cell survival and invasion in hepatocellular carcinomas, pituitary adenoma and prostate cancer. Resting Lymphocyte Kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the cooperative activation of Interleukin- 2 transcription in T-cells. Bone marrow X-linked kinase (BMX, also known as Etk) has been reported to be involved in cell proliferation, differentiation, apoptosis, migration and invasion in several types of tumors. Janus kinase 2 (JAK2) expression is associated with tumor- infiltrating lymphocytes and improved breast cancer outcomes.

Accordingly, the identification and development of small molecules that inhibit the activity of both wildtype and secondary mutant kinases of TRK, ROS1 , and ALK and other relevant kinases (ACK1, DDR1, TXK, BMX/ETK and JAK2) which overcome existing TKI resistance hold the promise of transforming effective cancer treatments and prolonging patients’ lives.

SUMMARY

This disclosure relates to certain optionally substituted macrocyclic compounds comprising at least two rings within the macrocyclic ring system, such as optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(3,2)-bicyclo[3.1.0]hexanacyclooctaphan-8-one (A-1), and its analogs, and a pharmaceutically acceptable salt thereof. These compounds described herein are novel potent multi-target kinase inhibitors showing activity against wild-type and mutant ALK, wild- type and mutant ROS1 , wild-type and mutant TRK kinases. A pharmaceutical composition or a dosage form containing an effective amount of one or more of these compounds described herein, such as a compound of Formula 1 or 2 shown below, may be used for treating ALK, ROS1, TRK, and other kinases related diseases or indications by administering such a pharmaceutical composition or dosage form to a patient in need thereof. Some embodiments include a compound represented by Formula 1:

(Formula 1) or a pharmaceutically acceptable salt thereof; wherein

(Ring A) is an optionally substituted 6-membered aromatic all carbon ring, or optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms;

(Ring B) is an optionally substituted fused bicyclic heteroaromatic ring system having 1, 2, 3, or 4 ring nitrogen atoms; L is - C(0)NR^A, wherein the C atom of L is directly connected to ring B; E is C_1-3 alkylene having 0, 1 , 2, 3, 4, 5, or 6 substituents, wherein the substituents of E are independently F, Cl, Br, I, OH, =0, C_1-6 alkyl or C_1-6 cycloalkyl, and wherein two of the substituents of E may connect to form a ring; W is a covalent bond, O, NR^A, CR^A1R^B1, CR^A1=CR^B1, or C=CR^A1R^B1, wherein R^A1 and R^B1 are independently H, F, Cl, Br, I, or C_1-6 hydrocarbyl, and R^A is H or C_1-6 hydrocarbyl; R^1a are R^2a are independently H, Me, F, Cl, or Br; and R represents 0, 1, 2, 3, 4, or 5 substituents at any ring carbon atom of the pyrrolidine ring and each R is independently H, Me, F, Cl, or Br.

Some embodiments include a method of treating cancer and other ALK, ROS1, TRK kinases related diseases or disorders comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Some embodiments include use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, particularly a type of cancer, in a patient in need thereof.

Some embodiments include use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer and other ALK, ROS1 , TRK kinases related diseases or disorders. Some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier. Some embodiments include a method of treating cancer and other ALK, ROS1 , TRK kinases related diseases or disorders comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier, to a patient in need thereof.

Some embodiments include a process for making a pharmaceutical composition comprising combining a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Some embodiments include a method of treating a disease in a patient comprising, administering a therapeutically effective dose of a compound described herein, such as (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(3,2)-bicyclo[3.1.0]hexana-cyclooctaphan-8-one, or a pharmaceutically acceptable salt thereof; wherein the disease is mediated by a tyrosine kinase of ROS1, ALK, TRK, ACK1, DDR1 , TXK, JAK2, BMX/ETK, or a combination thereof.

Some embodiments include use of a therapeutically effective amount of a compound described herein, such as (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexana-cyclooctaphan-8-one, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease in a patient; wherein the disease is mediated by a tyrosine kinase of ROS1, ALK, TRK, ACK1, DDR1 , TXK, JAK2, BMX/ETK, or a combination thereof.

Some embodiments include a method or the use of a compound described herein for treating diseases that include cancer, psoriasis, rheumatoid arthritis, polycythemia vera, essential thrombocythemia, ulcerative colitis.

Some embodiments include a method or the use of a compound described herein for treating cancer mediated by ROS1. In some embodiments, the disease is cancer mediated by genetically altered ROS1. In some embodiments, the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene of FIG, TPM3, SDC4, CD74, SLC34A2, LRIG3, EZR, KDEL R2, LIMA1, MSN, CLTC, CCDC6, TMEM106, orTPD52L1 fusion partner, or a combination thereof. In some embodiments, the fusion protein is a wild-type protein. In some embodiments, the fusion protein harbors at least one secondary mutation comprising G2032R, L2155S, L2026M, D2033N, or S1986Y/F point mutation, or a combination thereof. Some embodiments include a method or the use of a compound described herein for treating cancer, wherein the cancer is mediated by a fusion protein comprising a fragment of a protein encoded by a ALK gene and a fragment of a protein encoded by a gene of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, AL017, MYH9, KIF5B, KLC1 , HIPI, TPM3, CARS, RANBP2, SEC31A, SQSTM1, or VCL fusion partner, or a combination thereof. In some embodiments, the fusion protein is a wild-type protein. In some embodiments, the fusion protein harbors at least one secondary mutation comprising 1151Tins, L1152R, C1156Y, 11171T/N/S, F1174L/C, V1180L, L1196M, L1198F, G1202R/del, S1206F, D1203N, S1206Y/C, G1269A, or G1548E point mutation, or a combination thereof.

DETAILED DESCRIPTION

This disclosure relates to compounds of Formula 1 or 2, the pharmaceutical compositions containing one or more compounds of Formula 1 or 2, and methods of treatment of a disease or a disorder comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula 1 or 2 having activity against tyrosine kinase of ROS1 , ALK, ACK1 , DDR1 , TXK, JAK2, BMX/ETK, TRK, or a combination thereof.

In some embodiments, the compound has activity against at least one tyrosine or serine/threonine kinase of ROS1 , ALK, and TRK. In some embodiments, the compound has activity against at least two tyrosine or serine/threonine kinases of ROS1 and ALK. In some embodiments, the compound has activity against ROS1 kinase. In some embodiments, the at least one, or the at least two of the tyrosine or serine/threonine kinases are genetically altered.

In some embodiments, the compound described herein is represented by Formula l:

or a pharmaceutically acceptable salt thereof; wherein

(Ring B) is an optionally substituted fused bicyclic heteroaromatic ring system having 1, 2, 3, or 4 ring nitrogen atoms;

L is -C(0)NR^A wherein the C atom of L is directly connected to ring B;

E is Ci alkylene having 0, 1, 2, 3, 4, 5, or 6 substituents, wherein the substituents of E are independently F, Cl, Br, I, OH, =0, Ci-e alkyl, or Ci-e cycloalkyl, and wherein two of the substituents of E may connect to form a ring;

W is a covalent bond, O, NR^A, CR^A1R^B1, CR^A1=CR^B1, or C=CR^A1R^B1, wherein R^A1 and R^B1 are independently H, F, Cl, Br, I, or Ci-₆hydrocarbyl, and R^A is H or Ci-₆hydrocarbyl;

R^1a and R^2a are independently H, Me, F, Cl, or Br; and

R represents 0, 1, 2, 3, 4, or 5 substituents at any ring carbon atom of the pyrrolidine ring and each R is independently H, Me, F, Cl, or Br.

In some embodiments, the compound of Formula 1 described herein is further represented by Formula 2:

or a pharmaceutically acceptable salt thereof; wherein

(Ring A) is an optionally substituted 6-membered aromatic all carbon ring, or optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms; ( ) (Ring B) is an optionally substituted fused bicyclic heteroaromatic ring system having 1, 2, 3, or 4 ring nitrogen atoms;

E is Ci alkylene having 0, 1, 2, 3, 4, 5, or 6 substituents, wherein the substituents of E are independently F, Cl, Br, I, OH, =0, Ci-₆ alkyl or Ci-₆ cycloalkyl, wherein two of the substituents of E may connect to form a ring;

W is a covalent bond, O, NR^A, CR^A1R^B1, CR^A1=CR^B1, or C=CR^A1R^B1; wherein R^A1 and R^B1 are independently H, F, Cl, Br, I, or Ci-₆hydrocarbyl, and R^A is H or Ci-₆hydrocarbyl;

R^1a and R^2a are independently H, Me, F, Cl, or Br; and

In some embodiments, the disease is cancer, psoriasis, rheumatoid arthritis, polycythemia vera, essential thrombocythemia, ulcerative colitis, or a combination thereof.

In some embodiments, the disease is mediated by a tyrosine or serine/threonine kinase ROS1, ALK, ACK1, DDR1, TXK, JAK2, BMX/ETK, TRK, or a combination thereof. In some embodiments the disease is mediated by a receptor tyrosine kinase. In some embodiments, the receptor tyrosine kinase is ROS1, ALK, TRK, or a combination thereof. In some embodiments, the receptor tyrosine kinase is ROS1. In some embodiments, the receptor tyrosine kinase is ALK. In some embodiments, the receptor tyrosine kinase is TRK.

