Fused tricyclic pyrroles as alpha-1 antitrypsin modulators

Abstract

The present disclosure provides compounds according to Formula (I), their tautomers, pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable salts of the tautomers, deuterated derivatives of the compounds, deuterated derivatives of the tautomers, and deuterated derivatives of the salts, solid forms of the compounds, and processes for making the compounds, that are useful for treating alpha-1 antitrypsin deficiency (AATD). TIFF2022532340000552.tif5288

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Patent Application No. 62 / 847,562, filed May 14, 2019, and U.S. Patent Application No. 63 / 004,813, filed April 3, 2020, the contents of which are incorporated by reference in their entireties.

[0002] The present disclosure provides compounds capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds. [Background technology]

[0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments exist for AATD, there is currently no cure. AAT is primarily produced in hepatocytes and secreted into the blood, but is also made by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], proteinase 3, and cathepsin G), thus protecting organs such as the lungs from protease-induced damage, especially during periods of inflammation.

[0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, results in misfolding of the translated protein, so that it is not secreted into the bloodstream and can polymerize within the producing cells. As a result, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) are significantly reduced, and only approximately 15% of the mutant Z-AAT protein is correctly folded and secreted from cells. A further consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to the wild-type protein, with 40%-80% of normal antiprotease activity (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med. 2003;168(7):818-900 and Ogushi et al. J Clin Invest. 1987;80(5):1366-74).

[0005] Accumulation of polymerized Z-AAT protein within hepatocytes leads to gain-of-function cytotoxicity, which can lead to cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation can resolve spontaneously, but can be fatal in a small number of children. Deficiency of circulating AAT leads to uncontrolled protease activity that degrades lung tissue over time, resulting in emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ individuals, typically manifesting in middle age and resulting in a reduced quality of life and a shortened lifespan (average 68 years) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). This effect is more pronounced in PiZZ individuals who smoke, resulting in an even further shortened lifespan (58 years). Piitulainen and Tanash, COPD 2015;12(1):36-41. PiZZ individuals represent a large proportion of those with clinically relevant AATD lung disease. Thus, there is a need for additional and effective treatments for AATD.

[0006] A milder form of AATD is associated with the SZ genotype, in which the Z allele is combined with the S allele. The S allele is associated with slightly reduced levels of circulating AAT, but does not cause cytotoxicity in liver cells. The result is clinically significant lung disease, but not liver disease. Fregonese and Stolk, Orphanet J Rare Dis. 2008;33:16. Similar to the ZZ genotype, the lack of circulating AAT in subjects with the SZ genotype can lead to uncontrolled protease activity that degrades lung tissue over time, resulting in emphysema, especially in smokers. The current standard of care for AAT-deficient individuals who have developed or show signs of developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves administering purified human AAT protein concentrate from pooled donor plasma to enhance the deficient AAT. While plasma protein infusions have been shown to improve survival or slow the rate of emphysema progression, augmentation therapy is often insufficient under challenging conditions, such as during active pulmonary infection. Similarly, protein replacement therapy shows promise in slowing disease progression, but augmentation does not restore normal physiological regulation of AAT in patients, and efficacy has been difficult to demonstrate. Additionally, augmentation therapy requires weekly clinic visits for treatment, and augmentation therapy fails to address liver disease driven by the toxic gain-of-function of the Z allele. Thus, there is a continuing need for novel and more effective treatments for AATD. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Am J Respir Crit Care Med.2003;168(7):818-900 [Non-patent document 2] Ogushi et al.J Clin Invest.1987;80(5):1366-74 [Non-patent document 3] Tanash et al.Int J Chron Obstruct Pulm Dis.2016;11:1663-9 [Non-patent document 4] Piitulainen and Tanash, COPD 2015;12(1):36-41 [Non-Patent Document 5] Fregonese and Stolk,Orphanet J Rare Dis.2008;33:16 Summary of the Invention [Means for solving the problem]

[0008] One aspect of the present invention provides compounds of formula I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds and their tautomers, and deuterated derivatives of any of the above that can be used to treat AATD. For example, compounds of formula I can be represented as follows: [ka] During the ceremony, (i)R 0 is selected from the following: (a) C1-C8 straight-chain, branched-chain, and cyclic groups, wherein the C1-C8 straight-chain, branched-chain, and cyclic groups are independently selected from alkyl and alkoxy groups, and the C1-C8 straight-chain, branched-chain, and cyclic groups are each independently selected from 1 to 4 R A C1-C8 straight chain, branched chain, and cyclic groups optionally substituted with (b) 1 to 4 R A a 5- to 14-membered aromatic ring optionally substituted with Each R A are independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5-10 membered aromatic rings, and C1-C6 straight chain, branched chain, and cyclic groups; R A wherein the amide nitrogen atom in the amide is optionally substituted with a heterocyclyl group optionally further substituted with oxo; C1-C6 straight chain, branched chain, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido; The 5-10 membered aromatic rings and C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1-4 substituents selected from halogen, C1-C6 straight chain, branched chain, and cyclic groups, and methoxy; R A The group is R 2 R on the group B 1 to 4 R optionally bonded to the group A a 5- to 14-membered aromatic ring optionally substituted with (ii)R 1 is selected from the following: (a) hydrogen, (b) C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, cyanoalkyl, Hydroxy, alkylsulfonyl, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (c) halogen, Cyano, cyanoalkyl, sulfone, sulfonamides, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogen or alkoxy groups; (d) [ka] Group(R C is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 substituents independently selected from: halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (e) [ka] Group (each R D But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 substituents independently selected from: halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; or two R's D The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic groups; (f) [ka] Group(R E is selected from the following: (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1 to C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups), And R F is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (g) [ka] group (i is an integer ranging from 0 to 3, R G and R G’ Each of the following may independently: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R G and R G’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently; (h) [ka] (R H each of which is independently selected from: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (i) C1-C6 alkylamide, (iii)R 2 is selected from 5- and 6-membered heterocycles (optionally substituted with oxo and / or C1-C6 straight and branched chain alkyl groups), and 5-6-membered aromatic rings containing 0-4 heteroatoms selected from O, N, and S, and the 5-membered aromatic rings are selected from 1-4 R B and the 6-membered aromatic ring is optionally substituted with 1 to 5 R B optionally substituted with R B groups are independently selected from: (a) amides optionally substituted with 1 to 3 groups selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (optionally substituted with oxo, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, hydroxyalkyl, amido, alkylsulfonyl, and acetamido), or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or C1-C6 straight-chain, branched-chain, and cyclic alkyl groups); (b) imidazolidine-2,4-dione, (c) heterocyclyl optionally substituted with one or more groups independently selected from oxo, acyl, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally further substituted with 1 to 3 groups independently selected from oxo, hydroxy, and acyl); (d) phosphorous acid optionally esterified with a C1-C6 straight-chain, branched-chain, or cyclic alkyl group; (e) di(C1-C6) alkylphosphine oxide, (f) (C1-C6) alkylphosphinic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (g) halogens, (h) cyano, (i) hydroxy, (j) uronic acids or carboxylic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (k) oxo, (l)-B(OR I ) 2 units (each R I are independently selected from hydrogen and C1-C6 straight chain, branched, and cyclic alkyl groups, or two OR I The groups may form a 4-8 membered ring together with the boron atom to which they are attached, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (m) 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, optionally substituted with 1 or 2 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, Hydroxy, carboxylic acids, pyrrolidin-2-one, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (n) sulfonic acids, (o) [ka] Group(R J is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and C1-C8 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from amide; (cc) halogen, Cyano, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups), (p) [ka] Group (each R K But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; or two R's K The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (q) [ka] Group(R L and R L’ each of which is independently selected from: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R L and R L’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (r) halogen, Hydroxy, carboxylic acids, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and C1-C6 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from: (s) halogen, Hydroxy, carboxylic acids, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (t) [ka] Group(R M is selected from the following: (aa) hydrogen, (bb) carboxylic acids, (cc) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (dd) halogen, Cyano, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (ee) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ff) halogens, (gg) hydroxy), (u)OR N (R N is selected from the following: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (v) [ka] (Each R O are independently selected from hydrogen and C1-C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl groups are independently selected from: alkylsulfonyl, alkylamides, halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic alkoxy groups; or two R's O The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (w) [ka] (Y1 is oxygen, NR P , and [ka] Selected from R P is selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups, and the alkyl group is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; two adjacent hydrogens on a 5- or 6-membered aromatic ring are replaced by bonds to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S, and one to six R B Bicyclic R optionally substituted with a group 2 (capable of forming a group), (iv) X 1 and X 2are independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v)W 1 and W 2 are each independently selected from C and N; (vi) each [ka] represents a single or double bond, provided that one [ka] is the only double bond, (vii) Each R 3 are independently selected from hydrogen, halogen, cyano, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, wherein the C1-C6 straight-chain, branched-chain, and cyclic alkyl groups and the C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogen, hydroxyl groups, and carboxylic acids; (viii) n is an integer selected from 0, 1, 2, and 3; (ix)Z 1 , Z 2 , and / or Z 3 are independently selected from carbon, boron, nitrogen, sulfur, and oxygen; Z 1 , Z 2 , and / or Z 3is carbon or nitrogen, the valence electrons of the carbon or nitrogen are completed with a hydrogen atom, a halogen, a C1-C6 straight-chain, branched, and cyclic alkyl group, and a C1-C6 straight-chain, branched, and cyclic alkoxy group, and the C1-C6 straight-chain, branched, and cyclic alkyl group and the C1-C6 straight-chain, branched, and cyclic alkoxy group are optionally substituted with 1 to 4 substituents independently selected from a halogen, a hydroxy group, and a carboxylic acid; and Z 1 , Z 2 , or Z 3 When is boron, the valence electrons of the boron are completed with a hydrogen atom or a hydroxy group.

[0009] In one aspect of the invention, the compound of formula I is selected from compounds 1-342, and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing that can be used in the treatment of AATD.

[0010] In some embodiments, the present invention provides pharmaceutical compositions comprising at least one compound selected from the compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, and tautomers of those compounds, pharmaceutically acceptable salts of those compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing. In certain embodiments, the pharmaceutical compositions may comprise a compound selected from compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0011] Another aspect of the present invention provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from the compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds and tautomers thereof, and deuterated derivatives of any of the foregoing, or a pharmaceutical composition comprising at least one compound. In certain embodiments, the method comprises administering a compound selected from Compounds 1-342, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds and tautomers thereof, and deuterated derivatives of any of the foregoing.

[0012] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one compound selected from compounds of Formula I, IA, IB, IC, ID, IE, IF, IG, and IH, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing, either in the same pharmaceutical composition or in separate compositions, with at least one additional active agent. In certain embodiments, the method comprises administering to a subject in need thereof at least one compound selected from compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing, either in the same pharmaceutical composition or in separate compositions, with at least one additional active agent. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0013] Also provided are methods for modulating AAT, comprising administering to a subject in need thereof at least one compound selected from the compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, and tautomers of these compounds, pharmaceutically acceptable salts of these compounds and tautomers thereof, and deuterated derivatives of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, salt, or deuterated derivative. In certain embodiments, the method for modulating AAT comprises administering to a subject in need thereof at least one compound selected from compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds and tautomers thereof, and deuterated derivatives of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, salt, or deuterated derivative. [Brief explanation of the drawings]

[0014] [Figure 1A] 1 shows the XRPD diffractogram of Form A of Compound 33. [Figure 1B] 1 shows the solid-state 13C NMR spectrum of Form A of Compound 33. [Figure 1C] 1 shows the solid-state 19F NMR spectrum of Form A of Compound 33. [Figure 1D] 1 shows the TGA thermogram of Form A of Compound 33. [Figure 1E] 1 shows a DSC thermogram of Form A of Compound 33. [Figure 1F] 1 shows the IR spectrum of Form A of Compound 33. [Figure 2A] 1 shows the XRPD diffractogram of Form B of Compound 33. [Figure 2B] 1 shows the solid-state 13C NMR spectrum of Form B of Compound 33. [Figure 2C] 1 shows the solid-state 19F NMR spectrum of Form B of Compound 33. [Figure 2D] 1 shows the TGA thermogram of Form B of Compound 33. [Figure 2E]1 shows a DSC thermogram of Form B of Compound 33. [Figure 3A] 1 shows the XRPD diffractogram of DCM solvate form A of compound 33. [Figure 3B] 1 shows the TGA thermogram of DCM solvate Form A of Compound 33. [Figure 3C] 1 shows the DSC thermogram of DCM solvate Form A of Compound 33. [Figure 4A] 1 shows the XRPD diffractogram of hydrate form A of compound 33. [Figure 4B] 1 shows the solid-state 13C NMR spectrum of hydrate form A of compound 33. [Figure 4C] 1 shows the solid-state 19F NMR spectrum of hydrate form A of compound 33. [Figure 4D] 1 shows the TGA thermogram of hydrate form A of Compound 33. [Figure 4E] 1 shows a DSC thermogram of hydrate form A of Compound 33. [Figure 5A] 1 shows the XRPD diffractogram of MeOH / H2O solvate / hydrate form A of compound 33. [Figure 5B] 1 shows the TGA thermogram of MeOH / H2O solvate / hydrate Form A of Compound 33. [Figure 5C] 1 shows the DSC thermogram of MeOH / H2O solvate / hydrate Form A of Compound 33. [Figure 6A] 1 shows the XRPD diffractogram of Form C of Compound 33. [Figure 7A] 1 shows the XRPD diffractogram of Form D of Compound 33. [Figure 7B] 1 shows the TGA thermogram of Form D of Compound 33. [Figure 7C] 1 shows a DSC thermogram of Form D of Compound 33. [Figure 8A] 1 shows the XRPD diffractogram of Form E of Compound 33. [Figure 9A] 1 shows the XRPD diffractogram of Form F of Compound 33. [Figure 9B] 1 shows the TGA thermogram of Form F of Compound 33. [Figure 9C] 1 shows a DSC thermogram of Form F of Compound 33. [Figure 10A] 1 shows the XRPD diffractogram of Form G of Compound 33. [Figure 10B] 1 shows the TGA thermogram of Form G of Compound 33. [Figure 10C] 1 shows a DSC thermogram of Form G of Compound 33. [Figure 11A] 1 shows the XRPD diffractogram of Form H of Compound 33. [Figure 11B] 1 shows the TGA thermogram of Form H of Compound 33. [Figure 11C] 1 shows a DSC thermogram of Form H of Compound 33. [Figure 12A] Figure 1 shows the XRPD diffractogram of compound 33 first reacted with EtOH. [Figure 12B] Figure 1 shows the XRPD diffractogram of compound 33 reacted with EtOH overnight. [Figure 12C] 1 shows the XRPD diffractogram of Form I of Compound 33. [Figure 12D] 1 shows the TGA thermogram of Form I of Compound 33. [Figure 12E] 1 shows the DSC thermogram of Form I of Compound 33. [Figure 13A] 1 shows the XRPD diffractogram of THF solvate Form A of Compound 33. [Figure 13B] 1 shows the solid-state 13C NMR spectrum of THF solvate Form A of Compound 33. [Figure 13C] 1 shows the solid-state 19F NMR spectrum of THF solvate Form A of Compound 33. [Figure 13D] 1 shows the TGA thermogram of THF solvate Form A of Compound 33. [Figure 13E] 1 shows the DSC thermogram of THF solvate Form A of Compound 33. [Figure 14A] 1 shows the XRPD diffractogram of Form J of Compound 33. [Figure 14B] 1 shows the TGA thermogram of Form J of Compound 33. [Figure 15A] 1 shows the XRPD diffractogram of Form K of Compound 33. [Figure 15B] 1 shows the TGA thermogram of Form K of Compound 33. [Figure 15C] 1 shows a DSC thermogram of Form K of Compound 33. [Figure 16A] 1 shows the XRPD diffractogram of 2-MeTHF solvate Form A of compound 33. [Figure 16B] 1 shows the TGA thermogram of 2-MeTHF solvate Form A of Compound 33. [Figure 16C] 1 shows the DSC thermogram of 2-MeTHF solvate Form A of Compound 33. [Figure 17A] 1 shows the XRPD diffractogram of Form L of Compound 33. [Figure 17B] 1 shows the TGA thermogram of Form L of Compound 33. [Figure 17C] 1 shows a DSC thermogram of Form L of Compound 33. [Figure 18A] 1 shows the XRPD diffractogram of Form M of Compound 33. [Figure 18B] 1 shows a TGA thermogram of Form M of Compound 33. [Figure 18C] 1 shows a DSC thermogram of Form M of Compound 33. [Figure 19A] 1 shows the XRPD diffractogram of Form N of Compound 33. [Figure 19B] 1 shows the TGA thermogram of Form N of Compound 33. [Figure 19C] 1 shows a DSC thermogram of Form N of Compound 33. [Figure 20A] 1 shows the XRPD diffractogram of Form O of Compound 33. [Figure 20B] 1 shows the TGA thermogram of Form O of Compound 33. [Figure 21A] 1 shows the XRPD diffractogram of the K salt form A of compound 33. [Figure 21B] 1 shows the TGA thermogram of K salt form A of compound 33. [Figure 21C] 1 shows the DSC thermogram of the K salt form A of compound 33. [Figure 22A] 1 shows the XRPD diffractogram of the K salt form B of compound 33. [Figure 22B] 1 shows the TGA thermogram of the K salt form B of compound 33. [Figure 22C] 1 shows the DSC thermogram of the K salt form B of compound 33. [Figure 23A] 1 shows the XRPD diffractogram of the K salt form C of compound 33. [Figure 23B] 1 shows the TGA thermogram of the K salt form C of compound 33. [Figure 23C] 1 shows the DSC thermogram of the K salt form C of compound 33. [Figure 24A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / HPMCAS-H]. [Figure 24B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / HPMCAS-H]. [Figure 24C] FIG. 1 shows the TGA thermogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / HPMCAS-H]. [Figure 25A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / PVPVA]. [Figure 25B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / PVPVA]. [Figure 26A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / HPMC E15]. [Figure 26B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [10% water with DCM / EtOH / PVPVA]. [Figure 27A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 27B]FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 27C] FIG. 1 shows the TGA thermogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 28A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 28B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 28C] FIG. 1 shows the TGA thermogram of compound 33, 50% DL amorphous spray dried dispersion [DCM / EtOH / 1% water with HPMCAS-H]. [Figure 29A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 29B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [1% water with DCM / EtOH / HPMCAS-H]. [Figure 30A] FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [water with THF / HPMCAS-H]. [Figure 30B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [water with THF / HPMCAS-H]. [Figure 30C] FIG. 1 shows the TGA thermogram of compound 33, 50% DL amorphous spray dried dispersion [water with THF / HPMCAS-H]. [Figure 30D] 1 shows the solid-state 13C NMR spectrum of a spray-dried dispersion of 50% Compound 33 with HPMCAS. [Figure 30E] 1 shows the solid-state 19F NMR spectrum of a spray-dried dispersion of 50% Compound 33 with HPMCAS. [Figure 31A]FIG. 1 shows the XRPD diffractogram of compound 33, 50% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 31B] FIG. 1 shows the DSC thermogram of compound 33, 50% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 31C] FIG. 1 shows the TGA thermogram of compound 33, 50% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 32A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with DCM / EtOH / HPMCAS-H]. [Figure 32B] FIG. 1 shows the DSC thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with DCM / EtOH / HPMCAS-H]. [Figure 32C] FIG. 1 shows the TGA thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with DCM / EtOH / HPMCAS-H]. [Figure 33A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with DCM / EtOH / HPMCAS-H, starting from THF solvate DS]. [Figure 33B] FIG. 1 shows the DSC thermogram of Compound 33, 80% DL amorphous spray dried dispersion [water with DCM / EtOH / HPMCAS-H, starting from THF solvate DS]. [Figure 34A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with THF / HPMCAS-H]. [Figure 34B] FIG. 1 shows the DSC thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with THF / HPMCAS-H]. [Figure 34C] FIG. 1 shows the solid-state 13C NMR spectrum of a spray-dried dispersion of 80% Compound 33 with HPMCAS. [Figure 34D] 1 shows the solid-state 19F NMR spectrum of a spray-dried dispersion of 80% Compound 33 with HPMCAS. [Figure 35A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with THF / PVPVA]. [Figure 35B] FIG. 1 shows the DSC thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with THF / PVPVA]. [Figure 36A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with THF / HPMC E15]. [Figure 36B] FIG. 1 shows the DSC thermogram of Compound 33, 80% DL amorphous spray dried dispersion [water with THF / HPMC E15]. [Figure 37A] FIG. 1 shows the XRPD diffractogram of compound 33, 80% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 37B] FIG. 1 shows the DSC thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 37C] FIG. 1 shows the TGA thermogram of compound 33, 80% DL amorphous spray dried dispersion [water with 2-MeTHF / EtOH / HPMCAS-H]. [Figure 38A] Figure 1 shows the XRPD diffractogram of pure, spray-dried amorphous compound 33 [DCM / EtOH / polymer-free water]. [Figure 38B] Figure 1 shows the DSC thermogram of spray dried pure amorphous compound 33 [DCM / EtOH / polymer free water]. [Figure 38C] 1 shows the solid-state 13C NMR spectrum of pure amorphous compound 33. [Figure 38D] 1 shows the solid-state 19F NMR spectrum of the pure amorphous compound. DETAILED DESCRIPTION OF THE INVENTION

[0015] I. Definition As used herein, the term "AAT" refers to alpha-1 antitrypsin or a variant thereof, including, but not limited to, AAT gene variants such as the Z variant. As used herein, "Z-AAT" refers to an AAT variant having a Z variant.

[0016] As used herein, the term "AATD" means alpha-1 antitrypsin deficiency, which is an inherited disorder characterized by low circulating levels of AAT.

[0017] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist between the constituent atoms of the molecule. Thus, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also contains lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopologues in the compounds of the present disclosure depend on numerous factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amounts of such isotopologues are generally less than 49.9% of the compound as a whole. In other embodiments, the relative amount of such isotopologues is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound as a whole.

[0018] The compounds of the present invention can be optionally substituted with one or more substituents. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to replacing a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0019] The term "isotopologue" refers to a species whose chemical structure differs from a specific compound of the present disclosure only in isotopic composition. Additionally, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon by a C are within the scope of this disclosure.

[0020] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, atropisomers, diastereomeric mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0021] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by shifting of atoms or groups within the molecule.

[0022] "Stereoisomer" refers to both enantiomers and diastereomers.

[0023] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but in which one or more hydrogen atoms have been replaced by deuterium atoms ("D"). It will be recognized that some variation in natural isotopic abundance will occur in the synthesized compound depending on the origin of the chemicals used in synthesis. Regardless of this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise specified, when referring to a "deuterated derivative" of a compound of the present invention, at least one hydrogen is replaced with deuterium at a level far above its natural isotopic abundance (typically about 0.015%). In some embodiments, deuterated derivatives of the invention have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0024] The term "isotopic enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0025] The terms "alkyl" or "aliphatic," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, alkyl groups contain 1-20 alkyl carbon atoms. In some embodiments, alkyl groups contain 1-10 aliphatic carbon atoms. In other embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In still other embodiments, alkyl groups contain 1-6 alkyl carbon atoms, in other embodiments, alkyl groups contain 1-4 alkyl carbon atoms, and in still other embodiments, alkyl groups contain 1-3 alkyl carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (eg, decalin), bridged bicyclic alkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl.

[0026] The terms "cycloalkyl," "carbocycle," "alicyclic," or "cyclic alkyl" refer to a spirocyclic or monocyclic C 3~8 hydrocarbons or spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic C rings that are fully saturated or contain one or more unsaturated units but are not aromatic 8~14 It refers to a hydrocarbon, wherein any individual ring within the bicyclic ring system has from 3 to 7 members.

[0027] The terms "heteroalkyl" or "heteroaliphatic," as used herein, refer to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycles," "heterocyclic," "heteroaliphatic," or "heterocyclic" groups.

[0028] As used herein, the term "alkenyl" refers to a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon containing one or more units of unsaturation, but which is not aromatic (referred to herein as a "cyclic alkenyl").

[0029] As used herein, the terms "heterocycle," "heterocyclic," "heteroaliphatic," or "heterocyclic" refer to a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle," "heterocyclic," "heteroaliphatic," or "heterocyclic" group has 3 to 14 ring members, including 3 to 7 ring members, in which one or more ring members are independently selected heteroatoms from oxygen, sulfur, nitrogen, or phosphorus.

[0030] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N(3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including the case of N-substituted pyrrolidinyl).

[0031] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0032] The terms "alkoxy" or "thioalkyl," as used herein, refer to an alkyl group, as previously defined, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, respectively, provided that the oxygen or sulfur atom is bonded between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon containing at least one alkoxy group, but which is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. "Cyclic thioalkyl" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon containing at least one thioalkyl group, but which is not aromatic.

[0033] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" refers to F, Cl, Br, or I. Examples of haloalkyl include perhaloalkyl, such as -CHF, -CHF, -CF, -CF-, or -CFCF.

[0034] The term "aminoalkyl" means an alkyl group substituted with or containing an amino group. As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0035] The term "alkyl sulfoxide" refers to an alkyl group in which a carbon of the alkyl group is replaced by or substituted with a sulfoxide group. "Cyclic alkyl sulfoxide" refers to a monocyclic or bicyclic hydrocarbon that contains one or more alkyl sulfoxides, but is not aromatic. As used herein, "sulfoxide" refers to a sulfinyl (i.e., -S(O)-) bonded to two carbon atoms.

[0036] The term "alkylsulfinamide" refers to an alkyl group in which a carbon of the alkyl group is replaced or substituted with a sulfinamide group. As used herein, "sulfinamide" refers to -S(O)-, where the sulfur atom is bonded to a carbon that is independently bonded to an amine group.

[0037] The term "alkylsulfonyl" refers to an alkyl group in which a carbon of the alkyl group is replaced or substituted with a sulfonyl group. As used herein, "sulfonyl" refers to -S(O)-, where the sulfur is bonded to a carbon and to a different carbon.

[0038] The term "alkylsulfonamido" refers to an alkyl group in which a carbon of the alkyl group is replaced or substituted with a sulfonamido group. As used herein, "sulfonamido" refers to -S(O)-, where the sulfur is bonded to an amine group and also to a carbon.

[0039] The term "alkylamide" refers to an alkyl group in which a carbon of the alkyl group has been replaced with an amide. As used herein, "amide" refers to a carbonyl (i.e., -C(O)-) bonded to an amine group that is also bonded to a carbon. An optionally substituted amide may be mono- or di-substituted at the amide nitrogen. Alternatively, or in addition, an optionally substituted amide may be substituted at the carbonyl carbon.

[0040] As used herein, an "oxo" group refers to =O.

[0041] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0042] As used herein, a "hydroxy" group refers to an --OH group.

[0043] "Tert" and "t-" refer to grade 3, respectively.

[0044] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system with delocalized pi orbitals consisting of [4n+2]p electrons, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0045] The term "aryl," used alone or as part of a larger moiety, such as "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" also refers to heteroaryl ring systems, as defined herein below. Non-limiting examples of aryl groups include phenyl rings.

[0046] The term "heteroaryl," used alone or as part of a larger moiety, such as "heteroaralkyl," "heteroarylalkoxy," etc., refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members.

[0047] An aryl (including arylalkyl, arylalkoxy, etc.) or heteroaryl (including heteroarylalkyl and heteroarylalkoxy, etc.) group may contain one or more substituents.

[0048] An alkyl group or a non-aromatic heterocycle may contain one or more substituents.

[0049] For example, useful examples of protecting groups for nitrogen-containing groups such as amine groups include t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide.Methods for adding (commonly referred to as "protecting") and removing (commonly referred to as "deprotecting") such amine protecting groups are well known in the art and can be found, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994 (incorporated herein in its entirety by reference), and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999).

[0050] Examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl-tert-butyl butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolelidone (NMP).

[0051] Examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN, TEA), diisopropyl-ethylamine (i-PrEtN, DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe, NaOCH).

[0052] The present disclosure includes pharmaceutically acceptable salts of the compounds of the present invention. A salt of a compound of is formed between an acidic group of the compound and a basic group, such as an amino functional group, or a basic group of the compound and an acidic group, such as a carboxyl functional group.

[0053] As used herein, the term "pharmaceutically acceptable" refers to a component that is suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio within the scope of sound medical judgment. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0054] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as deuterium, hydrochloric, hydrobromic, iodic, sulfuric, and phosphoric acid, and organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, oxalate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6 ... benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, sulfonate, xylenesulfonate, phenylate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methylphonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0055] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4Examples of suitable pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Suitable pharmaceutically acceptable salts include besylate and glucosamine salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0056] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0057] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of compound to which it is administered that produces the desired effect (e.g., amelioration of AATD or AATD symptoms, reduction in the severity of AATD or AATD symptoms, and / or reduction in the onset or incidence of AATD or AATD symptoms). The exact amount of an effective dose will vary depending on the purpose of treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0058] As used herein, the term " treatment " and its cognate terms refer to the improvement of AATD or its symptoms in a subject, the delay in the onset of AATD or its symptoms in a subject, or the reduction in the severity of AATD or its symptoms in a subject.As used herein, " treatment " and its cognate terms include, but are not limited to, the improvement of liver and / or spleen function, the reduction of jaundice, the improvement of lung function, the reduction of lung disease and / or lung exacerbation (e.g., emphysema), the reduction of skin disease (e.g., necrotizing systemic inflammation), the increase in growth in children, the improvement of appetite, and the reduction of fatigue.The improvement or the reduction in the severity of any of these symptoms can be easily evaluated according to the methods and techniques known in the art or subsequently developed methods and techniques.

[0059] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include the specific dose, amount, or weight percent value, or a range of doses, amounts, or weight percents recognized by those skilled in the art to provide an equivalent pharmacological effect to that obtained from the specific dose, amount, or weight percent. In some embodiments, the term "about" reflects a ±10% variation of the stated value. In some embodiments, the term "about" reflects a ±5% variation of the stated value. In some embodiments, the term "about" reflects a ±2% variation of the stated value.

[0060] Any one or more of the compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the above, can be administered once daily, twice daily, or three times daily for the treatment of AATD. In certain embodiments, any one or more of the compounds is selected from compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the above. In some embodiments, at least one compound selected from the compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the above, is administered once daily. In certain embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds, and deuterated derivatives of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, tautomers of those compounds, pharmaceutically acceptable salts of those compounds, and tautomers of any of the foregoing, and deuterated derivatives of any of the foregoing are administered twice daily. In certain embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds, and tautomers of any of the foregoing, and deuterated derivatives of any of the foregoing are administered twice daily. In some embodiments, at least one compound selected from compounds of formula I, IA, IB, IC, ID, IE, IF, IG, and IH and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and tautomers thereof, and deuterated derivatives of any of the foregoing are administered three times daily.In certain embodiments, a compound selected from Compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and tautomers thereof, and deuterated derivatives of any of the foregoing are administered three times daily.

[0061] Any one or more of the compounds of formula I, IA, IB, IC, ID, IE, IF, IG, and IH, and tautomers thereof, pharmaceutically acceptable salts thereof, and deuterated derivatives thereof of any of the above, may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In certain embodiments, any one or more of the compounds is selected from compounds 1-342, tautomers thereof, pharmaceutically acceptable salts thereof, and deuterated derivatives thereof of any of the above.

[0062] As used herein, "AAT augmentation therapy" refers to the use of alpha-1 antitrypsin protein (AAT) from the plasma of healthy human donors to enhance (increase) circulating levels of alpha-1 antitrypsin in the blood. "AAT replacement therapy" refers to the administration of recombinant AAT.

[0063] In some embodiments, 10 mg to 1500 mg, 100 mg to 1800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg, or 400 mg to 600 mg of compounds of Formula I, IA, IB, IC, ID, IE, IF, IG, and IH and tautomers of those compounds, pharmaceutically acceptable salts of those compounds and tautomers thereof, or deuterated derivatives of such compounds, tautomers, or salts is administered once daily, twice daily, or three times daily. In certain embodiments, 10 mg to 1500 mg, 100 mg to 1800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2000 mg, or 400 mg to 600 mg of a compound selected from Compounds 1-342, a tautomer of those compounds, a pharmaceutically acceptable salt of those compounds and a tautomer thereof, or a deuterated derivative of such a compound, tautomer, or salt is administered once daily, twice daily, or three times daily.

[0064] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of the pharmaceutically acceptable salt form of the compound is the amount corresponding to the concentration of the free base of the compound.Please note that the disclosed amounts of compounds, tautomers, pharmaceutically acceptable salts, and deuterated derivatives are based on the free base form of the reference compound.For example, "10 mg of at least one compound selected from the compound of formula (I) and its pharmaceutically acceptable salts" includes the concentration of 10 mg of the compound of formula (I) and the pharmaceutically acceptable salt of the compound of formula (I) that corresponds to 10 mg of the compound of formula (I).

[0065] As used herein, the terms "crystalline form" and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA). Thus, as used herein, the terms "crystalline form [X] of compound ([Y])" and "crystalline form [C] of a [pharmaceutically acceptable] salt of compound ([Y])" refer to unique crystalline forms that can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, SSNMR, differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA). In some embodiments, novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more designated 2θ values ​​(°2θ).

[0066] As used herein, a crystalline form is "substantially pure" if it accounts for 90% or more by weight of the sum of all solid form(s) of that compound in a sample, as determined by art-recognized methods such as quantitative ssNMR and / or XRPD. In some embodiments, a solid form is "substantially pure" if it accounts for 95% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 99% or more by weight of the sum of all solid form(s) in a sample.

[0067] As used herein, a compound is "substantially crystalline" if it accounts for 70% or more by weight of the sum of all solid forms of that compound in a sample, as determined by art-recognized methods such as quantitative ssNMR and / or XRPD. In some embodiments, a solid form is "substantially crystalline" if it accounts for 75% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 80% or more by weight of the sum of all solid form(s) in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 85% or more by weight of the sum of all solid form(s) in a sample.

[0068] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. An amorphous solid is generally a supercooled liquid in which the molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., molecular packing, and no long-range order. For example, an amorphous material is a solid material that does not have sharp characteristic signal(s) in its X-ray power diffractogram (i.e., it is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are seen in the diffractogram. Broad peaks are characteristic of an amorphous solid. For a comparison of the diffractograms of amorphous and crystalline materials, see, for example, US2004 / 0006237. In addition, the diffractograms of amorphous materials are 13 C NMR and 19 The width of signals in F NMR spectra is typically 13 C NMR and 19 Substantially broader than the signals in the F NMR spectrum.

[0069] As used herein, a compound is "substantially amorphous" if it comprises 70% or more by weight of the sum of all solid forms of that compound in a sample, as determined by art-recognized methods such as quantitative ssNMR and / or XRPD. In some embodiments, the substantially amorphous compound comprises 75% or more by weight of the sum of all solid forms of that compound in a sample. In some embodiments, the substantially amorphous compound comprises 80% or more by weight of the sum of all solid forms of that compound in a sample. In some embodiments, the substantially amorphous compound comprises 85% or more by weight of the sum of all solid forms of that compound in a sample. In some embodiments, the substantially amorphous compound comprises 90% or more by weight of the sum of all solid forms of that compound in a sample. In some embodiments, the substantially amorphous compound comprises 95% or more by weight of the sum of all solid forms of that compound in a sample.

[0070] As used herein, "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary greatly (e.g., colloidal particles from nanometer dimensions to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In solid dispersions, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can contain a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, an amorphous solid dispersion includes a polymer that constitutes the dispersed phase, and the drug constitutes the continuous phase. In some embodiments, the dispersion includes amorphous or substantially amorphous compound 33.

[0071] The term "solid amorphous dispersion" generally refers to a solid dispersion containing two or more components, usually a drug and a polymer, but optionally other components such as surfactants or other pharmaceutical excipients, wherein Compound 33 is amorphous or substantially amorphous (e.g., substantially free of crystalline Compound 33), and the physical stability and / or solubility and / or dissolution of the amorphous drug are enhanced by the other components.

[0072] As used herein, the term "solvate" refers to a crystalline form that contains one or more molecules of a compound of the present disclosure and that contains one or more molecules of a stoichiometric or non-stoichiometric amount of solvent(s) incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate." The term "solvate / hydrate" refers to a crystalline form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a non-aqueous solvent incorporated into a crystal lattice and 0-50% water in stoichiometric or non-stoichiometric amounts such as 0-5%, 0-10%, 5-10%, 0-20%, 10-20%, 10-15%, 15-20%, 5-20%, 0-25%, 20-25%, 10-25%, 15-25%, 5-25%, 0-30%, 5-30%, 10-30%, 15-30%, 25-30%, 30-45%, 35-40%, 40-50%, and 45-50%.

[0073] As used herein, the term "XRPD" refers to an X-ray power diffraction XRPD pattern, which may be recorded in transmission or reflection geometry using a diffractometer at ambient conditions.

[0074] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer interchangeably to an experimentally obtained pattern plotting signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffractogram may include one or more broad signals; for crystalline materials, an X-ray powder diffractogram may include one or more signals, each identified by its angular value, measured in degrees 2θ (°2θ), shown on the abscissa of the X-ray powder diffractogram, and may be expressed as "a signal at ⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅⋅ degrees 2θ (°2θ)," "a signal at [one (a)] 2θ value(s) of ⋅⋅⋅⋅," and / or "a signal at at least 2θ value(s) selected from ⋅⋅⋅."

[0075] As used herein, the term "X-ray powder diffractogram having signals at 2θ values" refers to an XRPD pattern containing the positions of X-ray reflections (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0076] As used herein, an X-ray powder diffractogram is "substantially similar to that in a [particular] diffractogram" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining "substantially similar," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal position in an XRPD diffractogram. Thus, one skilled in the art will understand that signal maxima (referred to herein as degrees 2θ (°2θ)) in an XRPD diffractogram generally mean values ​​reported at ±0.2°2θ (an art-recognized variance) of the reported value.

[0077] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0078] As used herein, a "signal" or "peak" refers to a point in an XRPD pattern where there is a local intensity, measured in counts. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be clearly visible to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods are capable of and suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0079] As used herein, "signal at 2θ", "signal at [a]2θ value[] of 2θ", and / or "signal at at least 2θ value(s) selected from 2θ" refer to the X-ray reflection positions (° 2θ) measured and observed in an X-ray powder diffraction experiment.

[0080] The reproducibility of the angle values ​​is within ±0.2° 2θ, i.e., the angle value can be the recited angle value +0.2° 2θ, the angle value −0.2° 2θ, or any value between those two endpoints (angle value +0.2° 2θ and angle value −0.2° 2θ).

[0081] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect relative signal or peak intensity include sample thickness and preferred orientation (e.g., crystalline grains are not randomly distributed).

[0082] As used herein, the term "SSNMR" refers to the analytical characterization method of solid-state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient conditions on any magnetically active isotope present in the sample. Typical examples of active isotopes for small molecule active pharmaceutical ingredients include: 1 H, 2 H, 13 C. 19 F, 31 P, 15 N, 14 N, 35Cl, 11 B. 7 Li, 17 O. 23 Na, 79 Br, and 195 Examples include Pt.

[0083] As used herein, an SSNMR spectrum is "substantially similar to that in a [particular] figure" if at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining "substantially similar," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal position in an SSNMR spectrum. Thus, one skilled in the art will understand that signal maxima in an SSNMR spectrum (ppm) generally refer to values ​​reported ±0.2 ppm (a variance recognized in the art) of the reported value.

[0084] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0085] As used herein, the term "TGA" refers to the analytical method of thermogravimetry (or thermogravimetry) analysis.

[0086] II. Compounds and Compositions In some embodiments, the compound of the invention is a compound of Formula I, [ka] During the ceremony, (i)R 0 is selected from the following: (a) C1-C8 straight-chain, branched-chain, and cyclic groups, wherein the C1-C8 straight-chain, branched-chain, and cyclic groups are independently selected from alkyl and alkoxy groups, and the C1-C8 straight-chain, branched-chain, and cyclic groups are each independently selected from 1 to 4 R A C1-C8 straight chain, branched chain, and cyclic groups optionally substituted with (b) 1 to 4 RA a 5- to 14-membered aromatic ring optionally substituted with Each R A are independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5-10 membered aromatic rings, and C1-C6 straight chain, branched chain, and cyclic groups; R A wherein the amide nitrogen atom in the amide is optionally substituted with a heterocyclyl group optionally further substituted with oxo; C1-C6 straight chain, branched chain, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido; The 5-10 membered aromatic rings and C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1-4 substituents selected from halogen, C1-C6 straight chain, branched chain, and cyclic groups, and methoxy; R A The group is R 2 R on the group B 1 to 4 R optionally bonded to the group A a 5- to 14-membered aromatic ring optionally substituted with (ii)R 1 is selected from the following: (a) hydrogen, (b) C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, cyanoalkyl, Hydroxy, alkylsulfonyl, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (c) halogen, Cyano, cyanoalkyl, sulfone, sulfonamides, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogen or alkoxy groups; (d) [ka] Group(R C is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (e) [ka] Group (each R D But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: or two R's D The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic groups; (f) [ka] Group(R E but, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1 to C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (dd) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups; And R F but, (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (g) [ka] group (i is an integer ranging from 0 to 3, R G and R G’ Each of the following may independently: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R G and R G’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (h) [ka] (R H each of which is independently selected from: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (i) C1-C6 alkylamide, (iii)R 2 is selected from 5- and 6-membered heterocycles (optionally substituted with oxo and / or C1-C6 straight and branched chain alkyl groups), and 5-6-membered aromatic rings containing 0-4 heteroatoms selected from O, N, and S, and the 5-membered aromatic rings are selected from 1-4 R B and the 6-membered aromatic ring is optionally substituted with 1 to 5 R B optionally substituted with R B groups are independently selected from: (a) amides optionally substituted with 1 to 3 groups selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (optionally substituted with oxo, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, hydroxyalkyl, amido, alkylsulfonyl, and acetamido), or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or C1-C6 straight-chain, branched-chain, and cyclic alkyl groups); (b) imidazolidine-2,4-dione, (c) heterocyclyl optionally substituted with one or more groups independently selected from oxo, acyl, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally further substituted with 1 to 3 groups independently selected from oxo, hydroxy, and acyl); (d) phosphorous acid optionally esterified with a C1-C6 straight-chain, branched-chain, or cyclic alkyl group; (e) di(C1-C6) alkylphosphine oxide, (f) (C1-C6) alkylphosphinic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (g) halogens, (h) cyano, (i) hydroxy, (j) uronic acids or carboxylic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (k) oxo, (l)-B(OR I ) 2 units (each R I are independently selected from hydrogen and C1-C6 straight chain, branched, and cyclic alkyl groups, or two OR I The groups may form a 4-8 membered ring together with the boron atom to which they are attached, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (m) 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, optionally substituted with 1 or 2 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, Hydroxy, carboxylic acids, pyrrolidin-2-one, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (n) sulfonic acids, (o) [ka] Group(R J is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and C1-C8 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from amide; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups), (p) [ka] Group (each R K But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; or two R's K The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (q) [ka] Group(R L and R L’ Each of the following may independently: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R L and R L’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (r) halogen, Hydroxy, carboxylic acids, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and C1-C6 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from: (s) halogen, Hydroxy, carboxylic acids, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (t) [ka] Group(R M is selected from the following: (aa) hydrogen, (bb) carboxylic acids, (cc) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (dd) halogen, Cyano, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (ee) 1 to 4 R A a 5- to 10-membered aromatic ring optionally substituted with (ff) halogens, (gg) hydroxy), (u)OR N(R N is selected from the following: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (v) [ka] (Each R O are independently selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups, and the alkyl groups are independently alkylsulfonyl, alkylamides, halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic alkoxy groups; or two R's O The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (w) [ka] (Y1 is oxygen, NR P , and [ka] Selected from R P is selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups, and the alkyl group is halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; two adjacent hydrogens on a 5- or 6-membered aromatic ring are replaced by bonds to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S, and one to six R B Bicyclic R optionally substituted with a group 2 (capable of forming a group), (iv) X 1 and X 2 are independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v)W 1 and W 2 are each independently selected from C and N; (vi) each [ka] represents a single or double bond, with the proviso that [ka] is a double bond, (vii) Each R 3 are independently selected from hydrogen, halogen, cyano, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, wherein the C1-C6 straight-chain, branched-chain, and cyclic alkyl groups and the C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogen, hydroxyl groups, and carboxylic acids; (viii) n is an integer selected from 0, 1, 2, and 3; (ix)Z 1 , Z 2 , and / or Z 3 are independently selected from carbon, boron, nitrogen, sulfur, and oxygen; Z 1 , Z2 , and / or Z 3 is carbon or nitrogen, the valence electrons of the carbon or nitrogen are completed with a hydrogen atom, a halogen, a C1-C6 straight-chain, branched, and cyclic alkyl group, and a C1-C6 straight-chain, branched, and cyclic alkoxy group, and the C1-C6 straight-chain, branched, and cyclic alkyl group and the C1-C6 straight-chain, branched, and cyclic alkoxy group are optionally substituted with 1 to 4 substituents independently selected from a halogen, a hydroxy group, and a carboxylic acid; and Z 1 , Z 2 , or Z 3 is boron, the valence electrons of the boron are completed with a hydrogen atom or a hydroxy group.