In some embodiments, the disease is cancer. In some embodiments, the cancer is mediated by ROS1. In some embodiments, the cancer is mediated by a genetically altered ROS1. In some embodiments, the cancer is mediated by ALK. In some embodiments, the cancer is mediated by a genetically altered ALK. In some embodiments, the cancer is mediated by TRK. In some embodiments, the cancer is mediated by a genetically altered TRK.

In some embodiments, the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene of FIG, TPM3, SDC4, CD74, SLC34A2, LRIG3, EZR, KDEL R2, LIMA1, MSN, CLTC, CCDC6, TMEM106, TPD52L1, or other fusion partner, or a combination thereof. In some embodiments, the fusion protein is a wild-type protein. In some embodiments, the fusion protein harbors at least one secondary mutation comprising G2032R, L2155S, L2026M, D2033N, S1986Y/F, or other point mutation, or a combination thereof. In some embodiments, the disease is cancer, and the cancer is mediated by ROS1. In some embodiments, the cancer is mediated by a genetically altered ROS1. In some embodiments, the cancer is a cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, LRIG3, or a combination thereof. In some embodiments, the fusion protein comprises a fragment of a protein encoded by an ROS1 gene and a fragment of a protein encoded by a CD74 gene. In some embodiments, the genetically altered ROS1 is a CD74-ROS1 fusion protein. In some embodiments, the CD74-ROS1 fusion protein is a wild-type protein. In some embodiments, the CD74-ROS1 fusion protein comprises at least one resistance mutation. In some embodiments, the CD74-ROS1 fusion protein comprises a G2032R point mutation. In some embodiments, the genetically altered ROS1 is a SDC4-ROS1 fusion protein. In some embodiments, the SDC4-ROS1 fusion protein is a wild- type protein. In some embodiments, the SDC4-ROS1 fusion protein comprises at least one resistance mutation. In some embodiments, the SDC4-ROS1 fusion protein comprises a G2032R point mutation.

In some embodiments, the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ALK gene and a fragment of a protein encoded by a gene of NPM, EML4, TPR, TFG, ATIC, CLTC1 , TPM4, MSN, AL017, MYH9, KIF5B, KLC1, H I PI , TPM3, CARS, RANBP2, SEC31A, SQSTM1, VCL, or other fusion partner, or a combination thereof. In some embodiments, the fusion protein is a wild-type protein. In some embodiments, the fusion protein harbors at least one secondary mutation comprising 1151Tins, L1152R, C1156Y, I1171T/N/S, F1174L/C, V1180L, L1196M, L1198F, G1202R/del, S1206F, D1203N, S1206Y/C, G1269A, G1548E, or other point mutation, or a combination thereof.

In some embodiments, the disease is cancer, and the cancer is mediated by ALK. In some embodiments, the cancer is mediated by a genetically altered ALK. In some embodiments, the cancer is mediated by a fusion protein comprising a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a gene of NPM, EML4, TPR, TFG, ATIC, CLTC1 , TPM4, MSN, AL017, MYH9, or a combination thereof. In some embodiments, the fusion protein comprises a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by an EML4 gene. In some embodiments, the genetically altered ALK is an EML4-ALK fusion protein. In some embodiments, the EML4-ALK fusion protein is a wild-type protein. In some embodiments, the EML4-ALK fusion protein comprises at least one resistance mutation. In some embodiments, the EML4-ALK fusion protein comprises at least one of F1174L, G1202R, G1296A, 11171 N, L1196M, G2032R, L2026M or D2033N point mutation. In some embodiments, the EML4-ALK fusion protein comprises F1174L, G1202R, G1269A, 11171 N, or L1196M mutation. In some embodiments, the point mutation is a mutation of ALKat F1174. In some embodiments, the point mutation is a mutation of ALK at G1202R. In some embodiments, the point mutation is a mutation of ALK at G1269A. In some embodiments, the point mutation is a mutation of ALK at 11171 N point mutation. In some embodiments, the point mutation is a mutation of ALK at L1196M point mutation.

In some embodiments, the disease is cancer, and the cancer is mediated by TRK. In some embodiments, the cancer is mediated by a genetically altered TRK. In some embodiments, the cancer is mediated by a fusion protein comprising a fragment of a protein encoded by a TRK gene and a fragment of a protein encoded by a TPM3 or LMNA, gene. In some embodiments, the TRK fusion protein is a wild-type protein. In some embodiments, the TRK fusion protein comprises at least one resistance mutation comprising a G595R or G667C point mutation.

In some embodiments, the disease is cancer, and the cancer is ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, or anaplastic thyroid cancer, or a combination thereof.

In some embodiments, the cancer is glioblastoma, glioblastoma multiforme, NSCLC, cholangiocarcinoma, intrahepatic cholangiocarcinoma, colorectal cancer, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, breast cancer, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, colon adenocarcinoma, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, or pediatric glioma, or a combination thereof.

In some embodiments, a method for treating a disease, such as cancer, comprising administering a dosage form comprising a therapeutically effective amount of a compound described herein, such as a compound of Formula 1 or 2, to a patient in need thereof. A dosage form comprising an effective amount of a compound of Formula 1 or 2 may be about 0.01 mg to 1000 mg, about 0.01-1 mg, about 1-5 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about 20-30 mg, about 30-40 mg, about 40-50 mg, about 50-100 mg, about 100- 150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1000 mg, about 5-25 mg, about 25-50 mg, about 50-75 mg, about 75-100 mg, about 100-200 mg, about 200-300 mg, about 300-400 mg, about 400-500 mg, about 550-650 mg, about 650-750 mg, about 750-850 mg, about 850-950 mg, about 950-1000 mg, or in an amount in a range of or bounded by any of the above values. Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

If stereochemistry is not indicated, a name or structural depiction described herein includes any stereoisomer or any mixture of stereoisomers.

In some embodiments, a compound of Formula 1 or 2 is an R-enantiomer. In some embodiments, a compound of Formula 1 or 2 is an S-enantiomer.

A hydrogen atom in any position of a compound of Formula 1 or 2 may be replaced by a deuterium. In some embodiments, a compound of Formula 1 or 2 contains a deuterium atom. In some embodiment, a compound of Formula 1 or 2 contains multiple deuterium atoms. In some embodiments, a composition comprises a compound of Formula 1 or 2 containing deuterium at greater than natural abundance, e.g. at least 10% or at least 50% greater than natural abundance.

Unless otherwise indicated, when a compound or chemical structural feature such as aryl is referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is “substituted,” meaning that the feature has one or more substituents. The term “substituent” is broad, and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to 150 g/mol,15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some embodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom, wherein N or S can be oxidized. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, phosphonic acid, etc. For convenience, the term “molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.

The structures associated with some of the chemical names referred to herein are depicted below. These structures may be unsubstituted, as shown below, or substituted with a substituent that may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by , attachment may occur at any position normally occupied by a hydrogen atom.

(pyrid i n-3-yl )2-oxy-yl

imidazo[1 ,2-a]pyrazin-3,6-di-yl imidazo[1 ,2-a]pyridin-3,6-di-yl

3-azabicyclo[3.1.0]hexan-2,3-di-yl

With respect to any relevant structural representation, such as Formula 1 or 2, Ring A is optionally substituted 6-membered aromatic all carbon ring; or an optionally substituted 5- membered heteroaryl ring having 1, 2, or 3 heteroatoms independently selected from N, O and S, or optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms. In some embodiments, any or each of the substituents of Ring A may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol. Potential substituents of Ring A may include halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C₂ alkyl, C₂ alkenyl, C₂ alkynyl, C₃ alkyl, C₃ cycloalkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C₄ cycloalkyl, C₄ alkenyl, C₄ alkynyl, C₅ alkyl, C₅ cycloalkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆ cycloalkyl, C₆ alkenyl, C₆ alkynyl, phenyl, etc.; CN0-1O0-2F0-3H0-4; C2N0-1O0-3F0-5H0-6; C3N0-1O0-3F0-7H0-8; C4N0-1O0-3F0-9H0-10; C5N0-1O0-3F0-11 Ho-12; C6N0-1O0-3F0-13H0-14; etc. In some embodiments, Ring A is optionally substituted pyridin-di-yl having 0, 1 , 2, or 3 substituents, such as pyridin-2,3-di-yl substituted with F, Cl, Br, C_1-6 alkyl, -CO₂H, , -CN, -CO-Ci-₆-alkyl, -C(0)0-Ci-₆-alkyl, -C_1-6 alkyl-OH, OH, NH₂, etc. In some embodiments, Ring A is optionally substituted pyridin-di-yl. In some embodiments, Ring A is optionally substituted pyridin-2,6-di-yl. In some embodiments, Ring A is optionally substituted pyridin-2,3-di-yl. In some embodiments, Ring A is unsubstituted pyridin-2,3-di-yl. In some embodiments, Ring A is pyridin-2,3-di-yl having 2 substituents. In some embodiments, Ring A is pyridin-2,3-di-yl having 1 substituent. In some embodiments, Ring A is 5-fluoro-pyridine- 2,3-di-yl. In some embodiments, Ring A is optionally substituted 2-oxo-1 ,2-dihydropyridin-1 ,3- di-yl. In some embodiments, W-A is optionally substituted (pyridin-3-yl)2-oxy-yl.