[0087] In some embodiments, R 0 is selected from heteroaryl rings.

[0088] In some embodiments, R 0 is phenyl.

[0089] In some embodiments, R 0 is non-substituted.

[0090] In some embodiments, R 0 is substituted with 1 to 2 substituents.

[0091] In some embodiments, R 0 is independently substituted with 1 to 2 substituents selected from halogen, cyano, a C1 to C4 alkyl group, and a C1 to C4 alkoxy group.

[0092] In some embodiments, R 0 is independently substituted with 1 to 2 substituents selected from fluorine, chlorine, methyl, and methoxy.

[0093] In some embodiments, R 1 is selected from C1 to C6 straight and branched chain alkyl groups, and C3 to C6 cyclic alkyl groups.

[0094] In some embodiments, R 1 is selected from a C3 branched chain alkyl group and a C6 cyclic alkyl group.

[0095] In some embodiments, R 1 is selected from C4 to C6 cyclic alkyl groups in which one carbon atom is replaced by a heteroatom.

[0096] In some embodiments, R 1 is selected from C6 cyclic alkyl groups in which one carbon atom is replaced by a heteroatom.

[0097] In some embodiments, R 1 is selected from C1-C4 straight and branched chain alkyl groups, and C4-C6 cyclic alkyl groups, where the alkyl groups are substituted with methyl, ethyl, methoxy, isopropoxy, cyano, cyanoalkyl, alkylsulfonyl, and / or hydroxy substituents.

[0098] In some embodiments, R 1 teeth, [ka] R is selected from the group C is selected from C1 to C6 straight chain, branched chain, and cyclic alkyl groups.

[0099] In some embodiments, R 1 teeth, [ka] R is selected from the group C is selected from C1 to C6 straight chain, branched chain, and cyclic alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0100] In some embodiments, R 1 teeth, [ka] R is selected from the group C is selected from C1 to C6 linear alkyl groups.

[0101] In some embodiments, R 1 teeth, [ka] R is selected from the group C is selected from C1 to C6 straight chain alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0102] In some embodiments, R 1 teeth, [ka] and each R D are independently selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups.

[0103] In some embodiments, R 1 teeth, [ka] and each R D are independently selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups, substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0104] In some embodiments, R 1 teeth, [ka] and each R D are independently selected from hydrogen and C1 to C8 straight chain alkyl groups.

[0105] In some embodiments, R 1 teeth, [ka] R is selected from the group E is selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups.

[0106] In some embodiments, R 1 teeth, [ka] R is selected from the group E is selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0107] In some embodiments, R 1 teeth, [ka] R is selected from the group E is selected from hydrogen and C1 to C8 straight chain alkyl groups.

[0108] In some embodiments, R 1 teeth, [ka] R is selected from the group F is selected from hydroxy, and C1-C8 straight chain, branched chain, and cyclic alkyl groups.

[0109] In some embodiments, R 1 teeth, [ka] R is selected from the group Fis selected from hydroxy, and C1 to C8 straight chain, branched chain, and cyclic alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0110] In some embodiments, R 1 teeth, [ka] R is selected from the group F is selected from hydroxy and C1 to C8 straight chain alkyl groups.

[0111] In some embodiments, R 1 teeth, [ka] R is selected from the group G and R G’ are each independently selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups.

[0112] In some embodiments, R 1 teeth, [ka] R is selected from the group G and R G’ are each independently selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0113] In some embodiments, R 1 teeth, [ka] Each R H are independently selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups.

[0114] In some embodiments, R1 teeth, [ka] Each R H are independently selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups substituted with one or two substituents independently selected from C1 to C6 straight chain alkyl groups.

[0115] In some embodiments, R 1 teeth, [ka] Each R H are independently selected from C1 to C8 straight chain alkyl groups.

[0116] In some embodiments, R 1 is hydrogen, methyl, trimethylsilyl, trifluoromethyl, [ka] [ka] is selected from.

[0117] In some embodiments, R 2 is selected from a 5-membered aromatic ring containing 0-4 heteroatoms selected from O, N, and S, and the ring is B In some embodiments, R 2 is selected from a 6-membered aromatic ring containing 0-4 heteroatoms selected from O, N, and S, and the ring is B The group is optionally substituted.

[0118] In some embodiments, R 2 is selected from a 5-membered aromatic ring containing one or two nitrogen heteroatoms, and the ring is B In some embodiments, R2 is selected from a 6-membered aromatic ring containing one or two nitrogen heteroatoms, and the ring is B The group is optionally substituted.

[0119] In some embodiments, R B The groups are independently selected from halogen, cyano, hydroxy, carboxylic acid, C1-C6 straight chain, branched chain, and cyclic alkyl groups, and C1-C6 straight chain, branched chain, and cyclic alkoxy groups.

[0120] In some embodiments, R B The groups are independently selected from halogen, hydroxy, carboxylic acid, C1-C6 straight chain alkyl groups, and C1-C6 straight chain alkoxy groups.

[0121] In some embodiments, R B The groups are independently selected from fluorine, chlorine, methyl, methoxy, hydroxy, and carboxylic acid.

[0122] In some embodiments, Z 1 , Z 2 , and Z 3 is independently selected from carbon, nitrogen, sulfur, and oxygen.

[0123] In some embodiments, Z 1 , Z 2 , and / or Z 3 is carbon or nitrogen, the valence electrons of the carbon and nitrogen are completed with the hydrogen atom.

[0124] In some embodiments, Z 1 , Z 2 , or Z 3 is boron, and the valence electrons of the boron are completed with a hydrogen atom or a hydroxyl group.

[0125] In some embodiments, Z 1 , Z 2 , and Z 3At least one of Z is nitrogen. 1 , Z 2 , and Z 3 Two of the are nitrogen and one is selected from carbon and nitrogen.

[0126] In some embodiments, each R 3 are independently selected from hydrogen, C1-C6 straight chain alkyl groups, and heterocyclyl groups.

[0127] In some embodiments, X 1 and X 2 is independently selected from hydrogen and halogen.

[0128] In some embodiments, X 1 and X 2 are each hydrogen.

[0129] In some embodiments, the compound of the invention is a compound of any one of formulas IA, IB, IC, ID, IE, IF, IG, and IH: [ka] [ka] a tautomer thereof, a pharmaceutically acceptable salt of such a compound or tautomer, or a deuterated derivative of any of the above, wherein: R 0 , R 1 , R 2 , R 3 and n is defined for compounds of formula (I), X 1 and X 2 are independently selected from hydrogen and fluorine, or X 1 is fluorine, and X 2 is hydrogen or X 2 is fluorine, and X 1 is hydrogen or X1 and X 2 are each hydrogen, W 1 and W 2 are each independently selected from C and N; Y 1 , Y 2 , Y 3 , and Y 4 But independently, hydrogen, Cyano, halogen groups, C1-C6 straight chain, branched chain, and cyclic alkyl groups, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, Hydroxy, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; Y 5 , Y 6 , Y 7 , and Y 8 But independently, hydrogen, Halogen groups Hydroxy, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 independently selected halogen substituents, and C1-C6 straight chain, branched chain, and cyclic alkoxy groups; Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , and Y 16 But independently, carboxylic acids, hydrogen, halogen groups, C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 independently selected halogen substituents, and C1-C6 straight chain, branched chain, and cyclic alkoxy groups; Y 17 , Y 18 , Y 19 , Y 20 , and Y 21 But independently, hydrogen, carboxylic acids, halogen groups, Cyano, Hydroxy, C1-C6 straight chain, branched chain, and cyclic alkyl groups, halogen, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from: carboxylic acids; C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with carboxylic acid groups; dihydroxyboryl, sulfonic acids, a carboxylic acid optionally esterified with a uronic acid; a tetrazolyl group; an aminosulfonyl group, an aminosulfonyl group optionally substituted with one or two substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups; C1-C6 straight chain, branched chain, and cyclic alkylsulfonyl groups; However, in formulas I to E, Y 17 , Y 18 , Y 19 , Y 20 , and Y 21 is a compound of any one of formulas IA, IB, IC, ID, IE, IF, IG, and IH, a tautomer thereof, a pharmaceutically acceptable salt of such a compound or tautomer, or a deuterated derivative of any of the foregoing, provided that at least one of

[0130] In some embodiments, in the compound of any one of formulas IA, IB, IC, ID, IE, IF, IG, and IH, Y 17 , Y 18 , Y 19 , Y 20 , and Y 21 one or more of the following may be methyl, methoxy, cyano, fluorine, hydroxy, -CF3, -B(OH)2, -SO2NHMe, -SO2Me, -SO2H, -CH2CO2H-, [ka] is selected from.

[0131] In some embodiments, the compound of the invention is a compound of formula I': [ka] During the ceremony, (i)R 0 ' is selected from the following: (a) C1-C8 straight-chain, branched-chain, and cyclic groups, wherein the C1-C8 straight-chain, branched-chain, and cyclic groups are independently selected from alkyl and alkoxy groups, and the C1-C8 straight-chain, branched-chain, and cyclic groups are each independently selected from 1 to 4 R A C1-C8 straight chain, branched chain, and cyclic groups optionally substituted with '; and (b) 1 to 4 R A ' is a 5- to 14-membered aromatic ring optionally substituted with Each R Aare independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamido, sulfinamido, amino, amido, 5-10 membered aromatic rings, and C1-C6 straight chain, branched, and cyclic groups, wherein the C1-C6 straight chain, branched, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido, wherein the 5-10 membered aromatic rings and the C1-C6 straight chain, branched, and cyclic groups are optionally substituted with 1 to 4 substituents selected from halogen and methoxy; R A ' group is R 2 'R on the group B 1 to 4 R optionally bonded to the ' group A ', a 5- to 14-membered aromatic ring optionally substituted with (ii)R 1 ' is selected from the following: (a) hydrogen, (b) C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and Optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight chain, branched chain, and cyclic groups, wherein the C1 to C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkoxy groups, and the C1 to C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (c) halogen, Cyano, sulfone, sulfonamides, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (d) [ka] Group(R C ' is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (e) [ka] Group (each R D’ But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: or two R's D’ The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from: halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic groups; (f) [ka] Group(RE’ is selected from the following: (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) 1 to 4 R A’ a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups), And R F’ is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (g) [ka] group (i' is an integer ranging from 0 to 3, R G’’ and R G’’’ Each of the following may independently: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R G’’ and R G’’’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from (h) [ka] (R H’ each of which is independently selected from: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (iii)R 2 ' is selected from 5- and 6-membered aromatic rings containing 0-4 heteroatoms selected from O, N, and S, and the 5-membered ring is selected from 1-4 R B ' groups, and the six-membered ring is B optionally substituted with ' groups, R B 'The group is independent, (a) optionally substituted amides; (b) imidazolidine-2,4-dione, (c) optionally substituted heterocyclyl, (d) phosphorous acid optionally esterified with a C1-C6 straight-chain, branched-chain, or cyclic alkyl group; (e) di(C1-C6) alkylphosphine oxide, (f) (C1-C6) alkylphosphinic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (g) halogens, (h) cyano, (i) hydroxy, (j) uronic acids or carboxylic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; (k) oxo, (l)-B(OR I’ ) 2 units (each R I’ are independently selected from hydrogen and C1-C6 straight chain, branched, and cyclic alkyl groups, or two OR I’The groups may form a 4-8 membered ring together with the boron atom to which they are attached, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (m) 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, optionally substituted with 1 or 2 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, Hydroxy, carboxylic acids, pyrrolidin-2-one, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (n) sulfonic acids, (o) [ka] Group(R J’ is selected from the following: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (dd) 1 to 4 R A’ a 5- to 10-membered aromatic ring optionally substituted with (ee) C1-C8 straight-chain, branched-chain, and cyclic aminoalkyl groups), (p) [ka] Group (each R K’ But independently, (aa) hydrogen, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1-4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1-4 substituents independently selected from: or two R's K’ The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (q) [ka] Group(R L’’ and R L’’’ Each of the following may independently: (aa) hydroxy, (bb) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (cc) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (dd) amino group, (ee) C1-C8 straight chain, branched chain, and cyclic aminoalkyl groups; or R L’’ and R L’’’ may, together with the phosphorus atom to which they are attached, form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; (r) halogen, Hydroxy, Carboxylic acids, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (s) halogen, Hydroxy, carboxylic acids, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (t) [ka] Group(R M’ is selected from the following: (aa) hydrogen, (bb) carboxylic acids, (cc) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (dd) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (ee) 1 to 4 R A’ a 5- to 10-membered aromatic ring optionally substituted with (u)OR N’ (R N’ is selected from the following: (aa) C1 to C8 straight chain, branched chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (bb) halogen, Cyano, Hydroxy, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogens; C1-C8 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from: (v) [ka] (Each R O’ are independently selected from hydrogen and C1 to C8 straight chain, branched chain, and cyclic alkyl groups, and the alkyl group is alkylsulfonyl, alkylamides, halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; [ka] Selected from or or two R's O’ The groups may be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered ring, optionally containing one or two heteroatoms in addition to the nitrogen to which they are attached, and the ring is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; and (w) [ka] (Y1' is oxygen, NR P’ , and [ka] Selected from R P’ is selected from C1 to C8 straight chain, branched chain, and cyclic alkyl groups, and the alkyl group is halogen, Cyano, Hydroxy, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and optionally substituted with 1 to 4 substituents independently selected from C1 to C6 straight-chain, branched-chain, and cyclic alkoxy groups; two adjacent hydrogens on a 5- or 6-membered aromatic ring are replaced by bonds to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S, and one to six R B’ Bicyclic R optionally substituted with a group 2’ (capable of forming a group), (iv) X 1 ' and X 2 are independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v)Each [ka] represents a single or double bond, provided that one [ka] is the only double bond, (vi) Each R 3’ are independently selected from hydrogen, halogen, cyano, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, wherein the straight-chain, branched-chain, and cyclic alkyl and alkoxy groups are optionally substituted with 1 to 4 independently selected halogens; (vii)n ’is an integer selected from 0, 1, 2, and 3; (viii)Z 1 ', Z 2 ', and Z 3 are independently selected from carbon, nitrogen, sulfur, and oxygen; Z 1 ', Z 2 ', and / or Z 3 If ' is carbon or nitrogen, the valence electrons of carbon and nitrogen are completed with the hydrogen atom, and Z 1 ', Z 2 ', and Z 3 When ' is boron, the valence electrons of the boron are completed with a hydrogen atom or a hydroxy group.

[0132] In some embodiments, the compound of the present invention is selected from compounds 1-342 shown in Table 1. The wavy lines (i.e., [ka] ) indicates a bond between two atoms and indicates the location of mixed stereochemistry for a collection of molecules such as a racemic mixture, cis / trans isomers, or (E) / (Z) isomers. An asterisk (e.g., [ka] ) indicates a stereogenic center of a single unassigned stereoisomer in a molecule. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

[0133] Some embodiments of the present invention include derivatives of compounds 1-342 or compounds of formulas IA, IB, IC, ID, IE, IF, IG, and IH. In some embodiments, the derivatives are silicon derivatives, in which at least one carbon atom in compounds 1-342 or compounds selected from compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH is replaced by silicon. In some embodiments, the derivatives are boron derivatives, in which at least one carbon atom in compounds 1-342 or compounds selected from compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH is replaced by boron. In other embodiments, the derivatives are phosphate derivatives, in which at least one carbon atom in compounds 1-342 or compounds selected from compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, and IH is replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, the replacement of carbon with silicon, boron, or phosphorus can result in compounds with similar biological activity as the original carbon-containing compound.

[0134] In some embodiments, the derivative is a silicon derivative, in which one carbon atom in Compounds 1-342 or a compound selected from the compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH is replaced by silicon. In other embodiments, two carbon atoms are replaced by silicon. The carbon replaced by silicon can be a non-aromatic carbon. In some embodiments, a quaternary carbon atom in a tert-butyl moiety can be replaced by silicon. In certain embodiments, the silicon derivative of the present invention can contain one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogen atoms in a tert-butyl moiety where a carbon is replaced by silicon can be replaced by deuterium. In other embodiments, the silicon derivative of Compounds 1-342 or a compound selected from the compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH can have silicon incorporated into a heterocycle.

[0135] Solid forms of compound 33 In some embodiments, Compound 33 is an amorphous solid. In some embodiments, Compound 33 is a crystalline solid. In some embodiments, Compound 33 is in the form of Compound 33 Form A. In some embodiments, Compound 33 is in the form of Compound 33 Form B. In some embodiments, Compound 33 is in the form of Compound 33 dichloromethane (DCM) solvate Form A. In some embodiments, Compound 33 is in the form of Compound 33 hydrate Form A. In some embodiments, Compound 33 is in the form of Compound 33 methanol (MeOH) / HO solvate Form A. In some embodiments, Compound 33 is in the form of Compound 33 Form C. In some embodiments, Compound 33 is in the form of Compound 33 Form D. In some embodiments, Compound 33 is in the form of Compound 33 Form E. In some embodiments, Compound 33 is in the form of Compound 33 Form F. In some embodiments, Compound 33 is in the form of Compound 33 Form G. In some embodiments, Compound 33 is in the form of Compound 33 Form H. In some embodiments, Compound 33 is in the form of Compound 33 Form I. In some embodiments, Compound 33 is in the form of tetrahydrofuran (THF) solvate Form A of Compound 33. In some embodiments, Compound 33 is in the form of Compound 33 Form J. In some embodiments, Compound 33 is in the form of Compound 33 Form K. In some embodiments, Compound 33 is in the form of Compound 33 Form L. In some embodiments, Compound 33 is in the form of Compound 33 2-methyltetrahydrofuran (Me-THF) solvate Form A. In some embodiments, Compound 33 is in the form of Compound 33 Form M. In some embodiments, Compound 33 is in the form of Compound 33 Form N. In some embodiments, Compound 33 is in the form of Compound 33 Form O. In some embodiments, Compound 33 is in the form of the potassium salt Form A of Compound 33. In some embodiments, Compound 33 is in the form of the potassium salt Form B of Compound 33.In some embodiments, Compound 33 is in the form of the potassium salt Form C of Compound 33. In some embodiments, Compound 33 is a mixture of two or more of any of the foregoing.

[0136] 1. Form A of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form A. In some embodiments, the crystalline solid comprises 30% to 99% Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form A of Compound 33 based on the total weight of the solid Compound 33.

[0137] Thus, in some embodiments, Form A of Compound 33 is substantially crystalline. In some embodiments, Form A of Compound 33 is substantially pure crystalline. In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 1A provides the X-ray powder diffractogram of Form A of Compound 33 at room temperature.

[0138] In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 15.5±0.2°2θ, 17.5±0.2°2θ, 19.2±0.2°2θ, and 19.5±0.2°2θ. In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 15.5±0.2°2θ, 17.5±0.2°2θ, 19.2±0.2°2θ, and 19.5±0.2°2θ. In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffraction pattern having (a) signals at 19.2±0.2°2θ, 19.5±0.2°2θ, 15.5±0.2°2θ, and 17.5±0.2°2θ, and (b) at least one, at least two, at least three, at least four, or at least five signals selected from 11.0±0.2°2θ, 14.2±0.2°2θ, 16.0±0.2°2θ, 16.2±0.2°2θ, 20.9±0.2°2θ, 21.3±0.2°2θ, 21.8±0.2°2θ, and 25.5±0.2°2θ. In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 11.0±0.2°2θ, 14.2±0.2°2θ, 15.5±0.2°2θ, 16.0±0.2°2θ, 16.2±0.2°2θ, 17.5±0.2°2θ, 19.2±0.2°2θ, 19.5±0.2°2θ, 20.9±0.2°2θ, 21.3±0.2°2θ, 21.8±0.2°2θ, and 25.5±0.2°2θ.

[0139] In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1A.

[0140] In some embodiments, Form A of Compound 33 has at least one peak selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, the sodium salt hydrate Form A of Compound I is characterized by having a C ssNMR spectrum having at least two peaks selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least three peaks selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least four peaks selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least five peaks selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least six, at least seven, or at least eight peaks selected from 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum with peaks at 173.5±0.2 ppm, 142.9±0.2 ppm, 136.5±0.2 ppm, 131.8±0.2 ppm, 127.9±0.2 ppm, 112.8±0.2 ppm, 95.0±0.2 ppm, 67.4±0.2 ppm, and 30.8±0.2 ppm. 13 In some embodiments, Form A of Compound 33 is characterized by having a C ssNMR spectrum substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0141] In some embodiments, Form A of Compound 33 has a peak at -109.3±0.2 ppm 19 In some embodiments, Form A of Compound 33 is characterized by having a F ssNMR spectrum substantially similar to that shown in FIG. 19 Characterized by F ssNMR spectrum.

[0142] Another aspect of the present invention provides compositions comprising Form A of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form A of Compound 33. In some embodiments, the compositions consist essentially of Form A of Compound 33.

[0143] Another aspect of the present invention provides a method of making Form A of Compound 33. In some embodiments, Form A of Compound 33 is (a) contacting methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate with a first organic solvent and a first base to form a first reaction mixture; (b) adding water and a first acid to the first reaction mixture; (c) isolating the organic portion from step (b), adding an alcohol, optionally adding water to the organic portion, and concentrating the mixture by distillation; (d) isolating the compound 4-[5-(4-fluorophenyl)-6-tetrahydropyran-4-yl-1H-pyrrolo[2,3-f]indazol-7-yl]benzoic acid from the mixture from step (c) and drying the material to remove all water content.

[0144] 2. Form B of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form B. In some embodiments, the crystalline solid comprises 30% to 99% Form B of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form B of Compound 33, based on the total weight of the solid Compound 33.

[0145] Thus, in some embodiments, Form B of Compound 33 is substantially crystalline. In some embodiments, Form B of Compound 33 is substantially pure crystalline. In some embodiments, Form B of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 2A provides the X-ray powder diffractogram of Form B of Compound 33 at room temperature.

[0146] In some embodiments, Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 20.2±0.2°2θ, 9.2±0.2°2θ, 4.5±0.2°2θ, and 15.1±0.2°2θ. In some embodiments, Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at 20.2±0.2°2θ, 9.2±0.2°2θ, 4.5±0.2°2θ, and 15.1±0.2°2θ. In some embodiments, Form B of Compound 33 exhibits (a) signals at 20.2±0.2°2θ, 9.2±0.2°2θ, 4.5±0.2°2θ, and 15.1±0.2°2θ, and (b) signals at 9.9±0.2°2θ, 11.0±0.2°2θ, 12.7±0.2°2θ, 14.3±0.2°2θ, 16.2±0.2°2θ, 16.8±0.2°2θ, 17.1±0.2°2θ, 18.1±0.2°2θ, 18.4±0.2°2θ, 19.8±0.2°2θ, and an X-ray powder diffraction pattern having at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least ten signals selected from 20.6±0.2°2θ, 21.4±0.2°2θ, 22.3±0.2°2θ, 23.6±0.2°2θ, 24.7±0.2°2θ, 26.6±0.2°2θ, 27.4±0.2°2θ, and 28.9±0.2°2θ.

[0147] In some embodiments, Form B of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 2A.

[0148] In some embodiments, Form B of Compound 33 has at least one peak selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13In some embodiments, the sodium salt hydrate Form B of Compound I is characterized by having a C ssNMR spectrum having at least two peaks selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13 In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum with at least three peaks selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13 In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum with at least four peaks selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13 In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum with at least five peaks selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13 In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum with at least six or at least seven peaks selected from 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum with peaks at 167.9±0.2 ppm, 143.9±0.2 ppm, 133.1±0.2 ppm, 130.1±0.2 ppm, 120.4±0.2 ppm, 100.9±0.2 ppm, 34.1±0.2 ppm, and 31.9±0.2 ppm. 13 In some embodiments, Form B of Compound 33 is characterized by having a C ssNMR spectrum substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0149] In some embodiments, Form B of Compound 33 has peaks at one or more of -110.2±0.2 ppm, 111.6±0.2 ppm, and -115.6±0.2 ppm. 19 In some embodiments, Form B of Compound 33 is characterized by having a F ssNMR spectrum with peaks at -110.2±0.2 ppm, 111.6±0.2 ppm, and -115.6±0.2 ppm. 19 In some embodiments, Form B of Compound 33 is characterized by having a F ssNMR spectrum substantially similar to that shown in FIG. 19 Characterized by F ssNMR spectrum.

[0150] Another aspect of the present invention provides compositions comprising Form B of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form B of Compound 33. In some embodiments, the compositions consist essentially of Form B of Compound 33.

[0151] Another aspect of the present invention provides a method of making Form B of Compound 33. In some embodiments, Form B of Compound 33 is prepared by suspending Form A of Compound 33 in DCM, stirring, and isolating the air-dried solid.

[0152] 3. DCM solvate form A of compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline DCM solvate Form A. In some embodiments, the crystalline solid comprises 30% to 99% DCM solvate Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% DCM solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% DCM solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% DCM solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% DCM solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% DCM solvate form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% DCM solvate form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% DCM solvate form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% DCM solvate form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% DCM solvate form A of Compound 33, based on the total weight of the solid Compound 33.

[0153] Thus, in some embodiments, DCM solvate Form A of Compound 33 is substantially crystalline. In some embodiments, DCM solvate Form A of Compound 33 is substantially pure crystalline. In some embodiments, Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 3A provides the X-ray powder diffractogram of DCM solvate Form A of Compound 33 at room temperature.

[0154] In some embodiments, DCM solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 20.9±0.2°2θ, 18.3±0.2°2θ, and 14.4±0.2°2θ. In some embodiments, DCM solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 20.9±0.2°2θ, 18.3±0.2°2θ, and 14.4±0.2°2θ. In some embodiments, the DCM solvate Form A of Compound 33 exhibits (a) signals at 20.9±0.2°2θ, 18.3±0.2°2θ, and 14.4±0.2°2θ, and (b) signals at 7.1±0.2°2θ, 8.8±0.2°2θ, 9.0±0.2°2θ, 10.1±0.2°2θ, 13.3±0.2°2θ, 13.9±0.2°2θ, 17.2±0.2°2θ, 20.3±0.2°2θ, 21.7±0.2°2θ 2θ, 22.6±0.2°2θ, 22.8±0.2°2θ, 23.4±0.2°2θ, 24.0±0.2°2θ, 26.6±0.2°2θ, 27.1±0.2°2θ, 28.3±0.2°2θ, or 29.3±0.2°2θ.

[0155] In some embodiments, DCM solvate Form A of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 3A.

[0156] Another aspect of the present invention provides a composition comprising DCM solvate Form A of Compound 33. In some embodiments, the composition of the present invention comprises substantially pure crystalline DCM solvate Form A of Compound 33. In some embodiments, the composition consists essentially of DCM solvate Form A of Compound 33.

[0157] Another aspect of the present invention provides a method of making DCM solvate Form A of Compound 33. In some embodiments, DCM solvate Form A of Compound 33 is prepared by suspending and stirring Form A of Compound 33 in a mixture of DCM, EtOH, and THF (about 54:36:10 by volume), and then isolating the solid.

[0158] 4. Hydrate Form A of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline hydrate form A. In some embodiments, the crystalline solid comprises 30% to 99% hydrate form A of crystalline Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% hydrate form A of Compound 33 based on the total weight of the solid Compound 33.

[0159] Thus, in some embodiments, hydrate Form A of Compound 33 is substantially crystalline. In some embodiments, hydrate Form A of Compound 33 is substantially pure crystalline. In some embodiments, hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 4A provides the X-ray powder diffractogram of hydrate Form A of Compound 33 at room temperature.

[0160] In some embodiments, hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 19.5±0.2°2θ, 10.4±0.2°2θ, and 16.6±0.2°2θ. In some embodiments, hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 19.5±0.2°2θ, 10.4±0.2°2θ, and 16.6±0.2°2θ. In some embodiments, hydrate Form A of Compound 33 is characterized by an X-ray powder diffraction pattern having (a) signals at 19.5±0.2°2θ, 10.4±0.2°2θ, and 16.6±0.2°2θ, and (b) at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten signals selected from 13.6±0.2°2θ, 18.4±0.2°2θ, 17.5±0.2°2θ, 18.9±0.2°2θ, 20.8±0.2°2θ, 21.1±0.2°2θ, 21.4±0.2°2θ, 21.6±0.2°2θ, 21.8±0.2°2θ, and 24.8±0.2°2θ. In some embodiments, hydrate Form A of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 4A.

[0161] In some embodiments, hydrate Form A of Compound 33 has a triclinic crystal system, a P-1 space group, and Cu K α It is characterized by the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with a radiation (λ=1.54178 Å) and a CMOS detector: [Table A]

[0162] In some embodiments, hydrate Form A of Compound 33 has at least one peak selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least two peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least three peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least four peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least five peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least six peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least seven peaks selected from 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum with peaks at 172.3±0.2, 141.6±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 123.1±0.2, 32.8±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by having a C ssNMR spectrum of 172.3±0.2, 163.8±0.2, 161.3±0.2, 144.4±0.2, 141.6±0.2, 139.0±0.2, 136.8±0.2, 134.8±0.2, 132.4±0.2, 129.6±0.2, 128.9±0.2, 123.1±0.2, 117.2 ... and at least four, at least six, at least eight, at least 10, at least 12, or at least 15 ppm values ​​selected from 0.2, 116.5±0.2, 112.1±0.2, 97.7±0.2, 67.9±0.2, 36.1±0.2, 32.8±0.2, 29.4±0.2, and 28.4±0.2 ppm. 13 In some embodiments, hydrate Form A of Compound 33 is characterized by a C NMR spectrum substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0163] In some embodiments, hydrate form A of compound 33 has a signal at −103.1±0.2 ppm. 19 In some embodiments, hydrate Form A of Compound 33 is characterized by a F NMR spectrum substantially similar to that shown in FIG. 19 Characterized by F NMR spectrum.

[0164] Another aspect of the present invention provides compositions comprising hydrate Form A of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline hydrate Form A of Compound 33. In some embodiments, the compositions consist essentially of hydrate Form A of Compound 33.

[0165] Another aspect of the present invention provides a method of making hydrate Form A of Compound 33. In some embodiments, hydrate Form A of Compound 33 is prepared by adding water to Form A of Compound 33, stirring for about two weeks, and isolating the solid form.

[0166] 5. MeOH / HO solvate / hydrate form A of the compound In some embodiments, Compound 33 is a crystalline solid comprising crystalline MeOH / H2O solvate / hydrate Form A. In some embodiments, the crystalline solid comprises 30% to 99% Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% MeOH / H2O solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% MeOH / H2O solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% MeOH / H2O solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% MeOH / H2O solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% MeOH / HO solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% MeOH / HO solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% MeOH / HO solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% MeOH / HO solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% MeOH / HO solvate / hydrate Form A of Compound 33, based on the total weight of the solid Compound 33.

[0167] Thus, in some embodiments, MeOH / HO solvate / hydrate Form A of Compound 33 is substantially crystalline. In some embodiments, MeOH / HO solvate / hydrate Form A of Compound 33 is substantially pure crystalline. In some embodiments, MeOH / HO solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 5A provides the X-ray powder diffractogram of MeOH / HO solvate / hydrate Form A of Compound 33 at room temperature.

[0168] In some embodiments, MeOH / H2O solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 16.6±0.2°2θ and 17.4±0.2°2θ. In some embodiments, MeOH / H2O solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of: (a) 16.6±0.2°2θ and 17.4±0.2°2θ, and (b) 10.4±0.2°2θ, 18.2±0.2°2θ, and 19.4±0.2°2θ. In some embodiments, the MeOH / HO solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 10.4±0.2°2θ, 16.6±0.2°2θ, 17.4±0.2°2θ, 18.2±0.2°2θ, and 19.4±0.2°2θ.

[0169] In some embodiments, MeOH / HO solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, at least eight, or at least ten 2θ values ​​selected from 19.4±0.2, 10.4±0.2, 18.2±0.2, 16.6±0.2, 13.5±0.2, 21.0±0.2, 21.6±0.2, 18.8±0.2, 17.4±0.2, 21.3±0.2, 21.7±0.2, and 24.0±0.2. In some embodiments, MeOH / HO solvate / hydrate Form A of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 5A .

[0170] In some embodiments, the MeOH / HO solvate / hydrate Form A of compound 33 is characterized by a triclinic crystal system, a P-1 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector: [Table B]

[0171] Another aspect of the present invention provides compositions comprising MeOH / H2O solvate / hydrate Form A of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline MeOH / H2O solvate / hydrate Form A of Compound 33. In some embodiments, the compositions consist essentially of MeOH / H2O solvate / hydrate Form A of Compound 33.

[0172] Another aspect of the present invention provides a method of making MeOH / HO solvate / hydrate Form A of Compound 33. In some embodiments, MeOH / HO solvate / hydrate A of Compound 33 is prepared by adding MeOH to Form A of Compound 33, stirring at ambient temperature for about 2 weeks, and isolating the solid form.

[0173] 6. Form C of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form C. In some embodiments, the crystalline solid comprises 30% to 99% Form C of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form C of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form C of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form C of Compound 33 based on the total weight of the solid Compound 33.

[0174] Thus, in some embodiments, Form C of Compound 33 is substantially crystalline. In some embodiments, Form C of Compound 33 is substantially pure crystalline. In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 6A provides the X-ray powder diffractogram of Form C of Compound 33 at room temperature.

[0175] In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at 9.4±0.2°2θ and 15.4±0.2°2θ. In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at (a) 9.4±0.2°2θ and 15.4±0.2°2θ, and (b) 19.0±0.2°2θ and / or 21.0±0.2°2θ. In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at 9.4±0.2°2θ, 15.4±0.2°2θ, 19.0±0.2°2θ, and 21.0±0.2°2θ. In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, or eight 2θ values ​​selected from 9.4±0.2°2θ, 15.4±0.2°2θ, 18.2±0.2°2θ, 19.0±0.2°2θ, 19.6±0.2°2θ, 20.2±0.2°2θ, 21.0±0.2°2θ, and 21.5±0.2°2θ. In some embodiments, Form C of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 6A.

[0176] Another aspect of the present invention provides compositions comprising Form C of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form C of Compound 33. In some embodiments, the compositions consist essentially of Form C of Compound 33.

[0177] Another aspect of the present invention provides a method of making Form C of Compound 33. In some embodiments, Form C of Compound 33 is prepared by mixing samples of a stock solution in MeOH / HO (2:1 by volume) (prepared by dissolving Form A of Compound 33 in MeOH and warming to about 45° C., then warming to about 50° C.), stirring at about 45° C. for about 3 days, and isolating the solid form.

[0178] 7. Form D of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form D. In some embodiments, the crystalline solid comprises 30% to 99% Form D of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form D of Compound 33, based on the total weight of the solid Compound 33.

[0179] Thus, in some embodiments, Form D of Compound 33 is substantially crystalline. In some embodiments, Form D of Compound 33 is substantially pure crystalline. In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 7A provides the X-ray powder diffractogram of Form D of Compound 33 at room temperature.

[0180] In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram having signals at 14.4±0.2°2θ and 24.0±0.2°2θ. In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram having signals at (a) 14.4±0.2°2θ and 24.0±0.2°2θ, and (b) 10.4±0.2°2θ and / or 20.5±0.2°2θ. In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram having signals at 10.4±0.2°2θ, 14.4±0.2°2θ, 20.5±0.2°2θ, and 24.0±0.2°2θ. In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, at least eight, or at least ten 2θ values ​​selected from 7.8±0.2°2θ, 8.2±0.2°2θ, 8.6±0.2°2θ, 10.4±0.2°2θ, 13.7±0.2°2θ, 14.4±0.2°2θ, 15.3±0.2°2θ, 18.6±0.2°2θ, 18.9±0.2°2θ, 20.1±0.2°2θ, 20.5±0.2°2θ, 21.9±0.2°2θ, 24.0±0.2°2θ, and 24.3±0.2°2θ. In some embodiments, Form D of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 7A.

[0181] Another aspect of the present invention provides compositions comprising Form D of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form D of Compound 33. In some embodiments, the compositions consist essentially of Form D of Compound 33.

[0182] Another aspect of the present invention provides a method of making Form D of Compound 33. In some embodiments, Form D of Compound 33 is prepared by adding THF solvate Form A of Compound 33 to MeOH vapor in a container, sealing the container, storing at room temperature for about 10 days, and isolating the solid form.

[0183] 8. Form E of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form E. In some embodiments, the crystalline solid comprises 30% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form E of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form E of crystalline Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form E of crystalline Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form E of crystalline Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form E of crystalline Compound 33 based on the total weight of the solid Compound 33.

[0184] Thus, in some embodiments, Form E of Compound 33 is substantially crystalline. In some embodiments, Form E of Compound 33 is substantially pure crystalline. In some embodiments, Form E of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 8A provides the X-ray powder diffractogram of Form E of Compound 33 at room temperature.

[0185] In some embodiments, Form E of Compound 33 is characterized by an X-ray powder diffractogram having signals at 16.2±0.2°2θ and 17.9±0.2°2θ. In some embodiments, Form E of Compound 33 is characterized by an X-ray powder diffractogram having signals at (a) 16.2±0.2°2θ and 17.9±0.2°2θ, and (b) 12.6±0.2°2θ and / or 20.7±0.2°2θ. In some embodiments, Form E of Compound 33 is characterized by an X-ray powder diffractogram having signals at 12.6±0.2°2θ, 16.2±0.2°2θ, 17.9±0.2°2θ, and 20.7±0.2°2θ. In some embodiments, Form E of Compound 33 has peaks of 7.9±0.2°2θ, 11.2±0.2°2θ, 12.6±0.2°2θ, 12.8±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 16.2±0.2°2θ, 17.9±0.2°2θ, 19.9±0.2°2θ, 20.7±0.2°2θ, 21.1±0.2°2θ , 22.5±0.2°2θ, 22.8±0.2°2θ, 24.1±0.2°2θ, 25.0±0.2°2θ, 27.0±0.2°2θ, and 28.9±0.2°2θ. In some embodiments, Form E of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to Figure 8A.

[0186] Another aspect of the present invention provides compositions comprising Form E of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form E of Compound 33. In some embodiments, the compositions consist essentially of Form E of Compound 33.

[0187] Another aspect of the present invention provides a method of making Form E of Compound 33. In some embodiments, Form E of Compound 33 is prepared by dissolving Form A of Compound 33 in MeOH after warming to 45° C. and then to 50° C., cooling the solution, stirring in a cold room for about 3 days, and isolating the solid form.

[0188] 9. Form F of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form F. In some embodiments, the crystalline solid comprises 30% to 99% Form F of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form F of Compound 33, based on the total weight of the solid Compound 33.

[0189] Thus, in some embodiments, Form F of Compound 33 is substantially crystalline. In some embodiments, Form F of Compound 33 is substantially pure crystalline. In some embodiments, Form F of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 9A provides the X-ray powder diffractogram of Form F of Compound 33 at room temperature.

[0190] In some embodiments, Form F of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more 2θ values ​​selected from 8.6±0.2°2θ, 13.0±0.2°2θ, and 23.0±0.2°2θ. In some embodiments, Form F of Compound 33 is characterized by an X-ray powder diffractogram having signals at 8.6±0.2°2θ, 13.0±0.2°2θ, and 23.0±0.2°2θ. In some embodiments, Form F of Compound 33 has peaks at 7.7±0.2°2θ, 8.6±0.2°2θ, 11.4±0.2°2θ, 11.6±0.2°2θ, 12.2±0.2°2θ, 13.0±0.2°2θ, 14.2±0.2°2θ, 14.9±0.2°2θ, 17.3±0.2°2θ, 17.4±0.2°2θ, 17.8±0.2°2θ, 18.3±0.2°2θ, 19.0±0.2°2θ, 20.4±0.2°2θ, 21.4±0.2°2θ, 9A. In some embodiments, Form F of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, at least eight, at least ten, or at least twelve 2θ values ​​selected from 21.6±0.2°2θ, 22.6±0.2°2θ, 22.8±0.2°2θ, 23.0±0.2°2θ, 23.3±0.2°2θ, 24.0±0.2°2θ, 24.2±0.2°2θ, 24.9±0.2°2θ, 25.8±0.2°2θ, and 26.4±0.2°2θ. In some embodiments, Form F of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 9A.

[0191] Another aspect of the present invention provides compositions comprising Form F of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form F of Compound 33. In some embodiments, the compositions consist essentially of Form F of Compound 33.