With respect to Formula 1 or 2, in some embodiments, Ring A is represented by Formula A1 or A5:

Formula A1 or Formula A5

In some embodiments, Ring A is represented by Formula A1. In some embodiments, Ring A is represented by Formula A5.

With respect to Formula 1 or 2, in some embodiments,

Formula A13:

Formula A13

With respect to any relevant structural representation, such as Formula A1, A5, orA13, R¹ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -N0₂, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. Some of the structures with attachment points are shown below. In some embodiments, R¹ may be H; F; Cl; CN; CF₃; OH; NH₂; C1-6 alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), any one of the pentyl isomers, any one of the cyclopentyl isomers, any one of the hexyl isomers, and any one of the cyclohexyl isomers, etc.; or C1-6 alkoxy, such as -O-methyl, -O-ethyl, any one of the isomers of -O-propyl, -O-cyclopropyl, any one of the isomers of -O-butyl, any one of the isomers of -O-cyclobutyl, any one of the isomers of -O- pentyl, any one of the isomers of -O-cyclopentyl, any one of the isomers of -O-hexyl, any one of the isomers of -O-cyclohexyl, etc. In some embodiments, R¹ may be H, F, or Cl. In some embodiments, R¹ may be H. In some embodiments, R¹ is F.

-NR^ACOR^B -CONR^AR^B

With respect to any relevant structural representation, each R^A may independently be H, or Ci-i₂ hydrocarbyl, such as CM₂ alkyl, CM₂ alkenyl, CM₂ alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C_aH_2a+i, or cycloalkyl having a formula C_aH_2a-i, wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH₃, C2H5, C3H7, C4H9, C5H11, CeH , C7H15, CsH^, C9H19, C10H21, etc., or cycloalkyl with a formula: C3H5, C4H7, C5H9, CeHn, C7H13, CsHis, C9H17, C10H19, etc. In some embodiments, R^A may be H or C_1-6 alkyl. In some embodiments, R^A may be H or C_1-3 alkyl. In some embodiments, R^A may be H or CH₃. In some embodiments, R^A may be H.

With respect to any relevant structural representation, each R^B may independently be H, or Ci-12 hydrocarbyl, such as C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C_aFh_a+i, or cycloalkyl having a formula C_aH2_a-i, wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH₃, C2H5, C3H7, C4H9, C5H 11 , CeH , C7H15, CSHI₇, C9H 19, C10H21 , etc., or cycloalkyl with a formula: C3H5, C4H7, C5H9, CeHn, C7H13, CsHis, C9H17, C10H19, etc. In some embodiments, R^B may be H or C1-3 alkyl. In some embodiments, R^B may be H or CH3. In some embodiments, R^B may be H.

With respect to any relevant structural representation, such as Formula A1, A5, orA13, R² is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R² may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R² may be H, F, or Cl. In some embodiments, R² may be H. In some embodiments, R² is F.

With respect to any relevant structural representation, such as Formula A1, A5, orA13, R³ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R³ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R³ may be H, F, or Cl. In some embodiments, R³ may be Cl. In some embodiments, R³ is F.

With respect to any relevant structural representation, such as Formula A5, R⁴ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, C0₂R^A, -OCOR^A, NR^ACOR^B, or CONR^AR^B, etc. In some embodiments, R⁴ may be H, F, Cl, CN, CF₃, OH, NH₂, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R⁴ may be H. In some embodiments, R⁴ is F.

With respect to any relevant structural representation, such as Formula A1 , in some embodiments, R² is F. In some embodiments, R¹ and R³ are both H. In some embodiments, R¹ is H, R³ is H, and R² is F.

With respect to any relevant structural representation, such as Formula 1 or 2, Ring B is an optionally substituted fused bicyclic heteroaromatic ring system having 1, 2, 3, or 4 ring nitrogen atoms. In some embodiments, any or each of the substituents of Ring B may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol. Potential substituents of Ring B may include halo, such as F, Cl, Br, or I; hydrocarbyl, such as methyl, C2 alkyl, C2 alkenyl, C₂ alkynyl, C₃ alkyl, C₃ cycloalkyl, C₃ alkenyl, C₃ alkynyl, C₄ alkyl, C₄ cycloalkyl, C₄ alkenyl, C₄ alkynyl, C₅ alkyl, C₅ cycloalkyl, C₅ alkenyl, C₅ alkynyl, C₆ alkyl, C₆ cycloalkyl, C₆ alkenyl, Ce alkynyl, or phenyl, etc.; CN0-1O0-2F0-3H0-4; C2N0-1O0-3F0-5H0-6; C3N0-1O0-3F0-7H0-8; C4N0-1O0-3F0-9H0-10; C5N0-1O0-3F0-11H0-12; or C6N0-1O0-3F0-13H0-14; etc. In some embodiments, Ring B is optionally substituted pyrazolo[1,5-a]pyrimidin-3,5-di-yl having 0, 1, 2, or 3 substituents, such as pyrazolo[1,5- a]pyrimidin-3,5-di-yl substituted with F, Cl, Br, C_1-6 alkyl, - CO₂H, , -CN, -CO-Ci-₆-alkyl, -C(0)0-Ci-e-alkyl, -C_1-6 alkyl-OH, OH, NH₂, etc. In some embodiments, Ring B is pyrazolo[1,5-a]pyrimidin-3,5-di-yl having 2 substituents. In some embodiments, Ring B is pyrazolo[1,5-a]pyrimidin-3,5-di-yl having 1 substituent. In some embodiments, Ring B is unsubstituted pyrazolo[1,5-a]pyrimidin-3,5-di-yl. In some embodiments, Ring B is unsubstituted pyrazolo[1,5-a]pyrimidin-3,5-di-yl, and the pyrazole ring of the Ring B is attached to L. In some embodiments, Ring B is imidazo[1,2-Jb]pyridazin-3,6- di-yl having 2 substituents. In some embodiments, Ring B is imidazo[1,2-Jb]pyridazin-3,6-di-yl having 1 substituent. In some embodiments, Ring B is unsubstituted imidazo[1 ,2-Jb]pyridazin- 3,6-di-yl. In some embodiments, Ring B is unsubstituted imidazo[1,2-Jb]pyridazin-3,6-di-yl, and the imidazole ring of the Ring B is attached to L.

In some embodiments, Ring B is represented by formula B1 , B2, B3, B4, B5, B6, B7, B8, B9, or B10:

Formula B4 Formula B5 Formula B6

In some embodiments, B is represented by Formula B1. In some embodiments, B is represented by Formula B2.

With respect to any relevant structural representation, such as Formula B1, B2, B3, B4, B5, B6, B7, B8, B9, or B10, R⁵ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NO₂, -NR^AR^B, -COR^A, -C0₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R⁵ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R⁵ may be H, F, or Cl. In some embodiments, R⁵ may be H. In some embodiments, R⁵ is F.

With respect to any relevant structural representation, such as Formula B1, B2, B3, B4, B5, B6, B7, B8, B9, or B10, R⁶ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -N0₂, -NR^AR^b, -COR^a, -C0₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R⁶ may be H, F, Cl, CN, CF₃, OH, NH₂, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R⁶ may be H, F, or Cl. In some embodiments, R⁶ may be H. In some embodiments, R⁶ is F.

With respect to any relevant structural representation, such as Formula B1, B2, B3, B4, B5, B6, B7, B8, or B9, R⁷ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -N0₂, -NR^AR^B, -COR^A, -C0₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R⁷ may be H, F, Cl, CN, CF₃, OH, NH₂, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R⁷ may be H, F, or Cl. In some embodiments, R⁷ may be H. In some embodiments, R⁷ is F.

With respect to any relevant structural representation, such as Formula B4 or B10, R⁸ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -N0₂, -NR^AR^B, -COR^A, -C0₂R^A, - OCOR^A, -NR^ACOR^B, or-CONR^AR^B, etc. In some embodiments, R⁸ may be H, F, Cl, CN, CF₃, OH, NH₂, CI-₆ alkyl, or C1-6 alkoxy. In some embodiments, R⁸ may be H, F, or Cl. In some embodiments, R⁸ may be H. In some embodiments, R⁸ is F.

With respect to any relevant structural representation, such as Formula 1 or 2, R^1a is H, Me, F, Cl, or Br. In some embodiments, R^1a may be H. In some embodiments, R^1a may be F.

With respect to any relevant structural representation, such as Formula 1 or 2, R^2a is H, Me, F, Cl, or Br. In some embodiments, R^1a may be H. In some embodiments, R^1a may be F.

With respect to any relevant structural representation, such as Formula 1 or 2, R^1a and R^2a may be both H.

With respect to any relevant structural representation, such as Formula C4, R⁹ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, - NR^ACOR^B, or-CONR^AR^B, etc. In some embodiments, R⁹ may be H, F, Cl, CN, CF₃, OH, NH₂, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R⁹ may be H. In some embodiments, R⁹ is F.