[0192] Another aspect of the present invention provides a method of making Form F of Compound 33. In some embodiments, Form F of Compound 33 is prepared by adding THF solvate Form A of Compound 33 to EtOH, stirring and slurrying overnight at about 20° C., and isolating the solid form.

[0193] 10. Form G of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form G. In some embodiments, the crystalline solid comprises 30% to 99% Form G of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form G of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form G of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form G of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form G of Compound 33 based on the total weight of the solid Compound 33.

[0194] Thus, in some embodiments, Form G of Compound 33 is substantially crystalline. In some embodiments, Form G of Compound 33 is substantially pure crystalline. In some embodiments, Form G of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 10A provides the X-ray powder diffractogram of Compound G at room temperature.

[0195] In some embodiments, Form G of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more 2θ values ​​selected from 19.8±0.2°2θ, 20.2±0.2°2θ, and 20.8±0.2°2θ. In some embodiments, Form G of Compound 33 is characterized by an X-ray powder diffractogram having signals at 19.8±0.2°2θ, 20.2±0.2°2θ, and 20.8±0.2°2θ. In some embodiments, Form G of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, at least eight, at least ten, or at least twelve 2θ values ​​selected from 9.3±0.2°2θ, 10.8±0.2°2θ, 11.5±0.2°2θ, 12.6±0.2°2θ, 17.5±0.2°2θ, 18.4±0.2°2θ, 19.1±0.2°2θ, 19.8±0.2°2θ, 20.2±0.2°2θ, 20.8±0.2°2θ, 21.6±0.2°2θ, 22.6±0.2°2θ, 23.4±0.2°2θ, 24.2±0.2°2θ, and 25.5±0.2°2θ. In some embodiments, Form G of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 10A.

[0196] Another aspect of the present invention provides compositions comprising Form G of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form G of Compound 33. In some embodiments, the compositions consist essentially of Form G of Compound 33.

[0197] Another aspect of the present invention provides a method of making form G of compound 33. In some embodiments, form G of compound 33 is prepared by adding form A of compound 33 to EtOH, stirring at about 5° C. for about 1 day, and isolating the solid form.

[0198] 11. Form H of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form H. In some embodiments, the crystalline solid comprises 30% to 99% Form H of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form H of Compound 33, based on the total weight of the solid Compound 33.

[0199] Thus, in some embodiments, Form H of Compound 33 is substantially crystalline. In some embodiments, Form H of Compound 33 is substantially pure crystalline. In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 11A provides the X-ray powder diffractogram of Form H of Compound 33 at room temperature.

[0200] In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more 2θ values ​​selected from 5.0±0.2°2θ, 18.3±0.2°2θ, and 19.5±0.2°2θ. In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram having signals at 5.0±0.2°2θ, 18.3±0.2°2θ, and 19.5±0.2°2θ. In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least five, at least six, or at least seven 2θ values ​​selected from 5.0±0.2°2θ, 8.8°2θ, 15.0°2θ, 17.6°2θ, 18.3±0.2°2θ, 18.9°2θ, 19.5±0.2°2θ, and 20.7°2θ. In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram having signals at 5.0±0.2°2θ, 8.8°2θ, 15.0°2θ, 17.6°2θ, 18.3±0.2°2θ, 18.9°2θ, 19.5±0.2°2θ, and 20.7°2θ. In some embodiments, Form H of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 11A.

[0201] Another aspect of the present invention provides compositions comprising Form H of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form H of Compound 33. In some embodiments, the compositions consist essentially of Form H of Compound 33.

[0202] Another aspect of the present invention provides a method of making Form H of Compound 33. In some embodiments, Form H of Compound 33 is prepared by dissolving Form A of Compound 33 in EtOH, placing the solution in a water bath at room temperature for a time sufficient to allow water vapor to interact with the solution, and isolating the solid form.

[0203] 12. Form I of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form I. In some embodiments, the crystalline solid comprises 30% to 99% Form I of the crystalline compound, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form I of Compound 33, based on the total weight of the solid Compound 33.

[0204] Thus, in some embodiments, Form I of Compound 33 is substantially crystalline. In some embodiments, Form I of Compound 33 is substantially pure crystalline. In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 12C provides the X-ray powder diffractogram of Form I of Compound 33 at room temperature.

[0205] In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more 2θ values ​​selected from 9.3±0.2°2θ, 19.0±0.2°2θ, and 21.0±0.2°2θ. In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffractogram having signals at 9.3±0.2°2θ, 19.0±0.2°2θ, and 21.0±0.2°2θ. In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least five, or at least six 2θ values ​​selected from 9.3±0.2°2θ, 15.4±0.2°2θ, 18.3±0.2°2θ, 18.6±0.2°2θ, 19.0±0.2°2θ, 20.2±0.2°2θ, and 21.0±0.2°2θ. In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffraction pattern having signals at 9.3±0.2°2θ, 15.4°2θ, 18.3°2θ, 18.6°2θ, 19.0±0.2°2θ, 20.2°2θ, and 21.0±0.2°2θ. In some embodiments, Form I of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 12C.

[0206] Another aspect of the present invention provides compositions comprising Form I of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form I of Compound 33. In some embodiments, the compositions consist essentially of Form I of Compound 33.

[0207] Another aspect of the present invention provides a method for making Form I of Compound 33. In some embodiments, Form I of Compound 33 is prepared by distillation crystallization of Compound 33 from 2 Me-THF / THF into EtOH / HO, stirring overnight, drying in a vacuum oven with nitrogen at about 66° C. overnight, and isolating the solid form.

[0208] 13. THF solvate form A of compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline THF solvate Form A. In some embodiments, the crystalline solid comprises 30% to 99% THF solvate Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33.

[0209] Thus, in some embodiments, THF solvate Form A of Compound 33 is substantially crystalline. In some embodiments, THF solvate Form A of Compound 33 is substantially pure crystalline. In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 13A provides the X-ray powder diffractogram of THF solvate Form A of the compound at room temperature.

[0210] In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 8.2±0.2°2θ and / or 8.5±0.2°2θ. In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 19.1±0.2°2θ and / or 19.4±0.2°2θ. In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 8.2±0.2°2θ, 8.5±0.2°2θ, 19.1±0.2°2θ, and 19.4±0.2°2θ. In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least four, at least six, at least eight, or at least ten 2θ values ​​selected from 8.2±0.2°2θ, 8.5±0.2°2θ, 9.5±0.2°2θ, 11.3±0.2°2θ, 17.1±0.2°2θ, 17.8±0.2°2θ, 19.1±0.2°2θ, 19.4±0.2°2θ, 20.5±0.2°2θ, 21.1±0.2°2θ, 21.2±0.2°2θ, 21.5±0.2°2θ, 22.9±0.2°2θ, and 23.1±0.2°2θ. In some embodiments, THF solvate Form A of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 13A.

[0211] In some embodiments, THF solvate Form A of Compound 33 is characterized by an orthorhombic crystal system, a Pca21 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector: [Table C]

[0212] In some embodiments, THF solvate Form A of Compound 33 has at least one peak selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least two peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum having at least three peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least four peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least five peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least six peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum with at least seven peaks selected from 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum with peaks at 165.8±0.2, 140.0±0.2, 133.9±0.2, 121.2±0.2, 114.3±0.2, 96.1±0.2, 69.0±0.2, 25.7±0.2 ppm, and 25.3±0.2 ppm. 13 In some embodiments, the THF solvate Form A of Compound 33 is characterized by having a C ssNMR spectrum substantially similar to that shown in FIG. 13 Characterized by C ssNMR spectrum.

[0213] In some embodiments, the THF solvate Form A of Compound 33 has peaks at −110.5±0.2 ppm and / or −113.0±0.2 ppm. 19 In some embodiments, the THF solvate Form A of Compound 33 is characterized by a F NMR spectrum substantially similar to that shown in FIG. 19 Characterized by F ssNMR spectrum.

[0214] Another aspect of the present invention provides a composition comprising THF solvate Form A of Compound 33. In some embodiments, the composition of the present invention comprises substantially pure crystalline THF solvate Form A of Compound 33. In some embodiments, the composition consists essentially of THF solvate Form A of Compound 33.

[0215] Another aspect of the present invention provides a method of making THF solvate Form A of Compound 33. In some embodiments, THF solvate Form A of Compound 33 is prepared by adding Form A of Compound 33 to THF in a container, sealing the container, storing at room temperature for about 2 weeks, and isolating the solid form.

[0216] 14. Form J of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form J. In some embodiments, the crystalline solid comprises 30% to 99% Form J of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form J of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form J of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form J of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form J of Compound 33 based on the total weight of the solid Compound 33.

[0217] Thus, in some embodiments, Form J of Compound 33 is substantially crystalline. In some embodiments, Form J of Compound 33 is substantially pure crystalline. In some embodiments, Form J of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 14A provides the X-ray powder diffractogram of Form J of Compound 33 at room temperature.

[0218] In some embodiments, Form J of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 6.6±0.2°2θ, 7.5±0.2°2θ, and 15.0±0.2°2θ. In some embodiments, Form J of Compound 33 is characterized by an X-ray powder diffractogram having signals at 6.6±0.2°2θ, 7.5±0.2°2θ, and 15.0±0.2°2θ. In some embodiments, Form J of Compound 33 exhibits (a) signals at 6.6±0.2°2θ, 7.5±0.2°2θ, and 15.0±0.2°2θ, and (b) signals at 10.3±0.2°2θ, 15.6±0.2°2θ, 16.0±0.2°2θ, 16.8±0.2°2θ, 17.9±0.2°2θ, 19.4±0.2°2θ, 19.9±0.2°2θ, 20.1± 14A. In some embodiments, Form J of Compound 33 is characterized by an X-ray powder diffractogram having signals at at least one, at least two, at least three, at least four, at least six, at least eight, or at least ten 2θ values ​​selected from 0.2°2θ, 20.6±0.2°2θ, 20.8±0.2°2θ, 21.4±0.2°2θ, 21.7±0.2°2θ, and 22.5±0.2°2θ. In some embodiments, Form J of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to Figure 14A.

[0219] Another aspect of the present invention provides compositions comprising Form J of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form J of Compound 33. In some embodiments, the compositions consist essentially of Form J of Compound 33.

[0220] Another aspect of the present invention provides a method of making Form J of Compound 33. In some embodiments, Form J of Compound 33 is prepared by adding Form A of Compound 33 to THF:EtOH:water (6:1:1 by volume) in a container, slurrying for about 1 hour, filtering, then adding a polymer mixture comprising one or more polymers selected from polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), hypromellose (HPMC), methylcellulose (MC), stirring at room temperature for about 1 day, and isolating the solid form.

[0221] 15. Form K of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form K. In some embodiments, the crystalline solid comprises 30% to 99% Form K of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form K of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form K of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form K of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form K of Compound 33 based on the total weight of the solid Compound 33.

[0222] Thus, in some embodiments, Form K of Compound 33 is substantially crystalline. In some embodiments, Form K of Compound 33 is substantially pure crystalline. In some embodiments, Form K of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 15A provides the X-ray powder diffractogram of Form K of Compound 33 at room temperature.

[0223] In some embodiments, Form K of Compound 33 is characterized by an X-ray powder diffractogram having signals at 14.5±0.2°2θ. In some embodiments, Form K of Compound 33 is characterized by an X-ray powder diffractogram having signals at 14.5±0.2°2θ and one or more of 9.7±0.2°2θ, 19.7±0.2°2θ, and 20.5±0.2°2θ. In some embodiments, Form K of Compound 33 is characterized by an X-ray powder diffractogram having signals at 9.7±0.2°2θ, 14.5±0.2°2θ, 19.7±0.2°2θ, and 20.5±0.2°2θ. In some embodiments, Form K of Compound 33 is characterized by: (a) an X-ray powder diffraction pattern having signals at 9.7±0.2°2θ, 14.5±0.2°2θ, 19.7±0.2°2θ, and 20.5±0.2°2θ, and signals at at least one, at least two, at least three, at least four, at least five, or at least six 2θ values ​​selected from 11.2±0.2°2θ, 14.5±0.2°2θ, 17.0±0.2°2θ, 19.1±0.2°2θ, 19.4±0.2°2θ, 21.0±0.2°2θ, and 24.4±0.2°2θ. In some embodiments, Form K of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to FIG. 15A.

[0224] Another aspect of the present invention provides compositions comprising Form K of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form K of Compound 33. In some embodiments, the compositions consist essentially of Form K of Compound 33.

[0225] Another aspect of the present invention provides a method of making Form K of Compound 33. In some embodiments, Form K of Compound 33 is prepared by dissolving Form A of Compound 33 in THF in a container, adding water, sealing the container, storing at room temperature for a time sufficient for water vapor to interact with the solution, and isolating the precipitated solid.

[0226] 16. Compound 33 2 Me-THF solvate Form A In some embodiments, Compound 33 is a crystalline solid comprising crystalline 2 Me-THF solvate Form A. In some embodiments, the crystalline solid comprises 30% to 99% 2 Me-THF solvate Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% 2 Me-THF solvate Form A of Compound 33, based on the total weight of the solid Compound 33.

[0227] Thus, in some embodiments, 2 Me-THF solvate Form A of Compound 33 is substantially crystalline. In some embodiments, 2 Me-THF solvate Form A of Compound 33 is substantially pure crystalline. In some embodiments, 2 Me-THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 16A provides the X-ray powder diffractogram of 2 Me-THF solvate Form A of Compound 33 at room temperature.

[0228] In some embodiments, 2 Me-THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 18.1±0.2°2θ, 19.0±0.2°2θ, and / or 21.3±0.2°2θ. In some embodiments, 2 Me-THF solvate Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at (a) 18.1±0.2°2θ, 19.0±0.2°2θ, and 21.3±0.2°2θ, and (b) at least one, at least two, at least three, or at least four 2θ values ​​selected from 13.8±0.2°2θ, 18.7±0.2°2θ, 20.0±0.2°2θ, and 20.8±0.2°2θ. In some embodiments, 2 Me-THF solvate Form A of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 16A.

[0229] Another aspect of the present invention provides a composition comprising 2 Me-THF solvate Form A of Compound 33. In some embodiments, the composition of the present invention comprises substantially pure crystalline 2 Me-THF solvate Form A of Compound 33. In some embodiments, the composition consists essentially of 2 Me-THF solvate Form A of Compound 33.

[0230] Another aspect of the present invention provides a method of making 2 Me-THF solvate Form A of Compound 33. In some embodiments, 2 Me-THF solvate Form A of Compound 33 is prepared by dissolving Form A of Compound 33 in 2 Me-THF, stirring the slurry at room temperature for about 2 days or at 5° C. for 1 day, and isolating the solid form.

[0231] 17. Form L of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising crystalline Form L. In some embodiments, the crystalline solid comprises 30% to 99% Form L of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form L of Compound 33, based on the total weight of the solid Compound 33.

[0232] Thus, in some embodiments, Form L of Compound 33 is substantially crystalline. In some embodiments, Form L of Compound 33 is substantially pure crystalline. In some embodiments, Form L of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 17A provides the X-ray powder diffractogram of Form L of Compound 33 at room temperature.

[0233] Thus, in some embodiments, Form L of Compound 33 is substantially crystalline. In some embodiments, Form L of Compound 33 is substantially pure crystalline. In some embodiments, Form L of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 17A provides the X-ray powder diffractogram of Form L of Compound 33 at room temperature.

[0234] In some embodiments, Form L of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 14.5±0.2°2θ, 14.6±0.2°2θ, 16.3±0.2°2θ, and 17.3±0.2°2θ. In some embodiments, Form L of Compound 33 is characterized by an X-ray powder diffractogram having signals at 14.5±0.2°2θ, 14.6±0.2°2θ, 16.3±0.2°2θ, and 17.3±0.2°2θ. In some embodiments, Form L of Compound 33 exhibits (a) signals at 14.5±0.2°2θ, 14.6±0.2°2θ, 16.3±0.2°2θ, and 17.3±0.2°2θ, and (b) signals at 7.0±0.2°2θ, 8.8±0.2°2θ, 9.9±0.2°2θ, 13.7±0.2°2θ, 17.6±0.2°2θ, 17.9±0.2°2θ, 18.6±0.2°2θ, 18.8±0.2°2θ, 19.7±0.2°2θ, 20.2±0.2°2θ, 20.4±0.2°2θ. 20°2θ, 20.7±0.2°2θ, 20.9±0.2°2θ, 21.0±0.2°2θ, 21.9±0.2°2θ, 22.2±0.2°2θ, 23.1±0.2°2θ, 23.6±0.2°2θ, 27.1±0.2°2θ, 28.6±0.2°2θ, and 31.7±0.2°2θ. In some embodiments, Form L of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to Figure 17A.

[0235] Another aspect of the present invention provides compositions comprising Form L of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form L of Compound 33. In some embodiments, the compositions consist essentially of Form L of Compound 33.

[0236] Another aspect of the present invention provides a method of making form L of compound 33. In some embodiments, form L of compound 33 is prepared by dissolving form A of compound 33 in 2-MeTHF, allowing it to evaporate slowly at room temperature, and isolating the solid form. In some embodiments, form L of compound 33 is prepared by adding form A of compound 33 to 2-MeTHF / heptane (1:1 by volume), heating and stirring at about 50° C. for about 2 hours until equilibrium is reached, filtering the mixture, allowing it to cool slowly to about 5° C., and isolating the solid form.

[0237] 18. Form M of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising Form M. In some embodiments, the crystalline solid comprises 30% to 99% Form M of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form M of Compound 33, based on the total weight of the solid Compound 33.

[0238] Thus, in some embodiments, Form M of Compound 33 is substantially crystalline. In some embodiments, Form M of Compound 33 is substantially pure crystalline. In some embodiments, Form M of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 18A provides the X-ray powder diffractogram of Form M of Compound 33 at room temperature.

[0239] In some embodiments, Form M of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 18.3±0.2°2θ, 18.9±0.2°2θ, and 21.2±0.2°2θ. In some embodiments, Form M of Compound 33 is characterized by an X-ray powder diffractogram having signals at 18.3±0.2°2θ, 18.9±0.2°2θ, and 21.2±0.2°2θ. In some embodiments, Form M of Compound 33 is characterized by an X-ray powder diffractogram having (a) signals at 18.3±0.2°2θ, 18.9±0.2°2θ, and 21.2±0.2°2θ, and (b) signals at at least one, at least two, at least three, or at least four 2θ values ​​selected from 7.0±0.2°2θ, 8.4±0.2°2θ, 11.3±0.2°2θ, 13.8±0.2°2θ, 16.0±0.2°2θ, 9.4±0.2°2θ, 20.6±0.2°2θ, and 21.7±0.2°2θ. In some embodiments, Form M of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 18A.

[0240] Another aspect of the present invention provides compositions comprising Form M of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form M of Compound 33. In some embodiments, the compositions consist essentially of Form M of Compound 33.

[0241] Another aspect of the present invention provides a method of making Form M of Compound 33. In some embodiments, Form M of Compound 33 is prepared by adding THF solvate Form A of Compound 33 to methyl tert-butyl ether (MTBE) vapors in a container, sealing the container, storing at room temperature for about 10 days, and isolating the solid form.

[0242] 19. Form N of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising Form N. In some embodiments, the crystalline solid comprises 30% to 99% Form N of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form N of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form N of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form N of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form N of Compound 33 based on the total weight of the solid Compound 33.

[0243] Thus, in some embodiments, Form N of Compound 33 is substantially crystalline. In some embodiments, Form N of Compound 33 is substantially pure crystalline. In some embodiments, Form N of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 19A provides the X-ray powder diffractogram of Form N of Compound 33 at room temperature.

[0244] In some embodiments, Form N of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 13.0±0.2°2θ, 14.3±0.2°2θ, and 18.2±0.2°2θ. In some embodiments, Form N of Compound 33 is characterized by an X-ray powder diffractogram having signals at 13.0±0.2°2θ, 14.3±0.2°2θ, and 18.2±0.2°2θ. In some embodiments, Form N of Compound 33 exhibits (a) signals at 13.0±0.2°2θ, 14.3±0.2°2θ, and 18.2±0.2°2θ, and (b) signals at 4.2±0.2°2θ, 8.8±0.2°2θ, 11.7±0.2°2θ, 12.3±0.2°2θ, 12.6±0.2°2θ, 15.6±0.2°2θ, 17.1±0.2°2θ, 17.6±0.2°2θ, 18.7±0.2°2θ, 19.2±0.2°2θ, 19.6±0.2°2θ, 20.5±0.2°2θ, 19A , 21.5±0.2°2θ, 21.8±0.2°2θ, 22.2±0.2°2θ, 22.7±0.2°2θ, 23.1±0.2°2θ, 24.0±0.2°2θ, 25.6±0.2°2θ, 26.1±0.2°2θ, 26.8±0.2°2θ, 28.0±0.2°2θ, and 28.4±0.2°2θ. In some embodiments, Form N of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 19A .

[0245] Another aspect of the present invention provides compositions comprising Form N of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form N of Compound 33. In some embodiments, the compositions consist essentially of Form N of Compound 33.

[0246] Another aspect of the present invention provides a method of making Form N of Compound 33. In some embodiments, Form N of Compound 33 is prepared by adding Form A of Compound 33 to ethyl acetate (EtOAc), stirring at room temperature, and isolating the solid form.

[0247] 20. Form O of Compound 33 In some embodiments, Compound 33 is a crystalline solid comprising Form O. In some embodiments, the crystalline solid comprises 30% to 99% Form O of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% Form O of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% Form O of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% Form O of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% Form O of Compound 33 based on the total weight of the solid Compound 33.