With respect to Formula C4, R¹⁰ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CF₃, -NR^AR^b, -COR^a, -C0₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R¹⁰ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R¹⁰ may be H. In some embodiments, R¹⁰ is F.

With respect to Formula C4, R^{1 1} is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CFs, -NR^AR^b, -COR^a, -C0₂R^a, -OCOR^a, -NR^ACOR^b, or -CONR^AR^B, etc. In some embodiments, R^{1 1} may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R^{1 1} may be H. In some embodiments, R^{1 1} is F.

With respect to Formula C4, R¹² is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CFs, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R¹² may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R¹² may be H. In some embodiments, R¹² is F.

With respect to Formula C4, R¹³ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CFs, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R¹³ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R¹³ may be H. In some embodiments, R¹³ is F. In some embodiments, R¹⁴ is methyl. In some embodiments, both R¹³and R¹⁴ are methyl.

With respect to Formula C4, R¹⁴ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CFs, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R¹⁴ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R¹⁴ may be H. In some embodiments, R¹⁴ is F. In some embodiments, R¹⁴ is methyl. In some embodiments, both R¹³and R¹⁴ are methyl.

With respect to Formula C4, R¹⁵ is H or any substituent, such as R^A, F, Cl, CN, -OR^A, CFs, -NR^AR^B, -COR^A, -C0₂R^A, -OCOR^A, -NR^ACOR^B, or -CONR^AR^B, etc. In some embodiments, R¹⁴ may be H, F, Cl, CN, CF₃, OH, NH₂, C_1-6 alkyl, or C_1-6 alkoxy. In some embodiments, R¹⁴ may be H. In some embodiments, R¹⁴ is F. In some embodiments, R¹⁴ is methyl. In some embodiments, both R¹³and R¹⁴ are methyl.

With respect to Formula C4, in some embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, may be same. In some embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, may be different. In some embodiments, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, may be all H.

With respect to Formula C4, in some embodiments, R^{1 1} and R¹⁵ may be directly linked to form a ring. In some embodiments, R^{1 1} and R¹⁵together may form =0. With respect to Formula C4, in some embodiments,

comprises optionally substituted 5-oxopyrrolidin-1 ,2-di-yl, wherein R is =0 substituted at the ortho- position of the ring N atom of the pyrrolidine ring.

With respect to Formula C4, in some embodiments,

comprises optionally substituted 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2,3-di-yl, wherein both R^1a and R^2a are Me.

With respect to any relevant structural representation, such as Formula 1 , L is - C(0)NR^A-, wherein the C atom of L is directly attached to Ring B. In some embodiments, L is -C(0)NH-, wherein the C atom of L is directly attached to Ring B.

With respect to Formula 1 or 2, E is C1-3 alkylene having 0, 1, 2, 3, 4, 5, or 6 substituents, wherein the substituents of E are independently F, Cl, Br, I, OH, C1-6 alkyl, or Ci- ₆ cycloalkyl, wherein two of the substituents of E may connect to form a ring. In some embodiments, E is optionally substituted Ci alkylene, with 0, 1 or 2 substituents. In some embodiments, E is optionally substituted C2 alkylene, with 0, 1, 2, 3, or 4 substituents. In some embodiments, E is optionally substituted C3 alkylene, with 0, 1, 2, 3, 4, 5, or 6 substituents. In some embodiments, E is unsubstituted C1-3 alkylene. In some embodiments, E has an optionally substituted cyclopropyl substituent. In some embodiments, E is optionally substituted cyclopropylmethylene. In some embodiments, E is cyclopropylmethylene. In some embodiments, E is optionally substituted cyclopropylethylene. In some embodiments, E is cyclopropylethylene. In some embodiments, E has two substituents. In some embodiments, E has 1 substituent. In some embodiments, E has 1 substituent, and wherein the substituent is methyl.

In some embodiments, E is:

In some embodiments, E is:

In some embodiments, E is:

In some embodiments, E is:

In some embodiments, E is:

In some embodiments, E is:

With respect of Formula 1 or 2, W is a covalent bond, O, NR^A, CR^A1R^B1, or CR^A1=CR^B1, wherein R^A1 and R^B1 are independently H, F, Cl, Br, I, or Ci-₆ hydrocarbyl. In some embodiments, W is a covalent bond. In some embodiments, W is O. In some embodiments, W is NR^A. In some embodiments, W is CR^A1R^B1. In some embodiments, W is CR^A1=CR^B1. In some embodiments, W is -CH2-. In some embodiments, W is -CH(CH3)-. In some embodiments, W is C=CH2. In some embodiments, E-W is:

wherein the asterisk indicates the point of attachment of C atom to L. In some embodiments, E-W is:

, In some embodiments,

E-W is:

Some embodiments include optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S)-2³,7-diaza- 1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexanacyclooctaphan-8- one, optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S)-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(3,4)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S)-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina- 2(3,2)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted

(1³E,1⁴E,2¹R,2⁴S,2⁵S)-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina- 2(3,4)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted

(1³E,1⁴E,2¹R,2²R,2⁵S)-2³,6-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina-3(3,2)-pyridina-2(3,2)- bicyclo[3.1 0]hexanacycloheptaphan-7-one, optionally substituted

(3aR,5aE,9E, 12aS, 13aR, 13bR, 18aR)-1 ,2, 3, 3a, 4, 12a, 13, 13a, 13b, 18a-decahydro-5H,12H-

8,10-ethenocyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1 ]oxa[4,8, 10]triazacyclotridecin-5-one, optionally substituted

(3aR,5aE,9E,12aR,13aS,13bS,18aR)-1,2,3,3a,4,12a,13,13a,13b,18a-decahydro-5H,12H-

8.10-ethenocyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1 ]oxa[4,8, 10]triazacyclotridecin-5-one, optionally substituted

(1 aR, 1 bR,6aR, 10aR, 12aE, 16E, 19aS)-1 a, 1 b,7,8,9, 10, 10a, 11 , 19, 19a-decahydro-1 H-15, 17- ethenobenzo[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1]oxa[4,8,10]triazacyclotridecin-12(6aH)-one, optionally substituted

(1aS,1bS,6aR,10aR,12aE,16E,19aR)-1a,1b,7,8,9,10,10a,11,19,19a-decahydro-1 H-15,17- ethenobenzo[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1]oxa[4,8,10]triazacyclotridecin-12(6aH)-one, optionally substituted

(4aR,6aE,10E,13aS,14aR,14bR,19aS)-1 ,3,4,4a,5,13a,14,14a,14b,19a-decahydro-13H-9,11- ethenodibenzo[b,l]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8, 10]triazacyclotridecin-6(2H)-one; optionally substituted

(3aR,5aE,9E,12aS,13aR,13bR,18aS)-1,2,3,3a,4,12a,13,13a,13b,18a-decahydro-5H,12H-

8.10-ethenobenzo[l]cyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8,10]triazacyclotridecin-5-one; optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S)-4-oxa- 2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,4)-bicyclo[3.1.0]hexana-3(1,2)- benzenacyclooctaphan-8-one; optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S)-4-oxa-2³,7-diaza- 1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,4)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan- 8-one; optionally substituted (1 'R,2'R,3'E,4'E,5'S)-5'-fluorospiro[cyclopropane-1 ,6'-2³,7-diaza- 1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan]- 8'-one; optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S)-2³,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one; optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S)-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,4)- bicyclo[3.1.0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one; (1³E,1⁴E,2¹R,2²R,2⁵S)-2³,7-diaza- 1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan- 8-one; or optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S)-2³,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-2(3,4)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one.

Some embodiments include one of the compounds listed in Table 1 below, wherein each structure can be optionally substituted:

Table 1. Compound structures and their ID numbers

Some embodiments include an optionally substituted compound or core structure from Table 1. A core structure is a compound of Table 1 with all substituents removed.

A pharmaceutical composition comprising a compound described herein, such as a compound of Formula 1 or 2, for example optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵- fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina-2(3,2)- bicyclo[3.1.0]hexanacyclooctaphan-8-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,5S)- 3⁵-fluoro-5-methyl-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina-2(3,2)- bicyclo[3.1.0]hexanacyclooctaphan-8-one, optionally substituted (TR,2'R,3'E,4'E,5'S)-5'- fluorospiro[cyclopropane-1 ,6'-2³,7-diaza-1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-3(3,2)-pyridina- 2(3,2)-bicyclo[3.1.0]hexanacyclooctaphan]-8'-one, optionally substituted

(1³E,1⁴E,2¹R,2²R,2⁵S,6S)-6-cyclopropyl-3⁵-fluoro-2³,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidina-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,5R)-3⁵-fluoro-5-methyl-4-methylene-2³,6-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidine-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexanacycloheptaphan-7-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,6S)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidine-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S,6S)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidine-3(3,2)-pyridina-2(3,4)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (3aR,5aE,9E, 12aS, 13aR, 13bR, 18aR)- 15-fluoro-

1 ,2, 3, 3a, 4, 12a, 13, 13a, 13b, 18a-decahydro-5H, 12H-8, 10- ethenocyclopenta[b]cyclopropa[3,4]pyrrolo[1 ,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1 ]oxa[4,8, 10]triazacyclotridecin-5-one, optionally substituted

(3aR,5aE,9E,12aR,13aS,13bS,18aR)-15-fluoro-1,2,3,3a,4,12a,13,13a,13b,18a-decahydro- 5H,12H-8,10-ethenocyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1 ]oxa[4,8, 10]triazacyclotridecin-5-one, optionally substituted

(1aR,1bR,6aR,10aR,12aE,16E,19aS)-3-fluoro-1a,1b,7,8,9,10,10a,11,19,19a-decahydro-1H- 15, 17-ethenobenzo[b]cyclopropa[3,4]pyrrolo[1 ,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1]oxa[4,8,10]triazacyclotridecin-12(6aH)-one, optionally substituted

(1 aS, 1 bS,6aR, 10aR, 12aE, 16E, 19aR)-3-fluoro- 1 a, 1 b, 7, 8, 9, 10, 10a, 11 , 19, 19a-decahydro-1 H- 15, 17-ethenobenzo[b]cyclopropa[3,4]pyrrolo[1 ,2-j]pyrazolo[4,3-f]pyrido[3,2- l][1]oxa[4,8,10]triazacyclotridecin-12(6aH)-one, optionally substituted

(1³E,1⁴E,2¹R,2²R,2⁵S,5R)-3⁵-fluoro-5-methyl-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1,5- a]pyrimidine-3(3,2)-pyridina-2(3,2)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S,5R)-3⁵-fluoro-5-methyl-4-oxa-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidine-3(3,2)-pyridina-2(3,4)-bicyclo[3.1 0]hexanacyclooctaphan-8-one, optionally substituted (TR,2’R,3’E,4’E,5’S)-5’-fluorospiro[cyclopropane-1,6’-4-oxa-23,7- diaza-1 (5,3)-pyrazolo[1 ,5-a] 31 yrimidine-3(3,2)-pyridina-2(3,2)- bicyclo[3.1.0]hexanacyclooctaphan]-8’-one, optionally substituted (1’R,3’E,4’S,4’E,5’S)-5’- fluorospiro[cyclopropane-1 ,6’-4-oxa-23,7-diaza-1(5,3)-pyrazolo[1,5-a] 31 yrimidine-3(3,2)- pyridina-2(3,4)-bicyclo[3.1 0]hexanacyclooctaphan]-8’-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,5S)-3⁵-fluoro-5-methyl-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1 ,5- a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one, optionally substituted (TR,2'R,3'E,4'E,5'S)-5'-fluorospiro[cyclopropane-1,6'-4-oxa-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan]-8'-one, optionally substituted (3aR,5aE,9E, 12aS, 13aR, 13bR, 18aR)- 15-fluoro-

1 ,2, 3, 3a, 4, 12a, 13, 13a, 13b, 18a-decahydro-5H, 12H-8, 10- ethenobenzo[l]cyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8, 10]triazacyclotridecin-5-one, optionally substituted

(4aR,6aE,10E,13aS,14aR,14bR,19aR)-16-fluoro-1,3,4,4a,5,13a,14,14a,14b,19a-decahydro- 13H-9.11-ethenodibenzo[b,l]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8,10]triazacyclotridecin-6(2H)-one, optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S,5S)- 3⁵-fluoro-5-methyl-4-oxa-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,4)- bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one, optionally substituted

(4aR,6aE, 10E, 13aS, 14aR, 14bR, 19aS)-16-fluoro-1 ,3, 4, 4a, 5, 13a, 14, 14a, 14b, 19a-decahydro- 13H-9.11-ethenodibenzo[b,l]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8, 10]triazacyclotridecin-6(2H)-one, optionally substituted

(3aR,5aE,9E,12aS,13aR,13bR,18aS)-15-fluoro-1,2,3,3a,4,12a,13,13a,13b,18a-decahydro- 5H,12H-8,10-ethenobenzo[l]cyclopenta[b]cyclopropa[3,4]pyrrolo[1,2-j]pyrazolo[4,3- f][1]oxa[4,8,10]triazacyclotridecin-5-one, optionally substituted (TR,3'E,4'S,4'E,5'S)-5'- fluorospiro[cyclopropane-1 ,6'-4-oxa-2³,7-diaza-1 (5,3)-pyrazolo[1 ,5-a]pyrimidina-2(3,4)- bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan]-8'-one, optionally substituted

(TR,2'R,3'E,4'E,5'S)-5'-fluorospiro[cyclopropane-1 ,6'-2³,7-diaza-1(5,3)-pyrazolo[1 ,5- a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan]-8'-one, optionally substituted (TR,3'E,4'S,4'E,5'S)-5'-fluorospiro[cyclopropane-1 ,6'-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidina-2(3,4)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan]-8'-one, optionally substituted (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidina-2(3,2)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one, or optionally substituted (1³E,1⁴E,2¹R,2⁴S,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)- pyrazolo[1 ,5-a]pyrimidina-2(3,4)-bicyclo[3.1 0]hexana-3(1 ,2)-benzenacyclooctaphan-8-one, or a pharmaceutically acceptable salt thereof (Referred to herein as a “subject compound”), may be adapted for oral, or parental, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. The dosage of a subject compound may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated. A pharmaceutical composition provided herein may optionally comprise two or more subject compounds without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e. , a therapeutic agent other than a compound provided herein). For example, the compounds of the disclosure can be used in combination with at least one other therapeutic agent. Therapeutic agents include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, antiinflammatory agents, antiviral agents, and anticancer agents that are known in the art. The pharmaceutical composition may be used for the treatment of cancer, chronic pain, infectious diseases, neurodegenerative diseases, and certain infectious disorders in patients. The term "patient" herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.

The pharmaceutical composition described herein can be prepared by combining a subject compound, with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

An example, not as an attempt to limit the scope of the disclosure, of a useful composition for a dosage form containing about 20- 1000 mg of A-1 is shown in Table 2 below:

Table 2. Example of dosage form of A-1

Some embodiments include a method of treating a disease or disorder associated with ALK, ROS1, and other kinases, such as cancers comprising administering of a therapeutically effective amount of a subject compound or a pharmaceutical composition comprising a subject compound to a patient in need thereof. The term a "therapeutically effective amount" herein refers to an amount of a compound or a pharmaceutical composition of the present disclosure provided herein sufficient to be effective in inhibiting ALK, ROS1, and other kinase enzymes and thus providing a benefit in the treatment of cancer, infectious diseases and other TRK kinase associated disorders, to delay or minimize symptoms associated with cancer, infectious diseases and other ALK, ROS1 kinases associated disorders, or to ameliorate a disease or infection or cause thereof. In some embodiments, about 0.01-1000 mg of a subject compound may be a therapeutically effective amount. The term "treatment" refers to causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying causes of symptoms, postponing, preventing the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.

Experimental Section:

Preparation of Compounds

The compounds of the disclosure can be made using procedures known in the art. The following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable for using to prepare these compounds. For examples in Formula I, wherein R^A, R^B, or R^c is not hydrogen, those skilled in the art will recognize that changes to the requisite reagents can be made at the appropriate steps in the synthetic methods outlined below. Reactions may involve monitoring for consumption of starting materials, and there are many methods for the monitoring, including but not limited to thin layer chromatography (TLC), liquid chromatography mass spectrometry (LCMS), and Nuclear magnetic resonance spectroscopy (NMR). Those skilled in the art will recognize that any synthetic method specified in the examples shown below can be substituted by other non limiting methods when suitable.

Some of the techniques, solvents and reagents can be referred to by their abbreviations as follows:

Acetonitrile: MeCN or ACN Aqueous: aq.

Benzyl: Bn

1-[Bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate: HATU

Bis(pinacolato)diboron: B2(Pin)2

Copper (II) trifluoromethanesulfonate: Cu(OTf)2

Dichloromethane: DCM

Diethyl azodicarboxylate: DEAD

Diisopropylethylamine: DIPEA, DIEA or iP^Net

Dimethylaminopyridine: DMAP

Dimethylformamide: DMF Dimethylsulfoxide: DMSO Di-tert-butyl dicarbonate : (Bo O 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide: EDCI Equivalents: equiv.

Ether or diethyl ether: Et2<D

Ethyl acetate: AcOEt or EtOAc or EA

Example: Ex. or ex.

Pentafluorophenyl diphenylphosphinate: FDPP Grams: g

High performance liquid chromatography: HPLC 1 -Hydroxy-7-azabenzotriazole: HOAT 1-Hydroxybenzotriazole: HOBT or HOBt Inhibition: Inh.

Liquid chromatography mass spectrometry: LCMS

Methansulfonyl chloride: MeSOaCI or MsCI

Methanol: MeOH

Microliter: mI

Micrometer: mhi

Milligram: mg

Milliliter: mL

Millimole: mmol

Mesylate or Methanesulfonate : Ms

Nuclear magnetic resonance spectroscopy: NMR

Palladium (II) acetate: Pd(OAc)2

Palladium on activated carbon: Pd/C

N-Phenyl bis(trifluoromethanwsulfonimide): PhNTf2 p-Toluenesulfonic acid: PTSA

Preparative HPLC: Prep-HPLC

Retention time: tp

Room temperature (ambient, ~25 °C): rt or RT Supercritical Fluid Chromatography: SFC Temperature: temp.