[0248] Thus, in some embodiments, Form O of Compound 33 is substantially crystalline. In some embodiments, Form O of Compound 33 is substantially pure crystalline. In some embodiments, Form O of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 20A provides the X-ray powder diffractogram of Form O of Compound 33 at room temperature.

[0249] In some embodiments, Form O of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 7.0±0.2°2θ, 10.4±0.2°2θ, 17.4±0.2°2θ, and 21.2±0.2°2θ. In some embodiments, Form O of Compound 33 is characterized by an X-ray powder diffractogram having signals at 7.0±0.2°2θ, 10.4±0.2°2θ, 17.4±0.2°2θ, and 21.2±0.2°2θ. In some embodiments, Form O of Compound 33 is characterized by an X-ray powder diffractogram having (a) signals at 7.0±0.2°2θ, 10.4±0.2°2θ, 17.4±0.2°2θ, and 21.2±0.2°2θ, and (b) signals at at least one, at least two, at least four, or at least six 2θ values ​​selected from 8.3±0.2°2θ, 8.8±0.2°2θ, 15.5±0.2°2θ, 16.6±0.2°2θ, 16.9±0.2°2θ, 18.8±0.2°2θ, 19.5±0.2°2θ, 20.4±0.2°2θ, 21.6±0.2°2θ, 22.3±0.2°2θ, 22.9±0.2°2θ, and 23.3±0.2°2θ. In some embodiments, Form O of Compound 33 is characterized by an X-ray powder diffraction pattern substantially similar to Figure 20A.

[0250] Another aspect of the present invention provides compositions comprising Form O of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline Form O of Compound 33. In some embodiments, the compositions consist essentially of Form O of Compound 33.

[0251] Another aspect of the present invention provides a method of making Form O of Compound 33. In some embodiments, Form O of Compound 33 is prepared by suspending THF solvate Form A of Compound 33 in ethyl acetate (EtOAc), stirring the suspension at room temperature for about 2 days, and isolating the solid form.

[0252] 21. Potassium salt form A of compound 33 In some embodiments, Compound 33 is a crystalline solid comprising potassium salt Form A. In some embodiments, the crystalline solid comprises 30% to 99% of the potassium salt Form A of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% of the potassium salt Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% of the potassium salt Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% of the potassium salt Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% of the potassium salt Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% of the potassium salt Form A of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% potassium salt Form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% potassium salt Form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% potassium salt Form A of Compound 33 based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% potassium salt Form A of Compound 33 based on the total weight of the solid Compound 33.

[0253] Thus, in some embodiments, potassium salt Form A of Compound 33 is substantially crystalline. In some embodiments, potassium salt Form A of Compound 33 is substantially pure crystalline. In some embodiments, potassium salt Form A of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 21A provides the X-ray powder diffractogram of potassium salt Form A of Compound 33 at room temperature.

[0254] In some embodiments, potassium salt Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 11.7±0.2°2θ, 18.0±0.2°2θ, and 20.7±0.2°2θ. In some embodiments, potassium salt Form A of Compound 33 is characterized by an X-ray powder diffractogram having signals at 11.7±0.2°2θ, 18.0±0.2°2θ, and 20.7±0.2°2θ. In some embodiments, potassium salt Form A of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 21A .

[0255] Another aspect of the present invention provides compositions comprising potassium salt Form A of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline potassium salt Form A of Compound 33. In some embodiments, the compositions consist essentially of potassium salt Form A of Compound 33.

[0256] Another aspect of the present invention provides a method of making potassium salt Form A of Compound 33. In some embodiments, potassium salt Form A of Compound 33 is prepared by dissolving potassium salt Form A of Compound 33 in acetone at about 50° C., dispensing the acetone solution of Compound 33 Form A into a container at room temperature, adding aqueous KOH, and obtaining potassium salt Form A of Compound 33 via evaporation at room temperature.

[0257] 22. Potassium salt form B of compound 33 In some embodiments, Compound 33 is a crystalline solid comprising potassium salt form B. In some embodiments, the crystalline solid comprises 30% to 99% of the potassium salt form B of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% of the potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% of the potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% of the potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% of the potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% of the potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% potassium salt form B of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% potassium salt form B of Compound 33, based on the total weight of the solid Compound 33.

[0258] Thus, in some embodiments, potassium salt Form B of Compound 33 is substantially crystalline. In some embodiments, potassium salt Form B of Compound 33 is substantially pure crystalline. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 22A provides the X-ray powder diffractogram of Form B of Compound 33 at room temperature.

[0259] In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at one or more of 9.1±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 17.5±0.2°2θ, and 21.7±0.2°2θ. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at two or more of 9.1±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 17.5±0.2°2θ, and 21.7±0.2°2θ. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at three or more of: 9.1±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 17.5±0.2°2θ, and 21.7±0.2°2θ. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram having signals at 9.1±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 17.5±0.2°2θ, and 21.7±0.2°2θ. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram having (a) three or more signals from 9.1±0.2°2θ, 13.7±0.2°2θ, 15.3±0.2°2θ, 17.5±0.2°2θ, and 21.7±0.2°2θ, and (b) signals at at least one, at least two, or at least three 2θ values ​​selected from 6.9±0.2°2θ, 10.8±0.2°2θ, 20.0±0.2°2θ, and 20.6±0.2°2θ. In some embodiments, potassium salt Form B of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 22A.

[0260] Another aspect of the present invention provides compositions comprising potassium salt Form B of Compound 33. In some embodiments, the compositions of the present invention comprise substantially pure crystalline potassium salt Form B of Compound 33. In some embodiments, the compositions consist essentially of potassium salt Form B of Compound 33.

[0261] Another aspect of the present invention provides a method of making potassium salt Form B of Compound 33. In some embodiments, potassium salt Form B of Compound 33 is prepared by dissolving Compound 33 Form A in 1,4-dioxane with sonication at about 50° C., dispensing the 1,4-dioxane solution of Compound 33 into a container at room temperature, adding aqueous KOH, and isolating potassium salt Form B of Compound 33 at room temperature.

[0262] 23. Potassium salt form C of compound 33 In some embodiments, Compound 33 is a crystalline solid comprising potassium salt form C. In some embodiments, the crystalline solid comprises 30% to 99% of the potassium salt form C of crystalline Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 40% to 99% of the potassium salt form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 50% to 99% of the potassium salt form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 60% to 99% of the potassium salt form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 70% to 99% of the potassium salt form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 75% to 99% of the potassium salt form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 80% to 99% potassium salt Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 85% to 99% potassium salt Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 90% to 99% potassium salt Form C of Compound 33, based on the total weight of the solid Compound 33. In some embodiments, the crystalline solid comprises 95% to 99% potassium salt Form C of Compound 33, based on the total weight of the solid Compound 33.

[0263] Thus, in some embodiments, potassium salt Form C of Compound 33 is substantially crystalline. In some embodiments, potassium salt Form C of Compound 33 is substantially pure crystalline. In some embodiments, potassium salt Form C of Compound 33 is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. Figure 23A provides the X-ray powder diffractogram of potassium salt Form C of Compound 33 at room temperature.

[0264] In some embodiments, potassium salt Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at 16.8±0.2°2θ and 19.3±0.2°2θ. In some embodiments, potassium salt Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at (a) 16.8±0.2°2θ and 19.3±0.2°2θ, and (b) 6.7±0.2°2θ and / or 10.5±0.2°2θ. In some embodiments, potassium salt Form C of Compound 33 is characterized by an X-ray powder diffractogram having signals at 6.7±0.2°2θ, 10.5±0.2°2θ, 16.8±0.2°2θ, and 19.3±0.2°2θ. In some embodiments, potassium salt Form C of Compound 33 is characterized by an X-ray powder diffractogram substantially similar to FIG. 23A .

[0265] Another aspect of the present invention provides a composition comprising the potassium salt Form C of Compound 33. In some embodiments, the composition of the present invention comprises substantially pure crystalline potassium salt Form C of Compound 33. In some embodiments, the composition consists essentially of potassium salt Form C of Compound 33.

[0266] Another aspect of the present invention provides a method of making potassium salt Form C of Compound 33. In some embodiments, potassium salt Form C of Compound 33 is prepared by dissolving Form A of Compound 33 in an acetone / water solution (e.g., v / v 9:1) at about 50° C., dispensing a solution of Compound 33 in 4-dioxane into a container at room temperature, adding aqueous KOH (e.g., about a 1:1 molar ratio of K / Compound 33), and obtaining potassium salt Form C of Compound 33 via evaporation at room temperature.

[0267] Solid dispersion containing amorphous compound 33 In another aspect, the invention features a solid dispersion comprising amorphous Compound 33 and a polymer. In one embodiment, the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS). In another embodiment, the polymer is polyvinylpyrrolidone / vinyl acetate PVPVA. In another embodiment, the polymer is hydroxypropylmethylcellulose (HPMC). Other suitable exemplary polymers are as described in WO2011 / 119984, which is incorporated herein by reference in its entirety.

[0268] In one embodiment, the polymer is present in an amount of about 0.1% to about 10% by weight, based on the total weight of the dispersion (before drying or solidifying). In another embodiment, the polymer is present in an amount of about 0.2% to about 7.5% by weight, based on the total weight of the dispersion (before drying or solidifying). In another embodiment, the polymer is present in an amount of about 0.2% to about 5.0% by weight, based on the total weight of the dispersion (before drying or solidifying).

[0269] In another embodiment, Compound 33 is present in an amount of about 30% to about 80% by weight of the solid dispersion. In another embodiment, Compound 33 is present in an amount of about 50% by weight of the solid dispersion. In another embodiment, Compound 33 is present in an amount of about 80% by weight of the solid dispersion.

[0270] Some embodiments provide polymer-free spray-dried pure amorphous compound 33.

[0271] In another aspect, the invention features a pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable carrier. In some embodiments, the invention features a pharmaceutical composition comprising polymer-free, spray-dried, pure, substantially amorphous Compound 33.

[0272] Amorphous compounds and methods for preparing solid dispersions Amorphous forms of any of the compounds disclosed herein and solid dispersions comprising these amorphous compounds can be prepared. Starting with a compound of the present invention, or a salt, solvate, or hydrate thereof, the amorphous form of the compound can be prepared by rotary evaporation or spray drying. In some embodiments, the amorphous compound of the present invention is compound 33, or a pharmaceutically acceptable salt or deuterated derivative thereof. Some embodiments of the present invention provide pharmaceutical compositions comprising amorphous compound 33, or a pharmaceutically acceptable salt or deuterated derivative thereof. In some embodiments, the composition comprising amorphous compound 33, or a pharmaceutically acceptable salt or deuterated derivative thereof, is a spray-dried dispersion.

[0273] The amorphous form is produced when a compound, salt, solvate, or hydrate of the invention is dissolved in a suitable solvent, such as methanol, and the methanol is rotary evaporated to leave a foam. In some embodiments, a warm water bath is used to facilitate evaporation.

[0274] Amorphous forms can also be prepared from any of the compounds, salts, solvates, or hydrates described herein, including, for example, Compound 33 and salts, solvates, and hydrates of Compound 33, using spray drying. Spray drying is a process that converts liquid feed into a dry particulate form. Optionally, a secondary drying process, such as fluidized bed drying or vacuum drying, can be used to reduce residual solvent to a pharmaceutically acceptable level. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The preparation to be spray-dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using selected spray drying equipment. In a standard procedure, the preparation is sprayed into a stream of warm, filtered air, which evaporates the solvent and conveys the dried product into a collector (e.g., a cyclone). The spent air is then depleted with solvent, or alternatively, the spent air is sent to a cooler to capture and potentially recycle the solvent. Commercially available types of equipment can be used to perform the spray drying. For example, commercially available spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray dryers manufactured by Niro) (see US2004 / 0105820, US2003 / 0144257).

[0275] Spray drying typically uses a solids loading of about 3% to about 30% by weight of materials (i.e., drug and excipients), e.g., about 4% to about 20% by weight, preferably at least about 10%. Generally, the upper limit of solids loading is governed by the viscosity of the resulting solution (e.g., ability to be pumped) and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particles in the resulting powder product.

[0276] Techniques and methods for spray drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H.Perry, D.W.Green & J.O. Maloney, eds.), McGraw-Hill book co. (1984), and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). Generally, spray drying is carried out at an inlet temperature of about 60°C to about 200°C, e.g., about 95°C to about 185°C, about 110°C to about 182°C, about 96°C to about 180°C, e.g., about 145°C. Spray drying is generally carried out at an outlet temperature of about 30°C to about 90°C, e.g., about 40°C to about 80°C, about 45°C to about 80°C, e.g., about 75°C. The atomization flow rate is generally about 4 kg / h to about 12 kg / h, e.g., about 4.3 kg / h to about 10.5 kg / h, e.g., about 6 kg / h or about 10.5 kg / h. The feed flow rate is generally about 3 kg / h to about 10 kg / h, e.g., about 3.5 kg / h to about 9.0 kg / h, e.g., about 8 kg / h or about 7.1 kg / h. The atomization ratio is generally about 0.3 to 1.7, e.g., about 0.5 to 1.5, e.g., about 0.8 or about 1.5.

[0277] Removal of the solvent may require a subsequent drying step, such as tray drying, fluidized bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., from about room temperature to about 200°C).

[0278] In another aspect, the invention features a process for preparing amorphous Compound 33, comprising spray-drying the compound. In another embodiment, the process comprises combining Compound 33 (or a salt, solvate, or hydrate thereof) with a suitable solvent or mixture of solvents and then spray-drying the mixture to obtain amorphous Compound 33. In another embodiment, the solvent is an organic solvent or mixture of organic solvents. In another embodiment, the solvent is an organic solvent or mixture of organic solvents selected from dichloromethane (DCM), ethanol (EtOH), tetrahydrofuran (THF), and 2-methyltetrahydrofuran (Me-THF). In another embodiment, the solvent mixture comprises one or more organic solvents in combination with water, such as about 1% water, about 2% water, about 3% water, about 5% water, about 10% water, about 12.5% ​​water, about 15% water, or about 20% water, based on the total volume of the solvent mixture. In one embodiment, the solvent mixture comprises DCM, EtOH, and about 10% water. In one embodiment, the solvent mixture comprises about 70% DCM, about 29% EtOH, and about 1% water. In another embodiment, the solvent mixture comprises about 65.98% water, about 27.17% EtOH, and about 0.87% water. In another embodiment, the solvent mixture comprises about 59% DCM, about 40% EtOH, and about 1% water. In one embodiment, the solvent mixture comprises THF and water. In another embodiment, the solvent mixture comprises Me-THF, EtOH, and water. Other suitable exemplary solvents are as described in WO2011 / 119984, the entire contents of which are incorporated herein by reference.

[0279] In another embodiment, the process includes: a) forming a mixture comprising compound 33 (or a salt, solvate, or hydrate thereof), a polymer, and a solvent or a mixture of solvents; and b) spray-drying the mixture to form a solid dispersion.

[0280] Another aspect of the present invention provides pharmaceutical compositions comprising a compound according to any one of formulas selected from Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing, is administered to a patient in need of treatment.

[0281] The pharmaceutical composition can further comprise at least one pharmaceutically acceptable carrier.In some embodiments, at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants.In some embodiments, at least one pharmaceutically acceptable is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0282] It is also understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise another active therapeutic agent. Alternatively, pharmaceutical compositions comprising at least one compound of Formula I, IA, IB, IC, ID, IE, IF, IG, and IH, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and tautomers thereof, and deuterated derivatives of any of the foregoing, can be administered as separate compositions simultaneously with, before, or after a composition comprising at least one other active therapeutic agent. In certain embodiments, pharmaceutical compositions comprising at least one compound selected from Compounds 1-342 tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the foregoing, can be administered as separate compositions simultaneously with, before, or after a composition comprising at least one other active therapeutic agent.

[0283] As mentioned above, the pharmaceutical compositions disclosed herein can optionally further comprise at least one pharmaceutically acceptable carrier.At least one pharmaceutically acceptable carrier can be selected from adjuvants and vehicles.As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants that are suitable for the specific dosage form desired.Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, e.g., produces any undesired biological effect, or interacts in a deleterious manner with any component(s) of the other pharmaceutically acceptable compositions, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose), and the like. Ingredients include, but are not limited to, cellulose acetate, sodium cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, larkspur, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants.

[0284] In another aspect of the present invention, compounds and pharmaceutical compositions described herein are used to treat AATD.In some embodiments, the subject who needs to be treated with the compounds and compositions of the present invention has ZZ mutation.In some embodiments, the subject who needs to be treated with the compounds and compositions of the present invention has SZ mutation.

[0285] In some embodiments, the methods of the present invention comprise administering to a patient in need of treatment at least one compound selected from any of the compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the foregoing. In some embodiments, the compound of Formula I is selected from compounds 1-342, tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the foregoing. In some embodiments, the patient in need of treatment has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments, the patient in need of treatment is homozygous for the Z mutation in the alpha-1 antitrypsin gene.

[0286] Another aspect of the present invention provides a method of modulating alpha-1 antitrypsin activity, comprising contacting the alpha-1 antitrypsin with at least one compound of Formula I, IA, IB, IC, ID, IE, IF, IG, and IH, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the foregoing. In certain embodiments, the method comprises contacting the alpha-1 antitrypsin with at least one compound selected from Compounds 1-342, as well as tautomers of these compounds, pharmaceutically acceptable salts of these compounds, and deuterated derivatives of any of the foregoing.

[0287] Some embodiments of the present invention provide spray-dried dispersions of compounds of the present invention, pharmaceutically acceptable salts, and deuterated derivatives thereof. In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a salt or deuterated derivative thereof) and a polymer. In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a salt or deuterated derivative thereof) and polyvinylpyrrolidone / vinyl acetate (PVPVA). In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a salt or deuterated derivative thereof) and hydroxypropylmethylcellulose (HPMC). In some embodiments, the spray-dried dispersion comprises 30-50% Compound 33 (or a salt or deuterated derivative thereof) and HPMCAS. In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a salt or deuterated derivative thereof) and a polymer. In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a salt or deuterated derivative thereof) and polyvinylpyrrolidone / vinyl acetate (PVPVA). In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a salt or deuterated derivative thereof) and hydroxypropyl methylcellulose (HPMC). In some embodiments, the spray-dried dispersion comprises 50-80% Compound 33 (or a salt or deuterated derivative thereof) and HPMCAS.

[0288] III. Compound Preparation All general formulas, subgeneric formulas, and specific compound formulas disclosed herein are considered part of the present invention.

[0289] A. Compounds of Formula I The compounds of the invention can be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing the compounds of Formulas I, IA, IB, IC, ID, IE, IF, IG, and IH, compounds 1-342, tautomers of those compounds, pharmaceutically acceptable salts of those compounds and their tautomers, and deuterated derivatives of any of the foregoing, the following abbreviations are used: Abbreviation 18-Crown-6 = 1,4,7,10,13,16-Hexaoxacyclooctadecane BrettPhos Pd G1 = chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) or (BrettPhos)palladium(II) phenethylamine chloride BrettPhos Pd G4 = Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium CBzCl = benzyl chloroformate Chos = 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl Cs2CO3 = Cesium carbonate DCE = 1,2-dichloroethane DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide Dppf = 1,1'-ferrocenediyl-bis(diphenylphosphine) DTBPF = 1,1'-bis(di-tert-butylphosphino)ferrocene EtOAc = ethyl acetate HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) IPA = Isopropyl alcohol KOtBu = potassium tert-butoxide K3PO4 = potassium phosphate tribasic MeOH = methanol MP-TMT scavenger resin = macroporous polystyrene-bound trimercaptotriazine, the resin-bound equivalent of 2,4,6-trimercaptotriazine (TMT). MTBE = methyl tert-butyl ether NaCNBH3 = sodium cyanoborohydride NMM = N-methylmorpholine NaOtBu = sodium tert-butoxide Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2 = Palladium(II) acetate Pd(tBu3P)2 = bis(tri-tert-butylphosphine)palladium(0) PivCl = pivaloyl chloride PTSA = p-toluenesulfonic acid monohydrate rac-BINAP = (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene [Rh(COD)Cl]2 = chloro(1,5-cyclooctadiene)rhodium(I) dimer SEMCl = 2-(trimethylsilyl)ethoxymethyl chloride SFC = Supercritical Fluid Chromatography SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G4 = Dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium SPM32 = 3-mercaptopropyl ethyl sulfide silica TBAB = tetrabutylammonium bromide TBAF = tetrabutylammonium fluoride tBuXPhos Pd G1 = chloro[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) or t-BuXPhos palladium(II) phenethylamine chloride tBuXPhos Pd G3 = [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd G4 = methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran THP = tetrahydropyran TMSI = iodotrimethylsilane XantPhos Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate XPhos Pd G1 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride or (XPhos)palladium(II) phenethylamine chloride XPhos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0290] In some embodiments, processes for preparing compounds of Formula I, tautomers, pharmaceutically acceptable salts of the compounds or tautomers, or deuterated derivatives of any of the foregoing include the reactions shown in Schemes 1-9 below.