Tetrahydrofuran: THF Thin layer chromatography: TLC Triethylamine: Eΐ N Trifluoroacetic acid: TFA Triflic anhydride: (T 2O

In the synthetic schemes described below, unless otherwise indicated all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents and solvents were purchased from commercial suppliers such as Aldrich Chemical Company and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) were purchased from commercial sources in Sure Seal bottles and used as received.

The reactions set forth below were done generally under a positive pressure of argon or nitrogen at an ambient temperature (unless otherwise stated) in anhydrous solvents. Glassware was oven dried and/or heat dried. The reactions were assayed by TLC and/or analyzed by LC-MS and terminated as judged by the consumption of starting material. Analytical thin layer chromatography (TLC) was performed on glass plates pre-coated with silica gel 60 F254 0.25 mm plates (EM Science), and visualized with UV light (254 nm) and/ or heating with commercial ethanolic phosphomolybdic acid. Preparative thin layer chromatography (TLC) was performed on glass-plates pre-coated with silica gel 60 F254 0.5 mm plates (20 x 20 cm, from commercial sources) and visualized with UV light (254 nm).

Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated. Product solutions were dried over anhydrous Na2SC>4 and/or MgaSCL prior to filtration and evaporation of the solvents under reduced pressure on a rotary evaporator and sometimes noted as solvents removed in vacuo. Column chromatography was completed under positive pressure using 230-400 mesh silica gel.

One of the typical synthetic methods is described below.

Method 1:

Scheme 1

Step 1:

To a solution of 15.0 g (72.8 mmol) of 3-bromo-5-fluoro-2-methoxypyridine in 300 ml_ of dioxane were added 17.2 g (102 mmol) of tert- butyl 2, 3-dihydro-1 /-/-pyrrole-1 -carboxylate, 3.80 g (14.5 mmol) of PPh₃, 30.3 g (219 mmol) of K₂C0₃ and 1.60 g (7.30 mmol) of Pd(OAc)₂. The solution was stirred at 100 °C overnight under nitrogen atmosphere and cooled down to rt. The mixture was diluted with 1000 ml_ of water, extracted with three 300 ml_ portions of ethyl acetate. The combined organic layers were washed with 300 ml_ of brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 6 % ethyl acetate in petroleum ether to afford compound 1-1. LC-MS: m/e = 295 [M+H]⁺.

Step 2:

Into 1 L conical flask was added of 30.0 g (102 mmol) of compound 1-1 in 120 ml_ of DCM, 120 ml_ of 40% aqueous potassium hydroxide solution and 196 mg (0.510 mmol) of PdCl2(PhCN)2. To the reaction mixture was added 60.0 g (582 mmol, ~ 50% by weight) of 1- methyl-1-nitrosourea over 2 h in portions (-0.5 g/min) with ice-water bath cooling (internal temperature at - 10 °C). The mixture was stirred for additional 10 min. The mixture was diluted with 200 mL of water and extracted with three 300 ml_ portions of ethyl acetate. The combined organic extracts were washed with 600 mL of brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under vacuum to afford a residue, which was purified by chromatography on silica gel column eluting with PE:EA = 40:1 to afford_com pound 1 2 LC-MS: m/e = 309 [M+H]⁺.

Step 3:

A mixture of 103 g (334 mmol) of compound 1-2 and 1000 mL of 4 N HCI in dioxane was stirred for 3 h at room temperature and concentrated under vacuum to give compound 1-3 hydrochloride salt. LC-MS: m/e = 209 [M+H]⁺.

Step 4:

To a stirred solution of 30.0 g (123 mmol) of compound 1-3 hydrochloride and 29.1 g (129 mmol) of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate in 300 mL of EtOH was added 95.1 g (736 mmol) of DIEA at room temperature under nitrogen atmosphere. The mixture was stirred at 90 °C overnight and cooled to RT. It was diluted with water (600 mL) and the mixture was stirred at RT for 2 h. The mixture was filtered and the filter cake was washed with two 300 mL portions of water: EtOH (2:1) and 300 mL of hexane to give compound 1 4 LC-MS: m/e = 398 [M+H]⁺.

Step 5:

A mixture of 70.0 g (176 mmol) of compound 1-4 in 700 mL of 4 N HCI in dioxane was stirred at 40 °C for 26 h under nitrogen atmosphere. The mixture was filtered, the filter cake was washed with three 500 mL portions of EtOAc to give compound 1-5 HCI salt. LC-MS : m/e = 384 [M+H]⁺ Step 6:

To a stirred solution of 210 mg (0.55 mmol) of compound 1-5 HCI salt and 155 mg (1.53 mmol) of EΐbN in 5 ml_ of CH2CI2 was added 274 mg (0.77 mmol) of 1,1,1 -trifluoro-N- phenyl-N -trifluoromethanesulfonylm ethanesulfonamide dropwise at 0 °C. The mixture was stirred at room temperature overnight under nitrogen atmosphere, diluted with 50 ml_ H2O, and extracted with three 50 ml_ portions of CH2CI2. The combined organic layers were washed with 50 ml_ of brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 3% MeOH in CH2CI2 to afford compound 1-6. LC-MS: m/e = 516 [M+H]⁺.

Step 1:

To a stirred solution of 5.00 g (9.70 mmol) of compound 1-6, 1.36 g (1.94 mmol) of Pd(PPh3)2Cl2 and 0.37 g (1.94 mmol) of Cul under argon atmosphere in 20 ml_ of toluene were added 1.95 g (19.3 mmol) of i-P^NH and 2.87 g (17.0 mmol) of tert-butyl N-[(2S)-but-3-yn-2- yl]carbamate in 30 mL of toluene dropwise at RT under argon atmosphere. The mixture was stirred at 60 °C for 1 h and concentrated. The residue was diluted with water and extracted with three 200 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:2) to afford compound 1-7. LC-MS: m/e = 535 [M+H]⁺.

Step 8:

To a stirred solution of 5.30 g (9.91 mmol) of compound 1-7 in 53 mL of THF was added 1.06 g (7.55 mmol) of Pd(OH)2/C at RT under hydrogen atmosphere. The mixture was stirred overnight and filtered; the filter cake was washed with THF. The filtrate was concentrated, the residue was purified by silica gel column chromatography eluting with CH₂CI₂/MeOH (24:1) to afford compound 1-8. LC-MS: m/e = 539 [M+H]⁺.

Step 9:

To a stirred solution of 6.50 g (12.1 mmol) of compound 1-8 in 78 mL of EtOH was added a solution of 4.83 g (121 mmol) of NaOH in 39 mLof H2O dropwise at RT under nitrogen atmosphere. The mixture was stirred at 70 °C for 1 h and concentrated. The residue was diluted with water, basified to pH7 with citric acid, and extracted with three 250 mL portions of DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to compound 1-9, which was used in the next step directly without further purification. LC-MS: m/e = 511 [M+H]⁺.

Step 10: To a stirred solution of 6.00 g (11.8 mmol) of compound 1-9 in 60 ml_ of dioxane was added 60 ml_ (4 M in dioxane) of HCI dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 1h and concentrated to give a residue, which was purified by trituration with MeCN to afford compound 1-10. LC-MS: m/e = 411 [M+H]⁺.

Step 11:

To a stirred mixture of 16.4 g (127 mmol) of DIEA and 455 ml_ of DCM in 197 ml_ of DMF were added a solution of 3.17 g (5.28 mmol) of compound 1-10 in 98 ml_ of DMF and one third of 2.13 g (5.55 mmol) of FDPP in portions at RT. The mixture was stirred at RT for 1 h, quenched with 2 M Na2CC>3 aqueous solution and extracted with three 200 ml_ portions of DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with EtOAc/MeOH (24:1) to afford a crude product. The crude product was further purified by Prep-SFC with the following conditions (Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 mhi; Mobile Phase A:CC>2, Mobile Phase B:MeOH- Preparative; Flow rate:100 mL/min; Gradient:50% B; 220 nm) to afford compound 1-11 , LC- MS: m/e = 393 [M+H]⁺ and compound 1-12, LC-MS: m/e = 393 [M+H]⁺.

The synthesis of A-l, A-2, A-3, A-4, and A-5 have been described in an earlier application WO2019094143.

Method 2:

Scheme 2

Step 1:

To a stirred solution of 0.78 g (3.88 mmol) of tert-butyl N-[(1R,2S)-2- hydroxycyclopentyl]carbamate 1 in 10 ml_ of ACN were added 0.95 g (2.9 mmol) of CS2CO3 and 1.00 g (1.90 mmol) of compound 1-6 in portions at RT under argon atmosphere. The mixture was stirred at 80 °C for 2 h, cooled to RT, diluted with H2O, and extracted with three 20 ml_ portions of EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to afford compound 2-1. LC-MS: m/e = 567 [M+H]⁺.