[0291] Scheme 1 provides a method for preparing a compound of Formula I, a tautomer, salt, or derivative thereof, from a compound of Formula 1-1, wherein the variable X 1 , X 2 R 0 , R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 , and n is as defined in formula I above. 1 , Z 2 , or Z 3 When at least one of the protecting groups (PG 1 In some embodiments, PG 1is selected from p-toluenesulfonamide (tosyl), pivaloyl (Piv), trimethylsilylethoxymethyl (SEM), tetrahydropyranyl (THP), phenylsulfonyl, benzylcarbamate (Cbz), benzyl (Bn), p-methoxybenzyl (PMB), t-butylcarbamate (Boc), allyloxycarbamate (Alloc), 9-fluorenylmethylcarbamate (FMOC), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxyethyl (MEM), trifluoroacetamide, or any other suitable protecting group. Any suitable conditions known in the art, such as conditions for deprotection of nitrogen atoms, can be used to prepare compounds of Formula I from compounds of Formula 1-1. In some embodiments, the reaction shown in Scheme 1 is carried out in the presence of a base such as a metal hydroxide (e.g., aqueous NaOH or KOH). The reaction can be carried out at elevated temperatures (e.g., 60°C). A mixture of solvents such as MeOH and THF can be used. Alternative conditions known in the art include the use of PG 1 can be suitably used for deprotection of [ka]

[0292] In some embodiments, as shown in Scheme 2, the process for the preparation of a compound of formula 1-1 comprises preparing a compound of formula 2-1, where X 1 , X 2 R 0 , R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 and n is as defined in Formula I above) with a boronic acid or ester of Formula 2-3, a boronic ester of Formula 2-4, or a boronic ester of Formula 2-5. 11 can be hydrogen or a suitable alkyl such as Me, Et, propyl, isopropyl, or isobutyl. 12can independently be hydrogen, methyl, or any other suitable alkyl group. 3 is any suitable halide (e.g., I, Br, or Cl). The variable p can be 1 or 2. In some embodiments, the reaction to produce compound 1-1 is carried out in the presence of a base (Na2CO3, Cs2CO3, K3PO4) in the presence of any suitable coupling reagent, such as a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(OAc)2, Pd(PPh3)4, or XPhos Pd G3). In some embodiments, the reaction can be carried out in a polar solvent (1,4-dioxane) in the presence of heat (above 80°C). [ka]

[0293] Scheme 3 refers to an additional process for the preparation of compounds of formula 1-1 from compounds of formula 2-1, where the variables shown in Scheme 3 are defined as above. 13 is a hydrogen atom or any suitable alkyl group (e.g., Me, Et). X 4 is any suitable halogen (e.g., I, Br, or Cl). Compounds of formula 3-1 can be prepared from compounds of formula 2-1 using any suitable conditions for forming a boronate ester from an aryl halide. In some embodiments, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane can be used in the presence of a catalyst (e.g., Pd(dppf)Cl) and an organic base (e.g., triethylamine). Compounds of formula 3-1 can be converted to compounds of formula 1-1 via a cross-coupling reaction with halides of formula 3-2 in the presence of a suitable catalyst and base. For example, in some embodiments, the coupling reaction is carried out in the presence of a catalyst such as Pd(dppf)Cl, a base (e.g., NaCO). The reaction can be carried out in a polar solvent (e.g., 1,4-dioxane) at elevated temperatures (e.g., above 90°C). [ka]

[0294] Scheme 4 provides a process for the preparation of compounds of formula 2-1. 5 and X 6 is any suitable halogen (e.g., Cl, Br, or I). 1is hydrogen, SiMe3, or SnBu4. All other variables are defined as above. Compounds of Formula 2-1 can be used in Schemes 2 and 3 above. Any suitable conditions for alkyne coupling (e.g., Sonagashira coupling) known in the art can be used to prepare compounds of Formula 4-3 from compounds of Formula 2-1 and alkynes of Formula 4-2. In some embodiments, this reaction can be carried out in the presence of CuI and Pd(PPh3)2Cl2. In some embodiments, a base such as triethylamine or DIPEA can be used. In some additional embodiments, KOH or CsF can be present. Compounds of Formula 4-3 and amines of Formula 4-4 can be converted to compounds of Formula 4-5 using any amine coupling conditions known in the art. For example, in some embodiments, the reaction is carried out in the presence of a catalyst (e.g., BrettPhos Pd G1, tBuXPhos Pd G1, BrettPhos Pd G4, or tBuXPhos Pd G1). The reaction may be carried out in the presence of a suitable base (e.g., NaOtBu) and a solvent such as THF, tBuOH, or ethanol. In some embodiments, the reaction may be carried out with heating (70°C). The compound of formula 4-5 may be converted to the compound of formula 4-6 using any suitable conditions for the intramolecular reaction of an amine with an alkyne. The reaction may be carried out in the presence of a polar solvent (DMSO, EtOH, or AcOH) with heating (e.g., 60°C or 150°C). In some embodiments, the reaction is carried out in the presence of CuI. Any suitable conditions known to those skilled in the art, such as those used for protecting nitrogen atoms, may be used to generate the compound of formula 4-7 from the compound of formula 4-6. In some embodiments, the reaction is carried out in the presence of pivaloyl chloride (Piv-Cl) or p-toluenesulfonyl chloride (Ts-Cl). The reaction may be carried out in the presence of a base (e.g., K0tBu). A suitable halogenating agent (eg, N-iodosuccinimide) can be used to convert compounds of formula 4-7 to compounds of formula 2-1. [ka]

[0295] Scheme 5 provides a process for preparing compounds of formula 5-6 from compounds of formula 5-1. 7 is any suitable halogen (e.g., Cl, Br, or I). 8 is a suitable halogen (e.g., Cl, Br, or I). Other variables are defined as in Formula I. Compounds of Formula 5-6 can be used as compounds of Formula 1-1 in Scheme 1. Compounds of Formula 5-3 can be prepared by reacting compounds of Formula 5-1 with compounds of Formula 5-2. The reaction can be carried out in the presence of a catalyst system (e.g., tBuXPhos Pd G4) and a base (e.g., NaOtBu). The reaction can be carried out in a solvent such as tBuOH. Compounds of Formula 5-4 can be prepared from compounds of Formula 5-3 using any reagent suitable for protecting nitrogen atoms. In some embodiments, pivaloyl chloride (Piv-Cl) in the presence of a base (e.g., K0tBu) can be used. Compounds of Formula 5-6 can be prepared by reacting compounds of Formula 5-1 with compounds of Formula 5-2 in the presence of a catalyst (e.g., Pd(P t It can be prepared by reacting a compound of formula 5-4 with an alkyne of formula 5-5 in the presence of Bu3)2) and an amine base (e.g., N-methyldicyclohexylamine). In some embodiments, the reaction can be carried out in a polar solvent such as 1,4-dioxane with heating (110° C.). [ka]

[0296] Scheme 6 shows a process for the preparation of compounds of formula 6-8. Compounds of formula 6-8 can be used as compounds of formula 2-1 above. X 9 and X 10 is an independently selected halogen (e.g., Cl, Br, or I). 11 is a halogen (e.g., Br or I). 2 is a hydrogen atom, SnBu4, or SiMe3. All other variables are as defined in Formula I.

[0297] The compound of formula 6-1 can be coupled to an alkyne of formula 6-2 using any suitable conditions for coupling aryl halides to alkynes (e.g., Sonagashira coupling) known to those skilled in the art. In some embodiments, this reaction can be carried out in the presence of CuI and Pd(PPh3)2Cl2. In some embodiments, a base such as triethylamine or DIPEA can be used. In some alternative embodiments, a base such as KOH or CsF can be used. Any suitable conditions, such as conditions for carrying out an amination reaction, can be used to react a compound of formula 6-3 and an amine of formula 6-4 to obtain a compound of formula 6-5. For example, the reaction can be carried out in the presence of a catalyst (e.g., BrettPhos Pd G1, tBuXPhos Pd G1, BrettPhos Pd G4, or tBuXPhos Pd G1), a suitable base (e.g., NaOtBu), and a solvent such as THF, tBuOH, or ethanol. In some embodiments, the reaction can be carried out with heating (70 °C). Compounds of formula 6-6 can be prepared from compounds of formula 6-5 using any suitable conditions for the intramolecular addition of an amine to an alkyne. In some embodiments, the reaction can be carried out by heating compounds of formula 6-5 in a suitable solvent (e.g., DMSO at 150°C). In an alternative embodiment, compounds of formula 6-5 can be heated (60°C) in a solvent such as EtOH in the presence of AcOH. Compounds of formula 6-7 can be prepared from 6-6 using a suitable protecting group reagent. For example, PivCl, SEM-Cl, or PhSO2-Cl can be used. The reaction can be carried out in the presence of any suitable base (e.g., KOtBu or KOH). Compounds of formula 6-8 can be prepared by reacting compounds of formula 6-7 with a halogenating agent (e.g., N-iodosuccinimide or N-bromosuccinimide) in a solvent such as dichloromethane. [ka]

[0298] Scheme 7 provides a process for the preparation of compounds of formula 7-3.11 is a suitable halide (e.g., Cl, Br, I). 14 is a hydrogen atom or any suitable alkyl group (e.g., Me or Et). 14 The groups may also be linked through a single carbon-carbon bond to form a cyclic boronic ester. 15 is any suitable alkyl (e.g., Me or Et). Ar is any suitable 5- or 6-membered aromatic group, such that the compound of formula 7-3 can also be a compound of formula I. Any suitable conditions known to those skilled in the art can be used for coupling the compound of formula 6-8 with the boronic acid or boronic ester of formula 7-1. In some embodiments, the coupling reaction is carried out in the presence of a palladium-based catalyst (e.g., Pd(dppf)Cl2, Pd(PPh3)4, XPhos Pd G3, or Pd2(dba)3) and a base (e.g., Na2CO3 or K3PO4). The reaction can be carried out in a polar solvent (1,4-dioxane or DMF) at an elevated temperature (e.g., 70°C). Any suitable reagent known in the art, for example, suitable for hydrolysis of the ester, can be used to remove the protecting group PG from the nitrogen atom. 1 A reagent suitable for removing ##STR00001## can be used to prepare a compound of formula 7-3 from a compound of formula 7-2. In some embodiments, an aqueous solution of a base (e.g., NaOH or KOH) in a polar solvent (e.g., a mixture of THF and MeOH) can be used. The reaction can be carried out with heating (e.g., 55° C.). In an alternative embodiment, the reaction can be carried out in the presence of an amine (e.g., piperidine). [ka]

[0299] Scheme 8 shows an alternative process for the preparation of compounds of formula 7-3 from 6-8. 11 is a suitable halide (e.g., Cl, Br, I). 16 is any suitable alkyl (e.g., Me). 12 is any suitable halide (e.g., Cl, Br, I). 17is any suitable alkyl that forms an ester group (e.g., Me, Et, tBu). Compounds of formula 8-1 can be prepared from 7-3 using any suitable conditions known to those skilled in the art for the preparation of arylboronic esters. In some embodiments, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a catalyst (e.g., Pd(dppf)Cl) and an organic base (e.g., triethylamine) can be used. The reaction can be carried out in a solvent such as xylene with heating (150°C). Compounds of formula 8-1 can be reacted with aryl halides of formula 8-2 using any suitable conditions known to those skilled in the art, such as those for Suzuki coupling reactions. In some embodiments, a catalyst such as Pd(dppf)Cl is used. In some embodiments, this reaction can be carried out in a polar solvent (e.g., 1,4-dioxane) at elevated temperature (95°C) in the presence of a base (e.g., NaCO). Any suitable conditions for ester hydrolysis and nitrogen protecting group removal can be used to convert a compound of formula 8-3 to a compound of formula 7-3. In some embodiments, an aqueous solution of a base (e.g., NaOH or KOH) in a polar solvent (e.g., THF and MeOH mixture) can be used. The reaction can be carried out with heating (e.g., 55°C). In an alternative embodiment, the reaction can be carried out in the presence of an amine (e.g., piperidine). [ka]

[0300] Scheme 9 shows an alternative process for the preparation of compounds of formula 7-3. 13 is any suitable halogen (e.g., I, Br, or Cl). 14 is any suitable halogen (e.g., I, Br, or Cl). 18is any suitable alkyl group that forms an ester (e.g., Me or Et). Other variables are as defined in Formula I. In some embodiments, compounds of formula 9-3 can be prepared by the reaction of compounds of formula 9-1 with compounds of formula 9-2. Any suitable conditions for the coupling of amines and aryl halides can be used. For example, a palladium catalyst system (e.g., tBuXPhos Pd G4) and a base (e.g., NaOtBu) can be used. Compounds of formula 9-4 can be prepared from 9-3 using any suitable reagent for protecting the nitrogen atom. Compounds of formula 9-4 can be reacted with alkynes of formula 9-5 under suitable conditions to give compounds of formula 9-6. For example, catalyst systems (e.g., Pd(P) with a ligand such as DTBPF) can be used to give compounds of formula 9-6. t In some embodiments, the reaction is carried out in the presence of a base (e.g., N-methyldicyclohexylamine, KHCO3, or K2CO3). Compounds of formula 7-3 can be prepared by the reaction of PG 1 9-6 can be prepared from 9-6 using any suitable conditions for the removal of a nitrogen protecting group, such as 9-6 .... For example, in some embodiments, the reaction can be carried out in the presence of a base (e.g., NaOH, KOH, or NaOH and piperidine). The reaction can be carried out in a heated (70°C) polar solvent system (THF, MeOH, EtOH, water). [ka]

[0301] Non-limiting exemplary embodiments include: 1. A compound of formula (I), [ka] a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above, During the ceremony, (i)R 0 is selected from the following: (a) C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl group is selected from 1 to 4 R A C1-C8 straight chain, branched chain, and cyclic alkyl groups optionally substituted with (b) 1 to 4 R A a 5- to 14-membered aromatic ring optionally substituted with Each R A are independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5-10 membered aromatic rings, and C1-C6 straight chain, branched chain, and cyclic groups; R A wherein the amide nitrogen atom in the amide is optionally substituted with a heterocyclyl group optionally further substituted with oxo; The C1-C6 straight chain, branched chain, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido; the 5-10 membered aromatic ring and C1-C6 straight chain, branched chain, and cyclic group are optionally substituted with 1-4 substituents selected from halogen, C1-C6 straight chain, branched chain, and cyclic groups, and methoxy; R A The group is R 2 R on the group B 1 to 4 R optionally bonded to the group A a 5- to 14-membered aromatic ring optionally substituted with (ii)R 1 is selected from the following: (a) hydrogen, (b) C1 to C8 straight-chain, branched-chain, and cyclic alkyl groups, wherein the alkyl group is: halogen, Cyano, cyanoalkyl, Hydroxy, alkylsulfonyl, and C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, and the C1-C6 straight chain, branched chain, and cyclic groups are halogen, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; (c) halogen, Cyano, cyanoalkyl, sulfone, sulfonamides, Hydroxy, and C1-C8 straight-chain, branched-chain, and cyclic alkoxy or cyclic thioalkyl groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 halogen or alkoxy groups; (d) C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups optionally substituted with C1-C6 straight-chain or branched-chain alkyl groups; (e) an aminosulfonyl group optionally substituted with one or two substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups; (f) C1-C6 linear, branched, and cyclic alkylsulfonylamino groups, and (g) a phosphine oxide group, a phosphine oxide group optionally substituted with one or two substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups; (h) C1-C6 straight-chain, branched-chain, and cyclic trialkylsilyl groups; (i) C1-C6 alkylamide, (iii)R 2is selected from 5- and 6-membered heterocycles (optionally substituted with oxo and / or C1-C6 straight and branched chain alkyl groups), and 5-6-membered aromatic rings containing 0-4 heteroatoms selected from O, N and S, and said 5-membered aromatic rings are selected from 1-4 R B group, and the 6-membered aromatic ring is optionally substituted with 1 to 5 R B optionally substituted with a group, B The base is independent, Amides optionally substituted with 1 to 3 groups selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (optionally substituted with oxo, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, hydroxyalkyl, amido, alkylsulfonyl, and acetamido), or wherein the amide nitrogen atom forms part of a 3- to 8-membered heterocyclyl ring (optionally substituted with alkylsulfonyl or C1-C6 straight-chain, branched-chain, and cyclic alkyl groups); imidazolidine-2,4-dione, heterocyclyl optionally substituted with one or more groups independently selected from oxo, acyl, and C1-C6 straight-chain, branched-chain, and cyclic alkyl groups (optionally further substituted with 1-3 groups independently selected from oxo, hydroxy, and acyl); phosphorous acid optionally esterified with a C1-C6 straight-chain, branched-chain, or cyclic alkyl group; di(C1-C6) alkylphosphine oxide, (C1-C6) alkylphosphinic acids optionally esterified with C1-C6 straight-chain, branched-chain, or cyclic alkyl groups; halogen, Cyano, Hydroxy, Uronic acids or carboxylic acids optionally esterified with C1-C6 straight, branched, or cyclic alkyl groups; Oxo, dihydroxyboryl, 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, optionally substituted with 1 or 2 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, Hydroxy, carboxylic acids, pyrrolidin-2-one, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, and 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; sulfonic acids, alkylsulfonamides, C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, an aminosulfonyl group, an aminosulfonyl group optionally substituted with one or two substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups; C1-C6 straight chain, branched chain, and cyclic alkyl groups, halogen, Hydroxy, carboxylic acids, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, heterocyclyl optionally substituted with oxo, and C1-C6 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from: C1-C6 straight chain, branched chain, and cyclic alkoxy groups, halogen, Hydroxy, carboxylic acids, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; and a tetrazolyl group, halogen, Hydroxy, carboxylic acids, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and a tetrazolyl group optionally substituted with a substituent selected from a C1-C6 straight-chain, branched-chain, and cyclic alkoxy group; two adjacent hydrogens on a 5- or 6-membered aromatic ring are replaced by bonds to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S, and one to six R B Bicyclic R optionally substituted with a group 2 can form a group, (iv) X 1 and X 2 are independently selected from hydrogen, halogen, cyano, hydroxy, C1-C6 straight chain, branched chain, and cyclic groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups, wherein the C1-C6 straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v)W 1 and W 2 are each independently selected from C and N; (vi) each [ka] represents a single or double bond, provided that one [ka] is the only double bond, (vii) Each R 3are independently selected from hydrogen, halogen, cyano, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, wherein the C1-C6 straight-chain, branched-chain, and cyclic alkyl groups and the C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogen, hydroxyl groups, and carboxylic acids; (viii) n is an integer selected from 0, 1, 2, and 3; (ix)Z 1 , Z 2 , and Z 3 are independently selected from carbon, nitrogen, sulfur, and oxygen; Z 1 , Z 2 , and / or Z 3 is a carbon or nitrogen, the valence electrons of the carbon or nitrogen are completed by a hydrogen atom, a halogen, a C1-C6 straight-chain, branched-chain, and cyclic alkyl group, and a C1-C6 straight-chain, branched-chain, and cyclic alkoxy group, and said C1-C6 straight-chain, branched-chain, and cyclic alkyl group, and said C1-C6 straight-chain, branched-chain, and cyclic alkoxy group are optionally substituted with 1 to 4 substituents independently selected from a halogen, a hydroxy group, and a carboxylic acid, a compound of formula (I), a tautomer thereof, a pharmaceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above. 2.R 0 is selected from aryl rings, heteroaryl rings, and C1-C8 straight-chain, branched, and cyclic alkyl groups, each of which is optionally substituted with 1-2 substituents independently selected from halogen, carboxylic acid, C1-C6 straight-chain, branched, and cyclic alkyl groups, C1-C6 straight-chain, branched, and cyclic alkoxy groups, aryl rings, and heteroaryl rings, its tautomers, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts. 3.R 0 but, [ka] 3. The compound of embodiment 1 or 2, its tautomer, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, selected from: 4.R 1 but, Hydrogen, methyl, trimethylsilyl, trifluoromethyl, [ka] a compound of any one of embodiments 1-3, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, selected from: 5.R 2 but, [ka] 5. The compound of any one of embodiments 1-4, its tautomer, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, selected from: 6.Z 1 , Z 2 , and Z 3 is nitrogen and the other is selected from carbon and nitrogen, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, 7.Each R 3are independently selected from hydrogen, deuterium, halogen, a C1-C6 straight chain alkyl group, and a heterocyclyl group, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt. 8.X 1 and X 2 are independently selected from hydrogen and halogen, a tautomer thereof, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt. 9. The compound according to embodiment 1, selected from compounds of formulae IA, IB, IC, ID, IE, IF, IG, and IH, [ka] [ka] tautomers thereof, pharmaceutically acceptable salts of said compounds, pharmaceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts, wherein: R 0 , R 1 , R 2 , R 3 and n is defined for compounds of formula (I), X 1 and X 2 are independently selected from hydrogen and fluorine, or X 1 is fluorine, and X 2 is hydrogen or X 2 is fluorine, and X 1 is hydrogen or X 1 and X 2 are each hydrogen, W 1and W 2 are each independently selected from C and N; Y 1 , Y 2 , Y 3 , and Y 4 But independently, hydrogen, Cyano, halogen groups, C1-C6 straight chain, branched chain, and cyclic alkyl groups, C1-C6 straight chain, branched chain, and cyclic alkoxy groups, Hydroxy, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups, and C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups, optionally substituted with 1 to 4 substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups; Y 5 , Y 6 , Y 7 , and Y 8 But independently, hydrogen, halogen groups, Hydroxy, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 independently selected halogen substituents, and C1-C6 straight chain, branched chain, and cyclic alkoxy groups; Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , and Y 16 But independently, carboxylic acids, hydrogen, halogen groups, C1-C6 straight-chain, branched-chain, and cyclic alkylsulfonyl groups, C1-C6 straight-chain, branched-chain, and cyclic alkyl groups optionally substituted with 1 to 4 independently selected halogen substituents, and C1-C6 straight chain, branched chain, and cyclic alkoxy groups; Y 17 , Y 18 , Y 19 , Y 20 , and Y 21 But independently, hydrogen, carboxylic acids, halogen groups, Cyano, Hydroxy, C1-C6 straight chain, branched chain, and cyclic alkyl groups, halogen, hydroxy, and C1-C6 straight chain, branched chain, and cyclic alkyl groups optionally substituted with 1 to 4 substituents independently selected from: carboxylic acids; C1-C6 straight-chain, branched-chain, and cyclic alkoxy groups optionally substituted with carboxylic acid groups; dihydroxyboryl, sulfonic acids, a carboxylic acid optionally esterified with a uronic acid; tetrazolyl group, an aminosulfonyl group, an aminosulfonyl group optionally substituted with one or two substituents independently selected from C1-C6 straight-chain, branched-chain, and cyclic alkyl groups; C1-C6 straight chain, branched chain, and cyclic alkylsulfonyl groups; However, in formulas I to E, Y 17 , Y 18 , Y 19 , Y 20 , and Y 21 and IH, wherein at least one of is hydrogen; a tautomer thereof; a pharmaceutically acceptable salt of said compound; a pharmaceutically acceptable salt of said tautomer; a deuterated derivative of said compound; a deuterated derivative of said tautomer; and / or a deuterated derivative of said salt. 10.Y 17 , Y18 , Y 19 , Y 20 , and Y 21 one or more of the following may be methyl, methoxy, cyano, fluorine, hydroxy, -CF3, -B(OH)2, -SO2NHMe, -SO2Me, -SO2H, -CH2CO2H, [ka] the compound of embodiment 9, its tautomer, a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, selected from 11. A compound se...