Step 2:

To a stirred solution of 700 mg (1.24 mmol) of compound 2-1 in 8 ml_ of EtOH was added a solution of 494 mg (12.4 mmol) of NaOH in 4 ml_ of H2O dropwise at 0 °C. The resulting mixture was stirred at 70 C for 1 h and concentrated. The residue was diluted with water and neutralized to pH 7 with citric acid. The precipitates were collected by filtration and washed with water and dried under reduced pressure to afford compound 2-2, which was used in the next step directly without further purification. LC-MS: /e = 539 [M+H]⁺.

Step 3:

To a stirred solution 580 mg (1.08 mmol) of compound 2-2 in 1 ml_ of dioxane was added 3 ml_ (4 N in dioxane) of HCI dropwise at 0 °C. The mixture was stirred at RT for 1 h and concentrated to afford compound 2-3, which was used in the next step directly without further purification. LC-MS: m/e = 439 [M+H]⁺.

Step 4:

To a stirred mixture of 407 mg (2.12 mmol) of EDCI and 287 mg (2.121 mmol) of HOBt in 8 mL of DMF were added the solution of 310 mg (0.707 mmol) of compound 2-3 and 429 mg (4.24 mmol) of TEA in 8 mL of DMF at RT. The mixture was stirred at RT overnight, diluted with water and extracted with three 20 mL portions of EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to afford a crude, which was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 mhi; Mobile Phase A : Water(10 mM NH4HCO3), Mobile Phase B:ACN; Flow rate: 60 mL/min; Gradient:40 B to 70 B in 8 min; 254 nm) to afford 2-4 and 2-5. LC-MS for compound 2-4: m/e = 421 [M+H]⁺. LC-MS for compound 2-5: m/e = 421 [M+H]⁺.

The following compounds were prepared analogously by using appropriate amino alcohols:

Method 3:

Scheme 3

Step 1:

A mixture of 300 mg(0.78 mmol) of compound 1 -5 and 206 mg(1.17 mmol) of tert-butyl N-[(2R)-2-hydroxypropyl]carbamate was dried from co- evaporation with DCM/toluene and then dissolved in 8 ml_ of DCM. To the above mixture was added 308 mg (1.17 mmol) of PPhb in portions at RT under Ar atmosphere. The mixture was stirred for 30 min at RT until the starting materials were completely dissolved, 204 mg (1.17 mmol) of DEAD was added dropwise. The mixture was stirred for 3 h and concentrated under reduced pressure. The residue was dissolved in DCM (10 ml_), washed with brine (3x10 ml_), and dried over anhydrous Na2SC>4. It was filtered; the filtrate was concentrated to give a residue, which was purified by Prep-TLC eluting with 2 % MeOH in DCM to afford compound 3-1 as major product and minor compound 3-2. LC-MS for compound 3-1 : m/e = 553 [M+H]⁺. LC-MS for compound 3-2: m/e = 553 [M+H]⁺.

Step 2: Compound 3-1 was converted to compound 3-3 following similar procedures described in Method 1, step 9. LC-MS: m/e = 525 [M+H]⁺.

Step 3:

Compound 3-3 was converted to compound 3-4 following similar procedures described in Method 1, step 10. LC-MS: m/e = 425 [M+H]⁺.

Step 4:

Compound 3-4 was converted to compound 3-5 and 3-6 following similar procedures described in Method 2, step 4. LC-MS for 3-5: m/e = 407 [M+H]⁺. LC-MS for 3-6: m/e = 407 [M+H]⁺.

Method 4:

Scheme 4

Step 1:

To a stirred solution of 1.00 g (5.24 mmol) of 2-bromo-4-fluorophenol and 0.99 g (5.79 mmol) of benzyl bromide in 12 ml_ of DMF was added 1.45 g (10.5 mmol) of K₂CO₃ in portions at RT under nitrogen atmosphere. The mixture was stirred at 80 °C for 1 h under nitrogen atmosphere and cooled to RT. The mixture was diluted with water and extracted with two 50 mL portions of EtOAc. The combined organic layers were washed with brine and dried over Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford compound 4-1. ¹H NMR (300 MHz, CDC ) d 7.54 - 7.30 (m, 18 H), 7.03 - 6.84 (m, 6 H), 5.14 (s, 6 H), 4.15 (q, J= 7.1 Hz, 1 H), 2.07 (s, 1 H), 1.30 (s, 0 H), 1.29 (t, J = 7.1 Hz, 1 H), 0.12 (s, 1 H).

Step 2:

To a stirred mixture of 1.00 g (3.56 mmol) of compound 4-1 and 0.84 g (4.96 mmol) of tert-butyl 2,3-dihydropyrrole-1-carboxylate in 10 mL of dioxane were added 1.47 g (10.7 mmol) of K2CO3, 0.19 g (0.711 mmol) of PPhi3 and 0.080 g (0.356 mmol) of Pd(OAc)2 at RT under nitrogen atmosphere. The mixture was stirred overnight at 95 °C and cooled to RT. The mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated to give a residue, which was diluted with water and extracted with three 50 mL portions of EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂S0₄. It was filtered and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE/EtOAc (35:1) to afford compound 4-2. LC-MS for 4-2: m/e = 370 [M+H]⁺.

Step 3:

Compound 4-2 was converted to compound 4-3 following similar procedures described in Method 1 , step 2. LC-MS for 4-3: m/e = 384 [M+H]⁺.

Step 4:

Compound 4-3 was converted to compound 4-4 following similar procedures described in Method 1 , step 3. LC-MS for 4-4: m/e = 284 [M+H]⁺.

Step 5:

Compound 4-4 was converted to compound 4-5 following similar procedures described in Method 1 , step 4. LC-MS for 4-5: m/e = 473 [M+H]⁺.

Step 6:

Compound 4-5 was converted to compound 4-6 following similar procedures described in Method 1 , step 8. LC-MS for45-6: m/e = 383 [M+H]⁺.

Step 1:

To a stirred solution of 500 mg (1.31 mmol) of compound 4-6 in 20 mL of DMF were added 3.41 g (10.5 mmol) of CS2CO3 and 1.99 g (7.86 mmol) of intermediate 6 dropwise at RT. The mixture was stirred at 80 °C for 2 h under nitrogen atmosphere and cooled to RT. The mixture was diluted with water and extracted with three 60 mL portions of EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂S0₄. It was filtered and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE/EtOAc (6 : 4) to afford compound 4-7. LC-MS for 4- 7: m/e = 540 [M+H]⁺.

Step 8:

Compound 4-7 was converted to compound 4-8 following similar procedures described in Method 1 , step 9. LC-MS for 4-8: m/e = 512 [M+H]⁺.

Step 9:

Compound 4-8 was converted to compound 4-9 following similar procedures described in Method 1 , step 8. LC-MS for 4-9: m/e = 412 [M+H]⁺.

Step 10:

Compound 4-9 was converted to compound 4-10 and 4-11 following similar procedures described in Method 2, step 4. LC-MS for 4-10: m/e = 394 [M+H]⁺. LC-MS for 4-11: m/e = 394 [M+H]⁺.

The following compounds were prepared analogously by using appropriate mesylate intermediates:

Method 5:

Scheme 5

Step 1:

To a stirred solution of 3.00 g (7.85 mmol) of compound 4-6 and 0.48 g (3.92 mmol) of DMAP in 30 ml_ of pyridine were added 4.43 g (15.7 mmol) of triflic anhydride dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at RT overnight and concentrated. The residue was dissolved with 200 ml_ of EtOAc and washed with 1 M aqueous citric acid solution, brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with PE/EtOAc (74:26) to afford compound 5-1. LC-MS for 5-1: m/e = 515 [M+H]⁺.

Step 2:

To a stirred solution of 1.10 g (2.14 mmol) of compound 5-1 and 0.83 g (3.00 mol) of compound 7 in 10 ml_ of DME were added 0.12 g (0.10 mmol) of Pd(PPh3)4 and 1.10 g (13.0 mmol) of NaHCC>3 (dissolved in 5.00 ml_ of H2O) dropwise at 25 °C. The mixture was stirred at 90 °C for 30 min under nitrogen atmosphere and diluted with water. It was extracted with three 40 ml_ portions of EtOAc; the combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel eluting with PE/EtOAc (3:1) to afford to compound 5-2. LC-MS for 5-2: m/e = 548 [M+H]⁺.

Step 3:

Compound 5-2 was converted to compound 5-3 following similar procedures described in Method 1 , step 8. LC-MS for 5-3: m/e = 550 [M+H]⁺.

Step 4:

Compound 5-3 was converted to compound 5-4 following similar procedures described in Method 1 , step 9. LC-MS for 5-4: m/e = 512 [M+H]⁺.

Step 5:

Compound 5-4 was converted to compound 5-5 following similar procedures described in Method 1 , step 8. LC-MS for 5-5: m/e = 422 [M+H]⁺.

Step 6:

Compound 5-5 was converted to compound 5-6 and 5-7 following similar procedures described in Method 1 , step 11. LC-MS for 5-6: m/e = 404 [M+H]⁺. LC-MS for 5-7: m/e = 404 [M+H]⁺.