Claims

1. A compound of formula (I), 【Chemical 264】 a tautomer thereof, a pharma- ceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above, During the ceremony, (i) R ０ is selected from: (a) C １ ~C ８ Linear, branched, and cyclic alkyl groups, wherein the alkyl group is selected from 1 to 4 R Ａ Optionally substituted with １ ~C ８ Straight-chain, branched-chain, and cyclic alkyl groups, and (b) 1 to 4 R Ａ A 5- to 14-membered aromatic ring optionally substituted with Each R Ａ are independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, carboxylic acid, 5-10 membered aromatic rings, and C １ ~C ６ selected from linear, branched, and cyclic groups; R Ａ wherein the amide nitrogen atom in said amide is optionally substituted with a heterocyclyl group which is optionally further substituted with oxo; Said C １ ~C ６ the straight chain, branched chain, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido; The 5- to 10-membered aromatic ring and C １ ~C ６ The straight chain, branched chain and cyclic groups are preferably selected from the group consisting of halogen, C １ ~C ６ optionally substituted with 1 to 4 substituents independently selected from straight chain, branched chain, and cyclic groups and methoxy; R Ａ The group is R ２ R on the group Ｂ a 5- to 14-membered aromatic ring optionally attached to a group; (ii) R １ is selected from: (a) hydrogen, (b) C １ ~C ８ Straight chain, branched chain and cyclic alkyl groups, said alkyl groups being: halogen, Cyano, Cyanoalkyl, Hydroxy, Alkylsulfonyl, and C １ ~C ６ linear, branched, and cyclic groups, １ ~C ６ The straight chain, branched chain, and cyclic groups are independently selected from alkyl groups and alkyl groups, １ ~C ６ Straight chain, branched chain and cyclic groups include halogen, Hydroxy, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ８ Straight chain, branched chain and cyclic alkyl groups; (c) halogen, Cyano, Cyanoalkyl, Sulfone, Sulfonamides, Hydroxy, and C optionally substituted with 1 to 4 halogen or alkoxy groups １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkyl groups; １ ~C ８ linear, branched and cyclic alkoxy or cyclic thioalkyl groups; (d) C １ ~C ６ C optionally substituted with a straight or branched chain alkyl group １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups; (e) C １ ~C ６ an aminosulfonyl group, optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; (f) C １ ~C ６ Linear, branched, and cyclic alkylsulfonylamino groups, and (g) C １ ~C ６ a phosphine oxide group, optionally substituted with one or two substituents independently selected from linear, branched, and cyclic alkyl groups; (h) C １ ~C ６ Linear, branched, and cyclic trialkylsilyl groups; (i) C １ ~C ６ Alkyl amides, (iii) R ２ is selected from a 5-6 membered aromatic ring containing 0-4 heteroatoms independently selected from O, N and S, said 5 membered aromatic ring being selected from 1-4 R Ｂ groups, and the six-membered aromatic ring is optionally substituted with 1 to 5 R Ｂ R Ｂ The base is independently Amides, １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups (optionally substituted with heteroaryl), 4- to 6-membered heterocyclyl (oxo, C １ ~C ６ or the amide nitrogen atom is optionally substituted with 1 to 3 groups independently selected from linear, branched, and cyclic alkyl groups, hydroxyalkyl, amido, alkylsulfonyl, and acetamido; or the amido nitrogen atom is optionally substituted with a 3 to 8 membered heterocyclyl ring (alkylsulfonyl or １ ~C ６ amides, which form part of a cyclic alkyl group, optionally substituted with straight-chain, branched-chain, and cyclic alkyl groups; imidazolidine-2,4-dione, Heterocyclyl includes oxo, acyl, and C １ ~C ６ heterocyclyl, optionally substituted with one or more groups independently selected from straight-chain, branched-chain, and cyclic alkyl groups, optionally further substituted with 1 to 3 groups independently selected from oxo, hydroxy, and acyl; C １ ~C ６ phosphorous acid, optionally esterified with a straight-chain, branched-chain, or cyclic alkyl group; Ji (C １ ~C ６ ) alkylphosphine oxide, C １ ~C ６ Optionally esterified with a straight-chain, branched-chain, or cyclic alkyl group (C １ ~C ６ ) alkylphosphinic acids, halogen, Cyano, Hydroxy, Uronic acid or C １ ~C ６ Carboxylic acids optionally esterified with straight-chain, branched-chain, or cyclic alkyl groups; Oxo, Dihydroxyboryl, 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, １ ~C ６ straight chain, branched chain, and cyclic alkyl groups, which are optionally substituted with one or two substituents independently selected from: Hydroxy, Carboxylic acids, pyrrolidin-2-one, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups, and C １ ~C ６ 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from: straight chain, branched chain, and cyclic alkoxy groups; Sulfonic acid, Alkyl sulfonamides, C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups; an aminosulfonyl group, C １ ~C ６ an aminosulfonyl group, optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; C １ ~C ６ Linear, branched, and cyclic alkyl groups, halogen, Hydroxy, Carboxylic acids, C １ ~C ６ Linear, branched, and cyclic alkoxy groups; heterocyclyl optionally substituted with oxo, and amide, １ ~C ６ Straight chain, branched chain and cyclic alkyl groups; C １ ~C ６ Linear, branched, and cyclic alkoxy groups, halogen, Hydroxy, Carboxylic acids, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ６ Linear, branched, and cyclic alkoxy groups, and A tetrazolyl group, halogen, Hydroxy, Carboxylic acids, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ a tetrazolyl group, optionally substituted with substituents selected from linear, branched, and cyclic alkoxy groups; two adjacent hydrogens on the 5- or 6-membered aromatic ring are replaced by bonds to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S; Ｂ Bicyclic R optionally substituted with a group ２ can form a group, (iv) X １ and X ２ are independently hydrogen, halogen, cyano, hydroxy, C １ ~C ６ is selected from linear, branched, and cyclic groups; １ ~C ６ The straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups; １ ~C ６ The straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v) W １ and W. ２ each is independently selected from C and N; (vi) Between Z 2 and Z 3 【Chemistry 265】 is a double bond, and between Z 1 and Z 2 【Chemical 266】 is a single bond, (vii) Each R ３ are independently hydrogen, halogen, cyano, C １ ~C ６ Linear, branched, and cyclic alkyl groups, and C １ ~C ６ is selected from linear, branched, and cyclic alkoxy groups; １ ~C ６ Linear, branched, and cyclic alkyl groups, as well as the C １ ~C ６ The straight chain, branched chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogens, hydroxy groups, and carboxylic acids; (viii) n is an integer selected from 0, 1, 2, and 3; (ix) Z １ and Z ２ is nitrogen and Z ３ is selected from carbon and nitrogen, and the valence electrons of the carbon or nitrogen are selected from hydrogen atoms, halogens, C １ ~C ６ Linear, branched, and cyclic alkyl groups, and C １ ~C ６ Completed with straight chain, branched chain, and cyclic alkoxy groups, said C １ ~C ６ Linear, branched, and cyclic alkyl groups, as well as the C １ ~C ６ The straight chain, branched chain, and cyclic alkoxy groups are optionally substituted with 1 to 4 substituents independently selected from halogens, hydroxy groups, and carboxylic acids; A compound of formula (I), its tautomer, a pharma- ceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above.

2. R ０ is an aryl ring, a heteroaryl ring, and C １ ~C ８ are selected from linear, branched, and cyclic alkyl groups, each of which is independently selected from halogen, carboxylic acid, C １ ~C ６ Straight chain, branched chain and cyclic alkyl groups, C １ ~C ６ 2. The compound of claim 1, optionally substituted with 1 to 2 substituents independently selected from straight-chain, branched-chain, and cyclic alkoxy groups, aryl rings, and heteroaryl rings, its tautomers, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compound, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts.

3. R ０ but, 【Chemical 267】 3. The compound of claim 1 or 2, selected from: its tautomers, pharma- ceutically acceptable salts of said compounds, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts.

4. R １ but, Hydrogen, methyl, trimethylsilyl, trifluoromethyl, 【Chemical 268】 【Chemical 269】 The compound according to any one of claims 1 to 3, its tautomers, pharma- ceutically acceptable salts of said compounds, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts,

5. R ２ but, 【Chemistry 270】 The compound according to any one of claims 1 to 4, its tautomers, pharma- ceutically acceptable salts of said compounds, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts,

6. Each R ３ are independently hydrogen, deuterium, halogen, C １ ~C ６ A compound according to any one of claims 1 to 5, selected from a straight chain alkyl group, and a heterocyclyl group, a tautomer thereof, a pharma- ceutically acceptable salt of said compound, a pharma- ceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt.

7. X １ and X ２ is independently selected from hydrogen and halogen, its tautomers, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts.

8. The compound of claim 1 selected from the compounds of formulae IA, IB, IC, ID, IE, IF, IG, and IH; 【Chemistry 271】 a tautomer thereof, a pharma- ceutically acceptable salt of said compound, a pharma- ceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt, wherein R ０ , R １ , R ２ , R ３ and n is defined for compounds of formula (I), X １ and X ２ are independently selected from hydrogen and fluorine, or X １ is fluorine, and X ２ is hydrogen or X ２ is fluorine, and X １ is hydrogen or X １ and X ２ are each hydrogen, W １ and W. ２ each is independently selected from C and N; Y １ , Y ２ , Y ３ , and Y ４ But independently, hydrogen, Cyano, Halogen groups, C １ ~C ６ Straight chain, branched chain and cyclic alkyl groups; C １ ~C ６ Linear, branched, and cyclic alkoxy groups, Hydroxy, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ６ linear, branched, and cyclic alkoxy groups; Y ５ , Y ６ , Y ７ , and Y ８ But independently, hydrogen, Halogen groups, Hydroxy, C optionally substituted with 1 to 4 independently selected halogen substituents; １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ linear, branched, and cyclic alkoxy groups; Y ９ , Y １０ , Y １１ , Y １２ , Y １３ , Y １４ , Y １５ , and Y １６ But independently, Carboxylic acids, hydrogen, Halogen groups, C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups; C optionally substituted with 1 to 4 independently selected halogen substituents; １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ linear, branched, and cyclic alkoxy groups; Y １７ , Y １８ , Y １９ , Y ２０ , and Y ２１ But independently, hydrogen, Carboxylic acids, Halogen groups, Cyano, Hydroxy, C １ ~C ６ Straight chain, branched chain and cyclic alkyl groups, which are halogen, Hydroxy, and carboxylic acid, １ ~C ６ Straight chain, branched chain and cyclic alkyl groups; C optionally substituted with a carboxylic acid group １ ~C ６ Linear, branched, and cyclic alkoxy groups; Dihydroxyboryl, Sulfonic acid, a carboxylic acid optionally esterified with a uronic acid; Tetrazolyl group, an aminosulfonyl group, C １ ~C ６ an aminosulfonyl group, optionally substituted with one or two substituents independently selected from linear, branched, and cyclic alkyl groups; C １ ~C ６ linear, branched, and cyclic alkylsulfonyl groups; In the formulae I to E, Y １７ , Y １８ , Y １９ , Y ２０ , and Y ２１ is hydrogen; 2. The compound of claim 1 selected from compounds of formulas I-A, I-B, IC, ID, I-E, IF, IG, and I-H, its tautomers, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and / or deuterated derivatives of said salts.

9. Y １７ , Y １８ , Y １９ , Y ２０ , and Y ２１ At least one of the following is selected from the group consisting of methyl, methoxy, cyano, fluorine, hydroxy, and -CF ３ , -B(OH) ２ , -SO ２ NHMe, -SO ２ Me, -SO ２ H, -CH ２ CO ２ H. 【Chemical 272】 A compound according to claim 8 selected from: a tautomer thereof, a pharma- ceutically acceptable salt of said compound, a pharma- ceutically acceptable salt of said tautomer, a deuterated derivative of said compound, a deuterated derivative of said tautomer, and / or a deuterated derivative of said salt.

10. A compound selected from: 【Chemical 273】 【Chemical 274】 【Chemistry 275】 【Chemical 276】 【Chemical 277】 【Chemical 278】 【Chemical 279】 【Chemistry 280】 【Chemistry 281】 【Chemical 282】 【Chemistry 283】 【Chemical 284】 【Chemistry 285】 【Chemistry 286】 【Chemistry 287】 【Chemistry 288】 【Chemical 289】 【Chemistry 290】 【Chemical 291】 【Chemical 292】 【Chemical 293】 【Chemical Formula 294】 【Chemistry 295】 【Chemical 296】 【Chemical 297】 【Chemical 298】 【Chemical 299】 【Chemistry 300】 【Chemistry 301】 【Chemistry 302】 【Chemistry 303】 【Chemistry 304】 【Chemistry 305】 【Chemistry 306】 【Chemistry 307】 【Chemistry 308】 【Chemistry 309】 【Chemistry 310】 tautomers thereof, pharma- ceutically acceptable salts of said compounds, pharma- ceutically acceptable salts of said tautomers, deuterated derivatives of said compounds, deuterated derivatives of said tautomers, and deuterated derivatives of said salts.

11. A compound of formula (I'), 【Chemistry 311】 a tautomer thereof, a pharma- ceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above, During the ceremony, (i) R ０ ' is selected from the following: (a) C １ ~C ８ Straight-chain, branched-chain, and cyclic alkyl groups, said alkyl groups being optionally substituted with 1 to 4 R A '; １ ~C ８ Straight chain, branched chain and cyclic alkyl groups; (b) 1 to 4 R Ａ ', a 5-14 membered aromatic ring optionally substituted with Each R Ａ ' are independently selected from halogen, cyano, hydroxy, thiol, sulfonic acid, sulfonamide, sulfinamide, amino, amide, 5-10 membered aromatic rings, and C １ ~C ６ is selected from linear, branched, and cyclic groups; １ ~C ６ The straight chain, branched chain, and cyclic groups are selected from alkyl, alkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, alkylsulfonamido, alkylsulfinamido, aminoalkyl, and alkylamido, and the 5-10 membered aromatic ring, and C １ ~C ６ The straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 substituents independently selected from halogen and methoxy; R Ａ ' group is R ２ 'R on the group Ｂ 1 to 4 R Ａ ', a 5-14 membered aromatic ring optionally substituted with (ii) R １ ' is selected from the following: (a) hydrogen, (b) C １ ~C ８ Straight chain, branched chain and cyclic alkyl groups, said alkyl groups being: halogen, Cyano, Hydroxy, and C １ ~C ６ linear, branched, and cyclic groups, １ ~C ６ The straight chain, branched chain, and cyclic groups are independently selected from alkyl and alkoxy groups; １ ~C ６ Straight chain, branched chain and cyclic groups include halogen, Hydroxy, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ８ Straight chain, branched chain and cyclic alkyl groups; (c) halogen, Cyano, Sulfone, Sulfonamides, Hydroxy, and C optionally substituted with 1 to 4 halogens １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkyl groups; １ ~C ８ linear, branched and cyclic alkoxy or cyclic thioalkyl groups; (d) C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups; (e) C １ ~C ６ an aminosulfonyl group, optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; (f) C １ ~C ６ Linear, branched, and cyclic alkylsulfonylamino groups, and (g) a phosphine oxide group, C １ ~C ６ a phosphine oxide group, optionally substituted with one or two substituents independently selected from linear, branched, and cyclic alkyl groups; (h) C １ ~C ６ Linear, branched, and cyclic trialkylsilyl groups; (iii) R ２ is selected from 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, said 5-membered rings being selected from 1-4 R Ｂ ' groups, and the six-membered ring is optionally substituted with 1 to 5 R Ｂ Optionally substituted with a ' group, Ｂ 'The group is independent, optionally substituted amides, imidazolidine-2,4-dione, optionally substituted heterocyclyl; C １ ~C ６ phosphorous acid, optionally esterified with a straight-chain, branched-chain, or cyclic alkyl group; Ji (C １ ~C ６ ) alkylphosphine oxide, C １ ~C ６ Optionally esterified with a straight-chain, branched-chain, or cyclic alkyl group (C １ ~C ６ ) alkylphosphinic acids, halogen, Cyano, Hydroxy, Uronic acid or C １ ~C ６ Carboxylic acids optionally esterified with straight-chain, branched-chain, or cyclic alkyl groups; Oxo, Dihydroxyboryl, 5- and 6-membered aromatic rings containing 0-4 heteroatoms independently selected from O, N, and S, １ ~C ６ Optionally substituted with 1 or 2 substituents independently selected from straight chain, branched chain, and cyclic alkyl groups, which are Hydroxy, Carboxylic acids, pyrrolidin-2-one, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups, and C １ ~C ６ 5- and 6-membered aromatic rings optionally substituted with 1 to 4 substituents independently selected from: straight chain, branched chain, and cyclic alkoxy groups; Sulfonic acid, C １ ~C ６ Linear, branched, and cyclic alkylsulfonyl groups; an aminosulfonyl group, C １ ~C ６ an aminosulfonyl group, optionally substituted with one or two substituents independently selected from straight-chain, branched-chain, and cyclic alkyl groups; C １ ~C ６ Linear, branched, and cyclic alkyl groups, halogen, Hydroxy, Carboxylic acids, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ６ Straight chain, branched chain and cyclic alkyl groups; C １ ~C ６ Linear, branched, and cyclic alkoxy groups, halogen, Hydroxy, Carboxylic acids, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ C optionally substituted with 1 to 4 substituents independently selected from linear, branched, and cyclic alkoxy groups; １ ~C ６ Linear, branched, and cyclic alkoxy groups, and A tetrazolyl group, halogen, Hydroxy, Carboxylic acids, C １ ~C ６ Straight-chain, branched-chain, and cyclic alkyl groups, and C １ ~C ６ a tetrazolyl group, optionally substituted with substituents selected from linear, branched, and cyclic alkoxy groups; two adjacent hydrogens on the 5- or 6-membered aromatic ring are replaced by a bond to a second 5- or 6-membered aromatic ring containing 0-4 heteroatoms independently selected from O, N, and S; Ｂ Bicyclic R optionally substituted with a ２ ' group, (iv) X １ ' and X ２ ' are independently hydrogen, halogen, cyano, hydroxy, C １ ~C ６ is selected from linear, branched, and cyclic groups; １ ~C ６ The straight chain, branched chain, and cyclic groups are independently selected from alkyl, alkoxy, thioalkyl, and aminoalkyl groups; １ ~C ６ The straight chain, branched chain, and cyclic groups are optionally substituted with 1 to 4 independently selected halogens; (v) Between Z 2 ' and Z 3 ' 【Chemistry 312】 is a double bond, and between Z 1 ' and Z 2 ' 【Chemistry 313】 is a single bond, (vi) each R 3 ' is independently hydrogen, halogen, cyano, C １ ~C ６ Linear, branched, and cyclic alkyl groups, and C １ ~C ６ straight chain, branched chain, and cyclic alkoxy groups, said straight chain, branched chain, and cyclic alkyl and alkoxy groups being optionally substituted with 1 to 4 independently selected halogens; (vii) n′ is an integer selected from 0, 1, 2, and 3; (viii) Z １ ' and Z ２ ' is nitrogen and Z ３ ' is selected from carbon and nitrogen, and the valence electrons of carbon and nitrogen are completed with hydrogen atoms; A compound of formula (I'), its tautomers, a pharma- ceutically acceptable salt of any of the above, and / or a deuterated derivative of any of the above.

12. A pharmaceutical composition comprising a compound, tautomer, salt, or deuterated derivative of any one of claims 1 to 11 and a pharma- ceutically acceptable carrier.

13. A pharmaceutical composition comprising at least one compound selected from the compounds of any one of claims 1 to 11, tautomers, pharma- ceutically acceptable salts, and deuterated derivatives or the pharmaceutical composition of claim 12, for treating alpha-1 antitrypsin deficiency in a patient in need of such treatment.

14. The pharmaceutical composition of claim 13, wherein the patient has a Z mutation in alpha-1 antitrypsin.

15. The pharmaceutical composition of claim 13, wherein the patient has an SZ mutation in alpha-1 antitrypsin.

16. The method of claim 13, wherein the patient is homozygous for a Z mutation in alpha-1 antitrypsin.

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