The following compounds were prepared analogously by using intermediate 8 instead of intermediate 7 in the coupling reaction of Step 2, Scheme 5:

Syntheses of Intermediates

1. Synthesis of intermediate 1:

Scheme 6

step 1

1

Step 1:

To a stirred solution of 2.00 g(19.8 mmol) of (1S,2R)-2-aminocyclopentan-1-ol in 20 ml_ of DCM were added 7.67 g (59.3 mmol) of DIEA and 4.75 g (21.8 mmol) of (Boc)₂0 dropwise at 0 °C under argon atmosphere. The mixture was stirred at RT for 2 h and concentrated. The residue was diluted with H2O, extracted with three 20 mL portions of CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by silica gel column chromatography eluting with CH₂CI₂/EtOAc (10:1) to afford intermediate 1. LC-MS: m/e = 202 [M+H]⁺.

2. Synthesis of intermediate 2:

Scheme 7

Step 1:

Intermediate 2 was prepared from (lS,2R)-2-aminocyclohexan-l-ol similarly as described in Scheme 4, step 1. LC-MS: m/e = 216 [M+H]⁺.

3. Synthesis of intermediate 3: Scheme 8

Step 1:

To a stirred solution of 2.00 g (11.4 mmol) of tert-butyl N-[(2R)-2- hydroxypropyl]carbamate in 30 ml_ of DCM were added 1.27 g ( 12.6 mmol) of EΐbN and 1.37 g ( 12.0 mmol) of MsCI dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 2 h under nitrogen atmosphere and cooled to 0 °C. It was quenched with saturated NH4CI and extracted with three 50 ml_ portions of DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. It was filtered and the filtrate was concentrated to give a crude product 3, which was used in the next step directly without further purification. LC-MS: m/e = 254 [M+H]⁺.

The following mesylate compounds were prepared analogously by using the appropriate amino alcohols shown below:

4. Synthesis of intermediate 4:

Scheme 9

step 1 7 Step 1:

To a stirred mixture of 3.93 g (22.0 mmol) of tert-butyl N-(1- ethynylcyclopropyl)carbamate and 6.62 g ( 26.0 mmol) of bis(pinacolato)diboron in 35 ml_ of dioxane were added 2.09 g ( 65.0 mmol) of MeOH, 0.57 g (2.00 mmol) of PPh₃ and 0.21 g (2.0 mmol) of t-BuONa in portions at RT under nitrogen atmosphere. To the above mixture was added 0.39 g (1.00 mmol) of Cu(OTf)2 in portions at 0 °C. The mixture was stirred at RT overnight and diluted with water. It was extracted with three 150 ml_ portions of EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE/EtOAc (97:1) to afford compound 7. LC-MS for 7: m/e = 310 [M+H]⁺.

5. Synthesis of intermediate 5:

Scheme 10

step 1 8

Step 1:

Intermediate 8 was prepared from tert-butyl N-[(2R)-but-3-yn-2-yl]carbamate following similar procedure described in Scheme 9, step 1. LC-MS for 8: m/e = 298 [M+H]⁺.

ASSAYS

Protocols that may be used to determine the recited potency for the compounds of the disclosure are described below.

The HotSpot assay platform was used to measure kinase/inhibitor interactions as described in Anastassiadis et al., Nat Biotechnol. 29:1039-45, 2011. In brief, for each reaction, kinase and substrate were mixed in a buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCh, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na₃V0₄, 2mM DTT, and 1% DMSO. Compounds were then added to each reaction mixture. After a 20-min incubation, ATP (Sigma-Aldrich) and [y-33P] ATP (PerkinElmer) were added at a final total concentration of 100 mM. Reactions were carried out at room temperature for 2 h and spotted onto P81 ion exchange cellulose chromatography paper (Whatman). Filter paper was washed in 0.75% phosphoric acid to remove unincorporated ATP. The percent remaining kinase activity relative to a vehicle-containing (DMSO) kinase reaction was calculated for each kinase/inhibitor pair. Outliers were identified and removed as described in Anastassiadis et al., Nat Biotechnol. 29:1039-45, 2011. IC5₀ values were calculated using Prism 5 (GraphPad). The testing results for selected compounds are summarized in Table 3, wherein A represents the IC5₀ value of <10 nM; B represents the IC5₀ value of 10-1000 nM; and C represents the IC5₀ value of >1000 nM.

Table 3. ALK and ROS1 Inhibitory Activity of Representative Examples

ND means not determined.

Compound A-1 at a concentration of 1 mM also significantly inhibited the following kinases (>90%) : ACK1 , DDR1 , TXK, BMX/ETK, and JAK2 as shown in Table 4 below.

Table 4. Other Kinases Inhibitory Activity of Compound A-1

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and etc. used in herein are to be understood as being modified in all instances by the term “about.” Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters may be modified according to the desired properties sought to be achieved, and should, therefore, be considered as part of the disclosure. At the very least, the examples shown herein are for illustration only, not as an attempt to limit the scope of the disclosure.

The terms “a,” “an,” “the” and similar referents used in the context of describing embodiments of the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illustrate embodiments of the present disclosure and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the embodiments of the present disclosure. Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the embodiments of the present disclosure to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

What Is Claimed Is:

1. A compound represented by a formula:

wherein (A (Ring A) is an optionally substituted 6-membered aromatic all carbon ring, or optionally substituted 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms;

R^1a and R^2a are independently H, Me, F, Cl, or Br; and

2. The compound of claim 1, wherein Ring A is optionally substituted pyridin-2,3-di-yl.

3. The compound of claim 1, wherein Ring A is pyridin-2,3-di-yl.

4. The compound of claim 1 , 2, or 3, wherein Ring B is optionally substituted pyrazolo[1 ,5- a]pyrimidin-3,5-di-yl.

5. The compound of claim 4, wherein Ring B is pyrazolo[1,5-a]pyrimidin-3,5-di-yl.

6. The compound of claim 1,2, 3, 4, or 5, wherein W is CH2.

7. The compound of claim 1,2, 3, 4, or 5, wherein W is O.

8. The compound of claim 1,2, 3, 4, or 5, wherein W is C=CH2.

9. The compound of claim 1,2, 3, 4, 5, 6, 7, or 8, wherein E is:

10. The compound of claim 1,2, 3, 4, 5, 6, 7, or 8, wherein E is:

11. The compound of claim 1,2, 3, 4, 5, 6, 7, or 8, wherein E is:

12. The compound of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein E is:

13. The compound of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein E is:

14. The compound of claim 1 , 2, 3, 4, 5, 6, 7, or 8, wherein E is:

15. The compound of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein E is:

16. The compound of claim 1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein Ring A is optionally substituted phenyl.

17. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:

18. A method of treating a disease in a patient comprising, administering a therapeutically effective dose of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, or 17, or (1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1 ,5-a]pyrimidina- 3(3,2)-pyridina-2(3,2)-bicyclo[3.1.0]hexanacyclooctaphan-8-one, or a pharmaceutically acceptable salt thereof.

19. Use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17,

(1³E,1⁴E,2¹R,2²R,2⁵S,6R)-3⁵-fluoro-6-methyl-2³,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrimidina- 3(3,2)-pyridina-2(3,2)-bicyclo[3.1.0]hexanacyclooctaphan-8-one, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease.

20. The method or use of claim 18 or 19, wherein the disease is mediated by a tyrosine kinase comprising ROS1, ALK, TRK, ACK1 , DDR1 , TXK, JAK2, BMX/ETK, or a combination thereof.

21. The method or use of claim 18, 19, or 20, wherein the disease is cancer, psoriasis, rheumatoid arthritis, polycythemia vera, essential thrombocythemia, ulcerative colitis, or a combination thereof.

22. The method or use of claim 18, 19, 20, or 21, wherein the disease is cancer mediated by ROS1.

23. The method or use of claim 18, 19, 20, or 21, wherein the disease is cancer mediated by genetically altered ROS1.

24. The method or use of claim 18, 19, 20, or 21, wherein the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene comprising FIG, TPM3, SDC4, CD74, SLC34A2, LRIG3, EZR, KDEL R2, LIMA1, MSN, CLTC, CCDC6, TMEM106, or TPD52L1 fusion partner, or a combination thereof.

25. The method or use of claim 24, wherein the fusion protein is a wild-type protein.

26. The method or use of claim 24, wherein the fusion protein harbors at least one secondary mutation comprising G2032R, L2155S, L2026M, D2033N, or S1986Y/F point mutation, or a combination thereof.

27. The method or use of claim 18, 19, 20, or 21, wherein the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by a ALK gene and a fragment of a protein encoded by a gene comprising NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, AL017, MYH9, KIF5B, KLC1, HIPI, TPM3, CARS, RANBP2, SEC31A, SQSTM1, or VCL fusion partner, or a combination thereof.

28. The method or use of claim 27, the fusion protein is a wild-type protein.

29. The method or use of claim 27, the fusion protein harbors at least one secondary mutation comprising 1151Tins, L1152R, C1156Y, I1171T/N/S, F1174L/C, V1180L, L1196M, L1198F, G1202R/del, S1206F, D1203N, S1206Y/C, G1269A, or G1548E point mutation, or a combination thereof.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, or 17, in combination with at least one pharmaceutically acceptable carrier.

31. A process for making a pharmaceutical composition comprising combining a compound of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, and at least one pharmaceutically acceptable carrier.